US20100203144A1 - Immobilized Metallic Nanoparticles as Unique Materials for Therapeutic and Biosensor Applications - Google Patents
Immobilized Metallic Nanoparticles as Unique Materials for Therapeutic and Biosensor Applications Download PDFInfo
- Publication number
- US20100203144A1 US20100203144A1 US12/669,981 US66998108A US2010203144A1 US 20100203144 A1 US20100203144 A1 US 20100203144A1 US 66998108 A US66998108 A US 66998108A US 2010203144 A1 US2010203144 A1 US 2010203144A1
- Authority
- US
- United States
- Prior art keywords
- nanoparticles
- cells
- composition
- silver
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002105 nanoparticle Substances 0.000 title claims description 102
- 239000000463 material Substances 0.000 title description 48
- 230000001225 therapeutic effect Effects 0.000 title description 21
- 238000000034 method Methods 0.000 claims abstract description 236
- 239000000203 mixture Substances 0.000 claims abstract description 231
- 239000000758 substrate Substances 0.000 claims abstract description 103
- 229910052751 metal Inorganic materials 0.000 claims abstract description 92
- 239000002184 metal Substances 0.000 claims abstract description 92
- 229920001661 Chitosan Polymers 0.000 claims description 98
- -1 aromatic azide Chemical class 0.000 claims description 82
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 claims description 76
- 210000004027 cell Anatomy 0.000 claims description 74
- 229910052709 silver Inorganic materials 0.000 claims description 69
- 239000004332 silver Substances 0.000 claims description 69
- 229920000642 polymer Polymers 0.000 claims description 68
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 64
- 239000003814 drug Substances 0.000 claims description 60
- 239000008194 pharmaceutical composition Substances 0.000 claims description 50
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 45
- 239000010936 titanium Substances 0.000 claims description 45
- 229910052719 titanium Inorganic materials 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 32
- 229920001577 copolymer Polymers 0.000 claims description 30
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 25
- 210000000130 stem cell Anatomy 0.000 claims description 25
- 229920001983 poloxamer Polymers 0.000 claims description 24
- 239000004599 antimicrobial Substances 0.000 claims description 22
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 229960000502 poloxamer Drugs 0.000 claims description 17
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 16
- 239000004793 Polystyrene Substances 0.000 claims description 13
- 229940088597 hormone Drugs 0.000 claims description 13
- 229920002223 polystyrene Polymers 0.000 claims description 13
- 230000007704 transition Effects 0.000 claims description 13
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
- 239000005556 hormone Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 229920001987 poloxamine Polymers 0.000 claims description 10
- 229920002125 Sokalan® Polymers 0.000 claims description 9
- 210000001185 bone marrow Anatomy 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 210000004379 membrane Anatomy 0.000 claims description 7
- 239000012528 membrane Substances 0.000 claims description 7
- 229920002971 Heparan sulfate Polymers 0.000 claims description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 6
- 210000001612 chondrocyte Anatomy 0.000 claims description 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 6
- 210000004962 mammalian cell Anatomy 0.000 claims description 6
- 238000005530 etching Methods 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 230000000845 anti-microbial effect Effects 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 210000002950 fibroblast Anatomy 0.000 claims description 4
- 210000005260 human cell Anatomy 0.000 claims description 4
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims description 3
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 3
- 210000004504 adult stem cell Anatomy 0.000 claims description 3
- 210000004413 cardiac myocyte Anatomy 0.000 claims description 3
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 3
- 210000001608 connective tissue cell Anatomy 0.000 claims description 3
- 238000012258 culturing Methods 0.000 claims description 3
- 210000001951 dura mater Anatomy 0.000 claims description 3
- 210000001671 embryonic stem cell Anatomy 0.000 claims description 3
- 210000002889 endothelial cell Anatomy 0.000 claims description 3
- 210000002919 epithelial cell Anatomy 0.000 claims description 3
- 210000004602 germ cell Anatomy 0.000 claims description 3
- 210000002165 glioblast Anatomy 0.000 claims description 3
- 229960002897 heparin Drugs 0.000 claims description 3
- 210000003494 hepatocyte Anatomy 0.000 claims description 3
- 210000000987 immune system Anatomy 0.000 claims description 3
- 210000002510 keratinocyte Anatomy 0.000 claims description 3
- 239000013528 metallic particle Substances 0.000 claims description 3
- 210000003098 myoblast Anatomy 0.000 claims description 3
- 210000003757 neuroblast Anatomy 0.000 claims description 3
- 210000004498 neuroglial cell Anatomy 0.000 claims description 3
- 210000002569 neuron Anatomy 0.000 claims description 3
- 210000000963 osteoblast Anatomy 0.000 claims description 3
- 210000001778 pluripotent stem cell Anatomy 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 210000004116 schwann cell Anatomy 0.000 claims description 3
- 230000003248 secreting effect Effects 0.000 claims description 3
- 210000000329 smooth muscle myocyte Anatomy 0.000 claims description 3
- 210000003954 umbilical cord Anatomy 0.000 claims description 3
- 230000003100 immobilizing effect Effects 0.000 claims description 2
- 210000002997 osteoclast Anatomy 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- 239000001768 carboxy methyl cellulose Substances 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 1
- 150000004676 glycans Chemical class 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 abstract description 18
- 230000004048 modification Effects 0.000 abstract description 18
- 239000002082 metal nanoparticle Substances 0.000 abstract description 16
- 239000000243 solution Substances 0.000 description 176
- 150000001875 compounds Chemical class 0.000 description 110
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 94
- 238000009472 formulation Methods 0.000 description 77
- 239000002245 particle Substances 0.000 description 66
- 208000027418 Wounds and injury Diseases 0.000 description 64
- 239000010408 film Substances 0.000 description 61
- 201000010099 disease Diseases 0.000 description 53
- 230000006378 damage Effects 0.000 description 47
- 239000000499 gel Substances 0.000 description 47
- 208000014674 injury Diseases 0.000 description 44
- 208000035475 disorder Diseases 0.000 description 41
- 239000004480 active ingredient Substances 0.000 description 39
- 210000001519 tissue Anatomy 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 229940079593 drug Drugs 0.000 description 33
- 239000000126 substance Substances 0.000 description 32
- 239000000843 powder Substances 0.000 description 30
- 239000003102 growth factor Substances 0.000 description 28
- 241001465754 Metazoa Species 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 27
- 210000003491 skin Anatomy 0.000 description 27
- 239000007788 liquid Substances 0.000 description 26
- 108090000623 proteins and genes Proteins 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 23
- 206010052428 Wound Diseases 0.000 description 22
- 210000000988 bone and bone Anatomy 0.000 description 22
- 239000004615 ingredient Substances 0.000 description 21
- 235000018102 proteins Nutrition 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 21
- 230000009467 reduction Effects 0.000 description 21
- 230000008569 process Effects 0.000 description 20
- 238000011282 treatment Methods 0.000 description 20
- 239000002585 base Substances 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 230000017531 blood circulation Effects 0.000 description 18
- 239000002131 composite material Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 239000000443 aerosol Substances 0.000 description 15
- 238000000576 coating method Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 15
- 238000010521 absorption reaction Methods 0.000 description 14
- 239000011248 coating agent Substances 0.000 description 14
- 239000011159 matrix material Substances 0.000 description 14
- 230000000699 topical effect Effects 0.000 description 14
- 239000012620 biological material Substances 0.000 description 13
- 239000000178 monomer Substances 0.000 description 13
- 239000004094 surface-active agent Substances 0.000 description 13
- 239000013543 active substance Substances 0.000 description 12
- 239000002738 chelating agent Substances 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 230000003247 decreasing effect Effects 0.000 description 12
- 239000003623 enhancer Substances 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 150000007523 nucleic acids Chemical class 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 239000012279 sodium borohydride Substances 0.000 description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 description 12
- 238000011200 topical administration Methods 0.000 description 12
- 229920002367 Polyisobutene Polymers 0.000 description 11
- 239000003963 antioxidant agent Substances 0.000 description 11
- 235000006708 antioxidants Nutrition 0.000 description 11
- 238000004132 cross linking Methods 0.000 description 11
- 239000010931 gold Substances 0.000 description 11
- 239000007943 implant Substances 0.000 description 11
- 102000039446 nucleic acids Human genes 0.000 description 11
- 108020004707 nucleic acids Proteins 0.000 description 11
- 239000003755 preservative agent Substances 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 10
- 108090000695 Cytokines Proteins 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 10
- 102000053602 DNA Human genes 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 241000282414 Homo sapiens Species 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 10
- 239000006071 cream Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 239000000017 hydrogel Substances 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 239000003193 general anesthetic agent Substances 0.000 description 9
- 229910052737 gold Inorganic materials 0.000 description 9
- 150000002739 metals Chemical class 0.000 description 9
- 239000007921 spray Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 230000001070 adhesive effect Effects 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 230000036541 health Effects 0.000 description 8
- 238000005342 ion exchange Methods 0.000 description 8
- 239000003550 marker Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000002674 ointment Substances 0.000 description 8
- 239000003961 penetration enhancing agent Substances 0.000 description 8
- 229920001993 poloxamer 188 Polymers 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 239000010409 thin film Substances 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 241000282412 Homo Species 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 239000003443 antiviral agent Substances 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 230000000975 bioactive effect Effects 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 239000006210 lotion Substances 0.000 description 7
- 210000004877 mucosa Anatomy 0.000 description 7
- 239000006072 paste Substances 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- 239000003380 propellant Substances 0.000 description 7
- 230000002685 pulmonary effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 210000000434 stratum corneum Anatomy 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- 108010001478 Bacitracin Proteins 0.000 description 6
- 229920002101 Chitin Polymers 0.000 description 6
- 108010025020 Nerve Growth Factor Proteins 0.000 description 6
- 102000007072 Nerve Growth Factors Human genes 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 108010093965 Polymyxin B Proteins 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 229940035674 anesthetics Drugs 0.000 description 6
- 229940121375 antifungal agent Drugs 0.000 description 6
- 239000003429 antifungal agent Substances 0.000 description 6
- 229960003071 bacitracin Drugs 0.000 description 6
- 229930184125 bacitracin Natural products 0.000 description 6
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003431 cross linking reagent Substances 0.000 description 6
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000002270 dispersing agent Substances 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
- 238000000724 energy-dispersive X-ray spectrum Methods 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 238000001879 gelation Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 239000011572 manganese Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 229940044519 poloxamer 188 Drugs 0.000 description 6
- 229920000024 polymyxin B Polymers 0.000 description 6
- 229960005266 polymyxin b Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000005855 radiation Effects 0.000 description 6
- 230000008439 repair process Effects 0.000 description 6
- 241000894007 species Species 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 235000010443 alginic acid Nutrition 0.000 description 5
- 229920000615 alginic acid Polymers 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 239000002260 anti-inflammatory agent Substances 0.000 description 5
- 229940121363 anti-inflammatory agent Drugs 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 239000003086 colorant Substances 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000003974 emollient agent Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 229920005615 natural polymer Polymers 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 5
- 239000004584 polyacrylic acid Substances 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 230000002285 radioactive effect Effects 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 235000013343 vitamin Nutrition 0.000 description 5
- 239000011782 vitamin Substances 0.000 description 5
- 229940088594 vitamin Drugs 0.000 description 5
- 229930003231 vitamin Natural products 0.000 description 5
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 4
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 4
- 108010078777 Colistin Proteins 0.000 description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 4
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 4
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 4
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 4
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 102000013275 Somatomedins Human genes 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 229910052769 Ytterbium Inorganic materials 0.000 description 4
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000000783 alginic acid Substances 0.000 description 4
- 229960001126 alginic acid Drugs 0.000 description 4
- 150000004781 alginic acids Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000002421 anti-septic effect Effects 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 229940064004 antiseptic throat preparations Drugs 0.000 description 4
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 229920001400 block copolymer Polymers 0.000 description 4
- 230000008468 bone growth Effects 0.000 description 4
- 229940112869 bone morphogenetic protein Drugs 0.000 description 4
- 239000006172 buffering agent Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000011651 chromium Substances 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 229910001385 heavy metal Inorganic materials 0.000 description 4
- 239000003906 humectant Substances 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229960004194 lidocaine Drugs 0.000 description 4
- 239000000865 liniment Substances 0.000 description 4
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002493 microarray Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 4
- 239000002121 nanofiber Substances 0.000 description 4
- 239000010955 niobium Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 229920000058 polyacrylate Polymers 0.000 description 4
- 229920000867 polyelectrolyte Polymers 0.000 description 4
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 4
- 150000004804 polysaccharides Chemical class 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 229960001801 proxazole Drugs 0.000 description 4
- 239000010948 rhodium Substances 0.000 description 4
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 4
- 238000001878 scanning electron micrograph Methods 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 3
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 102000015696 Interleukins Human genes 0.000 description 3
- 108010063738 Interleukins Proteins 0.000 description 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 102000004067 Osteocalcin Human genes 0.000 description 3
- 108090000573 Osteocalcin Proteins 0.000 description 3
- 102000009890 Osteonectin Human genes 0.000 description 3
- 108010077077 Osteonectin Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 3
- 208000000558 Varicose Ulcer Diseases 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229940048053 acrylate Drugs 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 229920006318 anionic polymer Polymers 0.000 description 3
- 230000003474 anti-emetic effect Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000002111 antiemetic agent Substances 0.000 description 3
- 229940125683 antiemetic agent Drugs 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 229920001222 biopolymer Polymers 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- UHYPYGJEEGLRJD-UHFFFAOYSA-N cadmium(2+);selenium(2-) Chemical compound [Se-2].[Cd+2] UHYPYGJEEGLRJD-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000010109 chemoembolization Effects 0.000 description 3
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000004744 fabric Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 239000000122 growth hormone Substances 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000003165 hydrotropic effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229940047122 interleukins Drugs 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229960000988 nystatin Drugs 0.000 description 3
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 238000000059 patterning Methods 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 229960002702 piroxicam Drugs 0.000 description 3
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229920002477 rna polymer Polymers 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229920001059 synthetic polymer Polymers 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000013162 therapeutic embolization Methods 0.000 description 3
- 150000003608 titanium Chemical class 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 2
- XYRIRLDHOQSNLW-UHFFFAOYSA-N (3-oxo-1h-2-benzofuran-1-yl) 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound CC1=C(CC(=O)OC2C3=CC=CC=C3C(=O)O2)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 XYRIRLDHOQSNLW-UHFFFAOYSA-N 0.000 description 2
- SHCYQUDTKWHARF-UHFFFAOYSA-N (3-oxo-1h-2-benzofuran-1-yl) 2-acetyloxybenzoate Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC1C2=CC=CC=C2C(=O)O1 SHCYQUDTKWHARF-UHFFFAOYSA-N 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 2
- ZHXUEUKVDMWSKV-UHFFFAOYSA-N 1-(3,5-ditert-butyl-4-hydroxyphenyl)hex-5-yn-1-one Chemical compound CC(C)(C)C1=CC(C(=O)CCCC#C)=CC(C(C)(C)C)=C1O ZHXUEUKVDMWSKV-UHFFFAOYSA-N 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- KLIVRBFRQSOGQI-UHFFFAOYSA-N 2-(11-oxo-6h-benzo[c][1]benzothiepin-3-yl)acetic acid Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 KLIVRBFRQSOGQI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BUUODSZYUAZDIF-AOMKIAJQSA-N 2-[(1s,4r)-4-benzyl-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]acetic acid Chemical compound C([C@H]1CO[C@](C2=C1C1=CC=CC=C1N2)(CC(O)=O)CC)C1=CC=CC=C1 BUUODSZYUAZDIF-AOMKIAJQSA-N 0.000 description 2
- ANMLJLFWUCQGKZ-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]-3-pyridinecarboxylic acid (3-oxo-1H-isobenzofuran-1-yl) ester Chemical compound FC(F)(F)C1=CC=CC(NC=2C(=CC=CN=2)C(=O)OC2C3=CC=CC=C3C(=O)O2)=C1 ANMLJLFWUCQGKZ-UHFFFAOYSA-N 0.000 description 2
- XILVEPYQJIOVNB-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester Chemical compound OCCOCCOC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 XILVEPYQJIOVNB-UHFFFAOYSA-N 0.000 description 2
- PIAMNHTVFPWVHG-UHFFFAOYSA-N 4-(4-chlorophenyl)-5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.N1C=NC(C=2C=CC(Cl)=CC=2)=C1C PIAMNHTVFPWVHG-UHFFFAOYSA-N 0.000 description 2
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 2
- HEOZYYOUKGGSBJ-UHFFFAOYSA-N 5-(4-methoxybenzoyl)-2,3-dihydro-1h-pyrrolizine-1-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=C2N1CCC2C(O)=O HEOZYYOUKGGSBJ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 2
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- HNNIWKQLJSNAEQ-UHFFFAOYSA-N Benzydamine hydrochloride Chemical compound Cl.C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 HNNIWKQLJSNAEQ-UHFFFAOYSA-N 0.000 description 2
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 description 2
- 102100022544 Bone morphogenetic protein 7 Human genes 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- AFWTZXXDGQBIKW-UHFFFAOYSA-N C14 surfactin Natural products CCCCCCCCCCCC1CC(=O)NC(CCC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)O1 AFWTZXXDGQBIKW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- 241000238424 Crustacea Species 0.000 description 2
- 238000000018 DNA microarray Methods 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 240000001879 Digitalis lutea Species 0.000 description 2
- 229910052692 Dysprosium Inorganic materials 0.000 description 2
- 102000016942 Elastin Human genes 0.000 description 2
- 108010014258 Elastin Proteins 0.000 description 2
- 102400001047 Endostatin Human genes 0.000 description 2
- 108010079505 Endostatins Proteins 0.000 description 2
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 229910052691 Erbium Inorganic materials 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- WDZVGELJXXEGPV-YIXHJXPBSA-N Guanabenz Chemical compound NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-YIXHJXPBSA-N 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 229910052689 Holmium Inorganic materials 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 208000006877 Insect Bites and Stings Diseases 0.000 description 2
- 102100040018 Interferon alpha-2 Human genes 0.000 description 2
- 108010078049 Interferon alpha-2 Proteins 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 102000003996 Interferon-beta Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- ODYCAZSSUVCHNU-XLAORIBOSA-N Laurencin Natural products CC[C@H]1C[C@H](CC=CC[C@@H]1Br)[C@@H](CC=CC#C)OC(=O)C ODYCAZSSUVCHNU-XLAORIBOSA-N 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 229910052765 Lutetium Inorganic materials 0.000 description 2
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 2
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- 229910052779 Neodymium Inorganic materials 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- QSDSSSQWVNLFIG-UHFFFAOYSA-N Neosporin Natural products CC(O)CC1=C(OC)C(=O)C2=CC(O)=C3OCOC4=C(O)C=C5C6=C4C3=C2C1=C6C(CC(C)O)=C(OC)C5=O QSDSSSQWVNLFIG-UHFFFAOYSA-N 0.000 description 2
- 229940084576 Neurotransmitter agonist Drugs 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010040201 Polymyxins Proteins 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 229910052777 Praseodymium Inorganic materials 0.000 description 2
- 208000004210 Pressure Ulcer Diseases 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 229910052773 Promethium Inorganic materials 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- WFAULHLDTDDABL-UHFFFAOYSA-N Proxazole citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(CC)C1=NOC(CCN(CC)CC)=N1 WFAULHLDTDDABL-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 229910052772 Samarium Inorganic materials 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 238000003917 TEM image Methods 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229910052771 Terbium Inorganic materials 0.000 description 2
- 206010053615 Thermal burn Diseases 0.000 description 2
- 108060008245 Thrombospondin Proteins 0.000 description 2
- 102000002938 Thrombospondin Human genes 0.000 description 2
- 229910052775 Thulium Inorganic materials 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 230000001800 adrenalinergic effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229950004699 anirolac Drugs 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 229940069428 antacid Drugs 0.000 description 2
- 239000003159 antacid agent Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 230000003257 anti-anginal effect Effects 0.000 description 2
- 230000002456 anti-arthritic effect Effects 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 230000001022 anti-muscarinic effect Effects 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 230000002141 anti-parasite Effects 0.000 description 2
- 230000001139 anti-pruritic effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 230000003409 anti-rejection Effects 0.000 description 2
- 230000002921 anti-spasmodic effect Effects 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 229940124345 antianginal agent Drugs 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 229940124346 antiarthritic agent Drugs 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000003793 antidiarrheal agent Substances 0.000 description 2
- 229960002708 antigout preparations Drugs 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 229940125687 antiparasitic agent Drugs 0.000 description 2
- 239000003908 antipruritic agent Substances 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 229940005529 antipsychotics Drugs 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 229940125716 antipyretic agent Drugs 0.000 description 2
- 229940124575 antispasmodic agent Drugs 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 239000002830 appetite depressant Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 229960005430 benoxaprofen Drugs 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 229960005274 benzocaine Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960001689 benzydamine hydrochloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000007844 bleaching agent Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 210000002805 bone matrix Anatomy 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 229910052793 cadmium Inorganic materials 0.000 description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000002368 cardiac glycoside Substances 0.000 description 2
- 229940097217 cardiac glycoside Drugs 0.000 description 2
- 239000000799 cathartic agent Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 2
- 238000010382 chemical cross-linking Methods 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229960003260 chlorhexidine Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229960001747 cinchocaine Drugs 0.000 description 2
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 2
- UVTLONZTPXCUPU-ZNMIVQPWSA-N ciramadol Chemical compound C([C@@H]1[C@@H](N(C)C)C=2C=C(O)C=CC=2)CCC[C@H]1O UVTLONZTPXCUPU-ZNMIVQPWSA-N 0.000 description 2
- 229950007653 ciramadol Drugs 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 229960003346 colistin Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 230000035614 depigmentation Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 229960000616 diflunisal Drugs 0.000 description 2
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 2
- 239000003866 digestant Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 108010046161 drug combination polymyxin B neomycin sulfate bacitracin zinc Proteins 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 2
- 239000013057 ectoparasiticide Substances 0.000 description 2
- 229920002549 elastin Polymers 0.000 description 2
- 239000002895 emetic Substances 0.000 description 2
- 238000002149 energy-dispersive X-ray emission spectroscopy Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 229950003801 epirizole Drugs 0.000 description 2
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 description 2
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 229960003976 etidocaine Drugs 0.000 description 2
- 229960001493 etofenamate Drugs 0.000 description 2
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229960000588 flunixin Drugs 0.000 description 2
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 description 2
- MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 description 2
- 229960000469 flunixin meglumine Drugs 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 239000004088 foaming agent Substances 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 239000013022 formulation composition Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 239000003457 ganglion blocking agent Substances 0.000 description 2
- 230000000574 ganglionic effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- YUFWAVFNITUSHI-UHFFFAOYSA-N guanethidine monosulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.NC(=N)NCCN1CCCCCCC1 YUFWAVFNITUSHI-UHFFFAOYSA-N 0.000 description 2
- 229910052735 hafnium Inorganic materials 0.000 description 2
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000003326 hypnotic agent Substances 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 2
- 229950009183 ibufenac Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 229960004187 indoprofen Drugs 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 229960001388 interferon-beta Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 2
- 229960000511 lactulose Drugs 0.000 description 2
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 2
- 229910052746 lanthanum Inorganic materials 0.000 description 2
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 2
- 229960003639 laurocapram Drugs 0.000 description 2
- 239000008141 laxative Substances 0.000 description 2
- 229940125722 laxative agent Drugs 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- GQVWFGYYMWLERN-UHFFFAOYSA-J magnesium;2-carboxyphenolate;2-hydroxyethyl(trimethyl)azanium;sulfate;tetrahydrate Chemical compound O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O.C[N+](C)(C)CCO.C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O GQVWFGYYMWLERN-UHFFFAOYSA-J 0.000 description 2
- 238000001755 magnetron sputter deposition Methods 0.000 description 2
- 229910052748 manganese Inorganic materials 0.000 description 2
- MPQWSYJGFLADEW-UHFFFAOYSA-N medroxalol Chemical compound C=1C=C2OCOC2=CC=1CCC(C)NCC(O)C1=CC=C(O)C(C(N)=O)=C1 MPQWSYJGFLADEW-UHFFFAOYSA-N 0.000 description 2
- 229950008578 medroxalol Drugs 0.000 description 2
- 229960003464 mefenamic acid Drugs 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 239000002923 metal particle Substances 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000001333 moisturizer Effects 0.000 description 2
- 229910052750 molybdenum Inorganic materials 0.000 description 2
- 239000011733 molybdenum Substances 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 229940051866 mouthwash Drugs 0.000 description 2
- 239000003149 muscarinic antagonist Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229940035363 muscle relaxants Drugs 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- NKDJNEGDJVXHKM-UHFFFAOYSA-N n,2-dimethyl-4,5,6,7-tetrahydroindazol-3-amine Chemical compound C1CCCC2=NN(C)C(NC)=C21 NKDJNEGDJVXHKM-UHFFFAOYSA-N 0.000 description 2
- YKQOSKADJPQZHB-YNWHQGOSSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1s)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Polymers CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O YKQOSKADJPQZHB-YNWHQGOSSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 229960003940 naproxen sodium Drugs 0.000 description 2
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 2
- LTRANDSQVZFZDG-SNVBAGLBSA-N naproxol Chemical compound C1=C([C@H](C)CO)C=CC2=CC(OC)=CC=C21 LTRANDSQVZFZDG-SNVBAGLBSA-N 0.000 description 2
- 229950006890 naproxol Drugs 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 229940049337 neosporin Drugs 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000000842 neuromuscular blocking agent Substances 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 229910052758 niobium Inorganic materials 0.000 description 2
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 2
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 description 2
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 2
- 229960000564 nitrofurantoin Drugs 0.000 description 2
- 229960001907 nitrofurazone Drugs 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 229940115973 nystatin / triamcinolone Drugs 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 229940055577 oleyl alcohol Drugs 0.000 description 2
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 2
- 229910052762 osmium Inorganic materials 0.000 description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 2
- 238000010883 osseointegration Methods 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 230000002138 osteoinductive effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000734 parasympathomimetic agent Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229960003073 pirfenidone Drugs 0.000 description 2
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 2
- 239000000419 plant extract Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229940044476 poloxamer 407 Drugs 0.000 description 2
- 108010046630 polymyxin B drug combination bacitracin Proteins 0.000 description 2
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229940103255 polysporin Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- VQMWBBYLQSCNPO-UHFFFAOYSA-N promethium atom Chemical compound [Pm] VQMWBBYLQSCNPO-UHFFFAOYSA-N 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- OLTAWOVKGWWERU-UHFFFAOYSA-N proxazole Chemical compound C=1C=CC=CC=1C(CC)C1=NOC(CCN(CC)CC)=N1 OLTAWOVKGWWERU-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229910052761 rare earth metal Inorganic materials 0.000 description 2
- 150000002910 rare earth metals Chemical class 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 229960003471 retinol Drugs 0.000 description 2
- 235000020944 retinol Nutrition 0.000 description 2
- 239000011607 retinol Substances 0.000 description 2
- 229910052702 rhenium Inorganic materials 0.000 description 2
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 229940085605 saccharin sodium Drugs 0.000 description 2
- 229950000125 salcolex Drugs 0.000 description 2
- 229960000953 salsalate Drugs 0.000 description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 2
- 229910052706 scandium Inorganic materials 0.000 description 2
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- VSZWPYCFIRKVQL-UHFFFAOYSA-N selanylidenegallium;selenium Chemical compound [Se].[Se]=[Ga].[Se]=[Ga] VSZWPYCFIRKVQL-UHFFFAOYSA-N 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 239000013464 silicone adhesive Substances 0.000 description 2
- 150000003378 silver Chemical class 0.000 description 2
- 229960003600 silver sulfadiazine Drugs 0.000 description 2
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 2
- 230000009645 skeletal growth Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- SEEXPXUCHVGZGU-UHFFFAOYSA-M sodium;2-[5-(4-chlorobenzoyl)-1,4-dimethylpyrrol-2-yl]acetate Chemical compound [Na+].C1=C(CC([O-])=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C SEEXPXUCHVGZGU-UHFFFAOYSA-M 0.000 description 2
- QUCDWLYKDRVKMI-UHFFFAOYSA-M sodium;3,4-dimethylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1C QUCDWLYKDRVKMI-UHFFFAOYSA-M 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000004544 sputter deposition Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 229930002534 steroid glycoside Natural products 0.000 description 2
- 150000008143 steroidal glycosides Chemical class 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000000475 sunscreen effect Effects 0.000 description 2
- 239000000516 sunscreening agent Substances 0.000 description 2
- NJGWOFRZMQRKHT-UHFFFAOYSA-N surfactin Natural products CC(C)CCCCCCCCCC1CC(=O)NC(CCC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)O1 NJGWOFRZMQRKHT-UHFFFAOYSA-N 0.000 description 2
- NJGWOFRZMQRKHT-WGVNQGGSSA-N surfactin C Chemical compound CC(C)CCCCCCCCC[C@@H]1CC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O1 NJGWOFRZMQRKHT-WGVNQGGSSA-N 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229950005100 talmetacin Drugs 0.000 description 2
- 229960005262 talniflumate Drugs 0.000 description 2
- 229950005400 talosalate Drugs 0.000 description 2
- 229910052715 tantalum Inorganic materials 0.000 description 2
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000006068 taste-masking agent Substances 0.000 description 2
- 229950003441 tebufelone Drugs 0.000 description 2
- 229910052713 technetium Inorganic materials 0.000 description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 2
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 2
- 229960003676 tenidap Drugs 0.000 description 2
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 2
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 2
- 229960002372 tetracaine Drugs 0.000 description 2
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 229960000103 thrombolytic agent Drugs 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- FRNOGLGSGLTDKL-UHFFFAOYSA-N thulium atom Chemical compound [Tm] FRNOGLGSGLTDKL-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- CVWILQHZFWRYPB-UHFFFAOYSA-N tiamenidine Chemical compound CC1=CSC(Cl)=C1NC1=NCCN1 CVWILQHZFWRYPB-UHFFFAOYSA-N 0.000 description 2
- 229950000164 tiamenidine Drugs 0.000 description 2
- 229950002345 tiopinac Drugs 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 229950002569 trimecaine Drugs 0.000 description 2
- GOZBHBFUQHMKQB-UHFFFAOYSA-N trimecaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=C(C)C=C1C GOZBHBFUQHMKQB-UHFFFAOYSA-N 0.000 description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 239000010937 tungsten Substances 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 239000003357 wound healing promoting agent Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- 235000014692 zinc oxide Nutrition 0.000 description 2
- 229960003516 zomepirac sodium Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- YQYVFVRQLZMJKJ-JBBXEZCESA-N (+)-cyclazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CC1CC1 YQYVFVRQLZMJKJ-JBBXEZCESA-N 0.000 description 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- RBBBYDOGRKOESS-UHFFFAOYSA-N (1,2-dimethyl-3-phenylpyrrolidin-3-yl) propanoate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)C1C RBBBYDOGRKOESS-UHFFFAOYSA-N 0.000 description 1
- LCQSIRUFGUHZQH-YDALLXLXSA-N (1r)-1-(1,3-dioxan-5-yl)-n,n-dimethyl-1-pyridin-3-ylmethanamine;hydrochloride Chemical compound Cl.C1([C@@H](N(C)C)C=2C=NC=CC=2)COCOC1 LCQSIRUFGUHZQH-YDALLXLXSA-N 0.000 description 1
- RJNRORZRFGUAKL-ADMBVFOFSA-N (1r)-1-[(3ar,5r,6s,6ar)-6-[3-(dimethylamino)propoxy]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol;hydrochloride Chemical compound Cl.O1C(C)(C)O[C@@H]2[C@@H](OCCCN(C)C)[C@@H]([C@H](O)CO)O[C@@H]21 RJNRORZRFGUAKL-ADMBVFOFSA-N 0.000 description 1
- OTZOPAFTLUOBOM-LYCTWNKOSA-N (1r,5s)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1[C@]1(CNC2)[C@@H]2C1 OTZOPAFTLUOBOM-LYCTWNKOSA-N 0.000 description 1
- TWESTNYMJIMXRF-AIMMJYJASA-N (1s)-1-[(3r)-2,3-dihydro-1,4-benzodioxin-3-yl]-2-[[(2r)-2-[(3s)-2,3-dihydro-1,4-benzodioxin-3-yl]-2-hydroxyethyl]amino]ethanol;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1OC2=CC=CC=C2O[C@H]1[C@@H](O)CNC[C@@H](O)[C@H]1OC2=CC=CC=C2OC1 TWESTNYMJIMXRF-AIMMJYJASA-N 0.000 description 1
- PGEHZROVWYXBFH-DOPHYNLBSA-N (1s,15r,20s)-3-methyl-11,12,14,15,16,17,18,19,20,21-decahydro-1h-yohimban;hydrochloride Chemical compound Cl.C12=CC=CC=C2N(C)C2=C1CCN1C[C@@H]3CCCC[C@H]3C[C@H]12 PGEHZROVWYXBFH-DOPHYNLBSA-N 0.000 description 1
- YBNMDCCMCLUHBL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-pyren-1-ylbutanoate Chemical compound C=1C=C(C2=C34)C=CC3=CC=CC4=CC=C2C=1CCCC(=O)ON1C(=O)CCC1=O YBNMDCCMCLUHBL-UHFFFAOYSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- HJOUSWJOPKLCGA-SOFGYWHQSA-N (2e)-2-(aminomethylidene)-3h-inden-1-one Chemical compound C1=CC=C2C(=O)C(=C/N)/CC2=C1 HJOUSWJOPKLCGA-SOFGYWHQSA-N 0.000 description 1
- VYPKEODFNOEZGS-VIFPVBQESA-N (2r)-2-acetamido-3-(2-hydroxybenzoyl)sulfanylpropanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSC(=O)C1=CC=CC=C1O VYPKEODFNOEZGS-VIFPVBQESA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- BAVDEDVBIHTHJQ-UVJOBNTFSA-N (2s)-1-[(2s)-6-amino-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;hydrate Chemical compound O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 BAVDEDVBIHTHJQ-UVJOBNTFSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- GYPWNVSWCIMIHQ-GRTNUQQKSA-N (2s)-2-[(4s)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidine;hydrochloride Chemical compound Cl.C([C@H]1[C@@H]2OC(OC2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCN1 GYPWNVSWCIMIHQ-GRTNUQQKSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- AUDFHJLSHQWFQQ-SFHVURJKSA-N (2s)-2-[[2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetyl]amino]-3-hydroxypropanoic acid Chemical compound CC1=C(CC(=O)N[C@@H](CO)C(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 AUDFHJLSHQWFQQ-SFHVURJKSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- KNHOFQRNQBONFF-RWGZXCQOSA-N (2s)-2-benzyl-n-[(2s)-1-[[(2s,3r,4s)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]amino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]-3-(4-methylpiperazin-1-yl)sulfonylpropanamide;hydrochloride Chemical compound Cl.C([C@@H]([C@@H](O)[C@@H](O)CC(C)C)NC(=O)[C@H](CC=1N=CSC=1)NC(=O)[C@H](CC=1C=CC=CC=1)CS(=O)(=O)N1CCN(C)CC1)C1CCCCC1 KNHOFQRNQBONFF-RWGZXCQOSA-N 0.000 description 1
- HMVROCAATOPFHB-UHFFFAOYSA-N (3-hydrazinyl-7,8-dihydro-5h-pyrido[4,3-c]pyridazin-6-yl)-phenylmethanone;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1CC=2N=NC(NN)=CC=2CN1C(=O)C1=CC=CC=C1 HMVROCAATOPFHB-UHFFFAOYSA-N 0.000 description 1
- QDWFLIRNVGQZLD-UHFFFAOYSA-N (3-methyl-1,2-diphenyl-4-pyrrolidin-1-ylbutan-2-yl) acetate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1CC(C=1C=CC=CC=1)(OC(C)=O)C(C)CN1CCCC1 QDWFLIRNVGQZLD-UHFFFAOYSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- BVNJBATUHVXZKP-QXMHVHEDSA-N (3z)-6-chloro-5-fluoro-3-[hydroxy(thiophen-2-yl)methylidene]-2-oxoindole-1-carboxamide Chemical compound C12=CC(F)=C(Cl)C=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 BVNJBATUHVXZKP-QXMHVHEDSA-N 0.000 description 1
- ZDHHGGFQZRPUSN-UHFFFAOYSA-N (4-chlorophenyl)-[3-(2h-tetrazol-5-ylmethyl)indol-1-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)N1C2=CC=CC=C2C(CC2=NNN=N2)=C1 ZDHHGGFQZRPUSN-UHFFFAOYSA-N 0.000 description 1
- PPQZABOURJVKNI-UHFFFAOYSA-N (4-fluorophenyl)-[4-(4-fluorophenyl)-4-hydroxy-1-methylpiperidin-3-yl]methanone Chemical compound C1N(C)CCC(O)(C=2C=CC(F)=CC=2)C1C(=O)C1=CC=C(F)C=C1 PPQZABOURJVKNI-UHFFFAOYSA-N 0.000 description 1
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 1
- HJHVRVJTYPKTHX-HTMVYDOJSA-N (4ar,8ar)-5-propyl-1,4,4a,6,7,8,8a,9-octahydropyrazolo[3,4-g]quinoline;hydrochloride Chemical compound Cl.C([C@H]1CCCN([C@@H]1C1)CCC)C2=C1C=NN2 HJHVRVJTYPKTHX-HTMVYDOJSA-N 0.000 description 1
- CKEXIRBGGMFWOA-AVQDSJIMSA-N (4r,4ar,5s,7ar,12bs)-3-(cyclopropylmethyl)-5-ethyl-9-methoxy-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride Chemical compound Cl.C([C@@]12[C@@H]3[C@H]4CC=5C2=C(C(=CC=5)OC)O[C@H]1C(=O)C[C@@H]3CC)CN4CC1CC1 CKEXIRBGGMFWOA-AVQDSJIMSA-N 0.000 description 1
- ZGSZBVAEVPSPFM-HYTSPMEMSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC ZGSZBVAEVPSPFM-HYTSPMEMSA-N 0.000 description 1
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 1
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- BCXHDORHMMZBBZ-DORFAMGDSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;sulfuric acid Chemical compound OS(O)(=O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC BCXHDORHMMZBBZ-DORFAMGDSA-N 0.000 description 1
- PJDUKHQNUMOJLL-OPHZJPRHSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-3-(3-methylbut-2-enyl)-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride Chemical compound Cl.O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(CC=C(C)C)[C@@H]3CC5=CC=C4O PJDUKHQNUMOJLL-OPHZJPRHSA-N 0.000 description 1
- BTEYIHUKHHAVAN-KDKWOIFOSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BTEYIHUKHHAVAN-KDKWOIFOSA-N 0.000 description 1
- JFTOCKFCHJCDDX-UVTDQMKNSA-N (4z)-4-benzylidene-5,6,7,8-tetrahydroisoquinoline-1,3-dione Chemical compound C1CCCC2=C1C(=O)NC(=O)\C2=C/C1=CC=CC=C1 JFTOCKFCHJCDDX-UVTDQMKNSA-N 0.000 description 1
- WDEMLQIGYYLRRX-OWVUFADGSA-N (5ar,9ar)-6-propyl-5a,7,8,9,9a,10-hexahydro-5h-pyrido[2,3-g]quinazolin-2-amine;dihydrochloride Chemical compound Cl.Cl.NC1=NC=C2C[C@H]3N(CCC)CCC[C@@H]3CC2=N1 WDEMLQIGYYLRRX-OWVUFADGSA-N 0.000 description 1
- VDNZZIYSCXESNI-ILSZZQPISA-N (6s,8s,9s,10r,11s,13s,14s,17s)-17-acetyl-11-hydroxy-6,10,13-trimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C(C)=O)CC[C@H]21 VDNZZIYSCXESNI-ILSZZQPISA-N 0.000 description 1
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006313 (C5-C8) alkyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 1
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 description 1
- XWBHHRBXVHYWQU-UHFFFAOYSA-N (e)-[amino-(2,6-dichloroanilino)methylidene]urea;hydron;chloride Chemical compound Cl.NC(=O)\N=C(/N)NC1=C(Cl)C=CC=C1Cl XWBHHRBXVHYWQU-UHFFFAOYSA-N 0.000 description 1
- RZPZLFIUFMNCLY-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 RZPZLFIUFMNCLY-WLHGVMLRSA-N 0.000 description 1
- BRIPGNJWPCKDQZ-WXXKFALUSA-N (e)-but-2-enedioic acid;1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 BRIPGNJWPCKDQZ-WXXKFALUSA-N 0.000 description 1
- DOYGKOLTUWPTGK-BTJKTKAUSA-N (z)-but-2-enedioic acid;(4-methoxyphenyl)-[2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]methanone Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(OC)=CC=C1C(=O)C(C1=CC=CC=C11)=C(C)N1CCN1CCOCC1 DOYGKOLTUWPTGK-BTJKTKAUSA-N 0.000 description 1
- TZNOWAJJWCGILX-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl TZNOWAJJWCGILX-BTJKTKAUSA-N 0.000 description 1
- AEAIVULHCUHDDP-BTJKTKAUSA-N (z)-but-2-enedioic acid;7-[2-hydroxy-3-(propylamino)propoxy]-2-phenylchromen-4-one Chemical compound OC(=O)\C=C/C(O)=O.C=1C(OCC(O)CNCCC)=CC=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 AEAIVULHCUHDDP-BTJKTKAUSA-N 0.000 description 1
- DPYIXBFZUMCMJM-BTJKTKAUSA-N (z)-but-2-enedioic acid;ethyl n-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate Chemical compound OC(=O)\C=C/C(O)=O.N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 DPYIXBFZUMCMJM-BTJKTKAUSA-N 0.000 description 1
- WIUYTBGLPMBEKI-BTJKTKAUSA-N (z)-but-2-enedioic acid;n-[2-(diethylamino)ethyl]-2-hydroxybenzamide Chemical compound OC(=O)\C=C/C(O)=O.CCN(CC)CCNC(=O)C1=CC=CC=C1O WIUYTBGLPMBEKI-BTJKTKAUSA-N 0.000 description 1
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 description 1
- JIGAQXOHSFIRIS-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-n-(6,7-dimethoxyquinolin-4-yl)methanimine Chemical compound C1=C(OC)C(OC)=CC=C1C=NC1=CC=NC2=CC(OC)=C(OC)C=C12 JIGAQXOHSFIRIS-UHFFFAOYSA-N 0.000 description 1
- BAFOEQOGYLVKNR-UHFFFAOYSA-N 1-(tert-butylamino)-3-[2-(6-hydrazinylpyridazin-3-yl)phenoxy]propan-2-ol;hydrate;dihydrochloride Chemical compound O.Cl.Cl.CC(C)(C)NCC(O)COC1=CC=CC=C1C1=CC=C(NN)N=N1 BAFOEQOGYLVKNR-UHFFFAOYSA-N 0.000 description 1
- CQSTVPYARYSBNS-HZLAGBECSA-N 1-[(1S,9R,13S)-4-hydroxy-1,10,13-trimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-13-yl]octan-3-one methanesulfonic acid Chemical compound CS(O)(=O)=O.C1C2=CC=C(O)C=C2[C@@]2(C)[C@@](CCC(=O)CCCCC)(C)[C@@H]1N(C)CC2 CQSTVPYARYSBNS-HZLAGBECSA-N 0.000 description 1
- IEXXCIWKNWOEKZ-GVYCEHEKSA-N 1-[(2e)-2-benzylidenecyclohexyl]azetidine;butanedioic acid Chemical compound OC(=O)CCC(O)=O.C1CCN1C(CCCC\1)C/1=C/C1=CC=CC=C1 IEXXCIWKNWOEKZ-GVYCEHEKSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 1
- YETULFFXNIHQLK-UHFFFAOYSA-N 1-ethynyl-4-(2-fluorophenyl)benzene Chemical compound FC1=CC=CC=C1C1=CC=C(C#C)C=C1 YETULFFXNIHQLK-UHFFFAOYSA-N 0.000 description 1
- ARIWANIATODDMH-AWEZNQCLSA-N 1-lauroyl-sn-glycerol Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)CO ARIWANIATODDMH-AWEZNQCLSA-N 0.000 description 1
- GFOYERPBWJANDW-UHFFFAOYSA-L 1-methyl-4-phenyl-1-azoniabicyclo[2.2.2]octan-3-one;dibromide;hydrate Chemical compound O.[Br-].[Br-].C1C[N+](C)(CC2=O)CCC12C1=CC=CC=C1.C1C[N+](C)(CC2=O)CCC12C1=CC=CC=C1 GFOYERPBWJANDW-UHFFFAOYSA-L 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ULIDRMKBVYYVIQ-UHFFFAOYSA-N 1-phenyltetrazol-5-amine Chemical compound NC1=NN=NN1C1=CC=CC=C1 ULIDRMKBVYYVIQ-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- WHBHBVVOGNECLV-OBQKJFGGSA-N 11-deoxycortisol Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WHBHBVVOGNECLV-OBQKJFGGSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- SRETXDDCKMOQNE-UHFFFAOYSA-N 2,3-bis(4-methoxyphenyl)-1h-indole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)C2=CC=CC=C2N1 SRETXDDCKMOQNE-UHFFFAOYSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- SWYJYGCPTGKBDS-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-(3-chloro-2-methylanilino)pyridine-3-carboxylate Chemical compound CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(=O)OCC(O)CO SWYJYGCPTGKBDS-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- ZVVAINSYJGRDTR-TYLGTTGKSA-N 2-(1-benzofuran-4-yl)-n-methyl-n-[(5r,7s,8s)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide;hydrochloride Chemical compound Cl.C([C@@H]([C@H](C1)N2CCCC2)N(C)C(=O)CC=2C=3C=COC=3C=CC=2)C[C@]21CCCO2 ZVVAINSYJGRDTR-TYLGTTGKSA-N 0.000 description 1
- IZGMROSLQHXRDZ-UHFFFAOYSA-N 2-(1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=CC=C2C2=C1C(CCC)(CC(O)=O)OCC2 IZGMROSLQHXRDZ-UHFFFAOYSA-N 0.000 description 1
- OXWYHTHXCLDQCN-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)guanidine;sulfuric acid Chemical compound OS(O)(=O)=O.C1=CC=C2OC(CNC(=N)N)COC2=C1 OXWYHTHXCLDQCN-UHFFFAOYSA-N 0.000 description 1
- QRFSLMLESAIOMB-UHFFFAOYSA-N 2-(2,4,4-trimethylpentan-2-yl)guanidine;hydrochloride Chemical compound Cl.CC(C)(C)CC(C)(C)N=C(N)N QRFSLMLESAIOMB-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- FHEZDPDAYTVKKG-JLBKCEDKSA-N 2-(3,4-dichlorophenyl)-n-methyl-n-[(5r,7s,8s)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C([C@@H]([C@H](C1)N2CCCC2)N(C)C(=O)CC=2C=C(Cl)C(Cl)=CC=2)C[C@]21CCCO2 FHEZDPDAYTVKKG-JLBKCEDKSA-N 0.000 description 1
- HIOVQJCJNCRSCC-UHFFFAOYSA-N 2-(3-fluorobenzo[b][1]benzoxepin-5-yl)sulfanyl-n-methylethanamine;hydrochloride Chemical compound Cl.CNCCSC1=CC2=CC=CC=C2OC2=CC=C(F)C=C12 HIOVQJCJNCRSCC-UHFFFAOYSA-N 0.000 description 1
- CXDPVKRPWPEWCT-UHFFFAOYSA-N 2-(3-phenoxypropyl)guanidine;sulfuric acid Chemical compound OS(O)(=O)=O.NC(N)=NCCCOC1=CC=CC=C1.NC(N)=NCCCOC1=CC=CC=C1 CXDPVKRPWPEWCT-UHFFFAOYSA-N 0.000 description 1
- ODZUWQAFWMLWCF-UHFFFAOYSA-N 2-(3-phenyl-1-benzofuran-7-yl)propanoic acid Chemical compound C=1OC=2C(C(C(O)=O)C)=CC=CC=2C=1C1=CC=CC=C1 ODZUWQAFWMLWCF-UHFFFAOYSA-N 0.000 description 1
- LRXFKKPEBXIPMW-UHFFFAOYSA-N 2-(9h-fluoren-2-yl)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C(C(O)=O)C)C=C3CC2=C1 LRXFKKPEBXIPMW-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- SNUBSRMFCPAKSI-UHFFFAOYSA-N 2-(dimethylamino)ethanol;2-(4-phenylphenyl)butanoic acid Chemical compound CN(C)CCO.C1=CC(C(C(O)=O)CC)=CC=C1C1=CC=CC=C1 SNUBSRMFCPAKSI-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 description 1
- UCEXMJMSILZCHZ-UHFFFAOYSA-N 2-[(4-butoxybenzoyl)amino]acetic acid Chemical compound CCCCOC1=CC=C(C(=O)NCC(O)=O)C=C1 UCEXMJMSILZCHZ-UHFFFAOYSA-N 0.000 description 1
- PRKWVSHZYDOZLP-UHFFFAOYSA-N 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-3h-inden-5-yl)oxy]acetic acid Chemical compound C1C2=CC(OCC(O)=O)=C(Cl)C(Cl)=C2C(=O)C1(C)C1=CC=CC=C1 PRKWVSHZYDOZLP-UHFFFAOYSA-N 0.000 description 1
- DWWHMKBNNNZGHF-UHFFFAOYSA-N 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1h-imidazole;hydron;chloride Chemical compound Cl.N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl DWWHMKBNNNZGHF-UHFFFAOYSA-N 0.000 description 1
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 1
- OLLMPVQGLMNQQK-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenoxy)ethylamino]guanidine;sulfuric acid Chemical compound OS(O)(=O)=O.NC(N)=NNCCOC1=C(Cl)C=CC=C1Cl.NC(N)=NNCCOC1=C(Cl)C=CC=C1Cl OLLMPVQGLMNQQK-UHFFFAOYSA-N 0.000 description 1
- RCWLESWTVSJYOL-UHFFFAOYSA-N 2-[2-(4-methyl-3,6-dihydro-2h-pyridin-1-yl)ethyl]guanidine;sulfuric acid;dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.CC1=CCN(CCN=C(N)N)CC1 RCWLESWTVSJYOL-UHFFFAOYSA-N 0.000 description 1
- NCEAPFRHADKEHP-UHFFFAOYSA-N 2-[2-hydroxy-3-[[1-(1h-indol-3-yl)-2-methylpropan-2-yl]amino]propoxy]benzonitrile;hydrochloride Chemical compound Cl.C=1NC2=CC=CC=C2C=1CC(C)(C)NCC(O)COC1=CC=CC=C1C#N NCEAPFRHADKEHP-UHFFFAOYSA-N 0.000 description 1
- IDCAZKFFVIMCCS-UHFFFAOYSA-N 2-[3-(4-chlorophenyl)-4-imino-2-oxoimidazolidin-1-yl]acetonitrile Chemical compound C1=CC(Cl)=CC=C1N1C(=O)N(CC#N)CC1=N IDCAZKFFVIMCCS-UHFFFAOYSA-N 0.000 description 1
- NLGUJWNOGYWZBI-UHFFFAOYSA-N 2-[3-chloro-4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 NLGUJWNOGYWZBI-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- QKKLKGVIECOSRM-CODXZCKSSA-N 2-[4-[3-(2-chlorophenothiazin-10-yl)propyl]piperazin-1-yl]ethanol;4-[2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-4-oxobutanoic acid Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21.O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 QKKLKGVIECOSRM-CODXZCKSSA-N 0.000 description 1
- LNXXSBRGLBOASF-UHFFFAOYSA-N 2-[[2-(4-chlorophenyl)-4-methyl-1,3-oxazol-5-yl]methoxy]-2-methylpropanoic acid Chemical compound O1C(COC(C)(C)C(O)=O)=C(C)N=C1C1=CC=C(Cl)C=C1 LNXXSBRGLBOASF-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- GXEUNRBWEAIPCN-UHFFFAOYSA-N 2-chloro-2-(3-chloro-4-cyclohexylphenyl)acetic acid Chemical compound ClC1=CC(C(Cl)C(=O)O)=CC=C1C1CCCCC1 GXEUNRBWEAIPCN-UHFFFAOYSA-N 0.000 description 1
- NJYBZXINKWROMG-UHFFFAOYSA-N 2-chloro-5-(dimethylaminocarbamoyl)benzenesulfonamide Chemical compound CN(C)NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NJYBZXINKWROMG-UHFFFAOYSA-N 0.000 description 1
- DQPNQXUUCWOWCK-UHFFFAOYSA-N 2-ethoxy-n-methyl-n-[2-[methyl(2-phenylethyl)amino]ethyl]-2,2-diphenylacetamide;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC)C(=O)N(C)CCN(C)CCC1=CC=CC=C1 DQPNQXUUCWOWCK-UHFFFAOYSA-N 0.000 description 1
- UBUJQGDIGRPIEZ-LJTMIZJLSA-N 2-hydroxybenzoic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound OC(=O)C1=CC=CC=C1O.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO UBUJQGDIGRPIEZ-LJTMIZJLSA-N 0.000 description 1
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 1
- UJABSZITRMATFL-UHFFFAOYSA-N 2-methyl-5-phenylfuran-3-carbonyl chloride Chemical compound ClC(=O)C1=C(C)OC(C=2C=CC=CC=2)=C1 UJABSZITRMATFL-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- DFSFLZCLKYZYRD-UHFFFAOYSA-N 3,4-diethoxycyclobut-3-ene-1,2-dione Chemical compound CCOC1=C(OCC)C(=O)C1=O DFSFLZCLKYZYRD-UHFFFAOYSA-N 0.000 description 1
- PYSICVOJSJMFKP-UHFFFAOYSA-N 3,5-dibromo-2-chloropyridine Chemical compound ClC1=NC=C(Br)C=C1Br PYSICVOJSJMFKP-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- HRCGIZACAMIMII-UHFFFAOYSA-N 3-(1-methyl-3-propylpyrrolidin-3-yl)phenol;hydrochloride Chemical compound Cl.C=1C=CC(O)=CC=1C1(CCC)CCN(C)C1 HRCGIZACAMIMII-UHFFFAOYSA-N 0.000 description 1
- DQHRYCOJUKGIDH-WLHGVMLRSA-N 3-(12h-[1]benzofuro[3,2-c][1]benzoxepin-6-ylidene)-n,n-dimethylpropan-1-amine;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1OC2=CC=CC=C2C(=CCCN(C)C)C2=C1C1=CC=CC=C1O2 DQHRYCOJUKGIDH-WLHGVMLRSA-N 0.000 description 1
- JXZZEXZZKAWDSP-UHFFFAOYSA-N 3-(2-(4-Benzamidopiperid-1-yl)ethyl)indole Chemical compound C1CN(CCC=2C3=CC=CC=C3NC=2)CCC1NC(=O)C1=CC=CC=C1 JXZZEXZZKAWDSP-UHFFFAOYSA-N 0.000 description 1
- MPJUSISYVXABBH-UHFFFAOYSA-N 3-(3-ethyl-1-methylazepan-3-yl)phenol;hydron;chloride Chemical compound Cl.C=1C=CC(O)=CC=1C1(CC)CCCCN(C)C1 MPJUSISYVXABBH-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- GUSQVRBQQVKTMO-LINSIKMZSA-N 3-[(3r,4s)-1,3-dimethyl-4-propylpiperidin-4-yl]phenol;hydrochloride Chemical compound Cl.C=1C=CC(O)=CC=1[C@@]1(CCC)CCN(C)C[C@@H]1C GUSQVRBQQVKTMO-LINSIKMZSA-N 0.000 description 1
- RAGPBJMJHPNLAJ-QQTWVUFVSA-N 3-[(4ar,8ar)-2-(cyclopropylmethyl)-1,3,4,5,6,7,8,8a-octahydroisoquinolin-4a-yl]phenol;butanedioic acid Chemical compound OC(=O)CCC(O)=O.OC1=CC=CC([C@]23[C@@H](CCCC2)CN(CC2CC2)CC3)=C1 RAGPBJMJHPNLAJ-QQTWVUFVSA-N 0.000 description 1
- QPFDPUCWRFYCFB-UHFFFAOYSA-N 3-[2-(diethylamino)ethyl]-1,3-benzoxazine-2,4-dione;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)N(CCN(CC)CC)C(=O)OC2=C1 QPFDPUCWRFYCFB-UHFFFAOYSA-N 0.000 description 1
- PLZMRGRLCWCLFW-UHFFFAOYSA-N 3-[5-(3-bromophenyl)tetrazol-2-yl]-1-piperidin-1-ylpropan-1-one Chemical compound BrC1=CC=CC(C2=NN(CCC(=O)N3CCCCC3)N=N2)=C1 PLZMRGRLCWCLFW-UHFFFAOYSA-N 0.000 description 1
- YLJRTDTWWRXOFG-UHFFFAOYSA-N 3-[5-(4-chlorophenyl)furan-2-yl]-3-hydroxypropanoic acid Chemical compound O1C(C(CC(O)=O)O)=CC=C1C1=CC=C(Cl)C=C1 YLJRTDTWWRXOFG-UHFFFAOYSA-N 0.000 description 1
- ZSLYVCXNFQPCGT-UHFFFAOYSA-N 3-carboxy-3,5-dihydroxy-5-oxopentanoate;methyl 1-(2-phenylethyl)-4-(n-propanoylanilino)piperidin-1-ium-4-carboxylate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1CN(CCC=2C=CC=CC=2)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZSLYVCXNFQPCGT-UHFFFAOYSA-N 0.000 description 1
- NCPBMOFVRBEVJY-QPJJXVBHSA-N 3-chloro-6-[4-[(e)-3-phenylprop-2-enyl]piperazin-1-yl]pyridazine Chemical compound N1=NC(Cl)=CC=C1N1CCN(C\C=C\C=2C=CC=CC=2)CC1 NCPBMOFVRBEVJY-QPJJXVBHSA-N 0.000 description 1
- YUORBURTMIUPMW-UHFFFAOYSA-N 3-methyl-5-[2-(4-phenyl-3,6-dihydro-2h-pyridin-1-yl)ethyl]-1,3-oxazolidin-2-one Chemical compound O1C(=O)N(C)CC1CCN1CC=C(C=2C=CC=CC=2)CC1 YUORBURTMIUPMW-UHFFFAOYSA-N 0.000 description 1
- MSBSMNOJAAJSGG-UHFFFAOYSA-N 3-morpholin-4-yl-1,2,3-benzotriazin-4-one Chemical compound N1=NC2=CC=CC=C2C(=O)N1N1CCOCC1 MSBSMNOJAAJSGG-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- GFLJTEHFZZNCTR-UHFFFAOYSA-N 3-prop-2-enoyloxypropyl prop-2-enoate Chemical compound C=CC(=O)OCCCOC(=O)C=C GFLJTEHFZZNCTR-UHFFFAOYSA-N 0.000 description 1
- NBUHTTJGQKIBMR-UHFFFAOYSA-N 4,6-dimethylpyrimidin-5-amine Chemical compound CC1=NC=NC(C)=C1N NBUHTTJGQKIBMR-UHFFFAOYSA-N 0.000 description 1
- DYUTXEVRMPFGTH-UHFFFAOYSA-N 4-(2,5-dimethylphenyl)-5-methyl-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=CC=C(C)C=2)C)=C1C DYUTXEVRMPFGTH-UHFFFAOYSA-N 0.000 description 1
- INDZCVYWKNWKIQ-UHFFFAOYSA-N 4-(fluoren-9-ylidenemethyl)benzenecarboximidamide;hydrochloride Chemical compound Cl.C1=CC(C(=N)N)=CC=C1C=C1C2=CC=CC=C2C2=CC=CC=C21 INDZCVYWKNWKIQ-UHFFFAOYSA-N 0.000 description 1
- CCHPWFRRLJQTDO-UHFFFAOYSA-N 4-[2-(6,7-dimethoxy-1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]aniline;hydron;dichloride Chemical compound Cl.Cl.CC1C=2C=C(OC)C(OC)=CC=2CCN1CCC1=CC=C(N)C=C1 CCHPWFRRLJQTDO-UHFFFAOYSA-N 0.000 description 1
- UTINTLAUEVROEQ-UHFFFAOYSA-N 4-[2-(7,8-dimethoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)ethyl]aniline;dihydrochloride Chemical compound Cl.Cl.C1CC=2C=C(OC)C(OC)=CC=2CCN1CCC1=CC=C(N)C=C1 UTINTLAUEVROEQ-UHFFFAOYSA-N 0.000 description 1
- HIMOMFKFIYLRNY-UHFFFAOYSA-N 4-[2-(7-methoxy-4-methyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)ethyl]aniline;dihydrochloride Chemical compound Cl.Cl.CC1CC2=CC(OC)=CC=C2CCN1CCC1=CC=C(N)C=C1 HIMOMFKFIYLRNY-UHFFFAOYSA-N 0.000 description 1
- SDYAJRBHPPWHSF-UHFFFAOYSA-N 4-azidoaniline;hydrochloride Chemical compound Cl.NC1=CC=C(N=[N+]=[N-])C=C1 SDYAJRBHPPWHSF-UHFFFAOYSA-N 0.000 description 1
- XHCXKGFNPZETQY-YHPCKPBFSA-N 4-bromo-n-[(1s,2s)-2-(dimethylamino)cyclohexyl]benzamide;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.CN(C)[C@H]1CCCC[C@@H]1NC(=O)C1=CC=C(Br)C=C1 XHCXKGFNPZETQY-YHPCKPBFSA-N 0.000 description 1
- LBXHRAWDUMTPSE-AOOOYVTPSA-N 4-chloro-N-[(2S,6R)-2,6-dimethyl-1-piperidinyl]-3-sulfamoylbenzamide Chemical compound C[C@H]1CCC[C@@H](C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-AOOOYVTPSA-N 0.000 description 1
- REQFWARMBJWJAQ-UHFFFAOYSA-N 4-chloro-n-methyl-3-(methylsulfamoyl)benzamide Chemical compound CNC(=O)C1=CC=C(Cl)C(S(=O)(=O)NC)=C1 REQFWARMBJWJAQ-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- LQVMQEYROPXMQH-UHFFFAOYSA-N 4-dibenzofuran-2-yl-4-oxobutanoic acid Chemical compound C1=CC=C2C3=CC(C(=O)CCC(=O)O)=CC=C3OC2=C1 LQVMQEYROPXMQH-UHFFFAOYSA-N 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- TYJOQICPGZGYDT-UHFFFAOYSA-N 4-methylsulfonylbenzenesulfonyl chloride Chemical compound CS(=O)(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 TYJOQICPGZGYDT-UHFFFAOYSA-N 0.000 description 1
- KWFFVBCJCQQAIV-UHFFFAOYSA-N 4-phenylcyclohexan-1-amine;2-(4-phenylphenyl)butanoic acid Chemical compound C1CC(N)CCC1C1=CC=CC=C1.C1=CC(C(C(O)=O)CC)=CC=C1C1=CC=CC=C1 KWFFVBCJCQQAIV-UHFFFAOYSA-N 0.000 description 1
- CXSJGNHRBWJXEA-UHFFFAOYSA-N 5,12-dihydrophthalazino[3,2-b]phthalazine-7,14-dione Chemical compound C1C2=CC=CC=C2C(=O)N2N1C(=O)C1=CC=CC=C1C2 CXSJGNHRBWJXEA-UHFFFAOYSA-N 0.000 description 1
- YOIOINQCJZQHPS-YDBXVIRUSA-N 5-[[[(1s,2s,3s)-2-hydroxy-3-phenoxycyclopentyl]amino]methyl]-2-methyl-6,7-dihydro-5h-1-benzothiophen-4-one;hydrochloride Chemical compound Cl.O([C@H]1CC[C@@H]([C@@H]1O)NCC1CCC2=C(C1=O)C=C(S2)C)C1=CC=CC=C1 YOIOINQCJZQHPS-YDBXVIRUSA-N 0.000 description 1
- NXRJFNBTRPERHV-UHFFFAOYSA-N 6,7-dichloro-3-cyclopent-3-en-1-yl-4h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound N=1S(=O)(=O)C=2C=C(Cl)C(Cl)=CC=2NC=1C1CC=CC1 NXRJFNBTRPERHV-UHFFFAOYSA-N 0.000 description 1
- LJEPCGWMLNUFDA-UHFFFAOYSA-N 6,7-dimethoxy-2-(4-prop-2-enylpiperazin-1-yl)quinazolin-4-amine;dihydrochloride Chemical compound Cl.Cl.N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N1CCN(CC=C)CC1 LJEPCGWMLNUFDA-UHFFFAOYSA-N 0.000 description 1
- QJWVFNYHDZZWDS-UHFFFAOYSA-N 6,7-dimethoxyquinolin-4-amine;hydrate;hydrochloride Chemical compound O.Cl.C1=CC(N)=C2C=C(OC)C(OC)=CC2=N1 QJWVFNYHDZZWDS-UHFFFAOYSA-N 0.000 description 1
- VGLGVJVUHYTIIU-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3-[(prop-2-enylthio)methyl]-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC=C)NS2(=O)=O VGLGVJVUHYTIIU-UHFFFAOYSA-N 0.000 description 1
- BDNLIZHZILNCGI-UHFFFAOYSA-N 6-chloro-2-methyl-1,1-dioxo-3-(prop-2-enylsulfanylmethyl)-3,4-dihydro-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC=C)NC2=C1 BDNLIZHZILNCGI-UHFFFAOYSA-N 0.000 description 1
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 1
- OAIZNWQBWDHNIH-UHFFFAOYSA-N 6-chloro-4-phenyl-1-(2,2,2-trifluoroethyl)quinazolin-2-one Chemical compound N=1C(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 OAIZNWQBWDHNIH-UHFFFAOYSA-N 0.000 description 1
- DXPPIEDUBFUSEZ-UHFFFAOYSA-N 6-methylheptyl prop-2-enoate Chemical compound CC(C)CCCCCOC(=O)C=C DXPPIEDUBFUSEZ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- VCCNKWWXYVWTLT-CYZBKYQRSA-N 7-[(2s,3r,4s,5s,6r)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2s,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-one Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 VCCNKWWXYVWTLT-CYZBKYQRSA-N 0.000 description 1
- KUYDFFZBJGJAPK-UHFFFAOYSA-N 7-bromo-3,4-dihydro-1h-isoquinoline-2-carboximidamide;sulfuric acid Chemical compound OS(O)(=O)=O.C1=C(Br)C=C2CN(C(=N)N)CCC2=C1.C1=C(Br)C=C2CN(C(=N)N)CCC2=C1 KUYDFFZBJGJAPK-UHFFFAOYSA-N 0.000 description 1
- XWXVKXXKKLBDDJ-UHFFFAOYSA-N 7-chloro-3,3a-dihydro-2h-[1,2]oxazolo[3,2-b][1,3]benzoxazin-9-one Chemical compound O1C2CCON2C(=O)C2=CC(Cl)=CC=C21 XWXVKXXKKLBDDJ-UHFFFAOYSA-N 0.000 description 1
- HCKFPALGXKOOBK-NRYMJLQJSA-N 7332-27-6 Chemical compound C1([C@]2(O[C@]3([C@@]4(C)C[C@H](O)[C@]5(F)[C@@]6(C)C=CC(=O)C=C6CC[C@H]5[C@@H]4C[C@H]3O2)C(=O)CO)C)=CC=CC=C1 HCKFPALGXKOOBK-NRYMJLQJSA-N 0.000 description 1
- OZSPQIXKOVJJGE-UHFFFAOYSA-N 8-(2-ethoxyethyl)-7-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine Chemical compound N1=C(N)N2N=CN=C2C(CCOCC)=C1C1=CC=CC=C1 OZSPQIXKOVJJGE-UHFFFAOYSA-N 0.000 description 1
- ZOCUOMKMBMEYQV-GSLJADNHSA-N 9alpha-Fluoro-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ZOCUOMKMBMEYQV-GSLJADNHSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108010004032 Bromelains Proteins 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- VKSPIPWLHGKJQO-UHFFFAOYSA-N Bupicomide Chemical compound CCCCC1=CC=C(C(N)=O)N=C1 VKSPIPWLHGKJQO-UHFFFAOYSA-N 0.000 description 1
- 206010006797 Burns first degree Diseases 0.000 description 1
- 206010006802 Burns second degree Diseases 0.000 description 1
- 206010006803 Burns third degree Diseases 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 102100034871 C-C motif chemokine 8 Human genes 0.000 description 1
- RFYVFAJUSHHPPR-UHFFFAOYSA-N C.C1=CNC=C1.C1=CNC=N1 Chemical compound C.C1=CNC=C1.C1=CNC=N1 RFYVFAJUSHHPPR-UHFFFAOYSA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N C1=CNC=N1 Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- ZXFWJPKXEMFBOG-LWVMDMHWSA-N CC(O)=O.CC[C@H](C)[C@@H]1NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CSSC[C@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCNC(N)=N Chemical compound CC(O)=O.CC[C@H](C)[C@@H]1NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CSSC[C@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCNC(N)=N ZXFWJPKXEMFBOG-LWVMDMHWSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 description 1
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 1
- 208000009043 Chemical Burns Diseases 0.000 description 1
- CVKNDPRBJVBDSS-UHFFFAOYSA-N Cicletanine Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=C(Cl)C=C1 CVKNDPRBJVBDSS-UHFFFAOYSA-N 0.000 description 1
- KATBVKFXGKGUFE-UHFFFAOYSA-N Cintazone Chemical compound C12=CC=CC=C2N2C(=O)C(CCCCC)C(=O)N2C=C1C1=CC=CC=C1 KATBVKFXGKGUFE-UHFFFAOYSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- IWHXNINOLLNFGP-ZAGWXBKKSA-N Cl.CCOc1ccc(cc1)\N=N\c1ccc(N)cc1N Chemical compound Cl.CCOc1ccc(cc1)\N=N\c1ccc(N)cc1N IWHXNINOLLNFGP-ZAGWXBKKSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 description 1
- YXKFATPOEMHNMJ-KJEYTGHBSA-N Cormethasone acetate Chemical compound C1C(F)(F)C2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O YXKFATPOEMHNMJ-KJEYTGHBSA-N 0.000 description 1
- TVZCRIROJQEVOT-CABCVRRESA-N Cromakalim Chemical compound N1([C@@H]2C3=CC(=CC=C3OC([C@H]2O)(C)C)C#N)CCCC1=O TVZCRIROJQEVOT-CABCVRRESA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- YTBSYETUWUMLBZ-UHFFFAOYSA-N D-Erythrose Natural products OCC(O)C(O)C=O YTBSYETUWUMLBZ-UHFFFAOYSA-N 0.000 description 1
- RFSUNEUAIZKAJO-VRPWFDPXSA-N D-Fructose Natural products OC[C@H]1OC(O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-VRPWFDPXSA-N 0.000 description 1
- YTBSYETUWUMLBZ-IUYQGCFVSA-N D-erythrose Chemical compound OC[C@@H](O)[C@@H](O)C=O YTBSYETUWUMLBZ-IUYQGCFVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- SRBFZHDQGSBBOR-SOOFDHNKSA-N D-ribopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@@H]1O SRBFZHDQGSBBOR-SOOFDHNKSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- FDJCVHVKXFIEPJ-JCNFZFLDSA-N Delapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 FDJCVHVKXFIEPJ-JCNFZFLDSA-N 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- WYQPLTPSGFELIB-JTQPXKBDSA-N Difluprednate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CCC)[C@@]2(C)C[C@@H]1O WYQPLTPSGFELIB-JTQPXKBDSA-N 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- 206010069808 Electrical burn Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108010066671 Enalaprilat Proteins 0.000 description 1
- KQXVERRYBYGQJZ-WRPDIKACSA-N Enalkiren Chemical compound C1=CC(OC)=CC=C1C[C@H](NC(=O)CC(C)(C)N)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)CC1=CN=CN1 KQXVERRYBYGQJZ-WRPDIKACSA-N 0.000 description 1
- 108010044063 Endocrine-Gland-Derived Vascular Endothelial Growth Factor Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000005770 Eugenol Substances 0.000 description 1
- CVKUMNRCIJMVAR-UHFFFAOYSA-N Fenoldopam mesylate Chemical compound CS(O)(=O)=O.C1=CC(O)=CC=C1C1C2=CC(O)=C(O)C(Cl)=C2CCNC1 CVKUMNRCIJMVAR-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- APQPGQGAWABJLN-UHFFFAOYSA-N Floctafenine Chemical compound OCC(O)COC(=O)C1=CC=CC=C1NC1=CC=NC2=C(C(F)(F)F)C=CC=C12 APQPGQGAWABJLN-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229910005542 GaSb Inorganic materials 0.000 description 1
- 229910001218 Gallium arsenide Inorganic materials 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- DGFYECXYGUIODH-UHFFFAOYSA-N Guanfacine hydrochloride Chemical compound Cl.NC(N)=NC(=O)CC1=C(Cl)C=CC=C1Cl DGFYECXYGUIODH-UHFFFAOYSA-N 0.000 description 1
- 208000023329 Gun shot wound Diseases 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- YCISZOVUHXIOFY-HKXOFBAYSA-N Halopredone acetate Chemical compound C1([C@H](F)C2)=CC(=O)C(Br)=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@](OC(C)=O)(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O YCISZOVUHXIOFY-HKXOFBAYSA-N 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 1
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101000645296 Homo sapiens Metalloproteinase inhibitor 2 Proteins 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000026633 IL6 Human genes 0.000 description 1
- 108091058560 IL8 Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- ACEWLPOYLGNNHV-UHFFFAOYSA-N Ibuprofen piconol Chemical compound C1=CC(CC(C)C)=CC=C1C(C)C(=O)OCC1=CC=CC=N1 ACEWLPOYLGNNHV-UHFFFAOYSA-N 0.000 description 1
- 229910000673 Indium arsenide Inorganic materials 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000016921 Integrin-Binding Sialoprotein Human genes 0.000 description 1
- 108010028750 Integrin-Binding Sialoprotein Proteins 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 1
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- 102000007547 Laminin Human genes 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- UXBPQRGCVJOTNT-COBSGTNCSA-N Levomethadyl acetate hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 UXBPQRGCVJOTNT-COBSGTNCSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- MQHWFIOJQSCFNM-UHFFFAOYSA-L Magnesium salicylate Chemical compound [Mg+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O MQHWFIOJQSCFNM-UHFFFAOYSA-L 0.000 description 1
- 101710091439 Major capsid protein 1 Proteins 0.000 description 1
- 101710091437 Major capsid protein 2 Proteins 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- LEROTMJVBFSIMP-UHFFFAOYSA-N Mebutamate Chemical compound NC(=O)OCC(C)(C(C)CC)COC(N)=O LEROTMJVBFSIMP-UHFFFAOYSA-N 0.000 description 1
- PKVZBNCYEICAQP-UHFFFAOYSA-N Mecamylamine hydrochloride Chemical compound Cl.C1CC2C(C)(C)C(NC)(C)C1C2 PKVZBNCYEICAQP-UHFFFAOYSA-N 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- HUXCOHMTWUSXGY-GAPIFECDSA-N Meclorisone dibutyrate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CCC)(OC(=O)CCC)[C@@]1(C)C[C@@H]2Cl HUXCOHMTWUSXGY-GAPIFECDSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 102100026262 Metalloproteinase inhibitor 2 Human genes 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 description 1
- 229920001410 Microfiber Polymers 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- ZDZXCYHMVFLGMT-BTJKTKAUSA-N Monatepil maleate Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(F)=CC=C1N1CCN(CCCC(=O)NC2C3=CC=CC=C3SCC3=CC=CC=C32)CC1 ZDZXCYHMVFLGMT-BTJKTKAUSA-N 0.000 description 1
- 101100446513 Mus musculus Fgf4 gene Proteins 0.000 description 1
- OPZKBPQVWDSATI-KHPPLWFESA-N N-Vanillyloleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 OPZKBPQVWDSATI-KHPPLWFESA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- AYRXSINWFIIFAE-UHFFFAOYSA-N O6-alpha-D-Galactopyranosyl-D-galactose Natural products OCC1OC(OCC(O)C(O)C(O)C(O)C=O)C(O)C(O)C1O AYRXSINWFIIFAE-UHFFFAOYSA-N 0.000 description 1
- 102000004264 Osteopontin Human genes 0.000 description 1
- 108010081689 Osteopontin Proteins 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- BCGJBQBWUGVESK-KCTCKCTRSA-N Oxymorphone hydrochloride Chemical compound Cl.O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BCGJBQBWUGVESK-KCTCKCTRSA-N 0.000 description 1
- 101150062285 PGF gene Proteins 0.000 description 1
- 101150042788 PROK2 gene Proteins 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- VBCPVIWPDJVHAN-UHFFFAOYSA-N Phenoxybenzamine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C[NH+](CCCl)C(C)COC1=CC=CC=C1 VBCPVIWPDJVHAN-UHFFFAOYSA-N 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- XRKXJJYSKUIIEN-LLVKDONJSA-N Pivopril Chemical compound CC(C)(C)C(=O)SC[C@@H](C)C(=O)N(CC(O)=O)C1CCCC1 XRKXJJYSKUIIEN-LLVKDONJSA-N 0.000 description 1
- 102100035194 Placenta growth factor Human genes 0.000 description 1
- 102100040681 Platelet-derived growth factor C Human genes 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
- RETPFDTUCPKFEC-UHFFFAOYSA-N Primidolol Chemical compound CC1=CC=CC=C1OCC(O)CNCCN1C(=O)NC(=O)C(C)=C1 RETPFDTUCPKFEC-UHFFFAOYSA-N 0.000 description 1
- 102100040126 Prokineticin-1 Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 1
- 206010063562 Radiation skin injury Diseases 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 244000061121 Rauvolfia serpentina Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- 108010083387 Saralasin Proteins 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 208000026137 Soft tissue injury Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 206010041899 Stab wound Diseases 0.000 description 1
- 241000519995 Stachys sylvatica Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- OJCZPLDERGDQRJ-UHFFFAOYSA-N Sufentanil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 OJCZPLDERGDQRJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UNZIDPIPYUMVPA-UHFFFAOYSA-M Sulpyrine Chemical compound O.[Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 UNZIDPIPYUMVPA-UHFFFAOYSA-M 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- YCNTYPIGYVTFBO-UHFFFAOYSA-N Tinabinol Chemical compound CC1(C)OC2=CC(C(C)C(C)CCCCC)=CC(O)=C2C2=C1SCCC2 YCNTYPIGYVTFBO-UHFFFAOYSA-N 0.000 description 1
- MULPYFRDYRZMDS-UHFFFAOYSA-N Tiodazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=NN=C(SC)O1 MULPYFRDYRZMDS-UHFFFAOYSA-N 0.000 description 1
- 102100030859 Tissue factor Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 229910021541 Vanadium(III) oxide Inorganic materials 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 238000004125 X-ray microanalysis Methods 0.000 description 1
- 229910006501 ZrSiO Inorganic materials 0.000 description 1
- IUSFTUWHKCSCDY-QTKZZPNDSA-N [(2s,3s)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 IUSFTUWHKCSCDY-QTKZZPNDSA-N 0.000 description 1
- ZSYULWHBPBAOKV-TXEJJXNPSA-N [(3ar,6as)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-phenylmethanone Chemical compound C([C@H]1COC[C@H]1C1)N1C(=O)C1=CC=CC=C1 ZSYULWHBPBAOKV-TXEJJXNPSA-N 0.000 description 1
- NSOGAHPJIFTUHV-DVTLTWPTSA-N [(6s,6ar,9r,10ar)-9-hydroxy-6-methyl-3-(5-phenylpentan-2-yloxy)-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-1-yl] acetate;hydrochloride Chemical compound Cl.C=1([C@@H]2C[C@H](O)CC[C@H]2[C@H](C)NC=1C=1)C(OC(C)=O)=CC=1OC(C)CCCC1=CC=CC=C1 NSOGAHPJIFTUHV-DVTLTWPTSA-N 0.000 description 1
- NSOGAHPJIFTUHV-YINRMENDSA-N [(6s,6ar,9r,10ar)-9-hydroxy-6-methyl-3-[(2r)-5-phenylpentan-2-yl]oxy-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-1-yl] acetate;hydrochloride Chemical compound Cl.C([C@@H](C)OC=1C=C(OC(C)=O)C=2[C@@H]3C[C@H](O)CC[C@H]3[C@H](C)NC=2C=1)CCC1=CC=CC=C1 NSOGAHPJIFTUHV-YINRMENDSA-N 0.000 description 1
- MVLBCBPGBUAVJQ-CENSZEJFSA-N [(6s,8s,9r,10s,11s,13s,14s,16r,17r)-17-(chloromethylsulfanylcarbonyl)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O MVLBCBPGBUAVJQ-CENSZEJFSA-N 0.000 description 1
- XPHBRTNHVJSEQD-ATJXCDBQSA-N [(z)-[3-(diethylamino)-1-phenylpropylidene]amino] n-(4-methoxyphenyl)carbamate Chemical compound C=1C=CC=CC=1C(/CCN(CC)CC)=N\OC(=O)NC1=CC=C(OC)C=C1 XPHBRTNHVJSEQD-ATJXCDBQSA-N 0.000 description 1
- MJDIWCQJUPYRAF-UHFFFAOYSA-N [1-[1-(dimethylamino)propan-2-yl]-2-phenylcyclohexyl] acetate;hydrochloride Chemical compound Cl.CN(C)CC(C)C1(OC(C)=O)CCCCC1C1=CC=CC=C1 MJDIWCQJUPYRAF-UHFFFAOYSA-N 0.000 description 1
- FBRAWBYQGRLCEK-UHFFFAOYSA-N [17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3,11-dioxo-7,8,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-17-yl] butanoate Chemical compound C1CC2=CC(=O)C=CC2(C)C2(F)C1C1CC(C)C(C(=O)CCl)(OC(=O)CCC)C1(C)CC2=O FBRAWBYQGRLCEK-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 description 1
- MGOGSSZOPFFXLA-UHFFFAOYSA-N [4-(4-fluorophenyl)sulfonylpiperazin-1-yl]-[4-[[7-(trifluoromethyl)quinolin-4-yl]amino]phenyl]methanone;hydrochloride Chemical compound Cl.C1=CC(F)=CC=C1S(=O)(=O)N1CCN(C(=O)C=2C=CC(NC=3C4=CC=C(C=C4N=CC=3)C(F)(F)F)=CC=2)CC1 MGOGSSZOPFFXLA-UHFFFAOYSA-N 0.000 description 1
- QTBMDDQRDDABNC-UHFFFAOYSA-N [4-dibutoxyphosphoryl-3-(dibutoxyphosphorylmethyl)butoxy]benzene Chemical compound CCCCOP(=O)(OCCCC)CC(CP(=O)(OCCCC)OCCCC)CCOC1=CC=CC=C1 QTBMDDQRDDABNC-UHFFFAOYSA-N 0.000 description 1
- VYBDZIGAEAYRMM-UHFFFAOYSA-N [5,5-dimethyl-8-(3-methyloctan-2-yl)-2-prop-2-ynyl-3,4-dihydro-1h-chromeno[4,3-c]pyridin-10-yl] 2-methyl-4-(2-methylpiperidin-1-yl)butanoate;dihydrochloride Chemical compound Cl.Cl.C=12C(CN(CC#C)CC3)=C3C(C)(C)OC2=CC(C(C)C(C)CCCCC)=CC=1OC(=O)C(C)CCN1CCCCC1C VYBDZIGAEAYRMM-UHFFFAOYSA-N 0.000 description 1
- KWXQFOPVLBPXHY-UHFFFAOYSA-N [5,5-dimethyl-8-(3-methyloctan-2-yl)-2-prop-2-ynyl-3,4-dihydro-1h-chromeno[4,3-c]pyridin-10-yl] 4-piperidin-1-ylbutanoate;hydron;chloride Chemical compound Cl.C=12C(CN(CC#C)CC3)=C3C(C)(C)OC2=CC(C(C)C(C)CCCCC)=CC=1OC(=O)CCCN1CCCCC1 KWXQFOPVLBPXHY-UHFFFAOYSA-N 0.000 description 1
- QOWPUUFVFLIYRR-UHFFFAOYSA-N [6-(methylamino)-4,4-diphenylheptan-3-yl] acetate;hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(CC(C)[NH2+]C)(C(OC(C)=O)CC)C1=CC=CC=C1 QOWPUUFVFLIYRR-UHFFFAOYSA-N 0.000 description 1
- VRWTWCLVCNQJGM-ZBWZZBALSA-N a88bis7ibb Chemical compound CS(O)(=O)=O.C([C@@]12CC(=C)C[C@@H]([C@H]2[C@H]2CC=3C1=CC(O)=CC=3)C)CN2CC1CCC1 VRWTWCLVCNQJGM-ZBWZZBALSA-N 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- YBZYNINTWCLDQA-UHKVWXOHSA-N acetic acid;(2s)-2-[[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[2-(methylamino)acetyl]amino]pentanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]-3-(1h-imidazol-5-yl)prop Chemical compound O.CC(O)=O.C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 YBZYNINTWCLDQA-UHKVWXOHSA-N 0.000 description 1
- MCEMSMUXOSFTJG-KBUZRCILSA-N acetic acid;(2s)-2-[[(2s)-2-[[2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]-methylamino]-4-methylsulfanylbutanamide Chemical compound CC(O)=O.C([C@@H](C(=O)N(C)[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 MCEMSMUXOSFTJG-KBUZRCILSA-N 0.000 description 1
- XBMIVRRWGCYBTQ-UHFFFAOYSA-N acetylmethadol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-UHFFFAOYSA-N 0.000 description 1
- 229950005506 acetylmethadol Drugs 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002156 adsorbate Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 229960004229 alclometasone dipropionate Drugs 0.000 description 1
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960005380 alfentanil hydrochloride Drugs 0.000 description 1
- LSWBQIAZNGURQV-WTBIUSKOSA-N algestone acetonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)C)[C@@]1(C)CC2 LSWBQIAZNGURQV-WTBIUSKOSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229950009255 alipamide Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 102000012005 alpha-2-HS-Glycoprotein Human genes 0.000 description 1
- 108010075843 alpha-2-HS-Glycoprotein Proteins 0.000 description 1
- 102000004139 alpha-Amylases Human genes 0.000 description 1
- 108090000637 alpha-Amylases Proteins 0.000 description 1
- 229940024171 alpha-amylase Drugs 0.000 description 1
- 229950007522 altizide Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- NSZFBGIRFCHKOE-LFZVSNMSSA-N amcinafal Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(CC)(CC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O NSZFBGIRFCHKOE-LFZVSNMSSA-N 0.000 description 1
- 229950004850 amcinafal Drugs 0.000 description 1
- 229950003408 amcinafide Drugs 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- QZNJPJDUBTYMRS-UHFFFAOYSA-M amfenac sodium hydrate Chemical compound O.[Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=CC=C1 QZNJPJDUBTYMRS-UHFFFAOYSA-M 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960004238 anakinra Drugs 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 108010005565 anaritide Proteins 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 229950004733 anidoxime Drugs 0.000 description 1
- 229960002512 anileridine Drugs 0.000 description 1
- LKYQLAWMNBFNJT-UHFFFAOYSA-N anileridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 LKYQLAWMNBFNJT-UHFFFAOYSA-N 0.000 description 1
- ZYTHLJLPPSSDIP-UHFFFAOYSA-N anileridine dihydrochloride Chemical compound Cl.Cl.C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 ZYTHLJLPPSSDIP-UHFFFAOYSA-N 0.000 description 1
- 229960004812 anileridine hydrochloride Drugs 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- HDNJXZZJFPCFHG-UHFFFAOYSA-N anitrazafen Chemical compound C1=CC(OC)=CC=C1C1=NN=C(C)N=C1C1=CC=C(OC)C=C1 HDNJXZZJFPCFHG-UHFFFAOYSA-N 0.000 description 1
- 229950002412 anitrazafen Drugs 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960000560 balsalazide disodium Drugs 0.000 description 1
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Inorganic materials [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 1
- 229920005601 base polymer Polymers 0.000 description 1
- 210000003323 beak Anatomy 0.000 description 1
- 229950000537 belfosdil Drugs 0.000 description 1
- 229950004294 bemitradine Drugs 0.000 description 1
- 229960005149 bendazac Drugs 0.000 description 1
- BYFMCKSPFYVMOU-UHFFFAOYSA-N bendazac Chemical compound C12=CC=CC=C2C(OCC(=O)O)=NN1CC1=CC=CC=C1 BYFMCKSPFYVMOU-UHFFFAOYSA-N 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 1
- 229960001541 benzthiazide Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 229960004347 betaxolol hydrochloride Drugs 0.000 description 1
- YTIJUXVIZLYQTB-UHFFFAOYSA-N bethanidine sulfate Chemical compound [O-]S([O-])(=O)=O.CN\C(=[NH+]/C)NCC1=CC=CC=C1.CN\C(=[NH+]/C)NCC1=CC=CC=C1 YTIJUXVIZLYQTB-UHFFFAOYSA-N 0.000 description 1
- 229940007994 bethanidine sulfate Drugs 0.000 description 1
- 229960003588 bevantolol Drugs 0.000 description 1
- FJTKCFSPYUMXJB-UHFFFAOYSA-N bevantolol hydrochloride Chemical compound [Cl-].C1=C(OC)C(OC)=CC=C1CC[NH2+]CC(O)COC1=CC=CC(C)=C1 FJTKCFSPYUMXJB-UHFFFAOYSA-N 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 1
- UIDLJTHRRPMIQP-UHFFFAOYSA-L bis[2-[4-(2-methylpropyl)phenyl]propanoyloxy]aluminum;hydrate Chemical compound O.C1=CC(CC(C)C)=CC=C1C(C)C(=O)O[Al]OC(=O)C(C)C1=CC=C(CC(C)C)C=C1 UIDLJTHRRPMIQP-UHFFFAOYSA-L 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 229960005400 bisoprolol fumarate Drugs 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 1
- 235000019835 bromelain Nutrition 0.000 description 1
- 229960001780 bromelains Drugs 0.000 description 1
- 229960002716 bromfenac sodium Drugs 0.000 description 1
- HZFGMQJYAFHESD-UHFFFAOYSA-M bromfenac sodium Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 HZFGMQJYAFHESD-UHFFFAOYSA-M 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229950011622 broperamole Drugs 0.000 description 1
- 210000005178 buccal mucosa Anatomy 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 229950008162 bupicomide Drugs 0.000 description 1
- 229960001889 buprenorphine hydrochloride Drugs 0.000 description 1
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 description 1
- QTNZYVAMNRDUAD-UHFFFAOYSA-N butacetin Chemical compound CC(=O)NC1=CC=C(OC(C)(C)C)C=C1 QTNZYVAMNRDUAD-UHFFFAOYSA-N 0.000 description 1
- 229950011189 butacetin Drugs 0.000 description 1
- 229960001290 butanilicaine Drugs 0.000 description 1
- VWYQKFLLGRBICZ-UHFFFAOYSA-N butanilicaine Chemical compound CCCCNCC(=O)NC1=C(C)C=CC=C1Cl VWYQKFLLGRBICZ-UHFFFAOYSA-N 0.000 description 1
- 229950000699 butixirate Drugs 0.000 description 1
- HGBFRHCDYZJRAO-UHFFFAOYSA-N butizide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC(C)C)NC2=C1 HGBFRHCDYZJRAO-UHFFFAOYSA-N 0.000 description 1
- 229950008955 butizide Drugs 0.000 description 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 1
- 229960001113 butorphanol Drugs 0.000 description 1
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 description 1
- 229960001590 butorphanol tartrate Drugs 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- ZTWZVMIYIIVABD-OEMFJLHTSA-N candoxatril Chemical compound C([C@@H](COCCOC)C(=O)OC=1C=C2CCCC2=CC=1)C1(C(=O)N[C@@H]2CC[C@@H](CC2)C(O)=O)CCCC1 ZTWZVMIYIIVABD-OEMFJLHTSA-N 0.000 description 1
- 229950004548 candoxatril Drugs 0.000 description 1
- ACZWIDANLCXHBM-HRCADAONSA-N candoxatrilat Chemical compound N([C@@H]1CC[C@@H](CC1)C(O)=O)C(=O)C1(C[C@@H](COCCOC)C(O)=O)CCCC1 ACZWIDANLCXHBM-HRCADAONSA-N 0.000 description 1
- 229950001305 candoxatrilat Drugs 0.000 description 1
- 210000001736 capillary Anatomy 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- VYMUGTALCSPLDM-UHFFFAOYSA-L carbasalate calcium Chemical compound [Ca+2].NC(N)=O.CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O VYMUGTALCSPLDM-UHFFFAOYSA-L 0.000 description 1
- 229950003365 carbifene Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 229950005749 ceronapril Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- CEZCCHQBSQPRMU-UHFFFAOYSA-L chembl174821 Chemical compound [Na+].[Na+].COC1=CC(S([O-])(=O)=O)=C(C)C=C1N=NC1=C(O)C=CC2=CC(S([O-])(=O)=O)=CC=C12 CEZCCHQBSQPRMU-UHFFFAOYSA-L 0.000 description 1
- MPSLGGPOYBRWKD-ZKUJQEIMSA-N chembl2107675 Chemical compound OC(=O)\C=C/C(O)=O.C1=CC=C2N3CC[C@H]4N(C(C)C)CCN(CC)[C@@H]4C3=C(C)C2=C1 MPSLGGPOYBRWKD-ZKUJQEIMSA-N 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229960000437 chlorothiazide sodium Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960001932 cicletanine Drugs 0.000 description 1
- 229950002545 cicloprofen Drugs 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- JQRZBPFGBRIWSN-YOTVLOEGSA-N cilazapril monohydrate Chemical compound O.C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 JQRZBPFGBRIWSN-YOTVLOEGSA-N 0.000 description 1
- GPUVGQIASQNZET-CCEZHUSRSA-N cinnoxicam Chemical compound C=1C=CC=CC=1/C=C/C(=O)OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 GPUVGQIASQNZET-CCEZHUSRSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229950005384 cliprofen Drugs 0.000 description 1
- 229960004703 clobetasol propionate Drugs 0.000 description 1
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 1
- 229960005465 clobetasone butyrate Drugs 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229960002925 clonidine hydrochloride Drugs 0.000 description 1
- 229950001923 clonixeril Drugs 0.000 description 1
- CLOMYZFHNHFSIQ-UHFFFAOYSA-N clonixin Chemical compound CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CLOMYZFHNHFSIQ-UHFFFAOYSA-N 0.000 description 1
- 229960001209 clonixin Drugs 0.000 description 1
- 229960004070 clopamide Drugs 0.000 description 1
- 229960003958 clopidogrel bisulfate Drugs 0.000 description 1
- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 description 1
- SJCRQMUYEQHNTC-UHFFFAOYSA-N clopirac Chemical compound CC1=CC(CC(O)=O)=C(C)N1C1=CC=C(Cl)C=C1 SJCRQMUYEQHNTC-UHFFFAOYSA-N 0.000 description 1
- 229950009185 clopirac Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004415 codeine phosphate Drugs 0.000 description 1
- 229960003871 codeine sulfate Drugs 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229950002276 cortodoxone Drugs 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 229950002213 cyclazocine Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZHPBLHYKDKSZCQ-UHFFFAOYSA-N cyclooctylmethanol Chemical compound OCC1CCCCCCC1 ZHPBLHYKDKSZCQ-UHFFFAOYSA-N 0.000 description 1
- 229960003206 cyclopenthiazide Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960003176 cyclothiazide Drugs 0.000 description 1
- BOCUKUHCLICSIY-QJWLJZLASA-N cyclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2C1[C@H](C=C2)C[C@H]2C1 BOCUKUHCLICSIY-QJWLJZLASA-N 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- QERUYFVNIOLCHV-UHFFFAOYSA-N darodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC2=NON=C12 QERUYFVNIOLCHV-UHFFFAOYSA-N 0.000 description 1
- 229950009702 darodipine Drugs 0.000 description 1
- CAYGYVYWRIHZCQ-UHFFFAOYSA-N debrisoquin sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C1=CC=C2CN(C(=N)N)CCC2=C1.C1=CC=C2CN(C(=N)N)CCC2=C1 CAYGYVYWRIHZCQ-UHFFFAOYSA-N 0.000 description 1
- 229960004096 debrisoquine Drugs 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 229960001145 deflazacort Drugs 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229960002593 desoximetasone Drugs 0.000 description 1
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- CIWBQSYVNNPZIQ-PKWREOPISA-N dexamethasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-PKWREOPISA-N 0.000 description 1
- 229950000250 dexamethasone dipropionate Drugs 0.000 description 1
- 229950005512 dexpemedolac Drugs 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229960003461 dezocine Drugs 0.000 description 1
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229960004042 diazoxide Drugs 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 229960004515 diclofenac potassium Drugs 0.000 description 1
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- VMZCXIGDNRMWGI-GEEYTBSJSA-N diethyl 2-[(dimethylamino)methyl]-6-methyl-4-[2-[(e)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]phenyl]-1,4-dihydropyridine-3,5-dicarboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=C(C)NC(CN(C)C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C VMZCXIGDNRMWGI-GEEYTBSJSA-N 0.000 description 1
- 229960002124 diflorasone diacetate Drugs 0.000 description 1
- BOBLHFUVNSFZPJ-JOYXJVLSSA-N diflorasone diacetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)COC(C)=O)(OC(C)=O)[C@@]2(C)C[C@@H]1O BOBLHFUVNSFZPJ-JOYXJVLSSA-N 0.000 description 1
- 229960004875 difluprednate Drugs 0.000 description 1
- 229950007956 diftalone Drugs 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 229960002705 dihydrocodeine bitartrate Drugs 0.000 description 1
- WQVZLXWQESQGIF-WJKBNZMCSA-N dilevalol hydrochloride Chemical compound Cl.C([C@@H](C)NC[C@H](O)C=1C=C(C(O)=CC=1)C(N)=O)CC1=CC=CC=C1 WQVZLXWQESQGIF-WJKBNZMCSA-N 0.000 description 1
- 229960001758 diltiazem malate Drugs 0.000 description 1
- GAVBHVRHVQMWEI-UHFFFAOYSA-N dimefadane Chemical compound C12=CC=CC=C2C(N(C)C)CC1C1=CC=CC=C1 GAVBHVRHVQMWEI-UHFFFAOYSA-N 0.000 description 1
- 229950010893 dimefadane Drugs 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229940120889 dipyrone Drugs 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 1
- 108010083220 ditekiren Proteins 0.000 description 1
- 229950010513 ditekiren Drugs 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229960000220 doxazosin mesylate Drugs 0.000 description 1
- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 description 1
- 229950006157 drinidene Drugs 0.000 description 1
- GZBONOYGBJSTHF-QLRNAMTQSA-N drocinonide Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O GZBONOYGBJSTHF-QLRNAMTQSA-N 0.000 description 1
- 229950006082 drocinonide Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- ODUOJXZPIYUATO-LJQANCHMSA-N ecadotril Chemical compound C([C@H](CSC(=O)C)C(=O)NCC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 ODUOJXZPIYUATO-LJQANCHMSA-N 0.000 description 1
- 229950001184 ecadotril Drugs 0.000 description 1
- 230000001700 effect on tissue Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000007772 electroless plating Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- 229960000309 enalapril maleate Drugs 0.000 description 1
- 229960002680 enalaprilat Drugs 0.000 description 1
- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
- 108010049503 enalkiren Proteins 0.000 description 1
- 229950008153 enalkiren Drugs 0.000 description 1
- 229960002029 endralazine Drugs 0.000 description 1
- 229950002798 enlimomab Drugs 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000004783 epithelial tight junction Anatomy 0.000 description 1
- RINBGYCKMGDWPY-UHFFFAOYSA-N epitizide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC(F)(F)F)NS2(=O)=O RINBGYCKMGDWPY-UHFFFAOYSA-N 0.000 description 1
- 229950010350 epitizide Drugs 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229960000573 eprosartan mesylate Drugs 0.000 description 1
- DJSLTDBPKHORNY-XMMWENQYSA-N eprosartan methanesulfonate Chemical compound CS(O)(=O)=O.C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 DJSLTDBPKHORNY-XMMWENQYSA-N 0.000 description 1
- 229960001903 ergotamine tartrate Drugs 0.000 description 1
- MUWDJVKYGSDUSH-KALLACGZSA-N ethyl (1s,2r)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate;hydron;chloride Chemical compound Cl.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C MUWDJVKYGSDUSH-KALLACGZSA-N 0.000 description 1
- QSRVZCCJDKYRRF-YDALLXLXSA-N ethyl (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@](C)(N)CC1=CC=C(O)C(O)=C1 QSRVZCCJDKYRRF-YDALLXLXSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- ULANGSAJTINEBA-UHFFFAOYSA-N ethyl n-(3-benzoylphenyl)-n-(trifluoromethylsulfonyl)carbamate Chemical compound CCOC(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 ULANGSAJTINEBA-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960002217 eugenol Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229960000192 felbinac Drugs 0.000 description 1
- 229950003579 fenamole Drugs 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- 229950003537 fenclorac Drugs 0.000 description 1
- HAWWPSYXSLJRBO-UHFFFAOYSA-N fendosal Chemical compound C1=C(O)C(C(=O)O)=CC(N2C(=CC=3C4=CC=CC=C4CCC=32)C=2C=CC=CC=2)=C1 HAWWPSYXSLJRBO-UHFFFAOYSA-N 0.000 description 1
- 229950005416 fendosal Drugs 0.000 description 1
- 229960004009 fenoldopam mesylate Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960005341 fenoprofen calcium Drugs 0.000 description 1
- VHUXSAWXWSTUOD-UHFFFAOYSA-L fenoprofen calcium (anhydrous) Chemical compound [Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 VHUXSAWXWSTUOD-UHFFFAOYSA-L 0.000 description 1
- 229950002296 fenpipalone Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 229960004207 fentanyl citrate Drugs 0.000 description 1
- 229960002679 fentiazac Drugs 0.000 description 1
- ZEAJXCPGHPJVNP-UHFFFAOYSA-N fenyramidol Chemical compound C=1C=CC=CC=1C(O)CNC1=CC=CC=N1 ZEAJXCPGHPJVNP-UHFFFAOYSA-N 0.000 description 1
- 229960000555 fenyramidol Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 229950004322 flazalone Drugs 0.000 description 1
- 229960003240 floctafenine Drugs 0.000 description 1
- RSXGUJLKWYUPMC-UHFFFAOYSA-N flordipine Chemical compound CC1=C(C(=O)OCC)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C(C)N1CCN1CCOCC1 RSXGUJLKWYUPMC-UHFFFAOYSA-N 0.000 description 1
- 229950009366 flordipine Drugs 0.000 description 1
- 229960001606 flosequinan Drugs 0.000 description 1
- UYGONJYYUKVHDD-UHFFFAOYSA-N flosequinan Chemical compound C1=C(F)C=C2N(C)C=C(S(C)=O)C(=O)C2=C1 UYGONJYYUKVHDD-UHFFFAOYSA-N 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- BYZCJOHDXLROEC-RBWIMXSLSA-N fluazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O BYZCJOHDXLROEC-RBWIMXSLSA-N 0.000 description 1
- 229950002335 fluazacort Drugs 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229950007979 flufenisal Drugs 0.000 description 1
- OPYFPDBMMYUPME-UHFFFAOYSA-N flumizole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)NC(C(F)(F)F)=N1 OPYFPDBMMYUPME-UHFFFAOYSA-N 0.000 description 1
- 229950005288 flumizole Drugs 0.000 description 1
- WEGNFRKBIKYVLC-XTLNBZDDSA-N flunisolide acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WEGNFRKBIKYVLC-XTLNBZDDSA-N 0.000 description 1
- XWTIDFOGTCVGQB-FHIVUSPVSA-N fluocortin butyl Chemical group C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)C(=O)OCCCC)[C@@]2(C)C[C@@H]1O XWTIDFOGTCVGQB-FHIVUSPVSA-N 0.000 description 1
- 229950008509 fluocortin butyl Drugs 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 229960001629 fluorometholone acetate Drugs 0.000 description 1
- YRFXGQHBPBMFHW-SBTZIJSASA-N fluorometholone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 YRFXGQHBPBMFHW-SBTZIJSASA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960001655 flupirtine maleate Drugs 0.000 description 1
- ZWOUXWWGKJBAHQ-UHFFFAOYSA-N fluproquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=C(F)C=C1 ZWOUXWWGKJBAHQ-UHFFFAOYSA-N 0.000 description 1
- 229950004250 fluproquazone Drugs 0.000 description 1
- 229950007253 fluquazone Drugs 0.000 description 1
- 229950003750 fluretofen Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229960001880 fosinopril sodium Drugs 0.000 description 1
- WOIWWYDXDVSWAZ-RTWAWAEBSA-N fosinoprilat Chemical compound C([C@@H](C[C@H]1C(=O)O)C2CCCCC2)N1C(=O)CP(O)(=O)CCCCC1=CC=CC=C1 WOIWWYDXDVSWAZ-RTWAWAEBSA-N 0.000 description 1
- 229960003018 fosinoprilat Drugs 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 229950008156 furaprofen Drugs 0.000 description 1
- 229950006099 furobufen Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 description 1
- DLRVVLDZNNYCBX-CQUJWQHSSA-N gentiobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-CQUJWQHSSA-N 0.000 description 1
- 208000024693 gingival disease Diseases 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940080812 glyceryl caprate Drugs 0.000 description 1
- 229940087068 glyceryl caprylate Drugs 0.000 description 1
- 229940068939 glyceryl monolaurate Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229960004553 guanabenz Drugs 0.000 description 1
- 229960003050 guanabenz acetate Drugs 0.000 description 1
- 229950006795 guanacline Drugs 0.000 description 1
- RTEVGQJRTFFMLL-UHFFFAOYSA-N guanadrel sulfate Chemical compound OS(O)(=O)=O.O1C(CN=C(N)N)COC11CCCCC1.O1C(CN=C(N)N)COC11CCCCC1 RTEVGQJRTFFMLL-UHFFFAOYSA-N 0.000 description 1
- 229960004032 guanadrel sulfate Drugs 0.000 description 1
- VZVGEDRCVUKSEL-UHFFFAOYSA-N guancidine Chemical compound CCC(C)(C)N=C(N)NC#N VZVGEDRCVUKSEL-UHFFFAOYSA-N 0.000 description 1
- 229950007639 guancidine Drugs 0.000 description 1
- 229960002096 guanethidine monosulfate Drugs 0.000 description 1
- 229960004848 guanethidine sulfate Drugs 0.000 description 1
- 229960004746 guanfacine hydrochloride Drugs 0.000 description 1
- 229960001016 guanoxabenz Drugs 0.000 description 1
- QKIQJNNDIWGVEH-UUILKARUSA-N guanoxabenz Chemical compound ONC(/N)=N/N=C/C1=C(Cl)C=CC=C1Cl QKIQJNNDIWGVEH-UUILKARUSA-N 0.000 description 1
- 229960000760 guanoxan Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229950004611 halopredone acetate Drugs 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical class OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229960005384 hydralazine hydrochloride Drugs 0.000 description 1
- ZUXNZUWOTSUBMN-UHFFFAOYSA-N hydralazine hydrochloride Chemical compound Cl.C1=CC=C2C(NN)=NN=CC2=C1 ZUXNZUWOTSUBMN-UHFFFAOYSA-N 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 229960002738 hydromorphone hydrochloride Drugs 0.000 description 1
- WXMXALSEIGHTOR-UHFFFAOYSA-N hydron;(2-hydroxy-2-methylpropyl) 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-1-carboxylate;chloride;hydrate Chemical compound O.Cl.N1=C2C(OC)=C(OC)C(OC)=CC2=C(N)N=C1N1CCN(C(=O)OCC(C)(C)O)CC1 WXMXALSEIGHTOR-UHFFFAOYSA-N 0.000 description 1
- SXZRLCAHCIRKJU-UHFFFAOYSA-N hydron;3-[3-(4-phenylpiperazin-1-yl)propyl]-1h-quinazoline-2,4-dione;chloride Chemical compound Cl.O=C1NC2=CC=CC=C2C(=O)N1CCCN(CC1)CCN1C1=CC=CC=C1 SXZRLCAHCIRKJU-UHFFFAOYSA-N 0.000 description 1
- CNNVSINJDJNHQK-UHFFFAOYSA-N hydron;5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine;chloride Chemical compound [Cl-].C12=CC=CC=C2C[NH+](C)CCOC1C1=CC=CC=C1 CNNVSINJDJNHQK-UHFFFAOYSA-N 0.000 description 1
- AFJSFHAKSSWOKG-UHFFFAOYSA-N hydron;n-[1-[2-(1h-indol-3-yl)ethyl]piperidin-4-yl]benzamide;chloride Chemical compound Cl.C1CN(CCC=2C3=CC=CC=C3NC=2)CCC1NC(=O)C1=CC=CC=C1 AFJSFHAKSSWOKG-UHFFFAOYSA-N 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229950005954 ibuprofen piconol Drugs 0.000 description 1
- 229950011445 ilonidap Drugs 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 description 1
- 229940113174 imidurea Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 229950009607 indacrinone Drugs 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- KHLVKKOJDHCJMG-QDBORUFSSA-L indigo carmine Chemical compound [Na+].[Na+].N/1C2=CC=C(S([O-])(=O)=O)C=C2C(=O)C\1=C1/NC2=CC=C(S(=O)(=O)[O-])C=C2C1=O KHLVKKOJDHCJMG-QDBORUFSSA-L 0.000 description 1
- 239000004179 indigotine Substances 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- RPQDHPTXJYYUPQ-UHFFFAOYSA-N indium arsenide Chemical compound [In]#[As] RPQDHPTXJYYUPQ-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004260 indomethacin sodium Drugs 0.000 description 1
- 229960002056 indoramin Drugs 0.000 description 1
- 229960001649 indoramin hydrochloride Drugs 0.000 description 1
- 229950008443 indoxole Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229950004204 intrazole Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960003317 isoflupredone acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- HQBZLVPZOGIAIQ-SDDDUWNISA-N ketazocine Chemical compound N1([C@H]2[C@@H]([C@](CC1)(C)C=1C(=CC=C(O)C=1)C2=O)C)CC1CC1 HQBZLVPZOGIAIQ-SDDDUWNISA-N 0.000 description 1
- 229950007980 ketazocine Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- ORMBBVGVPWUEMQ-QKLQHJQFSA-N ketorfanol Chemical compound C([C@]12CC(=O)CC[C@H]1[C@H]1CC=3C=CC=C(C2=3)O)CN1CC1CC1 ORMBBVGVPWUEMQ-QKLQHJQFSA-N 0.000 description 1
- 229950011541 ketorfanol Drugs 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 229960004384 ketorolac tromethamine Drugs 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 description 1
- 229960004340 lacidipine Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229950009632 leniquinsin Drugs 0.000 description 1
- XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-AVRDEDQJSA-N 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 229940018399 levomethadyl acetate hydrochloride Drugs 0.000 description 1
- RWTWIZDKEIWLKQ-IWWMGODWSA-N levorphan tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 RWTWIZDKEIWLKQ-IWWMGODWSA-N 0.000 description 1
- 229960005157 levorphanol tartrate Drugs 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- 229960002058 lofexidine hydrochloride Drugs 0.000 description 1
- 229950002290 lorcinadol Drugs 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- 229960000519 losartan potassium Drugs 0.000 description 1
- DMKSVUSAATWOCU-HROMYWEYSA-N loteprednol etabonate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)OCCl)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O DMKSVUSAATWOCU-HROMYWEYSA-N 0.000 description 1
- 229960003744 loteprednol etabonate Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 229960005337 lysine hydrochloride Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940072082 magnesium salicylate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- GEYXPJBPASPPLI-UHFFFAOYSA-N manganese(III) oxide Inorganic materials O=[Mn]O[Mn]=O GEYXPJBPASPPLI-UHFFFAOYSA-N 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 102000043253 matrix Gla protein Human genes 0.000 description 1
- 108010057546 matrix Gla protein Proteins 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- 229960004119 mebutamate Drugs 0.000 description 1
- 229960001263 mecamylamine hydrochloride Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229940051129 meperidine hydrochloride Drugs 0.000 description 1
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 229960004473 meptazinol hydrochloride Drugs 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- OJGJQQNLRVNIKE-UHFFFAOYSA-N meseclazone Chemical compound O1C2=CC=C(Cl)C=C2C(=O)N2C1CC(C)O2 OJGJQQNLRVNIKE-UHFFFAOYSA-N 0.000 description 1
- 229950000701 meseclazone Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 229960005189 methadone hydrochloride Drugs 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 229940042053 methotrimeprazine Drugs 0.000 description 1
- VRQVVMDWGGWHTJ-CQSZACIVSA-N methotrimeprazine Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1 VRQVVMDWGGWHTJ-CQSZACIVSA-N 0.000 description 1
- 229960003739 methyclothiazide Drugs 0.000 description 1
- CBKLICUQYUTWQL-XWGBWKJCSA-N methyl (3s,4r)-3-methyl-1-(2-phenylethyl)-4-(n-propanoylanilino)piperidine-4-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.CCC(=O)N([C@]1([C@H](CN(CCC=2C=CC=CC=2)CC1)C)C(=O)OC)C1=CC=CC=C1 CBKLICUQYUTWQL-XWGBWKJCSA-N 0.000 description 1
- KLGSBANGKXGRTA-UHFFFAOYSA-N methyl 3-amino-2-(5-methoxy-1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=C(OC)C=C2C(C(CN)C(=O)OC)=CNC2=C1 KLGSBANGKXGRTA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001823 methyldopate hydrochloride Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- PSCNNGGPKIBAHB-WFVOKNHCSA-N methylprednisolone 21-suleptanic acid ester Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCCCCCC(=O)N(C)CCS(O)(=O)=O)CC[C@H]21 PSCNNGGPKIBAHB-WFVOKNHCSA-N 0.000 description 1
- 229950010796 methylprednisolone suleptanate Drugs 0.000 description 1
- 229960002704 metipranolol Drugs 0.000 description 1
- BLWNYSZZZWQCKO-UHFFFAOYSA-N metipranolol hydrochloride Chemical compound [Cl-].CC(C)[NH2+]CC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BLWNYSZZZWQCKO-UHFFFAOYSA-N 0.000 description 1
- 229960001980 metirosine Drugs 0.000 description 1
- 108700020603 metkephamid acetate Proteins 0.000 description 1
- YBCPYHQFUMNOJG-UHFFFAOYSA-N metofoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(C)C1CCC1=CC=C(Cl)C=C1 YBCPYHQFUMNOJG-UHFFFAOYSA-N 0.000 description 1
- 229950009818 metofoline Drugs 0.000 description 1
- 229960002817 metolazone Drugs 0.000 description 1
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
- 229960002005 metoprolol fumarate Drugs 0.000 description 1
- 229960000939 metoprolol succinate Drugs 0.000 description 1
- 238000010208 microarray analysis Methods 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 239000003658 microfiber Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002324 minimally invasive surgery Methods 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229950005152 molinazone Drugs 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002771 monosaccharide derivatives Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 229960003251 morniflumate Drugs 0.000 description 1
- LDXSPUSKBDTEKA-UHFFFAOYSA-N morniflumate Chemical compound FC(F)(F)C1=CC=CC(NC=2C(=CC=CN=2)C(=O)OCCN2CCOCC2)=C1 LDXSPUSKBDTEKA-UHFFFAOYSA-N 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- IOZWXJXXVLARQC-KURKYZTESA-N moxazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@H]1OC)CN2CC1CC1 IOZWXJXXVLARQC-KURKYZTESA-N 0.000 description 1
- 229950005103 moxazocine Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- RLWRMIYXDPXIEX-UHFFFAOYSA-N muzolimine Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C)N1N=C(N)CC1=O RLWRMIYXDPXIEX-UHFFFAOYSA-N 0.000 description 1
- 229960001788 muzolimine Drugs 0.000 description 1
- IUZMSSDQGOBJTG-UHFFFAOYSA-N n-(2-fluorophenyl)-2-methoxy-n-[1-(2-phenylethyl)piperidin-4-yl]acetamide;hydrochloride Chemical compound Cl.C=1C=CC=C(F)C=1N(C(=O)COC)C(CC1)CCN1CCC1=CC=CC=C1 IUZMSSDQGOBJTG-UHFFFAOYSA-N 0.000 description 1
- HWCORKBTTGTRDY-UHFFFAOYSA-N n-(4-chlorophenyl)-1,3-dioxo-4h-isoquinoline-4-carboxamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1C2=CC=CC=C2C(=O)NC1=O HWCORKBTTGTRDY-UHFFFAOYSA-N 0.000 description 1
- VHXNDLUDRKRBCQ-KPVRICSOSA-N n-[(3s,4r)-1-[2-(4-ethyl-5-oxotetrazol-1-yl)ethyl]-3-methylpiperidin-4-yl]-n-(2-fluorophenyl)-2-methoxyacetamide;hydrochloride Chemical compound Cl.O=C1N(CC)N=NN1CCN1C[C@H](C)[C@H](N(C(=O)COC)C=2C(=CC=CC=2)F)CC1 VHXNDLUDRKRBCQ-KPVRICSOSA-N 0.000 description 1
- KVCOVXMNIYUKBS-UHFFFAOYSA-N n-[1-(2-phenylethyl)piperidin-4-yl]-n-pyrazin-2-ylfuran-2-carboxamide;hydrochloride Chemical compound Cl.C=1C=COC=1C(=O)N(C=1N=CC=NC=1)C(CC1)CCN1CCC1=CC=CC=C1 KVCOVXMNIYUKBS-UHFFFAOYSA-N 0.000 description 1
- YMRJQYDWCFOMRR-UHFFFAOYSA-N n-[1-[2-(4-ethyl-5-oxotetrazol-1-yl)ethyl]-4-phenylpiperidin-4-yl]-n-(2-fluorophenyl)propanamide;hydrochloride Chemical compound Cl.C1CN(CCN2C(N(CC)N=N2)=O)CCC1(C=1C=CC=CC=1)N(C(=O)CC)C1=CC=CC=C1F YMRJQYDWCFOMRR-UHFFFAOYSA-N 0.000 description 1
- PVDGXEIFXYECGU-UHFFFAOYSA-N n-azidoaniline Chemical group [N-]=[N+]=NNC1=CC=CC=C1 PVDGXEIFXYECGU-UHFFFAOYSA-N 0.000 description 1
- BCXCABRDBBWWGY-UHFFFAOYSA-N n-benzyl-n-methylprop-2-yn-1-amine;hydrochloride Chemical compound Cl.C#CCN(C)CC1=CC=CC=C1 BCXCABRDBBWWGY-UHFFFAOYSA-N 0.000 description 1
- IXIZLCOBHRPNNI-UHFFFAOYSA-N n-methyl-1-(3,4,5-trimethoxyphenyl)pent-4-en-2-amine;hydrochloride Chemical compound Cl.C=CCC(NC)CC1=CC(OC)=C(OC)C(OC)=C1 IXIZLCOBHRPNNI-UHFFFAOYSA-N 0.000 description 1
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- YZLZPSJXMWGIFH-BCXQGASESA-N nalbuphine hydrochloride Chemical compound [H+].[Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 YZLZPSJXMWGIFH-BCXQGASESA-N 0.000 description 1
- 229960001513 nalbuphine hydrochloride Drugs 0.000 description 1
- 229950008948 namoxyrate Drugs 0.000 description 1
- 239000002120 nanofilm Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 229960000619 nebivolol Drugs 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229960004925 nefopam hydrochloride Drugs 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N nickel(II) oxide Inorganic materials [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- 229950006046 nimazone Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229920000847 nonoxynol Polymers 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- SNQQPOLDUKLAAF-UHFFFAOYSA-N nonylphenol Chemical class CCCCCCCCCC1=CC=CC=C1O SNQQPOLDUKLAAF-UHFFFAOYSA-N 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229950005023 octazamide Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- OPZKBPQVWDSATI-UHFFFAOYSA-N oleoyl vanillylamide Natural products CCCCCCCCC=CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 OPZKBPQVWDSATI-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229960004364 olsalazine sodium Drugs 0.000 description 1
- 229950010717 olvanil Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960004534 orgotein Drugs 0.000 description 1
- 108010070915 orgotein Proteins 0.000 description 1
- 229950003655 orpanoxin Drugs 0.000 description 1
- 210000005009 osteogenic cell Anatomy 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 229960000944 oxetorone fumarate Drugs 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229960003617 oxycodone hydrochloride Drugs 0.000 description 1
- 229960004004 oxycodone terephthalate Drugs 0.000 description 1
- 229960005374 oxymorphone hydrochloride Drugs 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- CNDQSXOVEQXJOE-UHFFFAOYSA-N oxyphenbutazone hydrate Chemical compound O.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 CNDQSXOVEQXJOE-UHFFFAOYSA-N 0.000 description 1
- 229940124583 pain medication Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229960004239 pargyline hydrochloride Drugs 0.000 description 1
- 229950001648 pazoxide Drugs 0.000 description 1
- 229950005386 pemedolac Drugs 0.000 description 1
- NRPCWSUJMWEFOK-KDXIVRHGSA-N pentamorphone Chemical compound O([C@H]1C(=O)C=C[C@@]23NCCCCC)C4=C5[C@]31CCN(C)[C@@H]2CC5=CC=C4O NRPCWSUJMWEFOK-KDXIVRHGSA-N 0.000 description 1
- 229950011592 pentamorphone Drugs 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- OQGYMIIFOSJQSF-DTOXXUQYSA-N pentazocine hcl Chemical compound Cl.C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 OQGYMIIFOSJQSF-DTOXXUQYSA-N 0.000 description 1
- 229960003809 pentazocine hydrochloride Drugs 0.000 description 1
- QNLDTXPVZPRSAM-DTOXXUQYSA-N pentazocine lactate Chemical compound CC(O)C(O)=O.C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 QNLDTXPVZPRSAM-DTOXXUQYSA-N 0.000 description 1
- 229960001246 pentazocine lactate Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 229960003820 pentosan polysulfate sodium Drugs 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 231100000435 percutaneous penetration Toxicity 0.000 description 1
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 description 1
- 229960003929 perindopril erbumine Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 229960003799 phenazopyridine hydrochloride Drugs 0.000 description 1
- 229960003006 phenoxybenzamine hydrochloride Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000005240 physical vapour deposition Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- OUNSOXPSCMCFHX-UHFFFAOYSA-N pinadoline Chemical compound ClCCCCC(=O)NNC(=O)N1CC2=CC=CC=C2OC2=CC=C(Cl)C=C12 OUNSOXPSCMCFHX-UHFFFAOYSA-N 0.000 description 1
- 229950006680 pinadoline Drugs 0.000 description 1
- 229960001369 piroxicam cinnamate Drugs 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 229950008688 pivopril Drugs 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 108010017992 platelet-derived growth factor C Proteins 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920000371 poly(diallyldimethylammonium chloride) polymer Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001083 polybutene Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- MZKKJVZIFIQOPP-UHFFFAOYSA-M potassium;4-aminobenzoate Chemical compound [K+].NC1=CC=C(C([O-])=O)C=C1 MZKKJVZIFIQOPP-UHFFFAOYSA-M 0.000 description 1
- IASZJGRIPLTJMA-UHFFFAOYSA-N potassium;[2-[3-bromo-5-[(5-carbamoyl-4-cyclopropyl-2-ethylimidazol-1-yl)methyl]-1-benzofuran-2-yl]phenyl]-(trifluoromethylsulfonyl)azanide Chemical compound [K+].NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)[N-]S(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CC1 IASZJGRIPLTJMA-UHFFFAOYSA-N 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229960002386 prazosin hydrochloride Drugs 0.000 description 1
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229950008421 prednazate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- WAAVMZLJRXYRMA-UHFFFAOYSA-N prifelone Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(C(=O)C=2SC=CC=2)=C1 WAAVMZLJRXYRMA-UHFFFAOYSA-N 0.000 description 1
- 229950004465 prifelone Drugs 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 1
- 229950003568 primidolol Drugs 0.000 description 1
- 229950003795 prodolic acid Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940065347 propoxyphene hydrochloride Drugs 0.000 description 1
- 229960002466 proquazone Drugs 0.000 description 1
- JTIGKVIOEQASGT-UHFFFAOYSA-N proquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=CC=C1 JTIGKVIOEQASGT-UHFFFAOYSA-N 0.000 description 1
- 238000003498 protein array Methods 0.000 description 1
- RLECFUYBVBJYHJ-ADFQYSHBSA-N proxorphan tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@]12COCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CC1CC1.C([C@]12COCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CC1CC1 RLECFUYBVBJYHJ-ADFQYSHBSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 229960003042 quinapril hydrochloride Drugs 0.000 description 1
- IBBLRJGOOANPTQ-JKVLGAQCSA-N quinapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 IBBLRJGOOANPTQ-JKVLGAQCSA-N 0.000 description 1
- FLSLEGPOVLMJMN-YSSFQJQWSA-N quinaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)C(O)=O)CC1=CC=CC=C1 FLSLEGPOVLMJMN-YSSFQJQWSA-N 0.000 description 1
- 229960001007 quinaprilat Drugs 0.000 description 1
- 229950004258 quinuclium bromide Drugs 0.000 description 1
- 108700040249 racecadotril Proteins 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229910001404 rare earth metal oxide Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- WFBMIPUMYUHANP-UHFFFAOYSA-N remifentanil hydrochloride Chemical compound [Cl-].C1C[NH+](CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 WFBMIPUMYUHANP-UHFFFAOYSA-N 0.000 description 1
- 229960003011 remifentanil hydrochloride Drugs 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 102000027483 retinoid hormone receptors Human genes 0.000 description 1
- 108091008679 retinoid hormone receptors Proteins 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- 229960001487 rimexolone Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 description 1
- 229950001166 romazarit Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229950009768 salnacedin Drugs 0.000 description 1
- GIZKAXHWLRYMLE-UHFFFAOYSA-M sanguinarium chloride Chemical compound [Cl-].C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 GIZKAXHWLRYMLE-UHFFFAOYSA-M 0.000 description 1
- 229950011197 sanguinarium chloride Drugs 0.000 description 1
- 229960001379 saralasin acetate Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 235000014102 seafood Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229950002093 seclazone Drugs 0.000 description 1
- SBIBMFFZSBJNJF-UHFFFAOYSA-N selenium;zinc Chemical compound [Se]=[Zn] SBIBMFFZSBJNJF-UHFFFAOYSA-N 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 238000011896 sensitive detection Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229950006250 sermetacin Drugs 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- HAAYBYDROVFKPU-UHFFFAOYSA-N silver;azane;nitrate Chemical compound N.N.[Ag+].[O-][N+]([O-])=O HAAYBYDROVFKPU-UHFFFAOYSA-N 0.000 description 1
- UANPKWBWEAQNQY-UHFFFAOYSA-N sodium 5-[[4-(2-carboxyethylcarbamoyl)phenyl]diazenyl]-2-hydroxybenzoic acid Chemical compound C1=CC(=CC=C1C(=O)NCCC(=O)O)N=NC2=CC(=C(C=C2)O)C(=O)O.[Na+] UANPKWBWEAQNQY-UHFFFAOYSA-N 0.000 description 1
- 229940047670 sodium acrylate Drugs 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical group [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 229940048842 sodium xylenesulfonate Drugs 0.000 description 1
- TVTJZMHAIQQZTL-WATAJHSMSA-M sodium;(2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylate Chemical compound [Na+].C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C([O-])=O)CCCC1=CC=CC=C1 TVTJZMHAIQQZTL-WATAJHSMSA-M 0.000 description 1
- HVBBVDWXAWJQSV-UHFFFAOYSA-N sodium;(3-benzoylphenyl)-(difluoromethylsulfonyl)azanide Chemical compound [Na+].FC(F)S(=O)(=O)[N-]C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 HVBBVDWXAWJQSV-UHFFFAOYSA-N 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- JMHRGKDWGWORNU-UHFFFAOYSA-M sodium;2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound [Na+].CC1=C(CC([O-])=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 JMHRGKDWGWORNU-UHFFFAOYSA-M 0.000 description 1
- DCTVJZGYZTWBLO-UHFFFAOYSA-M sodium;2-[7-(4-methylsulfanylbenzoyl)-1-benzofuran-5-yl]acetate;hydrate Chemical compound O.[Na+].C1=CC(SC)=CC=C1C(=O)C1=CC(CC([O-])=O)=CC2=C1OC=C2 DCTVJZGYZTWBLO-UHFFFAOYSA-M 0.000 description 1
- XETSAYZRDCRPJY-UHFFFAOYSA-M sodium;4-aminobenzoate Chemical compound [Na+].NC1=CC=C(C([O-])=O)C=C1 XETSAYZRDCRPJY-UHFFFAOYSA-M 0.000 description 1
- TVGNJNYKOTWAJQ-UHFFFAOYSA-M sodium;4-butyl-5-oxo-1,2-diphenylpyrazol-3-olate;propane-1,2,3-triol Chemical compound [Na+].OCC(O)CO.C=1C=CC=CC=1N1C(=O)C(CCCC)=C([O-])N1C1=CC=CC=C1 TVGNJNYKOTWAJQ-UHFFFAOYSA-M 0.000 description 1
- CPIWHAFLBZQYLQ-UHFFFAOYSA-N sodium;6-chloro-1,1-dioxo-1$l^{6},2,4-benzothiadiazin-2-ide-7-sulfonamide Chemical compound [Na+].N1=C[N-]S(=O)(=O)C2=C1C=C(Cl)C(S(=O)(=O)N)=C2 CPIWHAFLBZQYLQ-UHFFFAOYSA-N 0.000 description 1
- AVERBMQHYOZACV-UHFFFAOYSA-M sodium;7-chloro-4-[(3,4-dichlorophenyl)carbamoyl]-1,1-dioxo-2,3-dihydro-1$l^{6}-benzothiepin-5-olate;hydrate Chemical compound O.[Na+].C1CS(=O)(=O)C2=CC=C(Cl)C=C2C([O-])=C1C(=O)NC1=CC=C(Cl)C(Cl)=C1 AVERBMQHYOZACV-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910052950 sphalerite Inorganic materials 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- IATRAKWUXMZMIY-UHFFFAOYSA-N strontium oxide Inorganic materials [O-2].[Sr+2] IATRAKWUXMZMIY-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960001204 sufentanil citrate Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- TXDNPSYEJHXKMK-UHFFFAOYSA-N sulfanylsilane Chemical class S[SiH3] TXDNPSYEJHXKMK-UHFFFAOYSA-N 0.000 description 1
- PAQZZCOZHPGCFW-UHFFFAOYSA-N sulfinalol Chemical compound C1=CC(OC)=CC=C1CCC(C)NCC(O)C1=CC=C(O)C(S(C)=O)=C1 PAQZZCOZHPGCFW-UHFFFAOYSA-N 0.000 description 1
- 229950005165 sulfinalol Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- 238000005287 template synthesis Methods 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001909 terazosin hydrochloride Drugs 0.000 description 1
- 108010069247 terlakiren Proteins 0.000 description 1
- UZQBKCWYZBHBOW-YIPNQBBMSA-N terlakiren Chemical compound C([C@@H](C(=O)N[C@@H](CSC)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)OC(C)C)NC(=O)N1CCOCC1)C1=CC=CC=C1 UZQBKCWYZBHBOW-YIPNQBBMSA-N 0.000 description 1
- 229950003204 terlakiren Drugs 0.000 description 1
- SASWSEQJAITMKS-JJNNLWIXSA-N tert-butyl (2s)-2-[[(2s)-1-[[(2s)-1-[[(4s,5s,7s)-5-hydroxy-2,8-dimethyl-7-[[(2s,3s)-3-methyl-1-oxo-1-(pyridin-2-ylmethylamino)pentan-2-yl]carbamoyl]nonan-4-yl]amino]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]-methylamino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]p Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)[C@@H](O)C[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC=1N=CC=CC=1)C(C)C)N(C)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H]1N(CCC1)C(=O)OC(C)(C)C)C1=CN=CN1 SASWSEQJAITMKS-JJNNLWIXSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229950007324 tesicam Drugs 0.000 description 1
- 229950000997 tesimide Drugs 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000036575 thermal burns Effects 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 1
- 229960000356 tienilic acid Drugs 0.000 description 1
- 229960001502 tilidine hydrochloride Drugs 0.000 description 1
- 229950004087 tinabinol Drugs 0.000 description 1
- 229950000282 tiodazosin Drugs 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- 229960003114 tixocortol pivalate Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960003107 tramadol hydrochloride Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- VSVSLEMVVAYTQW-VSXGLTOVSA-N triclonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]2(C)C[C@@H]1Cl VSVSLEMVVAYTQW-VSXGLTOVSA-N 0.000 description 1
- 229950008073 triclonide Drugs 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 229950000451 triflumidate Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960002906 trimazosin Drugs 0.000 description 1
- HALWUDBBYKMYPW-STOWLHSFSA-M trimethaphan camsylate Chemical compound C1C[C@@]2(CS([O-])(=O)=O)C(=O)C[C@@H]1C2(C)C.C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 HALWUDBBYKMYPW-STOWLHSFSA-M 0.000 description 1
- 229940029774 trimethaphan camsylate Drugs 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- UHLOVGKIEARANS-QZHINBJYSA-N tripamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)NN2C[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3C2)=C1 UHLOVGKIEARANS-QZHINBJYSA-N 0.000 description 1
- 229950004678 tripamide Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229950008396 ulobetasol propionate Drugs 0.000 description 1
- BDSYKGHYMJNPAB-LICBFIPMSA-N ulobetasol propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 230000035901 vesication Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- SVKVWRTVTPUQBY-MORSLUCNSA-N volazocine Chemical compound C([C@@]1(C)C2=CC=CC=C2C[C@@H]2[C@@H]1C)CN2CC1CC1 SVKVWRTVTPUQBY-MORSLUCNSA-N 0.000 description 1
- 229950001292 volazocine Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229960000537 xipamide Drugs 0.000 description 1
- MTZBBNMLMNBNJL-UHFFFAOYSA-N xipamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1O MTZBBNMLMNBNJL-UHFFFAOYSA-N 0.000 description 1
- 229960004175 xylazine hydrochloride Drugs 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
- GLJVRAXBUACXBP-FMVQVTEISA-N zenazocine mesylate Chemical compound CS(O)(=O)=O.C1C2=CC=C(O)C=C2[C@@]2(C)[C@](CCC(=O)CCC(C)C)(C)[C@@H]1N(C)CC2 GLJVRAXBUACXBP-FMVQVTEISA-N 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229910052984 zinc sulfide Inorganic materials 0.000 description 1
- OSKWTWSFSUAPKP-KQUFBQNASA-N zofenoprilat arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.C1[C@@H](C(O)=O)N(C(=O)[C@@H](CS)C)C[C@H]1SC1=CC=CC=C1 OSKWTWSFSUAPKP-KQUFBQNASA-N 0.000 description 1
- YKPUWZUDDOIDPM-VURMDHGXSA-N zucapsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C/C(C)C)=CC=C1O YKPUWZUDDOIDPM-VURMDHGXSA-N 0.000 description 1
- 229960002860 zucapsaicin Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/38—Silver; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/736—Chitin; Chitosan; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
Definitions
- This invention relates generally to methods and compositions useful for adding metallic nanoparticles to various substrates.
- Nanoparticles have been broadly defined as particles having one or more dimensions of the order of 100 nm or less. Even though various materials such as polymers, ceramics, metals and organic molecules are being currently investigated for developing nanosized particles, metal nanoparticles have raised significant interest due to their unique properties.
- Nanosized metallic particles mainly gold and silver nanoparticles, have attracted attention because of their unique optical and electrical properties, as well as potential biomedical applications.
- these metallic nanoparticles are known to show distinct optical, magnetic, electrical and biological properties which are different from the bulk materials [1].
- nanoparticles of silver Due to their unique properties and various areas of applications such as infection resistance, catalysis, nanoelectronics, optical filters and surface raman scattering, nanoparticles of silver are one of the most extensively investigated metallic nanoparticles [2].
- Several techniques have already been developed to form metal nanoparticles in solution.
- silver nanoparticles are commonly prepared by the controlled reduction of silver salt solutions.
- the structure and corresponding physical, chemical, and biological properties of silver nanoparticles are known to strongly depend on the method of preparation and the experimental conditions [3].
- Several reduction techniques have been investigated.
- These reduction techniques include strong chemical reducing agents such as sodium borohydride and hydrazine, irradiation using gamma rays, ultra violet, and visible light, microwave as well as ultra sound, and weak reducing agents such as ascorbates, citrates, alcohol, as well as polyols.
- a surface produced by magnetron sputtering of silver has been shown to have strong antibacterial properties [10].
- the antibacterial property has been attributed to the release of silver ions from the surface in a controlled and appropriate concentration.
- the modified surface has wound healing properties, demonstrating the advantages of silver coated materials for biomedical applications [11].
- the fabrication process has several limitations to be used for practical applications. These include the lack of flexibility and controllability of the process, the limited range of materials that can be modified and the limited surface area that can be modified at a time.
- compositions and methods by which surface modification techniques can be used to modify wide range polymeric substrates using metal nanoparticles as well as for metallic substrates There is a long felt need in the art for compositions and methods by which surface modification techniques can be used to modify wide range polymeric substrates using metal nanoparticles as well as for metallic substrates.
- the present invention satisfies these needs.
- the present disclosure demonstrates the development of mild and cost effective methods to immobilize metallic nanoparticles on polymeric or metallic substrates.
- the immobilization on polymeric substrates involves coating the surface with a photoactive polymer capable of synthesizing metallic nanoparticle on the surface.
- the template can be immobilized on any polymeric substrate using a mild and fast (1-2 minutes) photoreaction.
- the process is highly versatile as it can be used to create metallic nanoparticles such as silver nanoparticles on a wide range of polymeric substrates irrespective of its physical form, shape, or chemistry.
- a related method has also been designed for metallic biomaterials such as titanium.
- the data disclosed herein demonstrate the feasibility of synthesizing silver nanoparticles of different size ranges on the substrate surface depending on the reaction conditions. Furthermore, the process allows the feasibility of patterning surfaces with metallic nanoparticles demonstrating its potential for biosensor applications.
- the procedure is based on the photochemistry of azide groups which has been extensively investigated previously for lithographic techniques [12].
- the present invention utilizes, inter alia, azide chemistry to immobilize a wide range of natural and synthetic polymers on biomaterial surfaces and use the immobilized polymers as templates to synthesis metallic nanoparticles.
- the present invention encompasses practical methods to immobilize metal nanoparticles on any polymeric substrates.
- the present invention encompasses a nondestructive modification process without the use of harsh chemicals or high energy radiation.
- the present invention encompasses modifying polymeric substrates having any shape or size or structure.
- the present invention encompasses a practical method to immobilize nanoparticles on a metal surface.
- the metal surface comprises titanium.
- the present invention encompasses compositions and methods useful for controlling the size and distribution of nanoparticles on the surface by varying parameters associated with the template as well as other reagents.
- the present invention also encompasses compositions and methods useful for developing a green process without the use of reducing agents.
- the surface is metal. In one aspect, the metal is titanium. In one aspect, the metal surface is etched. In one aspect, the metal surface comprises metal nanoparticles. In one aspect, the metal nanoparticles are silver nanoparticles. In one aspect, the silver particles are about, 0.1 to about 100 nm in size or from about 1 to about 100 nm in size. In another aspect, they are 2-75 nm in size. In yet another aspect, they are about 3-50 nm in size. In a further aspect, they are about 4-25 nm. In another aspect, they are about 5-10 nm in size.
- the metal substrates and metal films of the invention are useful as surfaces for culturing mammalian cells.
- culturing mammalian cells or “maintaining cells in culture” is meant that the cells will adhere to the surface, but does not exclude the possibility that the cells merely adhere and do not proliferate.
- the metal substrates and metal films of the invention support the proliferation and differentiation of cells selected from the group consisting of stem cells, pluripotent stem cells, committed stem cells, embryonic stem cells, adult stem cells, bone marrow stem cells, bone marrow-derived stem cells, adipose stem cells, umbilical cord stem cells, dura mater stem cells, precursor cells, differentiated cells, osteoblasts, osteoclasts, myoblasts, neuroblasts, fibroblasts, glioblasts, germ cells, hepatocytes, chondrocytes, keratinocytes, smooth muscle cells, cardiac muscle cells, connective tissue cells, glial cells, epithelial cells, endothelial cells, hormone-secreting cells, cells of the immune system, normal cells, cancer cells, Schwann cells, and neurons.
- the cells are human cells.
- metal substrates and films of the invention comprising cells can be used as delivery vehicles to deliver the cells to a site of interest in a subject in need thereof.
- metal films and substrates may also be added to the metal films and substrates, in addition to metal nanoparticles such as silver nanoparticles.
- the metal substrates and films of the invention are useful for inhibiting microbial growth.
- the microbial growth is bacterial growth.
- the metal substrates are useful as nanostructured implants.
- the nanostructured implants can increase osseointegration and provide matrices to be used to deliver cells such as hMSCs to an osseous defect and reduce implant associated infection. Therefore, the present invention encompasses the use of metal substrates, particularly those which are etched or comprise metallic nanoparticles, as delivery vehicles. These delivery vehicles can be used to deliver cells and other materials to a site in a subject in need thereof, including, but not limited to, a wound, an osseous defect, etc.
- the additional materials include, but are not limited, other cell types, additional therapeutic agents, hormones, growth factors, etc.
- the present application further discloses a versatile technique to develop nanostructured titanium containing silver nanoparticles as a potential biomaterial.
- the present application discloses a method of making polymeric substrates comprising metallic nanoparticles.
- This method comprises forming a photoactive polymer by contacting a polymer comprising a reactive group with an aromatic azide or aliphatic azide. It further comprises contacting the photoactive polymer with the polymeric substrate, and immobilizing the photoactive polymer to the polymeric substrate by irradiation.
- the method further encompasses contacting the polymeric substrate comprising immobilized photoactivated polymers with a composition comprising a metal for forming metallic nanoparticles and optionally washing the substrate after the contact.
- the polymeric substrate is polystyrene.
- the polymer comprising a reactive group is selected from the group consisting of poly(acrylic acid), alginica acid, heparin, and chondroitin sulfate.
- the azidated polymer is purified following azidation.
- the purified azidated polymer is dried.
- the dried purified azidated polymer is resuspended at concentrations selected from the group consisting of 10 mg/ml, 5.0 mg/ml, 1.0 mg/ml, and 0.05 mg/ml.
- the irradiation is ultraviolet irradiation.
- the wavelength of the ultraviolet irradiation is about 275 nm.
- the composition comprises silver.
- the immobilized silver is reduced from silver ion to silver metal.
- the silver nanoparticles are made using ammoniacal polysaccharides.
- the polymers are applied in patterns.
- the present invention further encompasses a polymeric substrate comprising metallic nanoparticles made by the method described herein.
- the metallic nanoparticles range in size from about 1.0 nm to about 100 nm. In another aspect, the nanoparticles range in size from about 2.0 nm to about 75 nm. In a further aspect, the nanoparticles range in size from about 3.0 nm to about 50 nm. In yet another aspect, the nanoparticles range in size from about 4.0 nm to about 25 nm. In another aspect, the nanoparticles range in size from about 5.0 nm to about 10.0 nm.
- silver particles are incorporated onto the surface.
- the present application encompasses the use of surface active copolymers.
- the surface active copolymers include, but are not limited to, poloxamers, meroxapols, and poloxamines.
- poloxamers examples include poloxamer-101, -105, -105 benzoate, -108, -122, -123, -124, -181, -182, -182 dibenzoate, -183, -184, -185, -188, -212, -215, -217, -231, -234, -235, -237, -238, -282, -284, -288, -331, -333, -334, -335, -338, -401, -402, -403, and -407.
- the poloxamer is poloxamer-188.
- the poloxamer is poloxamer-407.
- the surface active copolymer composition comprises PluroGelTM (PluroGen, Annapolis, Md.).
- Exemplary meroxapols include, but are not limited to, meroxapol 105, 108, 171, 172, 174, 178, 251, 252, 254, 258, 311, 312, and 314.
- Exemplary poloxamines include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508.
- the present invention further encompasses methods for making metallic nanoparticles in chitosan and carboxymethyl chitosan.
- chitosan or carboxymethyl chitosan solutions are prepared in layers, which after drying, are contacted with a composition comprising a metal, which metal permeates the layers and forms metallic nanoparticles.
- the layers are alternated between chitosan and carboxymethyl chitosan.
- the metal is silver.
- the present application further discloses a method of making a tri-layer membrane comprising metallic nanoparticles for use as a therapeutic agent or a biosensor.
- the method encompasses preparing a chitosan solution and preparing a carboxymethyl chitosan solution. Then, a first layer of solution is applied to a surface and allowed to dry. The method further encompasses applying a second layer comprising the other solution to the dried first layer and allowing the second layer to dry. The method also encompasses applying a third layer of the same solution as applied for the first layer over the second layer and allowing the third layer to dry.
- Optionally dried layers are heated. The dried layers are then neutralized. The neutralized layers are then contacted with a composition comprising a metal for forming metallic nanoparticles to form a tri-layer membrane comprising metallic nanoparticles.
- compositions of the invention can be varied or adjusted as needed to utilized different metals, form different numbers of nanoparticles, different sizes of nanoparticles, add additional agents, etc.
- reaction times, temperatures, concentrations of solutions, etc. can be varied.
- the metallic particles are about, 0.1 to about 100 nm in size or from about 1 to about 100 nm in size. In another aspect, they are 2-75 nm in size. In yet another aspect, they are about 3-50 nm in size. In a further aspect, they are about 4-25 nm In another aspect, they are about 5-10 nm in size.
- Metals encompassed by the invention include gold (Au), silver (Ag), platinum (Pt), aluminum (Al), nickel (Ni), iron (Fe), palladium (Pd), titanium (Ti), scandium (Sc), vanadium (V), chromium (Cr), magnesium (Mg), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), cadmium (Cd), lutetium (Lu), hafnium (Hf), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), tantalum (Ta), rhodium (Rh), rare-earth metals ytterbium (Yb), lanthanum (La), cerium (Ce), praseodymium (Pr
- FIG. 1 Surface morphology of titanium thin films illustrated by scanning electron microscopic images at two different magnifications ( 1 A—lower magnification ( ⁇ 350); 1 B—higher magnification ( ⁇ 4,500); lower portion of image has magnification and bars indicating relative length).
- FIG. 2 Surface elemental composition of titanium indicating the presence of only titanium atoms.
- FIG. 3 Surface morphology of etched titanium thin films illustrated by scanning electron microscopic images at two different magnifications ( 3 A— ⁇ 4,500; 3 B— ⁇ 15,000).
- FIG. 4 Surface morphology of etched titanium thin films at two different higher magnifications ( 4 A— ⁇ 50,000; 4 B— ⁇ 100,000)
- FIG. 5 Surface elemental composition of titanium indicating the presence of only titanium atom.
- FIG. 6 Surface morphology of silver nitrated treated etched titanium films ( 6 A— ⁇ 1,600; 6 B— ⁇ 5,500).
- FIG. 7 depicts surface morphology of silver nitrated treated etched titanium films at different magnifications ( 7 a — ⁇ 50,000; 7 b — ⁇ 300,000; 7 c — ⁇ 100,000).
- FIG. 8 Surface elemental composition of silver nitrated treated etched titanium films.
- FIG. 9 depicts surface morphologies of sodium borohydrode reduced titanium metal surface at various magnifications ( ⁇ 350, 10,000, 50,000, 100,000, and 250,000, respectively).
- FIG. 10 represents EDS spectra of the nanoparticles on the surface indicating the composition as silver.
- FIG. 11 represents photographic images of: A. titanium metal surface; B. Titanium surface alkali etched; C. Titanium surface after treating with silver salt solution; D. Titanium surface after reduction to silver nanoparticles.
- FIG. 12 graphically represents a UV spectrum of azidated alginic acid showing the presence of azide groups.
- the ordinate represents absorbance and the abscissa represent wavelength (nm)
- FIG. 13 Silver nanoparticles formed on polystyrene substrates coated with polyacrylic acid, silver ion exchange and subsequent reduction (two magnifications indicating particles with size less than 50 nm; 13 A— ⁇ 60,000; 13 B— ⁇ 120,000).
- FIG. 14 comprising FIGS. 14A-E , illustrates the different sizes and size distribution of silver nanoparticles formed on azidated alginic acid on polystyrene cover slips after ion exchanging with silver followed by reduction.
- FIG. 15 Silver particles formed on azidated poly(acrylic acid) where in silver ions were exchanged for 5 h followed by reduction using sodium borohydride. Comparatively larger particles were obtained in this process. 15 A indicates a lower magnification and 15 B, a higher magnification during scanning electron microscopy.
- FIG. 16 depicts photographic images illustrating the formation of silver nanoparticles on azidated heparin sulfate coated on polystyrene substrate, after silver ion exchange and reduction using sodium borohydride.
- FIG. 17 Formation of silver nanoparticles on azidated heparin sulfate coated on polystyrene substrate, after silver ion exchange and reduction using sodium borohydride.
- 17 a Silicon nanoparticles formed in solution w/o adding NaBH4;
- 17 b UV absorption spectra characteristic of Ag nanoparticle.
- FIG. 18 SEM showing the formation of silver nanoparticles on nanofiber matrices after a thin layer of coating with azidated polymers.
- FIG. 19 shows poly(acrylic azide) coated and shined with UV light through a photomask ( 19 A).
- the lighter colored region shows polyacrylic acid grafted on polystyrene surface.
- FIG. 19B shows silver nanoparticles formed on the polyacrylic acid patterns on polystyrene.
- FIG. 20 Scheme showing the preparation and photo-immobilization of azidated polymers.
- FIG. 21 Scheme showing the formation of silver nanoparticles on polymeric substrates.
- FIG. 22 represents a photographic image illustrating the phase transition of PluroGel in the presence of silver nanoparticles formed using Procedure 1, as described in Example 2. Three vials, labeled A, B, and C are depicted. The photograph of FIG. 22 also demonstrates visually the differences between PluroGel at 4° C. ( FIG. 22A ), PluroGel plus silver particles at 4° C. ( 22 B), and PluroGel plus silver particles at 37° C. ( 22 C). The phase transition is also apparent (note that the vial labeled C is upside down and the composition had gelled).
- FIG. 23 represents a photographic image illustrating the low temperature stability of PluroGel comprising silver nanoparticles after 4 days at 4° C. ( 23 A—PluroGel; 23 B—PluroGel comprising silver nanoparticles).
- FIG. 24 represents photographic images illustrating the phase transition of PluroGel in the presence of silver particles formed using Procedure 2, as described in Example 2: PluroGel ( FIG. 24A ); PluroGel plus silver particles at 4° C. ( 24 B); and PluroGel plus silver particles at 37° C. ( 24 C).
- FIG. 25 represents photographic images of the solutions of FIG. 24 (A and B) after 4 days at 4° C.
- FIG. 26 represents transmission electron micrographic images providing evidence of the silver nanoparticles prepared according to Procedure 1 of Example 2. It can be seen in FIG. 26A that there are silver nanoparticles and that the general size ranges are about 10-15 nm
- FIG. 26B represents a higher magnification image of silver nanoparticles and demonstrates the partially crystalline structure.
- FIG. 26C represents an x-ray diffraction pattern which confirms the partially crystalline structure of the particles.
- FIG. 27 graphically illustrates LTV absorption spectra collected at various times up to 24 hours and demonstrates the growth of silver particles as a function of time of incubation in silver nitrate solution. Data were obtained using a UV-Vis spectrophotometer and indicate the plasmon resonance of silver particles.
- the abscissa represents wavelength in nanometers (nm).
- the ordinate represents optical density (OD).
- FIG. 28 photographically illustrates a side by side comparison of a trilayer film with silver particles (left film; appears brown in a color photograph) and the control film on the right (no color change).
- FIG. 29 represents a transmission electron micrograph demonstrating the formation of particles in the middle layer of a trilayer film.
- the films were sectioned using a cryomicrotome and the cross-section of the film was observed using a transmission electron microscope.
- a reference length marker indicating 0.09 ⁇ m is provided in the lower right portion of the image.
- FIG. 30 graphically represents an EDS spectrum of the particles within a trilayer film.
- the presence of the silver peaks (Ag) confirms the composition of the particles.
- the ordinate represents counts.
- the abscissa represents x-ray energy in KeV.
- FIG. 31 represents an image of a transmission electron micrograph illustrating the distribution of silver particles within a trilayer film. More particle aggregates are found along the CMC layer compared to the chitosan layer. A reference length marker indicating 0.50 ⁇ m is provided in the lower right portion of the image.
- FIG. 32 represents the surface morphology of titanium thin films illustrated by scanning electron microscopic images.
- FIG. 32A depicts an image of a scanning electron micrograph showing human bone marrow-derived mesenchymal stem cells on base-etched titanium film after 14 days in culture.
- FIG. 32B depicts a film modified with silver nanoparticles (arrow indicating silver nanoparticles).
- additional therapeutically active compound refers to the use or administration of a compound for an additional therapeutic use for a particular injury, disease, or disorder being treated.
- a compound for example, could include one being used to treat an unrelated disease or disorder, or a disease or disorder which may not be responsive to the primary treatment for the injury, disease or disorder being treated.
- Disease and disorders being treated by the additional therapeutically active agent include, for example, hypertension and diabetes.
- the additional compounds may also be used to treat symptoms associated with the injury, disease or disorder, including, but not limited to, pain and inflammation.
- Such compounds or agents include, but are not limited to drugs, antimicrobials, growth factors, cytokines, etc.
- a disease, condition, or disorder is “alleviated” if the severity of a symptom of the disease, condition, or disorder, or the frequency with which such a symptom is experienced by a subject, or both, are reduced.
- an “analog” of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (e.g., 5-fluorouracil is an analog of thymine).
- antimicrobial agents refers to any naturally-occurring, synthetic, or semi-synthetic compound or composition or mixture thereof, which is safe for human or animal use as practiced in the methods of this invention, and is effective in killing or substantially inhibiting the growth of microbes.
- Antimicrobial as used herein, includes antibacterial, antifungal, and antiviral agents.
- Antiviral agent means a composition of matter which, when delivered to a cell, is capable of preventing replication of a virus in the cell, preventing infection of the cell by a virus, or reversing a physiological effect of infection of the cell by a virus.
- Antiviral agents are well known and described in the literature.
- AZT zidovudine, Retrovir® Glaxo Wellcome Inc., Research Triangle Park, NC
- NC is an antiviral agent which is thought to prevent replication of HIV in human cells.
- biocompatible refers to a material that does not elicit a substantial detrimental response in the host.
- biodegradable means capable of being biologically decomposed.
- a biodegradable material differs from a non-biodegradable material in that a biodegradable material can be biologically decomposed into units which may be either removed from the biological system and/or chemically incorporated into the biological system.
- bioresorbable refers to the ability of a material to be resorbed in vivo. “Full” resorption means that no significant extracellular fragments remain. The resorption process involves elimination of the original implant materials through the action of body fluids, enzymes, or cells. Resorbed calcium carbonate may, for example, be redeposited as bone mineral, or by being otherwise re-utilized within the body, or excreted. “Strongly bioresorbable,” as the term is used herein, means that at least 80% of the total mass of material implanted is resorbed within one year.
- burn refers to any detectable injury to tissue caused by energy applied to the tissue.
- the terms “burn” or “burns” further refer to any burning, or charring of the tissue, including thermal burns caused by contact with flames, hot liquids, hot surfaces, and other sources of high heat as well as steam, chemical burns, radiation, and electrical burns.
- First degree burns show redness; second degree burns show vesication; third degree burns show necrosis through the entire skin. Burns of the first and second degree are partial-thickness burns, those of the third degree are full-thickness burns.
- the term “clearance,” as used herein refers to the physiological process of removing a compound or molecule, such as by diffusion, exfoliation, removal via the bloodstream, and excretion in urine, or via sweat or other fluid.
- a “compound,” as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above.
- a “control” subject is a subject having the same characteristics as a test subject, such as a similar type of dependence, etc.
- the control subject may, for example, be examined at precisely or nearly the same time the test subject is being treated or examined.
- the control subject may also, for example, be examined at a time distant from the time at which the test subject is examined, and the results of the examination of the control subject may be recorded so that the recorded results may be compared with results obtained by examination of a test subject.
- test subject is a subject being treated.
- Cytokine refers to intercellular signaling molecules, the best known of which are involved in the regulation of mammalian somatic cells.
- cytokines A number of families of cytokines, both growth promoting and growth inhibitory in their effects, have been characterized including, for example, interleukins, interferons, and transforming growth factors.
- a number of other cytokines are known to those of skill in the art. The sources, characteristics, targets and effector activities of these cytokines have been described.
- decreased blood flow refers to a decrease in blood flow at a site of injury, disease, or disorder, and includes, but is not limited, a decrease in flow rate, an increase in stasis, and an increase in sludging in the vessels.
- delivery vehicle refers to any kind of device or material which can be used to deliver cells in vivo or can be added to a composition comprising cells administered to an animal. This includes, but is not limited to, implantable devices, matrix materials, gels, etc.
- a “derivative” of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.
- a “detectable marker” or a “reporter molecule” is an atom or a molecule that permits the specific detection of a compound comprising the marker in the presence of similar compounds without a marker.
- Detectable markers or reporter molecules include, but are not limited to, radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, fluorophores, chemiluminescent molecules, electrochemically detectable molecules, and molecules that provide for altered fluorescence polarization or altered light scattering.
- a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
- normal aging is included as a disease.
- a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
- an “effective amount” means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder.
- the amount of each compound, when administered in combination with another compound(s), may be different from when that compound is administered alone.
- an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary.
- the term “more effective” means that the selected effect is alleviated to a greater extent by one treatment relative to the second treatment to which it is being compared.
- enhancing bone repair refers to methods of speeding up or inducing better bone repair using compounds of the invention, relative to the speed or amount of bone repair that occurs without administration of compounds of the invention.
- a “functional” molecule is a molecule in a form in which it exhibits a property or activity by which it is characterized.
- a functional enzyme for example, is one that exhibits the characteristic catalytic activity by which the enzyme is characterized.
- “Graft” refers to any free (unattached) cell, tissue, or organ for transplantation.
- Allograft refers to a transplanted cell, tissue, or organ derived from a different animal of the same species.
- Xenograft refers to a transplanted cell, tissue, or organ derived from an animal of a different species.
- growth factor means a bioactive molecule that promotes the proliferation of a cell or tissue.
- Growth factors useful in the present invention include, but are not limited to, transforming growth factor-alpha (TGF- ⁇ ), transforming growth factor-beta (TGF- ⁇ ), platelet-derived growth factors including the AA, AB and BB isoforms (PDGF), fibroblast growth factors (FGF), including FGF acidic isoforms 1 and 2, FGF basic form 2, and FGF 4, 8, 9 and 10, nerve growth factors (NGF) including NGF 2.5s, NGF 7.0s and beta NGF and neurotrophins, brain derived neurotrophic factor, cartilage derived factor, bone growth factors (BGF), basic fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), EG-VEGF, VEGF-related protein, Bv8, VEGF-E, granulocyte colony stimulating factor (G-CSF), insulin like growth factor (IGF) I and II,
- improved blood flow refers to increased blood flow in a subject being treated according to the methods of the invention compared with the flow in a subject with an otherwise identical injury or condition not being treated according to the methods of the invention. Improved flow is determined by methods such as those described herein and can include less stasis, less sludging, or a combination of both, in the subject being treated compared with the untreated subject.
- inhibitor refers to the ability of a compound, agent, or method to reduce or impede a described function, level, activity, rate, etc., based on the context in which the term “inhibit” is used. Preferably, inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%.
- inhibitor is used interchangeably with “reduce” and “block.”
- injecting or applying includes administration of a compound of the invention by any number of routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
- injury generally refers to damage, harm, or hurt; usually applied to damage inflicted on the body by an external force.
- an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of a compound of the invention in the kit for effecting alleviation of the various diseases or disorders recited herein.
- the instructional material may describe one or more methods of alleviating the diseases or disorders in a subject.
- the instructional material of the kit of the invention may, for example, be affixed to a container which contains the identified compound invention or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
- in situ gelation refers herein to the thermogelling of chitosan/phosphate gels once the chitosan/phosphate solution is administered within specific sites of a subject. Such sites include, but are not limited to, any tissues, body cavities, muscles, fractures or bone defects, ligaments, cartilages or organs.
- the thermogelling of the chitosan/phosphate solution is induced by the physiological temperature.
- material refers to synthetic and natural materials such as matrix components.
- material and compounds refers to, inter alia, materials, compounds, cells, peptides, nucleic acids, drugs, matrix components, and imaging agents.
- metal surface refers to any metal surface, including films, which can be used to deposit or apply polymers or metallic nanoparticles encompassed by the present invention.
- a “mold” is a frame or model that shapes the gel system. Gels can be produced in, but are not limited to, glass or plastic-beakers, dishes, tubes or between two plates so as to obtain any expected shape.
- nanoparticle or “particle” refers to a particle of any shape having the size of up to about 100 nanometers.
- Ostogenesis refers to bone growth, bone remodeling, and repair of bone due to injury or disease.
- composition shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
- a mammal for example, without limitation, a human.
- the term “pharmaceutically-acceptable carrier” means a chemical composition with which an appropriate compound or derivative can be combined and which, following the combination, can be used to administer the appropriate compound to a subject.
- physiologically acceptable ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
- prevention means to stop something from happening, or taking advance measures against something possible or probable from happening.
- prevention generally refers to action taken to decrease the chance of getting a disease or condition.
- a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or injury or exhibits only early signs of the disease or injury for the purpose of decreasing the risk of developing pathology associated with the disease or injury.
- purified and like terms relate to an enrichment of a molecule or compound relative to other components normally associated with the molecule or compound in a native environment.
- purified does not necessarily indicate that complete purity of the particular molecule has been achieved during the process.
- a “highly purified” compound as used herein refers to a compound that is greater than 90% pure.
- stimulate refers to either stimulating or inhibiting a function or activity of interest.
- a “reversibly implantable” device is one which may be inserted (e.g. surgically or by insertion into a natural orifice of the animal) into the body of an animal and thereafter removed without great harm to the health of the animal.
- sample refers to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine.
- a sample can also be any other source of material obtained from a subject which contains cells, tissues, or fluid of interest.
- scaffold refers to a supporting framework, such as one for bone or tissue growth, either in vivo or in vitro.
- skin refers to the commonly used definition of skin, e.g., the epidermis and dermis, and the cells, glands, mucosa, and connective tissue which comprise the skin.
- solid support refers to a structural unit of any size, where said structural unit or substrate has a surface suitable for immobilization of molecular structure or modification of said structure and said substrate is made of a material such as, but not limited to, metal, metal films, glass, fused silica, synthetic polymers, and membranes.
- Standard refers to something used for comparison.
- it can be a known standard agent or compound which is administered and used for comparing results when administering a test compound, or it can be a standard parameter or function which is measured to obtain a control value when measuring an effect of an agent or compound on a parameter or function.
- Standard can also refer to an “internal standard”, such as an agent or compound which is added at known amounts to a sample and which is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured.
- Internal standards are often but are not limited to, a purified marker of interest which has been labeled, such as with a radioactive isotope, allowing it to be distinguished from an endogenous substance in a sample.
- a “subject” of diagnosis or treatment is a mammal, including a human.
- a “subject in need thereof” is a patient, animal, mammal, or human, who will benefit from the method of this invention.
- a “surface active agent” or “surfactant” is a substance that has the ability to reduce the surface tension of materials and enable penetration into and through materials.
- symptom refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease.
- a sign is objective evidence of disease. For example, a bloody nose is a sign. It is evident to the patient, doctor, nurse and other observers.
- a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
- a “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
- thermo injury is used interchangeably with “thermal burn” herein.
- thermo-sensitive gel system undergoes a phase transition when induced by temperature.
- thermo-gelling refers to the formation of a colloidal gel from solution as temperature increases.
- three-dimensional refers to the fact that the chitosan solution is simultaneously gelled and shaped by the mold wherein the solution was initially poured.
- tissue means (1) a group of similar cells united to perform a specific function; (2) a part of an organism consisting of an aggregate of cells having a similar structure and function; or (3) a grouping of cells that are similarly characterized by their structure and function, such as muscle or nerve tissue.
- tissue injury-associated decreased blood flow refers to the decrease in blood flow which occurs following an injury, such as a thermal injury, to a tissue.
- the decrease in blood flow includes, but is not limited to, decreased volume, rate, stasis, or sludging.
- tissue injury-associated decreased blood flow includes, but is not limited to, decreased volume, rate, stasis, or sludging.
- topical application refers to administration to a surface, such as the skin. This term is used interchangeably with “cutaneous application” in the case of skin. A “topical application” is a “direct application”.
- Transdermal delivery is meant delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream. Transdermal also refers to the skin as a portal for the administration of drugs or compounds by topical application of the drug or compound thereto. “Transdermal” is used interchangeably with “percutaneous.”
- treating may include prophylaxis of the specific injury, disease, disorder, or condition, or alleviation of the symptoms associated with a specific injury, disease, disorder, or condition and/or preventing or eliminating said symptoms.
- a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease. “Treating” is used interchangeably with “treatment” herein.
- wound or “wounds” may refer to any detectable break in the tissues of the body, such as injury to skin or to an injury or damage, or to a damaged site associated with a disease or disorder.
- wound and “injury” are not always defined exactly the same way, the use of one term herein, such as “injury”, is not meant to exclude the meaning of the other term.
- halogen or “halo” includes bromo, chloro, fluoro, and iodo.
- haloalkyl refers to an alkyl radical bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
- C 1 -C n alkyl wherein n is an integer, as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms.
- C 1 -C 6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.
- C 2 -C n alkenyl wherein n is an integer, as used herein, represents an olefinically unsaturated branched or linear group having from two to the specified number of carbon atoms and at least one double bond.
- examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
- C 2 -C n alkynyl wherein n is an integer refers to an unsaturated branched or linear group having from two to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.
- aryl refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. “Optionally substituted aryl” includes aryl compounds having from zero to four substituents, and “substituted aryl” includes aryl compounds having one or more substituents.
- the term (C 5 -C 8 alkyl)aryl refers to any aryl group which is attached to the parent moiety via the alkyl group.
- bicyclic represents either an unsaturated or saturated stable 7- to 12-membered bridged or fused bicyclic carbon ring.
- the bicyclic ring may be attached at any carbon atom which affords a stable structure.
- the term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
- heterocyclic group refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing from one to three heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen.
- heteroaryl refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings containing from one to three heteroatoms and includes, but is not limited to, furyl, thienyl, pyridyl and the like.
- a “meroxapol” is polyoxypropylene-polyoxyethylene block copolymer with the general formula HO(C 3 H 6 O) a (C 2 H 4 O) b (C 3 H 6 O) a H. It is available in different grades. Each meroxapol name is followed by a code number according to the average numerical values of the respective monomers units denoted by “a” and “b”.
- the term “optionally substituted” refers to from zero to four substituents, wherein the substituents are each independently selected. Each of the independently selected substituents may be the same or different than other substituents.
- a “poloxamer” is a nonionic polyoxyethylene-polyoxypropylene block co-polymer with the general formula HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H. It is available in different grades, which vary from liquids to solids. Each poloxamer name is followed by a code number according to the average numerical values of the respective monomers units denoted by “a” and “b”.
- a “poloxamine” is a polyoxyethylen-polyoxypropylene block copolymer of ethylene diamine with the general formula [HO(C 2 H 4 O) a (C 3 H 6 O) b C 3 H 6 ] 2 NCH 2 CH 2 N—[C 3 H 6 (OC 3 H 6 ) b (OC 2 H 4 ) a OH] 2 . It is available in different grades.
- Each poloxamine name is followed by a code number according to the average numerical values of the respective monomers units denoted by “a” and “b”.
- the compounds of the present invention contain one or more asymmetric centers in the molecule.
- a structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers, as well as racemic mixtures thereof.
- the compounds of the present invention may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
- the following structure :
- the present disclosure demonstrates the development of mild and cost effective methods to immobilize metallic nanoparticles on polymeric or metallic substrates.
- a metal substrate may be a metal or a metal film.
- the metal or metal film is titanium.
- the metal is one described below.
- the present invention includes nanoparticles comprising metals and composites including, but not limited to, various metals including gold (Au), silver (Ag), platinum (Pt), aluminum (Al), nickel (Ni), iron (Fe), palladium (Pd), titanium (Ti), scandium (Sc), vanadium (V), chromium (Cr), magnesium (Mg), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), cadmium (Cd), lutetium (Lu), hafnium (Hf), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), tantalum (Ta), rhodium (Rh), rare-earth metals ytterbium (Yb), lanthanum (
- Preferred metal oxides particles include particles of MgO, SrO, BaO, CaO, TiO 2 , ZrO 2 , FeO, V 2 O 3 , V 2 O 5 , Mn 2 O 3 , Fe 2 O 3 , NiO, CuO, Al 2 O 3 , SiO 2 , ZnO, Ag 2 O, TiSiO. 4 , ZrSiO.
- rare-earth metal oxides the corresponding hydroxides of the foregoing, particles and quantum dots of semiconducting materials (Si, CdSe, CdSe/CdS, CdSe/ZnSe, PbS, PbSe, ZnS, GaSb, GaAs, InAs), ceramic nano-particles, and mixtures thereof.
- Suspensions of nanoparticles and nanoscale powders of various compositions can be produced using different methods known in the art and are encompassed by the present invention (see Golovlev et al., U.S. Pat. Pub. 2008/0050842).
- One aspect of the present invention relates to osteogenic devices, and more specifically to synthetic implants which induce osteogenesis in vivo in mammals, including humans.
- the invention therefore encompasses metal films and substrates as described herein, as well as such films and substrates further comprising cells.
- Non-synthetic matrix proteins like collagen, glycosaminoglycans, and hyaluronic acid, which are enzymatically digested in the body, are useful for delivery to bone areas (see U.S. Pat. Nos. 4,394,320; 4,472,840; 5,366,509; 5,606,019; 5,645,591; and 5,683,459) and are suitable for use with the present invention.
- implantable media and devices can be used to assist, or as supplements to, the use of metal films and substrates for delivery of the cells of the invention in vivo.
- These include, but are not limited to, sponges, such as those from Integra, fibrin gels, scaffolds formed from sintered microspheres of polylactic acid glycolic acid copolymers (PLAGA), and nanofibers formed from native collagen, as well as other proteins.
- the cells of the present invention can be further combined with demineralized bone material, growth factors, nutrient factors, pharmaceuticals, calcium-containing compounds, anti-inflammatory agents, antimicrobial agents, or any other substance capable of expediting or facilitating bone growth.
- osteoinductive factors suitable for use with the compositions of the present invention include demineralized bone particles, a Bone Morphogenetic Protein, an osteoinductive extract of demineralized bone matrix, or a combination thereof.
- the metal substrates and films of the present invention are useful for growing cells.
- they support the proliferation and differentiation of cells selected from the group consisting of stem cells, pluripotent stem cells, committed stem cells, embryonic stem cells, adult stem cells, bone marrow stem cells, bone marrow-derived stem cells, adipose stem cells, umbilical cord stem cells, dura mater stem cells, precursor cells, differentiated cells, osteoblasts, myoblasts, neuroblasts, fibroblasts, glioblasts, germ cells, hepatocytes, chondrocytes, keratinocytes, smooth muscle cells, cardiac muscle cells, connective tissue cells, glial cells, epithelial cells, endothelial cells, hormone-secreting cells, cells of the immune system, normal cells, cancer cells, Schwann cells, and neurons.
- Maintaining cells in culture refers to feeding with the appropriate growth medium when necessary, passaging the cells when necessary, etc.
- metal films and substrates may also be added to the metal films and substrates, in addition to metal nanoparticles such as silver nanoparticles. These may be attached to the substrate, or in the case of administration to a subject, they can be added at the same time or before or after the metal film or substrate is administered.
- Compounds and substances that can provide favorable matrix or mesh characteristics also include drugs and other substances that can produce a therapeutic or other physiological effect on cells and tissues within or surrounding an implant. Any substance may be used.
- Several preferred embodiments include use of any therapeutic molecule including, without limitation, any pharmaceutical or drug.
- Examples of pharmaceuticals include, but are not limited to, anesthetics, hypnotics, sedatives and sleep inducers, antipsychotics, antidepressants, antiallergics, antianginals, antiarthritics, antiasthmatics, antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs, antihistamines, antipruritics, emetics, antiemetics, antispasmodics, appetite suppressants, neuroactive substances, neurotransmitter agonists, antagonists, receptor blockers and reuptake modulators, beta-adrenergic blockers, calcium channel blockers, disulfuram and disulfuram-like drugs, muscle relaxants, analgesics, antipyretics, stimulants, anticholinesterase agents, parasympathomimetic agents, hormones, anticoagulants, antithrombotics, thrombolytics, immunoglobulins, immunosuppressants, hormone agonists/antagonists,
- growth factors including more than one growth factor, as described herein.
- Other molecules useful as compounds or substances in the present invention include, but are not limited to, growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, angiostatin, thrombospondin, osteogenic protein-1, bone morphogenetic proteins 2 and 7, osteonectin, somatomedin-like peptide, osteocalcin, interferon alpha, interferon alpha A, interferon beta, interferon gamma, interferon 1 alpha, and interleukins 2, 3, 4, 5 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17 and 18.
- LIF leukemia inhibitory factor
- Embodiments involving amino acids, peptides, polypeptides, and proteins may include any type of such molecules of any size and complexity as well as combinations of such molecules. Examples include, but are not limited to, structural proteins, enzymes, and peptide hormones. These compounds can serve a variety of functions.
- the matrix may contain peptides containing a sequence that suppresses enzyme activity through competition for the active site.
- antigenic agents that promote an immune response and invoke immunity can be incorporated into a construct.
- any nucleic acid can be present. Examples include, but are not limited to deoxyribonucleic acid (DNA), ent-DNA, oligonucleotides, aptamers, and ribonucleic acid (RNA).
- DNA deoxyribonucleic acid
- ent-DNA oligonucleotides
- RNA ribonucleic acid
- Embodiments involving DNA include, but are not limited to, cDNA sequences, natural DNA sequences from any source, and sense or anti-sense oligonucleotides.
- DNA can be naked (e.g., U.S. Pat. Nos. 5,580,859; 5,910,488) or complexed or encapsulated (e.g., U.S. Pat. Nos. 5,908,777; 5,787,567).
- DNA can be present in vectors of any kind, for example in a viral or plasmid vector.
- nucleic acids used will serve to promote or to inhibit the expression of genes in cells inside and/or outside the electroprocessed matrix.
- the nucleic acids can be in any form that is effective to enhance uptake into cells.
- an additional step of blocking the surface of the solid support can be performed. Blocking prevents non-specific binding of target molecules to the solid support.
- the blocking also can be used to allocate specific chemical groups on the surface for maintaining desirable positive or negative net surface charge on the substrate surface. Different reagents can be used to block or cap an activated solid support, whereby blocking agents couple and block residual active sites and essentially eliminate said sites from non-specific binding of target biopolymers.
- Common blocking or capping agents can include glycine, ethanolamine, tris(hydroxymethyl)aminomethane, mercaptoethanol, mercaptoethylamine, cysteine, acetic anhydryde, succinic anhydride, albumine, sodium borohydride, ammonium chloride, sodium acrylate, etc. Maintaining desirable electric charge on the surface can be achieved by using poly-L-lysine, anionic and cationic polymers, for instance, PDDA, amino- and mercapto-silane derivatives, etc.
- concentration and time to optimize blocking treatment to a specific type of chemistry used to activate the solid support.
- the present invention also relates to the use of surface active copolymers, including, but not limited to poloxamers.
- the formulations of the invention may comprise additional therapeutic agents, for example, antimicrobial agents to prevent infection, growth factors or hormones to enhance healing, drugs to treat inflammation, or anesthetics to decrease pain.
- the present invention encompasses compositions and methods for preparing surface active copolymer compositions comprising metallic nanoparticles.
- a poloxamer such as poloxamer-188 (Pluronic F68) is the base compound of the composition of the invention.
- a poloxamer has the special ability to thicken at higher temperatures (such as body temperature) and liquefy at cooler temperatures (cool rinse water for example).
- the thickness, or viscosity varies depending on the amount or concentration of surface active copolymer used. These properties enable it to remain resident at tissue surfaces at body temperature but also enable it to be easily removed away with cool water.
- Preferred surface active copolymers are those which are biocompatible.
- dilutions of surface active copolymers such as Poloxamer-188 (Pluronic F68) are very biocompatible.
- formulations of poloxamers or other surface active agents for topical delivery to injured and diseased tissues and their ability to inhibit the decreased blood flow associated with the injuries, diseases, and disorders described herein.
- the compounds of the invention can inhibit decreased blood flow by influencing blood flow characteristics such as flow rate, stasis, and sludging.
- the invention includes a therapeutic composition comprising at least one surface active copolymer at about 1%-65% w/w.
- the therapeutic compositions of the invention may be formulated, for example, as liquids or as stable gels.
- the therapeutic compositions of the invention have use in treatment of exposed soft tissue or various injuries, for example, thermal injuries, venous stasis ulcers, diabetic wounds, skin grafts, tissue flaps, microvascular surgery, pressure ulcers.
- the route of administration can vary depending on the formulation of the pharmaceutical composition being administered as well as on the site of injury, disease, or disorder being treated.
- the present invention encompasses any useful means of topical administration of the pharmaceutical compositions of the invention to treat the injuries, diseases, and disorders encompassed by the methods of the invention.
- the compounds are administered via routes, including, but not limited to, direct, topical, cutaneous, mucosal, nasal, inhalation, oral, and ophthalmic.
- the means for the administration includes, but is not limited to, a dressing material, extruder, aerosol, spray delivery, iontophoresis, a patch, and a transdermal patch.
- the present invention further provides for administration of a compound or additional therapeutic agent of the invention as a controlled-release formulation.
- the dosage of the active compound(s) being administered will depend on the condition being treated, the particular compound, and other clinical factors such as age, sex, weight, and health of the subject being treated, the route of administration of the compound(s), and the type of composition being administered (gel, liquid, solution, suspension, aerosol, ointment, lotion, cream, paste, liniment, etc.). It is to be understood that the present invention has application for both human and veterinary use.
- the invention further encompasses administration of the pharmaceutical compositions of the invention at different times before and after an injury or surgical procedure, as well as varying the optional additional therapeutic agents and the surface active copolymers.
- poloxamers examples include poloxamer-101, -105, -105 benzoate, -108, -122, -123, -124, -181, -182, -182 dibenzoate, -183, -184, -185, -188, -212, -215, -217, -231, -234, -235, -237, -238, -282, -284, -288, -331, -333, -334, -335, -338, -401, -402, -403, and -407.
- the poloxamer is poloxamer-188.
- the poloxamer is poloxamer-407.
- the pharmaceutical composition of the invention comprises PluroGelTM (PluroGen, Annapolis, Md.).
- At least one of the surface active copolymers is a meroxapol.
- exemplary meroxapols include, but are not limited to, meroxapol 105, 108, 171, 172, 174, 178, 251, 252, 254, 258, 311, 312, and 314.
- At least one of the surface active copolymers is a poloxamine.
- exemplary poloxamines include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508.
- the therapeutic composition is formulated as a liquid or stable gel.
- the copolymer size may range, for example, from an M n of about 600 to about 20,000. In another aspect, the copolymer size may range, for example, from an M n of about 1,000 to about 10,000.
- the present invention encompasses a composition comprising a poloxamer at about 0.1% to about 85% w/w, or about 1% to about 65%, or about 1% to about 50%, or about 5% to about 40%, or about 10% to about 40%.
- a poloxamer at about 0.1% to about 85% w/w, or about 1% to about 65%, or about 1% to about 50%, or about 5% to about 40%, or about 10% to about 40%.
- Other surface active copolymers can be used at these concentrations as well.
- the surface active copolymers may be prepared at different temperatures depending on the type of formulation being prepared, the route of administration, the site of administration, etc. In one aspect, the surface active copolymer is prepared at a temperature ranging from about 0° F. to about 70° F. In another aspect, the surface active copolymer is prepared at a temperature ranging from about 5° F. to about 50° F. In yet another aspect, the surface active copolymer is prepared at a temperature ranging from about 10° F. to about 40° F.
- composition may further comprise an effective amount of at least one additional therapeutic agents which may be useful for the type of injury, disease, or disorder being treated.
- Additional therapeutic agents include, but are not limited to, anesthetic, analgesic, antimicrobial, steroid, growth factor, cytokine, and anti-inflammatory agents.
- Useful anesthetic agents include benzocaine, lidocaine, bupivocaine, dibucaine, mepivocaine, etidocaine, tetracaine, butanilicaine, and trimecaine.
- the agent is at least one analgesic. In yet another aspect, the agent is an additional therapeutic drug.
- the additional therapeutic agent is an antimicrobial agent.
- the antimicrobial agent is an antibacterial agent.
- the antimicrobial agent is an antifungal agent.
- the antimicrobial agent is an antiviral agent.
- Antimicrobial agents useful in the practice of the invention include, but are not limited to, silver sulfadiazine, Nystatin, Nystatin/triamcinolone, Bacitracin, nitrofurazone, nitrofurantoin, a polymyxin (e.g., Colistin, Surfactin, Polymyxin E, and Polymyxin B), doxycycline, antimicrobial peptides (e.g., natural and synthetic origin), Neosporin (i.e., Bacitracin, Polymyxin B, and Neomycin), Polysporin (i.e., Bacitracin and Polymyxin B).
- a polymyxin e.g., Colistin, Surfactin, Polymyxin E, and Polymyxin B
- doxycycline doxycycline
- antimicrobial peptides e.g., natural and synthetic origin
- Neosporin i.e., Bacitracin, Polymyxin B, and Neomycin
- Additional antimicrobials include topical antimicrobials (i.e., antiseptics), examples of which include silver salts, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, and chlorhexidine. It may be desirable for the antimicrobial to be other than Nystatin.
- the agent is selected from aspirin, pentoxifylline, and clopidogrel bisulfate, or other angiogenic, or a rheologic active agent.
- the present invention encompasses a method of treating a site of injury on a subject comprising topically administering a poloxamer to the subject in an amount effective to improve blood flow at the site of injury.
- the blood flow is microvascular blood flow.
- other agents can be added to the formulation.
- other additives may include, a moisturizer, a humectant, a demulcent, oil, water, an emulsifier, a thickener, a thinner, an additional surface active agent, a fragrance, a preservative, an antioxidant, a hydrotropic agent, a chelating agent, a vitamin, a mineral, a permeation enhancer, a cosmetic adjuvant, a bleaching agent, a depigmentation agent, a foaming agent, a conditioner, a viscosifier, a buffering agent, and a sunscreen.
- the microvasculature has a diameter ranging from about 5 ⁇ m to about 100 ⁇ m. In another aspect, the vessels have a diameter from about 10 ⁇ m to about 50 ⁇ m. Vessels encompassed by the treatment of the invention include, but are not limited to, capillaries, arterioles, and venules.
- the present invention provides a method of treating a site of injury on a subject comprising topically administering a poloxamer to the patient in an amount effective to reduce inflammation at the site of injury.
- the invention encompasses the preparation and use of pharmaceutical compositions comprising as an active ingredient a compound useful for treatment of decreased blood flow associated with injuries and diseases disclosed herein.
- a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
- the active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
- the present invention further contemplates the use of more than one active ingredient.
- At least two different surface active copolymers are used. In one aspect, at least three different surface active copolymers are used. These combinations may include, for example, one or more poloxamers, one or more meroxapols, and one or more poloxamines.
- compositions of this type are described in U.S. Pat. No. 5,635,540 (Edlich et al.), the contents of which are incorporated herein by reference.
- temperatures ranges for preparation include, but are not limited to, from about ⁇ 20° C. to about 15° C., in another aspect from about ⁇ 18° C. to about 8° C., and in another aspect, from about ⁇ 15° C. to about 5° C. These ranges also encompass about 0° F. to about 60° F.
- temperatures of preparation can be adjusted based on various criteria, such as the surface active copolymer being used, the amount or concentration being used, the type of formulation being prepared for administration, etc.
- the poloxamer base comprises 80% polyoxyethylene units and 20% polyoxypropylene units.
- a poloxamer such as poloxamer-188
- water at a ratio of from 1:0.8 to 1.2 w/w. This ratio can be varied.
- This combination may be mixed until the powder has been wetted.
- the mixture may then be placed in a freezer or refrigerator and cooled, preferably for at least 4 hours. While cooling, the mixture will undergo phase transition to a liquid, as demonstrated by Edlich et al. (U.S. Pat. No. 5,635,540).
- the mixture is then removed from the freezer and warmed to room temperature.
- Pharmaceutical agents such as antimicrobials and anesthetics can be added at this point, as demonstrated by Edlich et al. (U.S. Pat. No. 5,635,540).
- the poloxamer base used in preparing the topical preparation of the present invention is a polyoxyalkylene based polymer based on ethylene oxide and propylene oxide and comprises a series of closely related block polymers that may generally be classified as polyoxyethylene-polyoxypropylene condensates terminated in primary hydroxyl groups. They are formed by the condensation of propylene oxide onto a propylene glycol nucleus followed by condensation of ethylene oxide onto both ends of the polyoxypropylene base.
- the polyoxyethylene hydrophilic groups on the ends of the molecule are controlled in length to constitute anywhere from 10% to 90% by weight of the final molecule.
- compositions of the present invention may comprise one or more co-additives (e.g., solvent such as water).
- concentration of a surface active copolymer e.g., poloxamer 188) is about 0.01 to about 99.99% w/w. In another aspect, it is about 1 to about 90%. In yet another aspect, it is about 10 to about 80%. In a further aspect, it is about 20% to about 70%. In another aspect, it is about 50%. In a further aspect, it is about 5%.
- a formulation of the invention can be impregnated in a dressing material (or otherwise contained or encompassed by the dressing material).
- the dressing material is a pharmaceutically acceptable fabric. It can be, for example, gauze or any other type of medical fabric or material that can be used to cover a wound and/or to keep a therapeutic agent or composition in contact with a patient.
- the present invention further encompasses the use of a thermo-gelling chitosan solution that remains liquid at lower temperatures but gels at higher temperatures and requires a lower concentration of cross-linking agents, to which metals such as silver can be added.
- the present invention relates to a biocompatible thermo-gelling solution of chitosan and inorganic salts and methods for the preparation of and the use of such a solution.
- the invention encompasses the use of carboxymethyl chitosan.
- Chitosan is an N-deacetylated derivative of chitin which is the structural component of crustacean shells and fungal cell walls, and is obtained at a low cost from sea-food processing (Chitin: Fulfilling a Biomaterials Promise: Eugene Khor, Elsevier, Oxford, UK, 2001).
- the structure of chitin and chitosan are similar to cellulose where, carbon-2 of the cellulose has acetamide or amino groups, for chitin and chitosan respectively.
- Chitosan is an inert, hydrophilic, biocompatible, and biodegradable polymer and hence are attractive candidates for biomedical and pharmaceutical applications.
- Chitosan is currently investigated for various applications such as topical ocular application, as a bioadhesive polymer, penetration enhancer by opening epithelial tight junctions and as wound dressing (Berger, et al., European Journal of Pharmaceutics and Biopharmaceutics 57 (2004) 19-34).
- Chitosan has been extensively investigated for developing hydrogels with unique properties, due to the hydrophilicity of the base polymer, and the availability of active cross-linkable groups along the polymer chain. These chitosan hydrogels were found to be excellent candidates for a variety of applications, including, controlled release of bioactive/drug molecules, as cell encapsulation matrices, and as tissue engineering scaffolds. Chemical or covalent cross-linking of chitosan making use of mainly the active amino groups along the polymer chain and ionic cross-linking making use of the cationic nature of chitosan aqueous acid solutions, have been extensively investigated for developing hydrogels for various applications.
- the different chemical cross-linking agents reported for chitosan include dialdehydes such as glutaraldehyde, diethyl squarate, oxalic acid, and genipin.
- dialdehydes such as glutaraldehyde, diethyl squarate, oxalic acid, and genipin.
- functionalized biopolymers such as poly(ethylene glycol diacrylate), oxidized cyclodextrin, telechelic-PVA, PEG dialdehydes and scleroglucan have also been investigated.
- polyelectrolyte complexes of chitosan with a wide range of anionic polymers mainly chitosan alginate system have been extensively investigated for developing drug delivery systems and porous scaffolds for tissue engineering and wound dressings.
- Ionic cross-linking of chitosan has been extensively investigated, because it is a simple and mild process with no auxiliary catalyst requirements, and such a procedure has important ramifications for biomedical applications.
- Metallic anions such as Mo(VI) and Pt(II) have been extensively investigated for ionic cross-linking
- Various anions such as sulfates, citrates, oxalates, polyphosphates, and also calcium phosphate, have been tested for the ability to form ionically cross-linked gels with chitosan. All of these ions induce the formation of pure ionic cross-linking, where the chitosan solution instantaneously becomes a gel in the presence of these ions, due to the spontaneity of the ionic reactions.
- Injectable in situ forming hydrogels are receiving considerable attention for a variety of biomedical applications such as sustained drug delivery, cell encapsulation and as scaffolds for tissue engineering (Tae et al., Biomaterials, 26, 5259-66, 2005).
- An injectable system offers several advantages including conformal matching of the implant to complex tissue shapes, delivery of large volumes of implant via minimally invasive surgery, improved patient compliance and comfort, and allows for the delivery of sensitive biomolecules and living cells because it is a gentle process.
- In situ forming hydrogels are potential candidates specifically for developing sustained delivery vehicles for therapeutic proteins with short half lives.
- Chitosan is an N-acetylated derivative of the natural polymer Chitin. Chitin is the structural component of crustacean shells and fungal cell walls and is the second most abundant natural polymer.
- hydrogels based on chitosan Due to the excellent biocompatibility and enzymatic degradability of chitosan, hydrogels based on chitosan have been found to be excellent candidates for a variety of medical and pharmaceutical applications (Berger et al., Eur. J. Pharm. BioPharm., 57:19-34, 2004).
- cross-linking agents have been investigated for developing chitosan hydrogels. These include chemical cross-linking using various aldehydes, ionic cross-linking using various anions, and polyelectrolyte complexes using anionic polymers. Recently much research has gone into developing stimuli sensitive injectable systems based on chitosan. It has been found that addition of certain polyol counterionic monohead salts such as ⁇ -glycerophosphate can lead to the development of temperature and pH sensitive gelling systems (Chenite et al, Biomaterials, 21:2155-61, 2000). Grafting poly(ethylene glycol) of appropriate molecular weight to chitosan has been shown to act as a thermogelling system (Bhattarai et al., J. Control Rel. 103:609-624).
- thermo-gelling solution of the present invention can be prepared by mixing chitosan solution in very dilute acetic acid with appropriate amounts of inorganic salts, such as phosphate or sulfate salt powder or solution, at a low temperature, such as between about 0° C. and about 4° C., with rapid stirring.
- inorganic salts such as phosphate or sulfate salt powder or solution
- the addition of salt powder or solution rapidly increases the pH of the acidic chitosan solution to a pH between about 6.0 and about 8.0.
- Chitosan solutions are known generally to precipitate instantaneously as the pH of the solution is raised to above about 6.0. However, it has been found that in the presence of the inorganic phosphate described here the chitosan remains in solution even at about neutral pH between about 7.0 and about 7.2, so long as the solution is maintained at a temperature below about 10° C. When chitosan solutions are mixed with appropriate inorganic phosphates at low temperatures and are then heated to near-physiological temperatures, such as about 37° C., the solutions gel.
- the thermo-gelling solution of the present invention forms a gel within a temperature range from about 30° C. to about 50° C.
- thermo-gelling solution of the present invention may form a gel.
- the thermo-gelling solution of the present invention may also gel at temperatures above or below the temperature range from about 30° C. to about 50° C.
- the thermo-gelling solution of the present invention certainly gels at a temperature within this range, which encompasses near-physiological temperatures.
- the time of gelling has been found to depend on several factors including the concentration of the inorganic phosphate salts, concentration of chitosan solution and concentration of aqueous acetic acid solution.
- the final pH of the solution also correlates with the gelling time of the present thermo-gelling system.
- the pH of the final solution should be between about 6.0 and about 8.0.
- the final pH of the solution has been found to be equal to or higher than 6.8.
- thermo-gelling solution of the present invention has been found to be stable when stored over time at temperatures below about 5° C.
- Dilution of the thermo-gelling chitosan-inorganic salt solution has also been found not to significantly affect the gelling time of the solution. Because dilution does not significantly affect gelling times, thereto-gelling systems may be developed which will enable the formation of gels of different strengths and water contents for various applications.
- the strength of the gels and the water content of the gels can be varied by varying the concentration of the inorganic phosphate salts added or by diluting the chitosan-inorganic phosphate mixture with distilled water, phosphate buffer, or cell culture media.
- the present invention provides a method to develop a thermo-gelling system having different water content and gel strength depending on the planned application. Such methods and compositions for using chitosan are described in, for example, International Patent Publication WO 2007/087350 (Laurencin et al.) published Aug. 2, 2007.
- the present invention relates to the preparation of a chitosan solution having neutral pH, which can undergo thermogelation at about a physiological temperature and physiological pH.
- the solution undergoes gelation at near or above physiological temperature.
- the thermogelling or thermosetting solution can be prepared by mixing chitosan solution in very dilute acetic acid with appropriate amounts of inorganic phosphate salt powder or solution at 0-4° C. with rapid stirring. The addition of salt powder or solution rapidly increases the pH of the acid chitosan solution to near neutral pH. Chitosan solutions are known to precipitate instantaneously as the pH of the solution is raised to above ⁇ 6.0.
- the chitosan remains in solution even at neutral pH ( ⁇ pH 7.0-7.2).
- a chitosan solution of the invention is mixed with appropriate inorganic phosphates at low temperature and heated to near physiological temperature (37° C.) or above, the solutions gel.
- the time required for gelling to occur has been found herein to depend on several factors, including the concentration of the inorganic phosphate salts, concentration of chitosan solution, and the concentration of aqueous acetic acid solution.
- the final pH of the solution also correlates to regulation of the present thermogelling system. In one aspect, in an efficient gelling chitosan solution, the final pH of the solution should be approximately at least about 6.8.
- the strength of the gels and the water content of the gels can be varied by varying the concentration of the inorganic phosphate salts added, or by diluting the chitosan-inorganic phosphate mixture with distilled/deionized water, phosphate buffer, weak acid-base, or using cell culture medium.
- compositions are useful as, injectable compositions for various applications.
- the compositions can be developed mixing insoluble solid particulates with a chitosan-inorganic phosphate mixture, or by mixing water-soluble polymer solutions with chitosan-inorganic phosphate mixture.
- the invention provides a non-toxic, biodegradable, biocompatible and rapidly curing system at physiological temperature to use in a clinical or operating room setting.
- the invention provides a temperature induced rapidly curing two component solution which can solidify into a biodegradable gel for various applications.
- the invention provides a temperature induced rapidly curing system which can be used to develop novel blends or composite systems.
- the invention provides a temperature induced rapidly gelling polymer system as an injectable matrix for the controlled and prolonged delivery of drugs, growth factors, therapeutic proteins and peptides.
- the invention provides a temperature induced rapidly gelling polymer system as an injectable plug for therapeutic embolization and chemoembolization.
- the invention provides a method for preparing thermogelling chitosan solutions with variable gelation times.
- the gelation times are as short as about several minutes.
- the gelation times are from about 30 minutes to about several hours.
- gelation times range from about several hours to about 24 to 36 hours.
- the invention provides a temperature induced rapidly gelling polymer system as an injectable scaffold for various tissue engineering applications.
- the invention provides a temperature induced rapidly gelling polymer system as an injectable cell encapsulation system for various applications.
- the invention provides variable gelling time from a few minutes to a few hours depending on the kind of application the material is targeted.
- the invention provides a method to develop hydrogel system having different water content and gel strength depending on the kind of application the material is targeted.
- the invention provides a method to develop cross-linked systems having different architecture such as foams, spheres, fibers.
- the invention provides novel delivery systems.
- the present invention provides methods and composition for delivering cells, chondrocytes, stem cells, genes, matrix materials, drugs, proteins, and chemicals. Delivery of bioactive molecules such as nucleic acid molecules encoding a protein can be significantly enhanced by immobilization of the bioactive molecule in a composition of the invention adjacent to the cells where delivery is desired.
- the invention provides methods for administering novel delivery systems.
- the novel delivery systems are administered to treat diseases, disorders, and conditions in subjects in need thereof.
- the invention is useful for treating a musculoskeletal-associated disease or disorder. Musculoskeletal-associated diseases or disorders are described herein or are known in the art.
- the method is useful for enhancing bone repair.
- the method is useful for treating a bone-associated disease or disorder.
- treatment of a bone-associated disease or disorder can be done in conjunction with a surgical procedure.
- the present invention provides methods and compositions for fabricating three-dimensional structures.
- the present invention provides various fabrication techniques. One of ordinary skill in the art would appreciate that various fabrication techniques are available to practice the methods of the invention.
- the present invention provides compositions and methods for tissue regeneration.
- the tissues are selected from the group consisting of bone and spine.
- compositions and methods of the invention are useful for tissue engineering.
- compositions and methods of the invention are useful for preparing composites with organic or inorganic components.
- compositions and methods of the invention are useful in cell and tissue culture systems.
- the invention provides methods for encapsulating cells.
- thermo-gelling solution Such applications include use as scaffolds for tissue engineering applications, as tissue adhesive, as a wound dressing material, as injectable fillers or composites, and as an injectable solution for controlled and prolonged delivery of drugs, proteins, and growth factors.
- the invention provides advantages of a workable, flowable, injectable liquid at colder temperatures along with the advantages of a biocompatible viscous gel at higher, physiological temperatures.
- the teachings of the present invention also overcome limitations of the prior art by providing for simple, mild, and gentle cross-linking agents at lower concentrations than required by the prior art.
- the present invention features a solution of chitosan and inorganic salt maintained at a temperature below about 10° C. that forms a gel as the temperature rises to within a temperature range from about 20° C. to about 50° C.
- the temperature for gelling is from about 30° C. to about 40° C.
- the thermo-gelling solution has a pH between about 6.0 and about 8.0.
- the thermo-gelling solution comprises a solution of chitosan and inorganic phosphate or sulfate salts. In a preferred embodiment, the thermo-gelling solution comprises a solution of chitosan and ammonium hydrogen phosphate. In one embodiment, the thermo-gelling solution comprises between about 0.05 weight % and about 10.0 weight % chitosan and between about 0.5 weight % and about 2.8 weight % ammonium hydrogen phosphate. In embodiment, the thermo-gelling solution comprises a ratio of chitosan to ammonium hydrogen phosphate between about 1 and about 3.5.
- thermo-gelling solution is a solution at a pH between about 6.5 and about 7.5. In a more preferred embodiment, the thermo-gelling solution is a solution at a pH between about 6.8 and about 7.3. In a most preferred embodiment, the thermo-gelling solution is a solution at a pH between about 7.0 and about 7.2
- thermo-gelling solution is a solution maintained at a temperature below about 5° C. In a currently preferred embodiment, the thermo-gelling solution is maintained at a temperature between about 0° C. and about 4° C.
- thermo-gelling solution forms a gel as the temperature rises to within a temperature range from about 35° C. to about 45° C. In a more preferred embodiment, the thermo-gelling solution forms a gel within a temperature range from about 35° C. to about 40° C. In a most preferred embodiment, the thermo-gelling solution forms a gel at a temperature of about 37° C.
- the invention further encompasses chitosan of varied molecular weights.
- chitosan from about 20,000 to about 250,000 is encompassed within the methods described herein.
- a pharmaceutical composition comprising a thermo-gelling solution of chitosan and inorganic salts and insoluble solid particulates or water-soluble substances.
- a method for administering the pharmaceutical composition comprising injecting or applying the pharmaceutical composition.
- an inorganic salt includes inorganic phosphate and/or sulfate salts.
- an inorganic salt is ammonium hydrogen phosphate.
- the aqueous chitosan solution comprises between about 0.5 weight % and about 3.5 weight % chitosan.
- thermo-gelling solution is a solution having a concentration between about 0.5 weight % and about 2.8 weight % ammonium hydrogen phosphate.
- steps (a), (b), and (c) yield a thermo-gelling solution having a ratio of chitosan to ammonium hydrogen phosphate between about 1 and about 3.5.
- steps (a), (b), and (c) yield a thermo-gelling solution at pH between about 6.5 and about 7.5. In a more preferred embodiment, steps (a), (b), and (c) yield a thermo-gelling solution at pH between about 6.8 and about 7.3. In a most preferred embodiment, steps (a), (b), and (c) yield a thermo-gelling solution at pH between about 7.0 and about 7.2.
- the aqueous chitosan solution is maintained below about 5° C. In a currently preferred embodiment, the aqueous chitosan solution is maintained between about 0° C. and about 4° C.
- thermo-gelling solution formed by steps (a), (b), and (c) forms a gel as the temperature rises to within a temperature range from about 35° C. to about 45° C. In a more preferred embodiment, the thermo-gelling solution forms a gel within a temperature range from about 35° C. to about 40° C. In a most preferred embodiment, the thermo-gelling solution forms a gel at a temperature of about 37° C.
- thermo-gelling solution of the present invention provides a method of delivering the thermo-gelling solution as an injectable scaffold for tissue engineering comprising injecting an effective amount of the thermo-gelling solution.
- the invention further provides a method for delivering one or more substances from the group consisting of cells, fibroblasts, chondrocytes, osteogenic cells, stem cells, genes, drugs, proteins, chemicals, bioactive molecules, growth factors, and therapeutic proteins and peptides comprising administering the thermo-gelling solution as an injectable matrix for the delivery of these substances.
- the invention still further provides a method for providing the thermo-gelling solution as an injectable plug for therapeutic embolization and chemoembolization comprising injecting the thermo-gelling solution as an injectable plug for therapeutic embolization and chemoembolization.
- the embodiments of the invention can be useful for therapeutic purposes based on the properties of the metal nanoparticles, the silver comprising surfaces, substrates, and compositions themselves, or when additional therapeutic agents are used.
- additional therapeutic agents can be used.
- any therapeutic molecule including, without limitation, any pharmaceutical or drug.
- These can be added separately to the substrate or composition or in conjunction with the metal being added to the substrate or composition.
- additional therapeutic agents can also be administered to a subject in need thereof separately from the metal nanoparticle comprising surfaces and compositions of the invention.
- composition of the invention can further comprise additional therapeutic additives, alone or in combination (e.g., 2, 3, or 4 additional additives).
- additional additives include but are not limited to: (a) antimicrobials, (b) steroids (e.g., hydrocortisone, triamcinolone); (c) pain medications (e.g., aspirin, an NSAID, and a local anesthetic); (d) anti-inflammatory agents; (e) growth factors; (f) cytokines; (g) hormones; and (h) combinations thereof.
- a formulation of the invention contains an antimicrobial agent.
- the antimicrobial agent may be provided at, for example, a standard therapeutically effective amount.
- a standard therapeutically effective amount is an amount that is typically used by one of ordinary skill in the art or an amount approved by a regulatory agency (e.g., the FDA or its European counterpart).
- Antimicrobial agents useful for the invention include those directed against the spectrums of gram positive organisms, gram negative organisms, fungi, and viruses.
- suitable local anesthetic agents having a melting point of 30° to 70° C. are prilocaine, tetracaine, butanilcaine, trimecaine, benzocaine, lidocaine, bupivocaine, dibucaine, mepivocaine, and etidocaine.
- Examples of pharmaceuticals include, but are not limited to, anesthetics, hypnotics, sedatives and sleep inducers, antipsychotics, antidepressants, antiallergics, antianginals, antiarthritics, antiasthmatics, antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs, antihistamines, antipruritics, emetics, antiemetics, antispasmodics, appetite suppressants, neuroactive substances, neurotransmitter agonists, antagonists, receptor blockers and reuptake modulators, beta-adrenergic blockers, calcium channel blockers, disulfuram and disulfuram-like drugs, muscle relaxants, analgesics, antipyretics, stimulants, anticholinesterase agents, parasympathomimetic agents, hormones, anticoagulants, antithrombotics, thrombolytics, immunoglobulins, immunosuppressants, hormone agonists/antagonists,
- Antimicrobial agents include: silver sulfadiazine, Nystatin, Nystatin/triamcinolone, Bacitracin, nitrofurazone, nitrofurantoin, a polymyxin (e.g., Colistin, Surfactin, Polymyxin E, and Polymyxin B), doxycycline, antimicrobial peptides (e.g., natural and synthetic origin), Neosporin (i.e., Bacitracin, Polymyxin B, and Neomycin), Polysporin (i.e., Bacitracin and Polymyxin B).
- Additional antimicrobials include topical antimicrobials (i.e., antiseptics), examples of which include silver salts, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, and chlorhexidine.
- Analgesic Acetaminophen; Alfentanil Hydrochloride; Aminobenzoate Potassium; Aminobenzoate Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; Antipyrine; Aspirin; Benoxaprofen; Benzydamine Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride; Butacetin; Butixirate; Butorphanol; Butorphanol Tartrate; Carbamazepine; Carbaspirin Calcium; Carbiphene Hydrochloride; Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol Hydrochloride; Clonixeril; Clonixin; Codeine; Codeine Phosphate; Codeine S
- Antihypertensive Aflyzosin Hydrochloride; Alipamide; Althiazide; Amiquinsin Hydrochloride; Amlodipine Besylate; Amlodipine Maleate; Anaritide Acetate; Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflumethiazide; Benzthiazide; Betaxolol Hydrochloride; Bethanidine Sulfate; Bevantolol Hydrochloride; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril; Candoxatrilat; Captopril; Carvedilol; Ceronapril; Chlorothiazide Sodium; Cicletanine; Cilazapril; Clonidine; Clonidine Hydrochloride; Clo
- Anti-inflammatory Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflu
- an effective amount of at least one growth factor, cytokine, hormone, or extracellular matrix compound or protein useful for enhancing wound healing is administered.
- growth factors useful in the practice of the invention include, but are not limited to, EGF, PDGF, GCSF, IL6, IL8, IL10, MCP1, MCP2, Tissue Factor, FGFb, KGF, VEGF, PLGF, MMP1, MMP9, TIMP1, TIMP2, TGF ⁇ , and HGF.
- growth factor cytokine
- hormone or extracellular matrix protein
- extracellular matrix protein a growth factor, cytokine, hormone, or extracellular matrix protein used will vary depending on criteria such as the type of injury, disease, or disorder being treated, the age, health, sex, and weight of the subject, etc.
- the growth factors, cytokines, hormones, and extracellular matrix compounds and proteins are human.
- Proteins and other biologically active compounds that can be incorporated into, or included as an additive within, a composition comprising compounds of the present invention include, but are not limited to, collagen (including cross-linked collagen), fibronectin, laminin, elastin (including cross-linked elastin), osteopontin, osteonectin, bone sialoproteins (Bsp), alpha-2HS-glycoproteins, bone Gla-protein (Bgp), matrix Gla-protein, bone phosphoglycoprotein, bone phosphoprotein, bone proteoglycan, protolipids, bone morphogenetic protein, cartilage induction factor, skeletal growth factor, enzymes, or combinations and biologically active fragments thereof.
- Adjuvants that diminish an immune response can also be used in conjunction with the composite of the subject invention.
- Other molecules useful as compounds or substances in the present invention include, but are not limited to, growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, angiostatin, thrombospondin, osteogenic protein-1, bone morphogenetic proteins 2 and 7, osteonectin, somatomedin-like peptide, osteocalcin, interferon alpha, interferon alpha A, interferon beta, interferon gamma, interferon 1 alpha, and interleukins 2, 3, 4, 5 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17 and 18.
- Embodiments involving amino acids, peptides, polypeptides, and proteins may include any type of such molecules of any size and complexity as well as combinations of such molecules.
- the present invention encompasses treatment of various injuries, diseases, and disorders. These include, but are not limited to, thermal injury, skin injury, soft tissue injury, non-healing skin wound, burns, acute wound, chronic wound, scrape, cut, incision, laceration, decubitis, pressure ulcer, chronic venous ulcer, venous stasis ulcer, diabetic ulcer, arterial ulcer, radiation ulcer, traumatic wound, open complicated non-healing wound, body piercing, bite wound, insect bite, insect sting, stab wound, gunshot wound, stretch injury, crush wound, compression wound, fracture, sprain, strain, stroke, infarction, aneurism, herniation, ischemia, fistula, dislocation, radiation, surgery, cell, tissue or organ grafting, and cancer.
- the invention provides novel delivery systems.
- the present invention provides methods and composition for delivering cells, chondrocytes, stem cells, genes, matrix materials, drugs, proteins, and chemicals. Delivery of bioactive molecules such as nucleic acid molecules encoding a protein can be significantly enhanced by immobilization of the bioactive molecule in a composition of the invention adjacent to the cells where delivery is desired.
- the invention provides methods for administering novel delivery systems.
- the novel delivery systems are administered to treat diseases, disorders, and conditions in subjects in need thereof.
- the invention is useful for treating a musculoskeletal-associated disease or disorder. Musculoskeletal-associated diseases or disorders are described herein or are known in the art.
- the method is useful for enhancing bone repair.
- the method is useful for treating a bone-associated disease or disorder.
- treatment of a bone-associated disease or disorder can be done in conjunction with a surgical procedure.
- the present invention provides methods and compositions for fabricating three-dimensional structures.
- the present invention provides various fabrication techniques. One of ordinary skill in the art would appreciate that various fabrication techniques are available to practice the methods of the invention.
- the present invention provides compositions and methods for tissue regeneration.
- the tissues are selected from the group consisting of bone and spine.
- compositions and methods of the invention are useful for tissue engineering.
- compositions and methods of the invention are useful for preparing composites with organic or inorganic components.
- compositions and methods of the invention are useful in cell and tissue culture systems.
- the invention provides methods for encapsulating cells.
- the formulations of the invention may be prepared in a variety of forms known in the art, such as liquids, aerosols, or gels.
- Topical administration of the present formulation can be performed by, for example, hand, mechanically (e.g., extrusion and spray delivery) or as a component of a dressing (e.g., gauze or other wound covering).
- a dressing e.g., gauze or other wound covering.
- the administration of the formulation directly by hand to a tissue or biomaterial surface is preformed so as to achieve a therapeutic coating, which may be uniform, alone or in combination with an overlying dressing.
- the administration of the formulation mechanically is performed by using a device that physically pushes the composition onto a tissue or biomaterial surface so as to achieve a therapeutic coating, which may be uniform, alone or in combination with an overlying dressing.
- the formulation can be sprayed onto a tissue or biomaterial surface so as to achieve a therapeutic coating, which may be uniform, alone or in combination with an overlying dressing.
- a therapeutic coating which may be uniform, alone or in combination with an overlying dressing.
- the formulation is applied so as to achieve a therapeutic coating of the surface, which may be uniform.
- Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
- Topically-administrable formulations may, for example, comprise from about 1% to about 70% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
- Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- the invention encompasses the preparation and use of pharmaceutical compositions comprising a compound useful for treatment of various skin related injuries, trauma, diseases, disorders, or conditions described herein, including burns, wounds, surgical incisions, etc.
- the invention also encompasses other injuries, trauma, associated diseases and disorders other than those of the skin, including, but not limited to, gum diseases and disorders.
- Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
- the active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
- stratum corneum layer of the epidermis An obstacle for topical administration of pharmaceuticals to the skin is the stratum corneum layer of the epidermis.
- the stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells.
- One of the factors that limits the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance which can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal.
- compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology.
- preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
- the compounds of the invention may be administered to, for example, a cell, a tissue, or a subject by any of several methods described herein and by others which are known to those of skill in the art.
- the relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, sex, age, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
- a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active or therapeutic agents.
- additional agents include anti-emetics and scavengers such as cyanide and cyanate scavengers.
- Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
- Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
- Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
- Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- formulations for topical administration may include liquids, ointments, lotions, creams, gels (e.g., poloxamer gel), drops, suppositories, sprays, aerosols, and powders.
- Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
- compositions can be administered, for example, in a microfiber, polymer (e.g., collagen), nanosphere, aerosol, lotion, cream, fabric, plastic, tissue engineered scaffold, matrix material, tablet, implanted container, powder, oil, resin, wound dressing, bead, microbead, slow release bead, capsule, injectables, intravenous drips, pump device, silicone implants, or any bio-engineered materials.
- a microfiber polymer (e.g., collagen), nanosphere, aerosol, lotion, cream, fabric, plastic, tissue engineered scaffold, matrix material, tablet, implanted container, powder, oil, resin, wound dressing, bead, microbead, slow release bead, capsule, injectables, intravenous drips, pump device, silicone implants, or any bio-engineered materials.
- Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone.
- compositions of the invention may contain liposomes.
- the composition of the liposomes and their use are known in the art (for example, see Constanza, U.S. Pat. No. 6,323,219).
- the source of active compound to be formulated will generally depend upon the particular form of the compound. Small organic molecules and peptidyl or oligo fragments can be chemically synthesized and provided in a pure form suitable for pharmaceutical/cosmetic usage. Products of natural extracts can be purified according to techniques known in the art. Recombinant sources of compounds are also available to those of ordinary skill in the art.
- the topically active pharmaceutical composition may be optionally combined with other ingredients such as moisturizers, cosmetic adjuvants, anti-oxidants, chelating agents, bleaching agents, tyrosinase inhibitors, and other known depigmentation agents, surfactants, foaming agents, conditioners, humectants, wetting agents, emulsifying agents, fragrances, viscosifiers, buffering agents, preservatives, sunscreens, and the like.
- a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer.
- compositions may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum.
- hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art.
- compositions of this invention may also contain active amounts of retinoids (i.e., compounds that bind to any members of the family of retinoid receptors), including, for example, tretinoin, retinol, esters of tretinoin and/or retinol and the like.
- retinoids i.e., compounds that bind to any members of the family of retinoid receptors
- tretinoin i.e., compounds that bind to any members of the family of retinoid receptors
- esters of tretinoin and/or retinol i.e., esters of tretinoin and/or retinol and the like.
- compositions are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
- the present invention encompasses biologically active analogs, homologs, derivatives, and modifications of the compounds of the invention. Methods for the preparation of such compounds are known in the art.
- compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
- Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
- Liquid derivatives and natural extracts made directly from biological sources may be employed in the compositions of this invention in a concentration (w/w) from about 1 to about 99%.
- Fractions of natural extracts and protease inhibitors may have a different preferred rage, from about 0.01% to about 20% and, more preferably, from about 1% to about 10% of the composition.
- mixtures of the active agents of this invention may be combined and used together in the same formulation, or in serial applications of different formulations.
- the composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition.
- the preservative is used to prevent spoilage in the case of an aqueous gel because of repeated patient use when it is exposed to contaminants in the environment from, for example, exposure to air or the patient's skin, including contact with the fingers used for applying a composition of the invention such as a therapeutic gel or cream.
- a particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.
- the composition may include an antioxidant and a chelating agent which inhibit the degradation of the compound for use in the invention in the aqueous gel formulation.
- Preferred antioxidants for some compounds are BHT, BHA, alphatocopherol, and ascorbic acid in the preferred range of about 0.01% to 0.3% and more preferably BHT in the range of 0.03% to 0.1% by weight by total weight of the composition.
- the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition.
- Particularly preferred chelating agents include edetate salts (e.g.
- disodium edetate and citric acid in the weight range of about 0.01% to 0.20% and more preferably in the range of 0.02% to 0.10% by weight by total weight of the composition.
- the chelating agent is useful for chelating metal ions in the composition which may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefor as would be known to those skilled in the art.
- additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
- compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.), which is incorporated herein by reference.
- Suitable coloring agents include red, black, and yellow iron oxides and FD&C dyes such as FD&C Blue No. 2, FD&C Red No. 40, and the like.
- Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry grape flavors, combinations thereof, and the like.
- Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide, and the like.
- Suitable sweeteners include aspartame, acesulfame K, thaumatic, and the like.
- Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates, and the like.
- Absorption enhancers for use in accordance with the present invention include, for example, polysorbates, sorbitan esters, poloxamer block copolymers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric glycerides, sodium lauryl sulfate, dioctyl sulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids, oleic acid, linoleic acid, glyceryl caprylate/caprate, glyceryl monooleate, glyceryl monolaurate, caprylic/capric triglycerides, ethoxylated nonylphenols, PEG-(8-50) stearates, olive oil PEG-6 esters, trio
- the absorption enhancer is triacetin. In certain preferred embodiments wherein an absorption enhancer is included in the formulation, the absorption enhancer is included in an amount of from about 0.001% to about 10% by weight of the formulation, preferably in an amount of about 0.01% to about 5% by weight of the formulation.
- compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology.
- preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
- compositions are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs, and birds including commercially relevant birds such as chickens, ducks, geese, and turkeys.
- compositions of the invention can be administered in any suitable formulation, by any suitable means, and by any suitable route of administration.
- Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil in water or water in oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
- Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
- Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- Topical administration of compositions of the invention may include transdermal application.
- Transdermal application can be performed either passively or using iontophoresis or electroporation.
- compositions of the invention may be applied using transdermal patches.
- Transdermal patches are adhesive backed patches laced with an effective amount of compounds of the invention.
- the pressure-sensitive adhesive of the matrix will normally be a solution of polyacrylate, a silicone, or polyisobutylene (PIB).
- PIB polyisobutylene
- Pressure sensitive solution polyacrylate adhesives for transdermal patches are made by copolymerizing one or more acrylate monomers (“acrylate” is intended to include both acrylates and methacrylates), one or more modifying monomers, and one or more functional group-containing monomers in an organic solvent.
- the acrylate monomers used to make these polymers are normally alkyl acrylates of 4-17 carbon atoms, with 2-ethylhexyl acrylate, butyl acrylate, and isooctyl acrylate being preferred.
- Modifying monomers are typically included to alter the Tg of the polymer. Such monomers as vinyl acetate, ethyl acrylate and methacrylate, and methyl methacrylate are useful for this purpose.
- the functional group-containing monomer provides sites for crosslinking
- the functional groups of these monomers are preferably carboxyl, hydroxy or combinations thereof.
- monomers that provide such groups are acrylic acid, methacrylic acid and hydroxy-containing monomers such as hydroxyethyl acrylate.
- the polyacrylate adhesives are preferably crosslinked using a crosslinking agent to improve their physical properties, (e.g., creep and shear resistance).
- the crosslinking density should be low since high degrees of crosslinking may affect the adhesive properties of the copolymer adversely. Examples of crosslinking agents are disclosed in U.S. Pat. No. 5,393,529.
- Solution polyacrylate pressure sensitive adhesives are commercially available under tradenames such as GELVATM and DURO-TAKTM from 3M.
- Polyisobutylene adhesives are mixtures of high molecular weight (HMW) PIB and low molecular weight (LMW) PIB. Such mixtures are described in the art, e.g., PCT/US91/02516.
- the molecular weight of the HMW PIB will usually be in the range of about 700,000 to 2,000,000 Da, whereas that of the LMW PIB will typically range between 35,000 to 60,000.
- the molecular weights referred to herein are weight average molecular weight.
- the weight ratio of HMW PIB to LMW PIB in the adhesive will normally range between 1:1 to 1:10.
- the PIB adhesive will also normally include a tackifier such as polybutene oil and high Tg, low molecular weight aliphatic resins such as the ESCOREZTM resins available from Exxon Chemical.
- a tackifier such as polybutene oil and high Tg, low molecular weight aliphatic resins such as the ESCOREZTM resins available from Exxon Chemical.
- Polyisobutylene polymers are available commercially under the tradename VISTANEXTM from Exxon Chemical.
- silicone adhesives that may be used in forming the matrix are typically high molecular weight polydimethyl siloxanes or polydimethyldiphenyl siloxanes. Formulations of silicone adhesives that are useful in transdermal patches are described in U.S. Pat. Nos. 5,232,702, 4,906,169, and 4,951,622.
- Dosage forms for topical or transdermal administration of a compound of this invention include liquids, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, aerosols, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
- Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound(s) in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the ointments, pastes, creams, and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Topical administration may also be performed using iontophoresis devices.
- iontophoresis devices eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin.
- the process of iontophoresis has found commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine, and dexamethasone.
- ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
- the present invention provides a system for the direct application of compounds of the invention, including additional therapeutic agents such as anesthetic agents, by iontophoresis for the treatment of decreased blood flow and concurrent pain associated with injuries, diseases, and disorders. While many compounds may be useful with the invention, as will be discussed below, it is particularly useful for the delivery of anesthetic agents such as lidocaine, bupivicaine, ropivicaine, and mepivicaine to damaged skin.
- the methods of the invention provide a patch device with a donor or delivery chamber that is designed to be applied directly over an injury, incision, or wound site and utilizes an electric field to stimulate delivery of the active compound or additional therapeutic agents(s).
- the patch is sterilized so that risk of infection is minimal.
- the system delivers medication in a constant manner over an extended period of time. Generally, such time periods are at least 30 minutes and may extend to as many as 96 hours.
- a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity.
- a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers.
- Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container.
- such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
- Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
- Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure.
- the propellant may constitute about 50% to about 99.9% (w/w) of the composition, and the active ingredient may constitute about 0.1% to about 20% (w/w) of the composition.
- the propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
- compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension.
- Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device.
- Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate.
- the droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
- formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.
- Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to about 500 micrometers.
- Such a formulation is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
- Formulations suitable for nasal administration may, for example, comprise from about as little as about 0.1% (w/w) and as much as about 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.
- a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration.
- a formulation suitable for buccal administration may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, comprise about 0.1% to about 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein.
- formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient.
- Such powdered, aerosolized, or atomized formulations when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
- the formulation taken orally can be prepared as a pharmaceutical composition, including, but not limited to, a paste, a gel, a toothpaste, a mouthwash, a solution, an oral rinse, a suspension, an ointment, a cream, and a coating.
- a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration.
- Such formulations may, for example, be in the form of eye drops including, for example, a 0.1% to 1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily liquid carrier.
- Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein.
- Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.
- a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for intramucosal administration.
- the present invention provides for intramucosal administration of compounds to allow passage or absorption of the compounds across mucosa. Such type of administration is useful for absorption orally (gingival, sublingual, buccal, etc.), rectally, vaginally, pulmonary, nasally, etc.
- sublingual administration has an advantage for active ingredients, as well as additional therapeutic agents, which in some cases, when given orally, are subject to a substantial first pass metabolism and enzymatic degradation through the liver, resulting in rapid metabolization and a loss of therapeutic activity related to the activity of the liver enzymes that convert the molecule into inactive metabolites, or the activity of which is decreased because of this bioconversion.
- a sublingual route of administration is capable of producing a rapid onset of action due to the considerable permeability and vascularization of the buccal mucosa.
- sublingual administration can also allow the administration of active ingredients which are not normally absorbed at the level of the stomach mucosa or digestive mucosa after oral administration, or alternatively which are partially or completely degraded in acidic medium after ingestion of, for example, a tablet.
- the compounds of the invention can be prepared in a formulation or pharmaceutical composition appropriate for administration that allows or enhances absorption across mucosa.
- Mucosal absorption enhancers include, but are not limited to, a bile salt, fatty acid, surfactant, or alcohol.
- the permeation enhancer can be sodium cholate, sodium dodecyl sulphate, sodium deoxycholate, taurodeoxycholate, sodium glycocholate, dimethylsulfoxide, or ethanol.
- a compound of the invention can be formulated with a mucosal penetration enhancer to facilitate delivery of the compound.
- the formulation can also be prepared with pH optimized for solubility, drug stability, and absorption through mucosa such as nasal mucosa, oral mucosa, vaginal mucosa, respiratory, and intestinal mucosa.
- formulations comprising the active agent may also contain a hydrophilic low molecular weight compound as a base or excipient.
- a hydrophilic low molecular weight compound provides a passage medium through which a water-soluble active agent, such as a physiologically active peptide or protein, may diffuse through the base to the body surface where the active agent is absorbed.
- the hydrophilic low molecular weight compound optionally absorbs moisture from the mucosa or the administration atmosphere and dissolves the water-soluble active peptide.
- the molecular weight of the hydrophilic low molecular weight compound is generally not more than 10000 and preferably not more than 3000.
- hydrophilic low molecular weight compounds include polyol compounds, such as oligo-, di- and monosaccharides such as sucrose, mannitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, D-galactose, lactulose, cellobiose, gentibiose, glycerin, and polyethylene glycol.
- Other examples of hydrophilic low molecular weight compounds useful as carriers within the invention include N-methylpyrrolidone, and alcohols (e.g., oligovinyl alcohol, ethanol, ethylene glycol, propylene glycol, etc.). These hydrophilic low molecular weight compounds can be used alone or in combination with one another or with other active or inactive components of the intranasal formulation.
- hydrophilic polymers such as a polyethylene glycol and polyvinyl pyrrolidone, sugar alcohols such as D-sorbitol and xylitol, saccharides such as sucrose, maltose, lactulose, D-fructose, dextran, and glucose, surfactants such as polyoxyethylene-hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene sorbitan higher fatty acid esters, salts such as sodium chloride and magnesium chloride, organic acids such as citric acid and tartaric acid, amino acids such as glycine, beta-alanine, and lysine hydrochloride, and aminosaccharides such as meglumine are given as examples of the hydrophilic base.
- Polyethylene glycol, sucrose, and polyvinyl pyrrolidone are preferred and polyethylene glycol are further preferred.
- the present invention contemplates pulmonary, nasal, or oral administration through an inhaler.
- delivery from an inhaler can be a metered dose.
- An inhaler is a device for patient self-administration of at least one compound of the invention comprising a spray inhaler (e.g., a nasal, oral, or pulmonary spray inhaler) containing an aerosol spray formulation of at least one compound of the invention and a pharmaceutically acceptable dispersant.
- the device is metered to disperse an amount of the aerosol formulation by forming a spray that contains a dose of at least one compound of the invention effective to treat a disease or disorder encompassed by the invention.
- the dispersant may be a surfactant, such as, but not limited to, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohols, and polyoxyethylene sorbitan fatty acid esters. Phospholipid-based surfactants also may be used.
- the aerosol formulation is provided as a dry powder aerosol formulation in which a compound of the invention is present as a finely divided powder.
- the dry powder formulation can further comprise a bulking agent, such as, but not limited to, lactose, sorbitol, sucrose, and mannitol.
- the aerosol formulation is a liquid aerosol formulation further comprising a pharmaceutically acceptable diluent, such as, but not limited to, sterile water, saline, buffered saline and dextrose solution.
- a pharmaceutically acceptable diluent such as, but not limited to, sterile water, saline, buffered saline and dextrose solution.
- the aerosol formulation further comprises at least one additional compound of the invention in a concentration such that the metered amount of the aerosol formulation dispersed by the device contains a dose of the additional compound in a metered amount that is effective to ameliorate the symptoms of disease or disorder disclosed herein when used in combination with at least a first or second compound of the invention.
- Compounds of the invention will be prepared in a formulation or pharmaceutical composition appropriate for nasal administration.
- the compounds of the invention can be formulated with a mucosal penetration enhancer to facilitate delivery of the drug.
- the formulation can also be prepared with pH optimized for solubility, drug stability, absorption through nasal mucosa, and other considerations.
- Capsules, blisters, and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate.
- the lactose may be anhydrous or in the form of the monohydrate.
- Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
- the pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.
- the compounds for use according to the methods of the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the drugs and a suitable powder base such as lactose or starch.
- additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
- compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., which is incorporated herein by reference.
- dosages of the compounds of the invention which may be administered to an animal, preferably a human, range in amount from about 1.0 ⁇ g to about 100 g per kilogram of body weight of the animal.
- the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal and the route of administration.
- the dosage of the compound will vary from about 1 mg to about 10 g per kilogram of body weight of the animal. More preferably, the dosage will vary from about 10 mg to about 1 g per kilogram of body weight of the animal.
- the compounds may be administered to a subject as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less.
- the frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.
- compositions of the invention comprising metal nanoparticles are also useful for other methods, including, for example, as sensors and for data display.
- the method of present invention employs nanosize particles for detection of molecular structures of interest. It is appreciated that the method of present invention is not bound to any particular assumption or theory of the mechanism of interaction of the chemical groups present on the substrate surface and said nano-particles.
- the method of present invention can be practiced by many different ways. Various other embodiments and variations to the preferred embodiments will be apparent to those skilled in the art and may be made without departing from the spirit and scope of the following claims.
- Nucleic acid hybridization has become an increasingly important technology for DNA analysis and gene expression studies. For example, DNA and RNA hybridization techniques are very useful for detecting, identifying, fingerprinting, and mapping molecular structures. Recently developed combinatorial DNA chips, which rely on the specific hybridization of target and probe DNA on a solid surface, are also encompassed by the present invention. Proteomics has also introduced a very valuable complimentary approach to study the biological functions of a cell. Proteomics involves the qualitative and quantitative measurement of gene activity by detecting and quantifying expressions at the protein level, rather than at the messenger RNA level. Multianalyte assays, also known in the art as “protein chips”, involve the use of multiple antibodies and are directed towards assaying for multiple analytes. The approach enables rapid, simultaneous processing of thousands of proteins employing automation and miniaturization strategy introduced by DNA microarrays.
- the most common approach to detect DNA bound to a microarray is to label it with a reporter molecule that identifies DNA presence.
- the reporter molecules emits detectable light when excited by an external light source.
- Light emitted by a reporter molecule has a characteristic wavelength, which is different from the wavelength of the excitation light, and therefore a detector such as a Charge-Coupled Device (CCD) or a confocal microscope can selectively detect a reporter's emission.
- CCD Charge-Coupled Device
- a confocal microscope can selectively detect a reporter's emission.
- oligonucleotide fragments are end labeled, for example, with 32 P or 35 S. These end labeled fragments are then exposed to X-ray film for a specified amount of time. The amount of film exposure is determined by densitometry and is directly related to the amount of radioactivity of the labeled fragments adjacent to a region of film.
- radioactive label has several disadvantages.
- a method of using metal nanoparticles, as an alternative detection agent for detection of nucleic acids on microarrays without using specialized expensive equipment for detection is taught in U.S. Pat. Nos. 6,495,324 and 6,682,895.
- the nucleotides having sequence complimentary to the target nucleic acid first are attached to the surface of gold nano-particles (nanoparticle-oligonucleotide conjugates).
- the gold nano-particles conjugates that hybridized with target molecules hybridized to the probes on microarray surface. In this method the hybridization of gold conjugates marks array spots where target molecules are located.
- oligonucleotides-gold conjugates are often unstable under the typical hybridization conditions, which further complicates the use of gold-oligonucleotides conjugates (see Li et al., “Multiple thiol-anchor capped DNA-gold nanoparticle conjugates”, Nuc. Acids Res., 30(7), 1558-1562 (2202)).
- Yguerabide et al. U.S. Pat. No. 6,586,193, describes a method of using light scattering for sensitive detection of target biopolymers.
- this method another type of metal-conjugate particles described, which conjugates provides specific binding component to bind target molecules through hapten pairs, such as biotin/streptavidin or digoxigenin/antidigoxigenin and the similar binding systems.
- the particles are coated with, for instance, streptavidin wherein biotin is incorporated into the structure of target molecules during the steps of analyte preparation.
- the modification of target molecules by incorporating labeling group(s) e.g., biotin and the similar
- detection often introduces bias, reduces accuracy and increases the cost and complexity of microarray analysis.
- Remacle et al. US App. No. 2003/0096321
- a method for identification of a labeled target compound on a surface of solid support in one embodiment, the use of non-modified target molecules is described by employing a sandwich type assay, in which the target is hybridized with an additional labeled nucleotide sequence, which labeled nucleotide allows attachment of gold-conjugates to the target compound.
- the method requires the use of a large number of labeled sequence-specific oligonucleotides, which makes the method unpractical.
- the surface of the solid support (i.e., microarray) covered by nanoparticles can be analyzed and density of the bound nanoparticles can be measured using conventional optical techniques and a suitable image-capturing apparatus.
- a suitable image-capturing apparatus can include any device of plurality of devices capable of acquiring absorbance on the surface and reflectance from the surface of interest, and most preferably, includes flatbed scanners. The resolution of the image-capturing device must be sufficient to identify optical response from individual test sites on the surface of the substrate. Most preferably, the image-capturing device must be able to digitize the captured image and transfer the image to a computer for storage and further analysis.
- images of the same area of the substrate can be captured multiple times for averaging, reducing noise, color manipulations, filtering and performing other image-processing operations known to one skilled in the art.
- Specialized software can be implemented for obtaining quantitative characteristics of the optical response from each individual test site on the substrate. These quantitative parameters can be used to quantify the distribution of nano-particles bound to the substrate and accordingly to measure the quantity of molecular structure of interest in corresponded site(s) of the substrate.
- Titanium thin films were procured from Good Fellow Inc. The metal film was cut into 1 ⁇ 1 cm. square samples for surface modification. The samples were washed with acetone, 1% triton followed by mild sonication in distilled water.
- SEI secondary electron imaging
- SEM scanning electron microscope
- FIG. 1 shows images of scanning electron micrographs of unmodified titanium sample indicating the morphology.
- FIG. 2 shows the elemental composition of the unmodified metal film indicating that the surface is composed solely of titanium metal.
- FIGS. 3 and 4 represent scanning electron micrographs of base etched titanium sample showing the morphology. Under the present etching conditions, the surface of the metal showed a uniform nanofibrous structure. The gross morphology of the structure was found to be highly reproducible. The fibrous structure on the surface was found to have an average diameter of less than ⁇ 100 nm.
- FIG. 5 shows the EDS spectra of surface etched titanium films.
- the surface mainly shows the presence of titanium metal on the surface.
- the absence of sodium peak on the surface can be attributed to washing the surface with water.
- FIGS. 7 and 8 clearly demonstrate the presence of silver on the surface of base etched titanium surfaces. However, contrary to what was expected, high magnified image ( FIG. 7 b ) clearly shows the formation of few nanoparticles ( ⁇ 10 nm) on the surface of the metal even though no reducing agents have been used.
- FIGS. 7 b shows the formation of few nanoparticles ( ⁇ 10 nm) on the surface of the metal even though no reducing agents have been used.
- FIG. 9 and 10 shows the surface of alkali etched titanium surface treated with silver ions after reduction using sodium borohydride. As shown in the figure, reduction of silver ions significantly increased. The size of the silver particles were found to range from ⁇ 5-10 nm. The formation of silver nanoparticles was further confirmed by EDS spectra ( FIG. 10 ). The nanofibrous structure present on the surface due to titanium has been found to have very small diameter in the range of 10-20 nm. This unique structure results in the formation of unique color change to the metal.
- FIG. 11 shows the photographs of surface modified and unmodified titanium films. The formation of silver nanoparticles changed the color of the film to brown-blue color with a metallic luster. Further studies showed significant reduction of bacteria on the surface comprising metallic nanoparticles and showed the use for the metal substrates for growing mammalian cells (see Example 4 and FIG. 32 ).
- polymeric substrates we have developed an unique surface coating technique to modify the surfaces of polymeric biomaterials and devices with silver nanoparticles.
- the process is based on the photochemistry of azides.
- polymeric substrates either carboxylated, aminated or hydroxylated (any reactive functional groups) polymers can be functionalized with aromatic or aliphatic azides to make them photoactive.
- the photoactive polymers can be permanently coated on any substrates by photoirradiation. In the case of aromatic azides, the absorption occurs in the range of ⁇ 275 nm and therefore irradiation of the coated surface with UV radiation result in immobilization of the polymer on the surface due to an azide insertion reaction.
- FIG. 12 shows the UV spectra of azidated polymer showing strong absorbance in the 275-280 nm due to the aromatic azide groups.
- the azidated polymers was dissolved in double distilled water and coated onto polymeric substrates.
- Commercially available polystyrene cover slips were commonly used, however feasibility to coat on other polymers have also been demonstrated.
- Different polymer concentrations were used for coating including 10 mg/ml, 5.0 mg/ml, 1.0 mg/ml, and 0.05 mg/ml.
- the coating was allowed to dry over night in the dark.
- the coated surface was then irradiated with UV radiation at a wave length of 275 nm for 2-3 minutes for azidated polymer immobilization on the substrate ( FIG. 20 ).
- the coated substrate was then sonicated in water for 1-2 min to wash off the unattached polymer.
- the coated substrate was then dried under vacuum.
- the Photomodified Polymeric Substrates were Incubated in Silver Nitrate solution (10-50 ⁇ M) at 37° C. for various periods of time (5 h-24 h).
- the silver ion complexed surfaces were washed with distilled water and dried under vacuum.
- the reduction of silver ions to silver metal can be performed using various reducing agents. This includes, for example, 5-10 ⁇ M solution of sodium borohydride in water, solution of dextrose in water. In other cases, a basic ammoniacal silver nitrate solution can be used for ion exchange method for direct reduction of ions to metal.
- the modified polymeric substrates shows unique colors depending on the method of reduction and will be extensively washed with water and dried under vacuum. FIG.
- FIG. 13 shows silver nanoparticles formed on polystyrene surface coated with silver nanoparticles. The coated surfaces were incubated in silver nanoparticles for 24 h before reduction. The white spots have been identified as silver nanoparticles uniformly distributed in the surface of the polymer coating.
- FIG. 14 demonstrates the different sizes and distribution of silver nanoparticles formed on azidated alginic acid on polystyrene cover slips after ion exchanging with silver followed by reduction.
- Spot EDS spectra has identified the elemental composition of the surface ( FIG. 14E ).
- the arrows (and regions with similar color) indicates silver on the surface.
- the dark background indicated by the arrow on the far right indicates regions rich in carbon and oxygen and is therefore presumably the alginic acid substrate.
- FIGS. 18 a and 18 b shows nanoparticles formed on polymeric nanofiber matrices using two different concentrations of the azidated polymer coating solutions.
- FIG. 19A shows poly(acrylic azide) coated and shined with UV light through a photomask.
- the yellow region shows polyacrylic acid grafted on polystyrene surface.
- FIG. 19B shows silver nanoparticles formed on the polyacrylic acid patterns on polystyrene.
- FIG. 20 schematically illustrates the preparation and photo-immobilization of azidated polymers.
- FIG. 21 schematically illustrates the formation of silver nanoparticles on polymeric substrates.
- PluroGel 2 mL of PluroGel was aliquoted and stirred using a magnetic stirrer at 4° C. in an icebath. 0.01 gm of silver nitrate powder was then added to PluroGel. The color of the solution instantly turned to yellow. The solution was stirred for another 2-5 minutes to form the silver nanoparticle-PluroGel composite mixture. The solution showed phase transition (liquid to solid) when heated to 37° C. in a water bath.
- the procedure was also performed using a diluted formulation of PluroGel which is less viscous at room temperature. Using the diluted formulation, the above procedures were performed at room temperature rather than 4° C.
- the present invention further encompasses methods for preparing and using surface active polymers, including PluroGel and variations thereof as described in International Application No. PCT/US2008/066094 (Katz and Rodeheaver), filed Jun. 6, 2008, the contents of which are hereby incorporated in their entirety herein.
- FIG. 22 photographically illustrates silver particles formed using Procedure 1 as described above. Three vials, labeled A, B, and C are depicted. The photograph of FIG. 22 also demonstrates visually the difference between PluroGel ( FIG. 22A ), PluroGel plus silver particles at 4° C. ( 22 B), and PluroGel plus silver particles at 37° C. ( 22 C). The phase transition is also apparent (note that the vial labeled C is upside down and the composition had gelled).
- FIG. 23 illustrates the solutions of FIG. 22 (A and B) after 4 days at 4° C.
- FIG. 24 photographically illustrates silver particles formed using Procedure 2 described above.
- the photograph of FIG. 24 also demonstrates visually the difference between PluroGel ( FIG. 24A ), PluroGel plus silver particles at 4° C. ( 24 B), and PluroGel plus silver particles at 37° C. ( 24 C).
- the phase transition is also apparent.
- FIG. 25 illustrates the solutions of FIG. 24 (A and B) after 4 days at 4° C.
- FIG. 26 provides transmission electron micrographic evidence of the silver nanoparticles prepared according to Procedure 1. It can be seen in FIG. 26A that there are silver nanoparticles and that the general size ranges are about 10-15 nm.
- FIG. 26B represents a higher magnification image of silver nanoparticles and demonstrates the partially crystalline structure.
- FIG. 26C represents an x-ray diffraction pattern which confirms the partially crystalline structure of the particles.
- the PluroGelTM composition comprising metallic nanoparticles maintains the physical characteristics of PluroGel without the metallic nanoparticles, e.g., the liquid or gel states temperature dependent.
- Composite films created with nanoparticles evenly dispersed throughout the polymer can have very interesting properties.
- Layer by layer casting of polyelectrolytes Chosan and carboxymethyl chitosan (CMC) were used to create thin films to form silver nanoparticles in situ.
- chitosan 2% solution of chitosan in 0.5% acetic acid and 2% solution of carboxymethyl chitosan in distilled water were used to prepare the layer by layer casted films. Briefly, 6 mL of chitosan was poured into 100 mL petri dish and allowed to dry at 80° C. for 1.5 h. Then 6 mL of carboxymethyl chitosan solution was added and allowed to dry at 80° C. for 1.5 h. After than 6 mL of chitosan was added on top of it and allowed to dry at 80° C. for 1.5 h.
- Crosslinking the films Some of the films were further heated to 110° C. for 1 h to crosslink the different polymer layers. All the films were then subjected to neutralization using 0.4N sodium hydroxide solution.
- FIGS. 27A (1 hour), 27 B (3 hours), 27 C (5 hours), and 27 D (24 hours) provide UV absorption spectra for these experiments. It can be seen that by 3 hours ( FIG. 27B ), a characteristic peak of silver nanoparticles is present at 410-450 nm, and that by 24 hours ( FIG. 27D ) there is a significant increase in the peak.
- FIG. 28 photographically illustrates a side by side comparison of a film with silver particles (left film; appears brown in a color photograph) and the control film on the right (no color change).
- the formation of particles was further confirmed by transmission electron microscopy.
- the films were sectioned using a cryomicrotome and the cross-section of the film was observed using a transmission electron microscope (see FIG. 29 ).
- the study demonstrated the formation of large number of particles in the middle layer, however the chitosan layer also found to have particles and the particles in the chitosan layer was found to be less aggregated compared to the middle layer. Further studies are currently underway to optimize the size and distribution of the particles.
- FIG. 30 A trilayer film was also subjected to energy-dispersive x-ray microanalysis.
- the results ( FIG. 30 ) indicate the elemental contents of the particles in the film.
- FIG. 30 graphically represents an EDS spectrum of the particles within the trilayer film.
- the presence of the silver peaks (Ag) confirms the composition of the particles.
- FIG. 31 represents a photomicrographic image illustrating the distribution of the particles within a trilayer film. More particle aggregates are found along the CMC later compared to the chitosan layer.
- the marker in the photograph represents 50 ⁇ m.
- compositions comprising chitosan are known in the art and such methods and compositions are encompassed by the present application. Such methods and compositions are described in, for example, International Patent Publication WO 2007/087350 (Laurencin et al.) published Aug. 2, 2007, the contents of which are hereby incorporated by reference in their entirety.
- Titanium metal foil (0.25 mm) was procured from Good Fellow, Cambridge Ltd.
- Sodium hydroxide, silver nitrate, sodium borohydride and ethanol were procured from Sigma Aldrich (St, Louis USA).
- Human bone marrow-derived mesenchymal stem cells (hMSCs) were obtained from Cambrex and E. coli from ATCC.
- Titanium samples (1 ⁇ 1 cm) were then incubated in 5 M sodium hydroxide solution at 40° C. for 24 h.
- hMSCs were cultured for 14 days on modified titanium surfaces using basal growth media.
- Cell proliferation was determined using MTS colorimetric assay and alkaline phosphatase activity using standard alkaline phosphatase kit.
- the base etched films were incubated in 50 mM aqueous silver nitrate solution at 40° C. for 24 h. The films were then washed with a mild reducing agent such as 70% ethanol and then exposed to 10 mM aqueous sodium borohydride solution for 2-3 minutes. A fast reaction occurred and the color of the metal foil changed to dark brown. The modified substrates were further washed with 70% ethanol, twice with distilled water and dried under vacuum.
- a mild reducing agent such as 70% ethanol
- 10 mM aqueous sodium borohydride solution for 2-3 minutes. A fast reaction occurred and the color of the metal foil changed to dark brown.
- the modified substrates were further washed with 70% ethanol, twice with distilled water and dried under vacuum.
- SEI secondary electron imaging
- SEM scanning electron microscope
- the base etched titanium films were found to be cytocompatible as evidenced by the proliferation of human mesenchymal stem cells on the surface ( FIG. 32A ).
- the cells on nanostructured film showed higher alkaline phosphatase activity compared to control film.
- FIG. 32B shows the presence of near spherical shaped silver nanoparticles on the nanofibrous structures with a mean diameter of ⁇ 10 nm. This is highly significant since previous studies have demonstrated that the shape and size of the silver nanoparticles plays a significant role in its antibacterial activity with highest activity found for particles with sizes ranging from 1-10 nm.
- the composition of the silver nanoparticles was further confirmed by EDS.
- the high antibacterial property of surfaces containing silver nanoparticles was demonstrated using E. coli.
- nanostructured implants can be considered as one of the promising strategies to increase osseointegration and provides matrices to be used to deliver cells such as hMSCs to an osseous defect and reduce implant associated infection.
- the study shows a versatile technique to develop nanostructured titanium containing silver nanoparticles as a potential biomaterial.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nanotechnology (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Oral & Maxillofacial Surgery (AREA)
- General Physics & Mathematics (AREA)
- Materials Engineering (AREA)
- Crystallography & Structural Chemistry (AREA)
- Physics & Mathematics (AREA)
- Transplantation (AREA)
- Composite Materials (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to compositions and methods by which surface modification techniques can be used to modify wide range polymeric or metal substrates using metal nanoparticles.
Description
- This application is entitled to priority pursuant to 35 U.S.C. §119(e) to U.S. provisional patent application No. 60/961,587, filed on Jul. 23, 2007. The entire disclosure of the afore-mentioned patent application is incorporated herein by reference.
- This invention relates generally to methods and compositions useful for adding metallic nanoparticles to various substrates.
- Nanoparticles have been broadly defined as particles having one or more dimensions of the order of 100 nm or less. Even though various materials such as polymers, ceramics, metals and organic molecules are being currently investigated for developing nanosized particles, metal nanoparticles have raised significant interest due to their unique properties.
- Nanosized metallic particles, mainly gold and silver nanoparticles, have attracted attention because of their unique optical and electrical properties, as well as potential biomedical applications. Thus, depending upon their size, shape, surface area, surface plasmon and surface chemistry, these metallic nanoparticles are known to show distinct optical, magnetic, electrical and biological properties which are different from the bulk materials [1].
- Due to their unique properties and various areas of applications such as infection resistance, catalysis, nanoelectronics, optical filters and surface raman scattering, nanoparticles of silver are one of the most extensively investigated metallic nanoparticles [2]. Several techniques have already been developed to form metal nanoparticles in solution. Thus, silver nanoparticles are commonly prepared by the controlled reduction of silver salt solutions. The structure and corresponding physical, chemical, and biological properties of silver nanoparticles are known to strongly depend on the method of preparation and the experimental conditions [3]. Several reduction techniques have been investigated. These reduction techniques include strong chemical reducing agents such as sodium borohydride and hydrazine, irradiation using gamma rays, ultra violet, and visible light, microwave as well as ultra sound, and weak reducing agents such as ascorbates, citrates, alcohol, as well as polyols.
- Even though colloidal solutions of silver exhibit unique optical and biological properties, the assembly of these particles into thin films is highly recommended for the development of practical applications [4]. Recently, techniques have been developed to immobilize silver nanoparticles on surfaces via surface modification techniques [5].
- Various preparation routes for composite materials have been proposed. These include self assembly [6], electroless plating [7], layer by layer (LBL) self assembly of polyelectrolytes and metal nanoparticles [8] and ultra sound irradiation [9]. Most of these approaches tend to produce surfaces coated with metal nanoparticles by physical adsorption or electrostatic interactions and are not highly suitable for practical biomedical applications. Recently, physical vapor deposition or magnetron sputtering has been investigated to develop thin nanostructured silver surfaces for a variety of applications. A radiofrequency magnetron source is commonly used for the sputtering process to deposit porous nanocrystalline metallic silver on surfaces.
- A surface produced by magnetron sputtering of silver has been shown to have strong antibacterial properties [10]. The antibacterial property has been attributed to the release of silver ions from the surface in a controlled and appropriate concentration. In addition to antibacterial properties, the modified surface has wound healing properties, demonstrating the advantages of silver coated materials for biomedical applications [11]. Even though it is highly effective, the fabrication process has several limitations to be used for practical applications. These include the lack of flexibility and controllability of the process, the limited range of materials that can be modified and the limited surface area that can be modified at a time.
- There is a long felt need in the art for compositions and methods by which surface modification techniques can be used to modify wide range polymeric substrates using metal nanoparticles as well as for metallic substrates. The present invention satisfies these needs.
- The present disclosure demonstrates the development of mild and cost effective methods to immobilize metallic nanoparticles on polymeric or metallic substrates. This involves unique and mild processes to immobilize soft templates on the surface of polymeric materials which can be used to fabricate silver or gold nanoparticles by ion exchange method. The immobilization on polymeric substrates involves coating the surface with a photoactive polymer capable of synthesizing metallic nanoparticle on the surface. In one aspect, the template can be immobilized on any polymeric substrate using a mild and fast (1-2 minutes) photoreaction. The process is highly versatile as it can be used to create metallic nanoparticles such as silver nanoparticles on a wide range of polymeric substrates irrespective of its physical form, shape, or chemistry. A related method has also been designed for metallic biomaterials such as titanium. The data disclosed herein demonstrate the feasibility of synthesizing silver nanoparticles of different size ranges on the substrate surface depending on the reaction conditions. Furthermore, the process allows the feasibility of patterning surfaces with metallic nanoparticles demonstrating its potential for biosensor applications.
- In one aspect, the procedure is based on the photochemistry of azide groups which has been extensively investigated previously for lithographic techniques [12]. The present invention utilizes, inter alia, azide chemistry to immobilize a wide range of natural and synthetic polymers on biomaterial surfaces and use the immobilized polymers as templates to synthesis metallic nanoparticles.
- In one aspect, the present invention encompasses practical methods to immobilize metal nanoparticles on any polymeric substrates. In another aspect, the present invention encompasses a nondestructive modification process without the use of harsh chemicals or high energy radiation. In another aspect, the present invention encompasses modifying polymeric substrates having any shape or size or structure. In yet another aspect, the present invention encompasses a practical method to immobilize nanoparticles on a metal surface. In one aspect, the metal surface comprises titanium.
- In a further aspect, the present invention encompasses compositions and methods useful for controlling the size and distribution of nanoparticles on the surface by varying parameters associated with the template as well as other reagents. The present invention also encompasses compositions and methods useful for developing a green process without the use of reducing agents.
- In one aspect, the surface is metal. In one aspect, the metal is titanium. In one aspect, the metal surface is etched. In one aspect, the metal surface comprises metal nanoparticles. In one aspect, the metal nanoparticles are silver nanoparticles. In one aspect, the silver particles are about, 0.1 to about 100 nm in size or from about 1 to about 100 nm in size. In another aspect, they are 2-75 nm in size. In yet another aspect, they are about 3-50 nm in size. In a further aspect, they are about 4-25 nm. In another aspect, they are about 5-10 nm in size.
- In one aspect, the metal substrates and metal films of the invention are useful as surfaces for culturing mammalian cells. By the term “culturing” mammalian cells or “maintaining cells in culture” is meant that the cells will adhere to the surface, but does not exclude the possibility that the cells merely adhere and do not proliferate. In one aspect, the metal substrates and metal films of the invention support the proliferation and differentiation of cells selected from the group consisting of stem cells, pluripotent stem cells, committed stem cells, embryonic stem cells, adult stem cells, bone marrow stem cells, bone marrow-derived stem cells, adipose stem cells, umbilical cord stem cells, dura mater stem cells, precursor cells, differentiated cells, osteoblasts, osteoclasts, myoblasts, neuroblasts, fibroblasts, glioblasts, germ cells, hepatocytes, chondrocytes, keratinocytes, smooth muscle cells, cardiac muscle cells, connective tissue cells, glial cells, epithelial cells, endothelial cells, hormone-secreting cells, cells of the immune system, normal cells, cancer cells, Schwann cells, and neurons. In one aspect, the cells are human cells. In one aspect, metal substrates and films of the invention comprising cells can be used as delivery vehicles to deliver the cells to a site of interest in a subject in need thereof.
- Other materials may also be added to the metal films and substrates, in addition to metal nanoparticles such as silver nanoparticles.
- In one aspect, the metal substrates and films of the invention are useful for inhibiting microbial growth. In one aspect, the microbial growth is bacterial growth.
- In one embodiment, the metal substrates are useful as nanostructured implants. In one aspect, the nanostructured implants can increase osseointegration and provide matrices to be used to deliver cells such as hMSCs to an osseous defect and reduce implant associated infection. Therefore, the present invention encompasses the use of metal substrates, particularly those which are etched or comprise metallic nanoparticles, as delivery vehicles. These delivery vehicles can be used to deliver cells and other materials to a site in a subject in need thereof, including, but not limited to, a wound, an osseous defect, etc. The additional materials include, but are not limited, other cell types, additional therapeutic agents, hormones, growth factors, etc. The present application further discloses a versatile technique to develop nanostructured titanium containing silver nanoparticles as a potential biomaterial.
- In one embodiment, the present application discloses a method of making polymeric substrates comprising metallic nanoparticles. This method comprises forming a photoactive polymer by contacting a polymer comprising a reactive group with an aromatic azide or aliphatic azide. It further comprises contacting the photoactive polymer with the polymeric substrate, and immobilizing the photoactive polymer to the polymeric substrate by irradiation. The method further encompasses contacting the polymeric substrate comprising immobilized photoactivated polymers with a composition comprising a metal for forming metallic nanoparticles and optionally washing the substrate after the contact. In one aspect, the polymeric substrate is polystyrene. In one aspect, the polymer comprising a reactive group is selected from the group consisting of poly(acrylic acid), alginica acid, heparin, and chondroitin sulfate. In one aspect, the azidated polymer is purified following azidation. In one aspect, the purified azidated polymer is dried. In one aspect, before contacting the polymeric substrate the dried purified azidated polymer is resuspended at concentrations selected from the group consisting of 10 mg/ml, 5.0 mg/ml, 1.0 mg/ml, and 0.05 mg/ml. In one aspect, the irradiation is ultraviolet irradiation. In one aspect, the wavelength of the ultraviolet irradiation is about 275 nm. In one aspect, the composition comprises silver. In one aspect, the immobilized silver is reduced from silver ion to silver metal. In one aspect, the silver nanoparticles are made using ammoniacal polysaccharides.
- In one embodiment, the polymers are applied in patterns.
- The present invention further encompasses a polymeric substrate comprising metallic nanoparticles made by the method described herein.
- In one aspect, the metallic nanoparticles range in size from about 1.0 nm to about 100 nm. In another aspect, the nanoparticles range in size from about 2.0 nm to about 75 nm. In a further aspect, the nanoparticles range in size from about 3.0 nm to about 50 nm. In yet another aspect, the nanoparticles range in size from about 4.0 nm to about 25 nm. In another aspect, the nanoparticles range in size from about 5.0 nm to about 10.0 nm.
- In one aspect, silver particles are incorporated onto the surface.
- The present application encompasses the use of surface active copolymers. In one aspect, the surface active copolymers, include, but are not limited to, poloxamers, meroxapols, and poloxamines.
- Examples of poloxamers include poloxamer-101, -105, -105 benzoate, -108, -122, -123, -124, -181, -182, -182 dibenzoate, -183, -184, -185, -188, -212, -215, -217, -231, -234, -235, -237, -238, -282, -284, -288, -331, -333, -334, -335, -338, -401, -402, -403, and -407. In one aspect, the poloxamer is poloxamer-188. In another aspect, the poloxamer is poloxamer-407.
- In one embodiment, the surface active copolymer composition comprises PluroGel™ (PluroGen, Annapolis, Md.).
- Exemplary meroxapols include, but are not limited to, meroxapol 105, 108, 171, 172, 174, 178, 251, 252, 254, 258, 311, 312, and 314.
- Exemplary poloxamines include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508.
- The present invention further encompasses methods for making metallic nanoparticles in chitosan and carboxymethyl chitosan. In one aspect, chitosan or carboxymethyl chitosan solutions are prepared in layers, which after drying, are contacted with a composition comprising a metal, which metal permeates the layers and forms metallic nanoparticles. In one aspect, the layers are alternated between chitosan and carboxymethyl chitosan. In one aspect, the metal is silver. One of ordinary skill in the art will appreciate that the conditions may be varied to adjust the size of nanoparticles formed, the number of nanoparticles formed, etc.
- The present application further discloses a method of making a tri-layer membrane comprising metallic nanoparticles for use as a therapeutic agent or a biosensor. The method encompasses preparing a chitosan solution and preparing a carboxymethyl chitosan solution. Then, a first layer of solution is applied to a surface and allowed to dry. The method further encompasses applying a second layer comprising the other solution to the dried first layer and allowing the second layer to dry. The method also encompasses applying a third layer of the same solution as applied for the first layer over the second layer and allowing the third layer to dry. Optionally dried layers are heated. The dried layers are then neutralized. The neutralized layers are then contacted with a composition comprising a metal for forming metallic nanoparticles to form a tri-layer membrane comprising metallic nanoparticles.
- One of ordinary skill in the art will appreciate that the methods and compositions of the invention can be varied or adjusted as needed to utilized different metals, form different numbers of nanoparticles, different sizes of nanoparticles, add additional agents, etc. For example, one of ordinary skill in the art will appreciate that reaction times, temperatures, concentrations of solutions, etc. can be varied.
- In one aspect, the metallic particles are about, 0.1 to about 100 nm in size or from about 1 to about 100 nm in size. In another aspect, they are 2-75 nm in size. In yet another aspect, they are about 3-50 nm in size. In a further aspect, they are about 4-25 nm In another aspect, they are about 5-10 nm in size.
- Metals encompassed by the invention include gold (Au), silver (Ag), platinum (Pt), aluminum (Al), nickel (Ni), iron (Fe), palladium (Pd), titanium (Ti), scandium (Sc), vanadium (V), chromium (Cr), magnesium (Mg), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), cadmium (Cd), lutetium (Lu), hafnium (Hf), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), tantalum (Ta), rhodium (Rh), rare-earth metals ytterbium (Yb), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), and lutecium (Lu). In one aspect, the metals are useful for making nanoparticles. In another aspect, the metals are useful in surfaces for immobilization of nanoparticles.
- Various aspects and embodiments of the invention are described in further detail below.
- The foregoing summary, as well as the following detailed description of preferred embodiments of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. In the drawings:
-
FIG. 1 . Surface morphology of titanium thin films illustrated by scanning electron microscopic images at two different magnifications (1A—lower magnification (×350); 1B—higher magnification (×4,500); lower portion of image has magnification and bars indicating relative length). -
FIG. 2 . Surface elemental composition of titanium indicating the presence of only titanium atoms. -
FIG. 3 . Surface morphology of etched titanium thin films illustrated by scanning electron microscopic images at two different magnifications (3A—×4,500; 3B—×15,000). -
FIG. 4 . Surface morphology of etched titanium thin films at two different higher magnifications (4A—×50,000; 4B—×100,000) -
FIG. 5 . Surface elemental composition of titanium indicating the presence of only titanium atom. -
FIG. 6 . Surface morphology of silver nitrated treated etched titanium films (6A—×1,600; 6B—×5,500). -
FIG. 7 , comprisingFIGS. 7 a-7 c, depicts surface morphology of silver nitrated treated etched titanium films at different magnifications (7 a—×50,000; 7 b—×300,000; 7 c—×100,000). -
FIG. 8 . Surface elemental composition of silver nitrated treated etched titanium films. -
FIG. 9 , comprisingFIGS. 9A-E , depicts surface morphologies of sodium borohydrode reduced titanium metal surface at various magnifications (×350, 10,000, 50,000, 100,000, and 250,000, respectively). -
FIG. 10 represents EDS spectra of the nanoparticles on the surface indicating the composition as silver. -
FIG. 11 , comprisingFIGS. 11A-11D , represents photographic images of: A. titanium metal surface; B. Titanium surface alkali etched; C. Titanium surface after treating with silver salt solution; D. Titanium surface after reduction to silver nanoparticles. -
FIG. 12 graphically represents a UV spectrum of azidated alginic acid showing the presence of azide groups. The ordinate represents absorbance and the abscissa represent wavelength (nm) -
FIG. 13 . Silver nanoparticles formed on polystyrene substrates coated with polyacrylic acid, silver ion exchange and subsequent reduction (two magnifications indicating particles with size less than 50 nm; 13A—×60,000; 13B—×120,000). -
FIG. 14 , comprisingFIGS. 14A-E , illustrates the different sizes and size distribution of silver nanoparticles formed on azidated alginic acid on polystyrene cover slips after ion exchanging with silver followed by reduction. -
FIG. 15 . Silver particles formed on azidated poly(acrylic acid) where in silver ions were exchanged for 5 h followed by reduction using sodium borohydride. Comparatively larger particles were obtained in this process. 15A indicates a lower magnification and 15B, a higher magnification during scanning electron microscopy. -
FIG. 16 , comprisingFIGS. 16A-16D , depicts photographic images illustrating the formation of silver nanoparticles on azidated heparin sulfate coated on polystyrene substrate, after silver ion exchange and reduction using sodium borohydride. -
FIG. 17 . Formation of silver nanoparticles on azidated heparin sulfate coated on polystyrene substrate, after silver ion exchange and reduction using sodium borohydride. 17 a—Silver nanoparticles formed in solution w/o adding NaBH4; 17 b—UV absorption spectra characteristic of Ag nanoparticle. -
FIG. 18 . SEM showing the formation of silver nanoparticles on nanofiber matrices after a thin layer of coating with azidated polymers. A. Coating with dilute solution; B. Coating with concentrated solution. -
FIG. 19 , comprisingFIGS. 19A and 19B , shows poly(acrylic azide) coated and shined with UV light through a photomask (19A). The lighter colored region (appears yellow in a color photograph) shows polyacrylic acid grafted on polystyrene surface.FIG. 19B shows silver nanoparticles formed on the polyacrylic acid patterns on polystyrene. -
FIG. 20 . Scheme showing the preparation and photo-immobilization of azidated polymers. -
FIG. 21 . Scheme showing the formation of silver nanoparticles on polymeric substrates. -
FIG. 22 represents a photographic image illustrating the phase transition of PluroGel in the presence of silver nanoparticles formed usingProcedure 1, as described in Example 2. Three vials, labeled A, B, and C are depicted. The photograph ofFIG. 22 also demonstrates visually the differences between PluroGel at 4° C. (FIG. 22A ), PluroGel plus silver particles at 4° C. (22B), and PluroGel plus silver particles at 37° C. (22C). The phase transition is also apparent (note that the vial labeled C is upside down and the composition had gelled). -
FIG. 23 represents a photographic image illustrating the low temperature stability of PluroGel comprising silver nanoparticles after 4 days at 4° C. (23A—PluroGel; 23B—PluroGel comprising silver nanoparticles). -
FIG. 24 represents photographic images illustrating the phase transition of PluroGel in the presence of silver particles formed usingProcedure 2, as described in Example 2: PluroGel (FIG. 24A ); PluroGel plus silver particles at 4° C. (24B); and PluroGel plus silver particles at 37° C. (24C). -
FIG. 25 represents photographic images of the solutions ofFIG. 24 (A and B) after 4 days at 4° C. -
FIG. 26 , comprisingFIGS. 26A-C , represents transmission electron micrographic images providing evidence of the silver nanoparticles prepared according toProcedure 1 of Example 2. It can be seen inFIG. 26A that there are silver nanoparticles and that the general size ranges are about 10-15 nmFIG. 26B represents a higher magnification image of silver nanoparticles and demonstrates the partially crystalline structure.FIG. 26C represents an x-ray diffraction pattern which confirms the partially crystalline structure of the particles. -
FIG. 27 , comprisingFIGS. 27A-27D , graphically illustrates LTV absorption spectra collected at various times up to 24 hours and demonstrates the growth of silver particles as a function of time of incubation in silver nitrate solution. Data were obtained using a UV-Vis spectrophotometer and indicate the plasmon resonance of silver particles. FIGS. 27A—1 hour; 27B—3 hours; 27C—5 hours; and 27D—24 hours. It can be seen that by 3 hours (FIG. 27B ), a characteristic peak of silver nanoparticles is present at 410-450 nm, and that by 24 hours (FIG. 27D ) there is a significant increase in the peak. The abscissa represents wavelength in nanometers (nm). The ordinate represents optical density (OD). -
FIG. 28 photographically illustrates a side by side comparison of a trilayer film with silver particles (left film; appears brown in a color photograph) and the control film on the right (no color change). -
FIG. 29 represents a transmission electron micrograph demonstrating the formation of particles in the middle layer of a trilayer film. The films were sectioned using a cryomicrotome and the cross-section of the film was observed using a transmission electron microscope. A reference length marker indicating 0.09 μm is provided in the lower right portion of the image. -
FIG. 30 graphically represents an EDS spectrum of the particles within a trilayer film. The presence of the silver peaks (Ag) confirms the composition of the particles. The ordinate represents counts. The abscissa represents x-ray energy in KeV. -
FIG. 31 represents an image of a transmission electron micrograph illustrating the distribution of silver particles within a trilayer film. More particle aggregates are found along the CMC layer compared to the chitosan layer. A reference length marker indicating 0.50 μm is provided in the lower right portion of the image. -
FIG. 32 , comprisingFIGS. 32A and 32B , represents the surface morphology of titanium thin films illustrated by scanning electron microscopic images.FIG. 32A depicts an image of a scanning electron micrograph showing human bone marrow-derived mesenchymal stem cells on base-etched titanium film after 14 days in culture.FIG. 32B depicts a film modified with silver nanoparticles (arrow indicating silver nanoparticles). - In describing and claiming the invention, the following terminology will be used in accordance with the definitions set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein. As used herein, each of the following terms has the meaning associated with it in this section. Specific and preferred values listed below for radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
- As used herein, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.
- The term “about,” as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%. In one aspect, the term “about” means plus or minus 20% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%. Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.”
- The terms “additional therapeutically active compound” or “additional therapeutic agent”, as used in the context of the present invention, refers to the use or administration of a compound for an additional therapeutic use for a particular injury, disease, or disorder being treated. Such a compound, for example, could include one being used to treat an unrelated disease or disorder, or a disease or disorder which may not be responsive to the primary treatment for the injury, disease or disorder being treated. Disease and disorders being treated by the additional therapeutically active agent include, for example, hypertension and diabetes. The additional compounds may also be used to treat symptoms associated with the injury, disease or disorder, including, but not limited to, pain and inflammation. Such compounds or agents include, but are not limited to drugs, antimicrobials, growth factors, cytokines, etc.
- A disease, condition, or disorder is “alleviated” if the severity of a symptom of the disease, condition, or disorder, or the frequency with which such a symptom is experienced by a subject, or both, are reduced.
- As used herein, an “analog” of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (e.g., 5-fluorouracil is an analog of thymine).
- The term “antimicrobial agents” as used herein refers to any naturally-occurring, synthetic, or semi-synthetic compound or composition or mixture thereof, which is safe for human or animal use as practiced in the methods of this invention, and is effective in killing or substantially inhibiting the growth of microbes. “Antimicrobial” as used herein, includes antibacterial, antifungal, and antiviral agents.
- “Antiviral agent,” as used herein means a composition of matter which, when delivered to a cell, is capable of preventing replication of a virus in the cell, preventing infection of the cell by a virus, or reversing a physiological effect of infection of the cell by a virus. Antiviral agents are well known and described in the literature. By way of example, AZT (zidovudine, Retrovir® Glaxo Wellcome Inc., Research Triangle Park, NC) is an antiviral agent which is thought to prevent replication of HIV in human cells.
- The term “biocompatible,” as used herein, refers to a material that does not elicit a substantial detrimental response in the host.
- The term “biodegradable,” as used herein, means capable of being biologically decomposed. A biodegradable material differs from a non-biodegradable material in that a biodegradable material can be biologically decomposed into units which may be either removed from the biological system and/or chemically incorporated into the biological system.
- The term “bioresorbable,” as used herein, refers to the ability of a material to be resorbed in vivo. “Full” resorption means that no significant extracellular fragments remain. The resorption process involves elimination of the original implant materials through the action of body fluids, enzymes, or cells. Resorbed calcium carbonate may, for example, be redeposited as bone mineral, or by being otherwise re-utilized within the body, or excreted. “Strongly bioresorbable,” as the term is used herein, means that at least 80% of the total mass of material implanted is resorbed within one year.
- As used herein “burn” or “burns” refer to any detectable injury to tissue caused by energy applied to the tissue. The terms “burn” or “burns” further refer to any burning, or charring of the tissue, including thermal burns caused by contact with flames, hot liquids, hot surfaces, and other sources of high heat as well as steam, chemical burns, radiation, and electrical burns. First degree burns show redness; second degree burns show vesication; third degree burns show necrosis through the entire skin. Burns of the first and second degree are partial-thickness burns, those of the third degree are full-thickness burns.
- The term “clearance,” as used herein refers to the physiological process of removing a compound or molecule, such as by diffusion, exfoliation, removal via the bloodstream, and excretion in urine, or via sweat or other fluid.
- A “compound,” as used herein, refers to any type of substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above.
- A “control” subject is a subject having the same characteristics as a test subject, such as a similar type of dependence, etc. The control subject may, for example, be examined at precisely or nearly the same time the test subject is being treated or examined. The control subject may also, for example, be examined at a time distant from the time at which the test subject is examined, and the results of the examination of the control subject may be recorded so that the recorded results may be compared with results obtained by examination of a test subject.
- A “test” subject is a subject being treated.
- “Cytokine,” as used herein, refers to intercellular signaling molecules, the best known of which are involved in the regulation of mammalian somatic cells. A number of families of cytokines, both growth promoting and growth inhibitory in their effects, have been characterized including, for example, interleukins, interferons, and transforming growth factors. A number of other cytokines are known to those of skill in the art. The sources, characteristics, targets and effector activities of these cytokines have been described.
- The term “decreased blood flow”, as used herein, refers to a decrease in blood flow at a site of injury, disease, or disorder, and includes, but is not limited, a decrease in flow rate, an increase in stasis, and an increase in sludging in the vessels.
- The term “delivery vehicle” refers to any kind of device or material which can be used to deliver cells in vivo or can be added to a composition comprising cells administered to an animal. This includes, but is not limited to, implantable devices, matrix materials, gels, etc.
- As used herein, a “derivative” of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.
- The use of the word “detect” and its grammatical variants is meant to refer to measurement of the species without quantification, whereas use of the word “determine” or “measure” with their grammatical variants are meant to refer to measurement of the species with quantification. The terms “detect” and “identify” are used interchangeably herein.
- As used herein, a “detectable marker” or a “reporter molecule” is an atom or a molecule that permits the specific detection of a compound comprising the marker in the presence of similar compounds without a marker. Detectable markers or reporter molecules include, but are not limited to, radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, fluorophores, chemiluminescent molecules, electrochemically detectable molecules, and molecules that provide for altered fluorescence polarization or altered light scattering.
- A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate. As used herein, normal aging is included as a disease.
- A “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
- As used herein, an “effective amount” means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder. In the context of administering compounds in the form of a combination, such as multiple compounds, the amount of each compound, when administered in combination with another compound(s), may be different from when that compound is administered alone. Thus, an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary. The term “more effective” means that the selected effect is alleviated to a greater extent by one treatment relative to the second treatment to which it is being compared.
- The term “enhancing bone repair” as used herein refers to methods of speeding up or inducing better bone repair using compounds of the invention, relative to the speed or amount of bone repair that occurs without administration of compounds of the invention.
- As used herein, a “functional” molecule is a molecule in a form in which it exhibits a property or activity by which it is characterized. A functional enzyme, for example, is one that exhibits the characteristic catalytic activity by which the enzyme is characterized.
- “Graft” refers to any free (unattached) cell, tissue, or organ for transplantation.
- “Allograft” refers to a transplanted cell, tissue, or organ derived from a different animal of the same species.
- “Xenograft” refers to a transplanted cell, tissue, or organ derived from an animal of a different species.
- The term “growth factor” as used herein means a bioactive molecule that promotes the proliferation of a cell or tissue. Growth factors useful in the present invention include, but are not limited to, transforming growth factor-alpha (TGF-α), transforming growth factor-beta (TGF-β), platelet-derived growth factors including the AA, AB and BB isoforms (PDGF), fibroblast growth factors (FGF), including FGF
acidic isoforms basic form 2, andFGF 4, 8, 9 and 10, nerve growth factors (NGF) including NGF 2.5s, NGF 7.0s and beta NGF and neurotrophins, brain derived neurotrophic factor, cartilage derived factor, bone growth factors (BGF), basic fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), EG-VEGF, VEGF-related protein, Bv8, VEGF-E, granulocyte colony stimulating factor (G-CSF), insulin like growth factor (IGF) I and II, hepatocyte growth factor, glial neurotrophic growth factor, stem cell factor (SCF), keratinocyte growth factor (KGF), skeletal growth factor, bone matrix derived growth factors, and bone derived growth factors and mixtures thereof. Some growth factors may also promote differentiation of a cell or tissue. TGF, for example, may promote growth and/or differentiation of a cell or tissue. - The term “improved blood flow,” as used herein, refers to increased blood flow in a subject being treated according to the methods of the invention compared with the flow in a subject with an otherwise identical injury or condition not being treated according to the methods of the invention. Improved flow is determined by methods such as those described herein and can include less stasis, less sludging, or a combination of both, in the subject being treated compared with the untreated subject.
- The term “inhibit,” as used herein, refers to the ability of a compound, agent, or method to reduce or impede a described function, level, activity, rate, etc., based on the context in which the term “inhibit” is used. Preferably, inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%. The term “inhibit” is used interchangeably with “reduce” and “block.”
- As used herein “injecting or applying” includes administration of a compound of the invention by any number of routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
- As used herein, “injury” generally refers to damage, harm, or hurt; usually applied to damage inflicted on the body by an external force.
- As used herein, an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of a compound of the invention in the kit for effecting alleviation of the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of alleviating the diseases or disorders in a subject. The instructional material of the kit of the invention may, for example, be affixed to a container which contains the identified compound invention or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
- The term “in situ gelation” refers herein to the thermogelling of chitosan/phosphate gels once the chitosan/phosphate solution is administered within specific sites of a subject. Such sites include, but are not limited to, any tissues, body cavities, muscles, fractures or bone defects, ligaments, cartilages or organs. The thermogelling of the chitosan/phosphate solution is induced by the physiological temperature.
- The term ‘material”, as used herein, refers to synthetic and natural materials such as matrix components. The term “materials and compounds” as used herein, refers to, inter alia, materials, compounds, cells, peptides, nucleic acids, drugs, matrix components, and imaging agents.
- The term “metal surface”, as used herein, refers to any metal surface, including films, which can be used to deposit or apply polymers or metallic nanoparticles encompassed by the present invention.
- A “mold” is a frame or model that shapes the gel system. Gels can be produced in, but are not limited to, glass or plastic-beakers, dishes, tubes or between two plates so as to obtain any expected shape.
- The term “nanoparticle” or “particle” refers to a particle of any shape having the size of up to about 100 nanometers.
- “Osteogenesis” as used herein refers to bone growth, bone remodeling, and repair of bone due to injury or disease.
- The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
- As used herein, the term “pharmaceutically-acceptable carrier” means a chemical composition with which an appropriate compound or derivative can be combined and which, following the combination, can be used to administer the appropriate compound to a subject.
- As used herein, the term “physiologically acceptable” ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
- The term “prevent,” as used herein, means to stop something from happening, or taking advance measures against something possible or probable from happening. In the context of medicine, “prevention” generally refers to action taken to decrease the chance of getting a disease or condition.
- A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or injury or exhibits only early signs of the disease or injury for the purpose of decreasing the risk of developing pathology associated with the disease or injury.
- As used herein, the term “purified” and like terms relate to an enrichment of a molecule or compound relative to other components normally associated with the molecule or compound in a native environment. The term “purified” does not necessarily indicate that complete purity of the particular molecule has been achieved during the process. A “highly purified” compound as used herein refers to a compound that is greater than 90% pure.
- The term “regulate” refers to either stimulating or inhibiting a function or activity of interest.
- A “reversibly implantable” device is one which may be inserted (e.g. surgically or by insertion into a natural orifice of the animal) into the body of an animal and thereafter removed without great harm to the health of the animal.
- A “sample,” as used herein, refers to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine. A sample can also be any other source of material obtained from a subject which contains cells, tissues, or fluid of interest.
- As used herein, “scaffold” refers to a supporting framework, such as one for bone or tissue growth, either in vivo or in vitro.
- The term “skin,” as used herein, refers to the commonly used definition of skin, e.g., the epidermis and dermis, and the cells, glands, mucosa, and connective tissue which comprise the skin.
- The terms “solid support”, “surface” and “substrate” are used interchangeably and refer to a structural unit of any size, where said structural unit or substrate has a surface suitable for immobilization of molecular structure or modification of said structure and said substrate is made of a material such as, but not limited to, metal, metal films, glass, fused silica, synthetic polymers, and membranes.
- The term “standard,” as used herein, refers to something used for comparison. For example, it can be a known standard agent or compound which is administered and used for comparing results when administering a test compound, or it can be a standard parameter or function which is measured to obtain a control value when measuring an effect of an agent or compound on a parameter or function. “Standard” can also refer to an “internal standard”, such as an agent or compound which is added at known amounts to a sample and which is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured. Internal standards are often but are not limited to, a purified marker of interest which has been labeled, such as with a radioactive isotope, allowing it to be distinguished from an endogenous substance in a sample.
- A “subject” of diagnosis or treatment is a mammal, including a human.
- As used herein, a “subject in need thereof” is a patient, animal, mammal, or human, who will benefit from the method of this invention.
- A “surface active agent” or “surfactant” is a substance that has the ability to reduce the surface tension of materials and enable penetration into and through materials.
- Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary.
- The term “symptom,” as used herein, refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease. In contrast, a sign is objective evidence of disease. For example, a bloody nose is a sign. It is evident to the patient, doctor, nurse and other observers.
- A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
- A “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
- The term “thermal injury” is used interchangeably with “thermal burn” herein.
- A “thermal-sensitive” gel system undergoes a phase transition when induced by temperature.
- As used herein, “thermo-gelling” refers to the formation of a colloidal gel from solution as temperature increases.
- The term “three-dimensional” refers to the fact that the chitosan solution is simultaneously gelled and shaped by the mold wherein the solution was initially poured.
- “Tissue” means (1) a group of similar cells united to perform a specific function; (2) a part of an organism consisting of an aggregate of cells having a similar structure and function; or (3) a grouping of cells that are similarly characterized by their structure and function, such as muscle or nerve tissue.
- The term “tissue injury-associated decreased blood flow”, as used herein, refers to the decrease in blood flow which occurs following an injury, such as a thermal injury, to a tissue. The decrease in blood flow includes, but is not limited to, decreased volume, rate, stasis, or sludging. One of ordinary skill in the art will appreciate that there are multiple parameters which can be used as measures or signs of decreased blood flow, as well as multiple techniques to determine decreased blood flow.
- The term “topical application,” as used herein, refers to administration to a surface, such as the skin. This term is used interchangeably with “cutaneous application” in the case of skin. A “topical application” is a “direct application”.
- By “transdermal” delivery is meant delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream. Transdermal also refers to the skin as a portal for the administration of drugs or compounds by topical application of the drug or compound thereto. “Transdermal” is used interchangeably with “percutaneous.”
- As used herein, the term “treating” may include prophylaxis of the specific injury, disease, disorder, or condition, or alleviation of the symptoms associated with a specific injury, disease, disorder, or condition and/or preventing or eliminating said symptoms. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease. “Treating” is used interchangeably with “treatment” herein.
- As used herein “wound” or “wounds” may refer to any detectable break in the tissues of the body, such as injury to skin or to an injury or damage, or to a damaged site associated with a disease or disorder. Although the terms “wound” and “injury” are not always defined exactly the same way, the use of one term herein, such as “injury”, is not meant to exclude the meaning of the other term.
- As used herein, the term “halogen” or “halo” includes bromo, chloro, fluoro, and iodo.
- The term “haloalkyl” as used herein refers to an alkyl radical bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
- The term “C1-Cn alkyl” wherein n is an integer, as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms. Typically, C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.
- The term “C2-Cn alkenyl” wherein n is an integer, as used herein, represents an olefinically unsaturated branched or linear group having from two to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
- The term “C2-Cn alkynyl” wherein n is an integer refers to an unsaturated branched or linear group having from two to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.
- The term “C3-Cn cycloalkyl” wherein n=8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- As used herein the term “aryl” refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. “Optionally substituted aryl” includes aryl compounds having from zero to four substituents, and “substituted aryl” includes aryl compounds having one or more substituents. The term (C5-C8 alkyl)aryl refers to any aryl group which is attached to the parent moiety via the alkyl group.
- The term “bicyclic” represents either an unsaturated or saturated stable 7- to 12-membered bridged or fused bicyclic carbon ring. The bicyclic ring may be attached at any carbon atom which affords a stable structure. The term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
- The term “heterocyclic group” refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing from one to three heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen.
- As used herein the term “heteroaryl” refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings containing from one to three heteroatoms and includes, but is not limited to, furyl, thienyl, pyridyl and the like.
- A “meroxapol” is polyoxypropylene-polyoxyethylene block copolymer with the general formula HO(C3H6O)a(C2H4O)b(C3H6O)aH. It is available in different grades. Each meroxapol name is followed by a code number according to the average numerical values of the respective monomers units denoted by “a” and “b”.
- As used herein, the term “optionally substituted” refers to from zero to four substituents, wherein the substituents are each independently selected. Each of the independently selected substituents may be the same or different than other substituents.
- A “poloxamer” is a nonionic polyoxyethylene-polyoxypropylene block co-polymer with the general formula HO(C2H4O)a(C3H6O)b(C2H4O)aH. It is available in different grades, which vary from liquids to solids. Each poloxamer name is followed by a code number according to the average numerical values of the respective monomers units denoted by “a” and “b”.
- A “poloxamine” is a polyoxyethylen-polyoxypropylene block copolymer of ethylene diamine with the general formula [HO(C2H4O)a(C3H6O)bC3H6]2NCH2CH2N—[C3H6(OC3H6)b(OC2H4)aOH]2. It is available in different grades. Each poloxamine name is followed by a code number according to the average numerical values of the respective monomers units denoted by “a” and “b”.
- The compounds of the present invention contain one or more asymmetric centers in the molecule. In accordance with the present invention a structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers, as well as racemic mixtures thereof.
- The compounds of the present invention may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. For example the following structure:
- is understood to represent a mixture of the structures:
- The terminology used herein is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention. All publications mentioned herein are incorporated by reference in their entirety.
- The present disclosure demonstrates the development of mild and cost effective methods to immobilize metallic nanoparticles on polymeric or metallic substrates.
- Metal Substrates
- A metal substrate may be a metal or a metal film. In one aspect, the metal or metal film is titanium. In another aspect, the metal is one described below.
- Metallic Nanoparticles
- The present invention includes nanoparticles comprising metals and composites including, but not limited to, various metals including gold (Au), silver (Ag), platinum (Pt), aluminum (Al), nickel (Ni), iron (Fe), palladium (Pd), titanium (Ti), scandium (Sc), vanadium (V), chromium (Cr), magnesium (Mg), manganese (Mn), cobalt (Co), copper (Cu), zinc (Zn), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), cadmium (Cd), lutetium (Lu), hafnium (Hf), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), tantalum (Ta), rhodium (Rh), rare-earth metals ytterbium (Yb), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutecium (Lu), and alloys thereof. Preferred metal oxides particles include particles of MgO, SrO, BaO, CaO, TiO2, ZrO2, FeO, V2O3, V2O5, Mn2O3, Fe2O3, NiO, CuO, Al2O3, SiO2, ZnO, Ag2O, TiSiO.4, ZrSiO.4, rare-earth metal oxides, the corresponding hydroxides of the foregoing, particles and quantum dots of semiconducting materials (Si, CdSe, CdSe/CdS, CdSe/ZnSe, PbS, PbSe, ZnS, GaSb, GaAs, InAs), ceramic nano-particles, and mixtures thereof. Suspensions of nanoparticles and nanoscale powders of various compositions can be produced using different methods known in the art and are encompassed by the present invention (see Golovlev et al., U.S. Pat. Pub. 2008/0050842). Some illustrative but not exhaustive lists of manufacturing methods include precipitation, hydrothermal processing, combustion, arcing, template synthesis, milling, sputtering and thermal plasma taught by Yadav and Pfaffenbach in US. Pat. App. Nos. 20050274447 and 20050063889, and by Reed et al., in U.S. Pat. No. 6,976,647, each of these patents and publications is herein incorporated by reference in its entirety and specifically for description of various methods of manufacturing nano-particles and methods and instruments for milling and reconstituting powders of nano-particles from solid composites.
- One aspect of the present invention relates to osteogenic devices, and more specifically to synthetic implants which induce osteogenesis in vivo in mammals, including humans. The invention therefore encompasses metal films and substrates as described herein, as well as such films and substrates further comprising cells. Non-synthetic matrix proteins like collagen, glycosaminoglycans, and hyaluronic acid, which are enzymatically digested in the body, are useful for delivery to bone areas (see U.S. Pat. Nos. 4,394,320; 4,472,840; 5,366,509; 5,606,019; 5,645,591; and 5,683,459) and are suitable for use with the present invention.
- Other implantable media and devices can be used to assist, or as supplements to, the use of metal films and substrates for delivery of the cells of the invention in vivo. These include, but are not limited to, sponges, such as those from Integra, fibrin gels, scaffolds formed from sintered microspheres of polylactic acid glycolic acid copolymers (PLAGA), and nanofibers formed from native collagen, as well as other proteins. The cells of the present invention can be further combined with demineralized bone material, growth factors, nutrient factors, pharmaceuticals, calcium-containing compounds, anti-inflammatory agents, antimicrobial agents, or any other substance capable of expediting or facilitating bone growth.
- Examples of osteoinductive factors suitable for use with the compositions of the present invention include demineralized bone particles, a Bone Morphogenetic Protein, an osteoinductive extract of demineralized bone matrix, or a combination thereof.
- In one aspect, the metal substrates and films of the present invention are useful for growing cells. In one aspect, they support the proliferation and differentiation of cells selected from the group consisting of stem cells, pluripotent stem cells, committed stem cells, embryonic stem cells, adult stem cells, bone marrow stem cells, bone marrow-derived stem cells, adipose stem cells, umbilical cord stem cells, dura mater stem cells, precursor cells, differentiated cells, osteoblasts, myoblasts, neuroblasts, fibroblasts, glioblasts, germ cells, hepatocytes, chondrocytes, keratinocytes, smooth muscle cells, cardiac muscle cells, connective tissue cells, glial cells, epithelial cells, endothelial cells, hormone-secreting cells, cells of the immune system, normal cells, cancer cells, Schwann cells, and neurons.
- Maintaining cells in culture refers to feeding with the appropriate growth medium when necessary, passaging the cells when necessary, etc.
- Other materials may also be added to the metal films and substrates, in addition to metal nanoparticles such as silver nanoparticles. These may be attached to the substrate, or in the case of administration to a subject, they can be added at the same time or before or after the metal film or substrate is administered. Compounds and substances that can provide favorable matrix or mesh characteristics also include drugs and other substances that can produce a therapeutic or other physiological effect on cells and tissues within or surrounding an implant. Any substance may be used. Several preferred embodiments include use of any therapeutic molecule including, without limitation, any pharmaceutical or drug. Examples of pharmaceuticals include, but are not limited to, anesthetics, hypnotics, sedatives and sleep inducers, antipsychotics, antidepressants, antiallergics, antianginals, antiarthritics, antiasthmatics, antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs, antihistamines, antipruritics, emetics, antiemetics, antispasmodics, appetite suppressants, neuroactive substances, neurotransmitter agonists, antagonists, receptor blockers and reuptake modulators, beta-adrenergic blockers, calcium channel blockers, disulfuram and disulfuram-like drugs, muscle relaxants, analgesics, antipyretics, stimulants, anticholinesterase agents, parasympathomimetic agents, hormones, anticoagulants, antithrombotics, thrombolytics, immunoglobulins, immunosuppressants, hormone agonists/antagonists, vitamins, antimicrobial agents, antineoplastics, antacids, digestants, laxatives, cathartics, antiseptics, diuretics, disinfectants, fungicides, ectoparasiticides, antiparasitics, heavy metals, heavy metal antagonists, chelating agents, gases and vapors, alkaloids, salts, ions, autacoids, digitalis, cardiac glycosides, antiarrhythmics, antihypertensives, vasodilators, vasoconstrictors, antimuscarinics, ganglionic stimulating agents, ganglionic blocking agents, neuromuscular blocking agents, adrenergic nerve inhibitors, antioxidants, vitamins, cosmetics, anti-inflammatories, wound care products, antithrombogenic agents, antitumoral agents, antiangiogenic agents, anesthetics, antigenic agents, wound healing agents, plant extracts, growth factors, emollients, humectants, rejection/anti-rejection drugs, spermicides, conditioners, antibacterial agents, antifungal agents, antiviral agents, antibiotics, tranquilizers, cholesterol-reducing drugs, antitussives, histamine-blocking drugs, monoamine oxidase inhibitor. All substances listed by the U.S. Pharmacopeia are also included within the substances of the present invention.
- Other preferred embodiments involve the use of growth factors, including more than one growth factor, as described herein.
- Other molecules useful as compounds or substances in the present invention include, but are not limited to, growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, angiostatin, thrombospondin, osteogenic protein-1,
bone morphogenetic proteins 2 and 7, osteonectin, somatomedin-like peptide, osteocalcin, interferon alpha, interferon alpha A, interferon beta, interferon gamma,interferon 1 alpha, andinterleukins - Embodiments involving amino acids, peptides, polypeptides, and proteins may include any type of such molecules of any size and complexity as well as combinations of such molecules. Examples include, but are not limited to, structural proteins, enzymes, and peptide hormones. These compounds can serve a variety of functions. In some embodiments, the matrix may contain peptides containing a sequence that suppresses enzyme activity through competition for the active site. In other applications, antigenic agents that promote an immune response and invoke immunity can be incorporated into a construct.
- For substances such as nucleic acids, any nucleic acid can be present. Examples include, but are not limited to deoxyribonucleic acid (DNA), ent-DNA, oligonucleotides, aptamers, and ribonucleic acid (RNA). Embodiments involving DNA include, but are not limited to, cDNA sequences, natural DNA sequences from any source, and sense or anti-sense oligonucleotides. For example, DNA can be naked (e.g., U.S. Pat. Nos. 5,580,859; 5,910,488) or complexed or encapsulated (e.g., U.S. Pat. Nos. 5,908,777; 5,787,567). DNA can be present in vectors of any kind, for example in a viral or plasmid vector. In some embodiments, nucleic acids used will serve to promote or to inhibit the expression of genes in cells inside and/or outside the electroprocessed matrix. The nucleic acids can be in any form that is effective to enhance uptake into cells.
- Substrates with Nanoparticles
- When immobilization of the polymers or the metal particles on the surface has been completed, an additional step of blocking the surface of the solid support can be performed. Blocking prevents non-specific binding of target molecules to the solid support. The blocking also can be used to allocate specific chemical groups on the surface for maintaining desirable positive or negative net surface charge on the substrate surface. Different reagents can be used to block or cap an activated solid support, whereby blocking agents couple and block residual active sites and essentially eliminate said sites from non-specific binding of target biopolymers. Common blocking or capping agents can include glycine, ethanolamine, tris(hydroxymethyl)aminomethane, mercaptoethanol, mercaptoethylamine, cysteine, acetic anhydryde, succinic anhydride, albumine, sodium borohydride, ammonium chloride, sodium acrylate, etc. Maintaining desirable electric charge on the surface can be achieved by using poly-L-lysine, anionic and cationic polymers, for instance, PDDA, amino- and mercapto-silane derivatives, etc. One of ordinary skill in the art will understand if there is a need to adjust concentration and time to optimize blocking treatment to a specific type of chemistry used to activate the solid support.
- Polymers, Including Surface Active Copolymers
- The present invention also relates to the use of surface active copolymers, including, but not limited to poloxamers. The formulations of the invention may comprise additional therapeutic agents, for example, antimicrobial agents to prevent infection, growth factors or hormones to enhance healing, drugs to treat inflammation, or anesthetics to decrease pain. The present invention encompasses compositions and methods for preparing surface active copolymer compositions comprising metallic nanoparticles.
- According to one embodiment, a poloxamer such as poloxamer-188 (Pluronic F68) is the base compound of the composition of the invention. A poloxamer has the special ability to thicken at higher temperatures (such as body temperature) and liquefy at cooler temperatures (cool rinse water for example). The thickness, or viscosity, varies depending on the amount or concentration of surface active copolymer used. These properties enable it to remain resident at tissue surfaces at body temperature but also enable it to be easily removed away with cool water. Preferred surface active copolymers are those which are biocompatible. In addition, dilutions of surface active copolymers such as Poloxamer-188 (Pluronic F68) are very biocompatible.
- Disclosed herein are formulations of poloxamers or other surface active agents for topical delivery to injured and diseased tissues and their ability to inhibit the decreased blood flow associated with the injuries, diseases, and disorders described herein. The compounds of the invention can inhibit decreased blood flow by influencing blood flow characteristics such as flow rate, stasis, and sludging.
- The invention includes a therapeutic composition comprising at least one surface active copolymer at about 1%-65% w/w. The therapeutic compositions of the invention may be formulated, for example, as liquids or as stable gels.
- The therapeutic compositions of the invention have use in treatment of exposed soft tissue or various injuries, for example, thermal injuries, venous stasis ulcers, diabetic wounds, skin grafts, tissue flaps, microvascular surgery, pressure ulcers.
- The route of administration can vary depending on the formulation of the pharmaceutical composition being administered as well as on the site of injury, disease, or disorder being treated. The present invention encompasses any useful means of topical administration of the pharmaceutical compositions of the invention to treat the injuries, diseases, and disorders encompassed by the methods of the invention. In one aspect, the compounds are administered via routes, including, but not limited to, direct, topical, cutaneous, mucosal, nasal, inhalation, oral, and ophthalmic. The means for the administration includes, but is not limited to, a dressing material, extruder, aerosol, spray delivery, iontophoresis, a patch, and a transdermal patch.
- The present invention further provides for administration of a compound or additional therapeutic agent of the invention as a controlled-release formulation.
- The dosage of the active compound(s) being administered will depend on the condition being treated, the particular compound, and other clinical factors such as age, sex, weight, and health of the subject being treated, the route of administration of the compound(s), and the type of composition being administered (gel, liquid, solution, suspension, aerosol, ointment, lotion, cream, paste, liniment, etc.). It is to be understood that the present invention has application for both human and veterinary use.
- The invention further encompasses administration of the pharmaceutical compositions of the invention at different times before and after an injury or surgical procedure, as well as varying the optional additional therapeutic agents and the surface active copolymers.
- Examples of poloxamers include poloxamer-101, -105, -105 benzoate, -108, -122, -123, -124, -181, -182, -182 dibenzoate, -183, -184, -185, -188, -212, -215, -217, -231, -234, -235, -237, -238, -282, -284, -288, -331, -333, -334, -335, -338, -401, -402, -403, and -407. In one aspect, the poloxamer is poloxamer-188. In another aspect, the poloxamer is poloxamer-407.
- In one embodiment, the pharmaceutical composition of the invention comprises PluroGel™ (PluroGen, Annapolis, Md.).
- In one embodiment, at least one of the surface active copolymers is a meroxapol. Exemplary meroxapols include, but are not limited to, meroxapol 105, 108, 171, 172, 174, 178, 251, 252, 254, 258, 311, 312, and 314.
- In one embodiment, at least one of the surface active copolymers is a poloxamine. Exemplary poloxamines include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508.
- In one embodiment, the therapeutic composition is formulated as a liquid or stable gel. The copolymer size may range, for example, from an Mn of about 600 to about 20,000. In another aspect, the copolymer size may range, for example, from an Mn of about 1,000 to about 10,000.
- In another embodiment, the present invention encompasses a composition comprising a poloxamer at about 0.1% to about 85% w/w, or about 1% to about 65%, or about 1% to about 50%, or about 5% to about 40%, or about 10% to about 40%. Other surface active copolymers can be used at these concentrations as well.
- The surface active copolymers may be prepared at different temperatures depending on the type of formulation being prepared, the route of administration, the site of administration, etc. In one aspect, the surface active copolymer is prepared at a temperature ranging from about 0° F. to about 70° F. In another aspect, the surface active copolymer is prepared at a temperature ranging from about 5° F. to about 50° F. In yet another aspect, the surface active copolymer is prepared at a temperature ranging from about 10° F. to about 40° F.
- The composition may further comprise an effective amount of at least one additional therapeutic agents which may be useful for the type of injury, disease, or disorder being treated. Additional therapeutic agents include, but are not limited to, anesthetic, analgesic, antimicrobial, steroid, growth factor, cytokine, and anti-inflammatory agents. Useful anesthetic agents include benzocaine, lidocaine, bupivocaine, dibucaine, mepivocaine, etidocaine, tetracaine, butanilicaine, and trimecaine.
- In another aspect, the agent is at least one analgesic. In yet another aspect, the agent is an additional therapeutic drug.
- In a further aspect, the additional therapeutic agent is an antimicrobial agent. In one aspect, the antimicrobial agent is an antibacterial agent. In another aspect, the antimicrobial agent is an antifungal agent. In yet another aspect, the antimicrobial agent is an antiviral agent. Antimicrobial agents useful in the practice of the invention include, but are not limited to, silver sulfadiazine, Nystatin, Nystatin/triamcinolone, Bacitracin, nitrofurazone, nitrofurantoin, a polymyxin (e.g., Colistin, Surfactin, Polymyxin E, and Polymyxin B), doxycycline, antimicrobial peptides (e.g., natural and synthetic origin), Neosporin (i.e., Bacitracin, Polymyxin B, and Neomycin), Polysporin (i.e., Bacitracin and Polymyxin B). Additional antimicrobials include topical antimicrobials (i.e., antiseptics), examples of which include silver salts, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, and chlorhexidine. It may be desirable for the antimicrobial to be other than Nystatin.
- In another aspect, the agent is selected from aspirin, pentoxifylline, and clopidogrel bisulfate, or other angiogenic, or a rheologic active agent.
- In one embodiment, the present invention encompasses a method of treating a site of injury on a subject comprising topically administering a poloxamer to the subject in an amount effective to improve blood flow at the site of injury. In one aspect, the blood flow is microvascular blood flow.
- Depending on such things as the type of formulation being prepared, the location to which it is to be applied, and the type of injury, disease, or disorder being treated, other agents can be added to the formulation. For example, other additives may include, a moisturizer, a humectant, a demulcent, oil, water, an emulsifier, a thickener, a thinner, an additional surface active agent, a fragrance, a preservative, an antioxidant, a hydrotropic agent, a chelating agent, a vitamin, a mineral, a permeation enhancer, a cosmetic adjuvant, a bleaching agent, a depigmentation agent, a foaming agent, a conditioner, a viscosifier, a buffering agent, and a sunscreen.
- In one aspect, the microvasculature has a diameter ranging from about 5 μm to about 100 μm. In another aspect, the vessels have a diameter from about 10 μm to about 50 μm. Vessels encompassed by the treatment of the invention include, but are not limited to, capillaries, arterioles, and venules.
- In another embodiment, the present invention provides a method of treating a site of injury on a subject comprising topically administering a poloxamer to the patient in an amount effective to reduce inflammation at the site of injury.
- Compositions and Formulations of the Base Surface Active Copolymer
- The invention encompasses the preparation and use of pharmaceutical compositions comprising as an active ingredient a compound useful for treatment of decreased blood flow associated with injuries and diseases disclosed herein. Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art. The present invention further contemplates the use of more than one active ingredient.
- In one embodiment, at least two different surface active copolymers are used. In one aspect, at least three different surface active copolymers are used. These combinations may include, for example, one or more poloxamers, one or more meroxapols, and one or more poloxamines.
- Compositions of this type are described in U.S. Pat. No. 5,635,540 (Edlich et al.), the contents of which are incorporated herein by reference.
- Examples of temperature ranges for preparation include, but are not limited to, from about −20° C. to about 15° C., in another aspect from about −18° C. to about 8° C., and in another aspect, from about −15° C. to about 5° C. These ranges also encompass about 0° F. to about 60° F. One of ordinary skill in the art will understand that the temperatures of preparation can be adjusted based on various criteria, such as the surface active copolymer being used, the amount or concentration being used, the type of formulation being prepared for administration, etc.
- In one embodiment of the invention, the poloxamer base comprises 80% polyoxyethylene units and 20% polyoxypropylene units.
- One of ordinary skill in the art will appreciate that the formulations, method of preparation, and amount of surface active copolymer used may vary, depending on the type or location of the site to be treated. For example, in one embodiment, a poloxamer, such as poloxamer-188, is mixed with water at a ratio of from 1:0.8 to 1.2 w/w. This ratio can be varied. This combination may be mixed until the powder has been wetted. The mixture may then be placed in a freezer or refrigerator and cooled, preferably for at least 4 hours. While cooling, the mixture will undergo phase transition to a liquid, as demonstrated by Edlich et al. (U.S. Pat. No. 5,635,540). The mixture is then removed from the freezer and warmed to room temperature. Pharmaceutical agents such as antimicrobials and anesthetics can be added at this point, as demonstrated by Edlich et al. (U.S. Pat. No. 5,635,540).
- The poloxamer base used in preparing the topical preparation of the present invention is a polyoxyalkylene based polymer based on ethylene oxide and propylene oxide and comprises a series of closely related block polymers that may generally be classified as polyoxyethylene-polyoxypropylene condensates terminated in primary hydroxyl groups. They are formed by the condensation of propylene oxide onto a propylene glycol nucleus followed by condensation of ethylene oxide onto both ends of the polyoxypropylene base. The polyoxyethylene hydrophilic groups on the ends of the molecule are controlled in length to constitute anywhere from 10% to 90% by weight of the final molecule.
- The compositions of the present invention may comprise one or more co-additives (e.g., solvent such as water). In one aspect, the concentration of a surface active copolymer (e.g., poloxamer 188) is about 0.01 to about 99.99% w/w. In another aspect, it is about 1 to about 90%. In yet another aspect, it is about 10 to about 80%. In a further aspect, it is about 20% to about 70%. In another aspect, it is about 50%. In a further aspect, it is about 5%.
- In another embodiment, a formulation of the invention can be impregnated in a dressing material (or otherwise contained or encompassed by the dressing material). The dressing material is a pharmaceutically acceptable fabric. It can be, for example, gauze or any other type of medical fabric or material that can be used to cover a wound and/or to keep a therapeutic agent or composition in contact with a patient.
- Chitosan and Carboxymethyl Chitosan
- The present invention further encompasses the use of a thermo-gelling chitosan solution that remains liquid at lower temperatures but gels at higher temperatures and requires a lower concentration of cross-linking agents, to which metals such as silver can be added. The present invention relates to a biocompatible thermo-gelling solution of chitosan and inorganic salts and methods for the preparation of and the use of such a solution. In one aspect, the invention encompasses the use of carboxymethyl chitosan.
- Chitosan is an N-deacetylated derivative of chitin which is the structural component of crustacean shells and fungal cell walls, and is obtained at a low cost from sea-food processing (Chitin: Fulfilling a Biomaterials Promise: Eugene Khor, Elsevier, Oxford, UK, 2001). The structure of chitin and chitosan are similar to cellulose where, carbon-2 of the cellulose has acetamide or amino groups, for chitin and chitosan respectively. Chitosan is an inert, hydrophilic, biocompatible, and biodegradable polymer and hence are attractive candidates for biomedical and pharmaceutical applications. Chitosan is currently investigated for various applications such as topical ocular application, as a bioadhesive polymer, penetration enhancer by opening epithelial tight junctions and as wound dressing (Berger, et al., European Journal of Pharmaceutics and Biopharmaceutics 57 (2004) 19-34).
- Various chemically modified chitosan derivatives with unique properties have been developed (Hitoshi et al., Prog. Polym. Sci. 29 (2004) 887-908). The excellent biocompatibility of chitosan, combined with its enzymatic biodegradability, makes chitosan an excellent candidate for various in vivo applications. In addition, the low cost of chitosan and its wide availability as a natural waste product, makes chitosan a very attractive polymer for wide range of applications.
- Chitosan has been extensively investigated for developing hydrogels with unique properties, due to the hydrophilicity of the base polymer, and the availability of active cross-linkable groups along the polymer chain. These chitosan hydrogels were found to be excellent candidates for a variety of applications, including, controlled release of bioactive/drug molecules, as cell encapsulation matrices, and as tissue engineering scaffolds. Chemical or covalent cross-linking of chitosan making use of mainly the active amino groups along the polymer chain and ionic cross-linking making use of the cationic nature of chitosan aqueous acid solutions, have been extensively investigated for developing hydrogels for various applications.
- The different chemical cross-linking agents reported for chitosan include dialdehydes such as glutaraldehyde, diethyl squarate, oxalic acid, and genipin. Apart from these small molecules, functionalized biopolymers such as poly(ethylene glycol diacrylate), oxidized cyclodextrin, telechelic-PVA, PEG dialdehydes and scleroglucan have also been investigated.
- In addition to covalent cross-linking, polyelectrolyte complexes of chitosan with a wide range of anionic polymers mainly chitosan alginate system have been extensively investigated for developing drug delivery systems and porous scaffolds for tissue engineering and wound dressings.
- Ionic cross-linking of chitosan has been extensively investigated, because it is a simple and mild process with no auxiliary catalyst requirements, and such a procedure has important ramifications for biomedical applications. Metallic anions such as Mo(VI) and Pt(II) have been extensively investigated for ionic cross-linking Various anions such as sulfates, citrates, oxalates, polyphosphates, and also calcium phosphate, have been tested for the ability to form ionically cross-linked gels with chitosan. All of these ions induce the formation of pure ionic cross-linking, where the chitosan solution instantaneously becomes a gel in the presence of these ions, due to the spontaneity of the ionic reactions.
- Recently a novel temperature and pH sensitive gelling system was developed using chitosan in the presence of β-glycerophosphate. In addition to β-glycerophosphate, corresponding sulfates and monosaccharide derivatives were found to exhibit the characteristic properties of β-glycerophosphate (Chenite et al., U.S. Pat. No. 6,344,488; Chenite et al., Biomaterials 21 (2000) 2155-2161; Ruel-Gariepy et al., European Journal of Pharmaceutics and Biopharmaceutics, 57 (2004) 53-63; Ruel-Gariepy et al., J Controlled Release. 82 (2002) 373-383; Molinaro et al., Biomaterials 23 (2002), 2717-2722).
- Injectable in situ forming hydrogels are receiving considerable attention for a variety of biomedical applications such as sustained drug delivery, cell encapsulation and as scaffolds for tissue engineering (Tae et al., Biomaterials, 26, 5259-66, 2005). An injectable system offers several advantages including conformal matching of the implant to complex tissue shapes, delivery of large volumes of implant via minimally invasive surgery, improved patient compliance and comfort, and allows for the delivery of sensitive biomolecules and living cells because it is a gentle process. In situ forming hydrogels are potential candidates specifically for developing sustained delivery vehicles for therapeutic proteins with short half lives.
- Various materials have been investigated for the development of injectable hydrogel systems based on non-degradable synthetic polymers such as poloxamers, N-isopropylacrylamide and a variety of degradable natural polymers (Hatefi and Amsden, J. Control Rel., 80:9-28, 2002). One of the most extensively investigated natural polymers for hydrogel development is chitosan. Chitosan is an N-acetylated derivative of the natural polymer Chitin. Chitin is the structural component of crustacean shells and fungal cell walls and is the second most abundant natural polymer. Due to the excellent biocompatibility and enzymatic degradability of chitosan, hydrogels based on chitosan have been found to be excellent candidates for a variety of medical and pharmaceutical applications (Berger et al., Eur. J. Pharm. BioPharm., 57:19-34, 2004).
- Different types of cross-linking agents have been investigated for developing chitosan hydrogels. These include chemical cross-linking using various aldehydes, ionic cross-linking using various anions, and polyelectrolyte complexes using anionic polymers. Recently much research has gone into developing stimuli sensitive injectable systems based on chitosan. It has been found that addition of certain polyol counterionic monohead salts such as β-glycerophosphate can lead to the development of temperature and pH sensitive gelling systems (Chenite et al, Biomaterials, 21:2155-61, 2000). Grafting poly(ethylene glycol) of appropriate molecular weight to chitosan has been shown to act as a thermogelling system (Bhattarai et al., J. Control Rel. 103:609-624).
- The thermo-gelling solution of the present invention can be prepared by mixing chitosan solution in very dilute acetic acid with appropriate amounts of inorganic salts, such as phosphate or sulfate salt powder or solution, at a low temperature, such as between about 0° C. and about 4° C., with rapid stirring. The addition of salt powder or solution rapidly increases the pH of the acidic chitosan solution to a pH between about 6.0 and about 8.0.
- Chitosan solutions are known generally to precipitate instantaneously as the pH of the solution is raised to above about 6.0. However, it has been found that in the presence of the inorganic phosphate described here the chitosan remains in solution even at about neutral pH between about 7.0 and about 7.2, so long as the solution is maintained at a temperature below about 10° C. When chitosan solutions are mixed with appropriate inorganic phosphates at low temperatures and are then heated to near-physiological temperatures, such as about 37° C., the solutions gel. The thermo-gelling solution of the present invention forms a gel within a temperature range from about 30° C. to about 50° C. This temperature range is not intended to be exclusive of other temperatures where the thermo-gelling solution of the present invention may form a gel. On the other hand, the thermo-gelling solution of the present invention may also gel at temperatures above or below the temperature range from about 30° C. to about 50° C. However, the thermo-gelling solution of the present invention certainly gels at a temperature within this range, which encompasses near-physiological temperatures.
- The time of gelling has been found to depend on several factors including the concentration of the inorganic phosphate salts, concentration of chitosan solution and concentration of aqueous acetic acid solution. The final pH of the solution also correlates with the gelling time of the present thermo-gelling system. In one aspect, the pH of the final solution should be between about 6.0 and about 8.0. For efficiently gelling chitosan solutions, the final pH of the solution has been found to be equal to or higher than 6.8.
- The time of gelling has been found to be independent of storage time and dilution of the solution. The thermo-gelling solution of the present invention has been found to be stable when stored over time at temperatures below about 5° C. Dilution of the thermo-gelling chitosan-inorganic salt solution has also been found not to significantly affect the gelling time of the solution. Because dilution does not significantly affect gelling times, thereto-gelling systems may be developed which will enable the formation of gels of different strengths and water contents for various applications. It has been found that the strength of the gels and the water content of the gels can be varied by varying the concentration of the inorganic phosphate salts added or by diluting the chitosan-inorganic phosphate mixture with distilled water, phosphate buffer, or cell culture media. In one embodiment, the present invention provides a method to develop a thermo-gelling system having different water content and gel strength depending on the planned application. Such methods and compositions for using chitosan are described in, for example, International Patent Publication WO 2007/087350 (Laurencin et al.) published Aug. 2, 2007.
- The present invention relates to the preparation of a chitosan solution having neutral pH, which can undergo thermogelation at about a physiological temperature and physiological pH. In one aspect, the solution undergoes gelation at near or above physiological temperature. In one aspect, the thermogelling or thermosetting solution can be prepared by mixing chitosan solution in very dilute acetic acid with appropriate amounts of inorganic phosphate salt powder or solution at 0-4° C. with rapid stirring. The addition of salt powder or solution rapidly increases the pH of the acid chitosan solution to near neutral pH. Chitosan solutions are known to precipitate instantaneously as the pH of the solution is raised to above ˜6.0. However, it has been found that in the presence of the inorganic phosphate described here, the chitosan remains in solution even at neutral pH (˜pH 7.0-7.2). When a chitosan solution of the invention is mixed with appropriate inorganic phosphates at low temperature and heated to near physiological temperature (37° C.) or above, the solutions gel. The time required for gelling to occur has been found herein to depend on several factors, including the concentration of the inorganic phosphate salts, concentration of chitosan solution, and the concentration of aqueous acetic acid solution. The final pH of the solution also correlates to regulation of the present thermogelling system. In one aspect, in an efficient gelling chitosan solution, the final pH of the solution should be approximately at least about 6.8.
- In one embodiment, the strength of the gels and the water content of the gels can be varied by varying the concentration of the inorganic phosphate salts added, or by diluting the chitosan-inorganic phosphate mixture with distilled/deionized water, phosphate buffer, weak acid-base, or using cell culture medium.
- In one embodiment of the invention, thereto-gelling composite systems are useful as, injectable compositions for various applications. The compositions can be developed mixing insoluble solid particulates with a chitosan-inorganic phosphate mixture, or by mixing water-soluble polymer solutions with chitosan-inorganic phosphate mixture.
- In one embodiment, the invention provides a non-toxic, biodegradable, biocompatible and rapidly curing system at physiological temperature to use in a clinical or operating room setting.
- In one embodiment, the invention provides a temperature induced rapidly curing two component solution which can solidify into a biodegradable gel for various applications.
- In one embodiment, the invention provides a temperature induced rapidly curing system which can be used to develop novel blends or composite systems.
- In one embodiment, the invention provides a temperature induced rapidly gelling polymer system as an injectable matrix for the controlled and prolonged delivery of drugs, growth factors, therapeutic proteins and peptides.
- In one embodiment, the invention provides a temperature induced rapidly gelling polymer system as an injectable plug for therapeutic embolization and chemoembolization.
- In one embodiment, the invention provides a method for preparing thermogelling chitosan solutions with variable gelation times. In one aspect, the gelation times are as short as about several minutes. In another aspect, the gelation times are from about 30 minutes to about several hours. In yet another aspect of the invention, gelation times range from about several hours to about 24 to 36 hours.
- In one embodiment, the invention provides a temperature induced rapidly gelling polymer system as an injectable scaffold for various tissue engineering applications.
- In one embodiment, the invention provides a temperature induced rapidly gelling polymer system as an injectable cell encapsulation system for various applications.
- In one embodiment, the invention provides variable gelling time from a few minutes to a few hours depending on the kind of application the material is targeted.
- In one embodiment, the invention provides a method to develop hydrogel system having different water content and gel strength depending on the kind of application the material is targeted.
- In one embodiment, the invention provides a method to develop cross-linked systems having different architecture such as foams, spheres, fibers.
- In one embodiment, the invention provides novel delivery systems. In one aspect, the present invention provides methods and composition for delivering cells, chondrocytes, stem cells, genes, matrix materials, drugs, proteins, and chemicals. Delivery of bioactive molecules such as nucleic acid molecules encoding a protein can be significantly enhanced by immobilization of the bioactive molecule in a composition of the invention adjacent to the cells where delivery is desired.
- In one embodiment, the invention provides methods for administering novel delivery systems. In one aspect, the novel delivery systems are administered to treat diseases, disorders, and conditions in subjects in need thereof. In one aspect, the invention is useful for treating a musculoskeletal-associated disease or disorder. Musculoskeletal-associated diseases or disorders are described herein or are known in the art. In one aspect, the method is useful for enhancing bone repair. In another aspect, the method is useful for treating a bone-associated disease or disorder. In one aspect, treatment of a bone-associated disease or disorder can be done in conjunction with a surgical procedure. In one embodiment, the present invention provides methods and compositions for fabricating three-dimensional structures. In one aspect, the present invention provides various fabrication techniques. One of ordinary skill in the art would appreciate that various fabrication techniques are available to practice the methods of the invention.
- In one embodiment, the present invention provides compositions and methods for tissue regeneration. In one aspect, the tissues are selected from the group consisting of bone and spine.
- In one embodiment, the compositions and methods of the invention are useful for tissue engineering.
- In one embodiment, the compositions and methods of the invention are useful for preparing composites with organic or inorganic components.
- In one embodiment, the compositions and methods of the invention are useful in cell and tissue culture systems. In one aspect, the invention provides methods for encapsulating cells.
- The skilled practitioner, practicing the invention, could find wide applications for this thermo-gelling solution. Such applications include use as scaffolds for tissue engineering applications, as tissue adhesive, as a wound dressing material, as injectable fillers or composites, and as an injectable solution for controlled and prolonged delivery of drugs, proteins, and growth factors. The invention provides advantages of a workable, flowable, injectable liquid at colder temperatures along with the advantages of a biocompatible viscous gel at higher, physiological temperatures. The teachings of the present invention also overcome limitations of the prior art by providing for simple, mild, and gentle cross-linking agents at lower concentrations than required by the prior art.
- In one aspect, the present invention features a solution of chitosan and inorganic salt maintained at a temperature below about 10° C. that forms a gel as the temperature rises to within a temperature range from about 20° C. to about 50° C. In one aspect, the temperature for gelling is from about 30° C. to about 40° C. The thermo-gelling solution has a pH between about 6.0 and about 8.0.
- In one embodiment, the thermo-gelling solution comprises a solution of chitosan and inorganic phosphate or sulfate salts. In a preferred embodiment, the thermo-gelling solution comprises a solution of chitosan and ammonium hydrogen phosphate. In one embodiment, the thermo-gelling solution comprises between about 0.05 weight % and about 10.0 weight % chitosan and between about 0.5 weight % and about 2.8 weight % ammonium hydrogen phosphate. In embodiment, the thermo-gelling solution comprises a ratio of chitosan to ammonium hydrogen phosphate between about 1 and about 3.5.
- In another embodiment, the thermo-gelling solution is a solution at a pH between about 6.5 and about 7.5. In a more preferred embodiment, the thermo-gelling solution is a solution at a pH between about 6.8 and about 7.3. In a most preferred embodiment, the thermo-gelling solution is a solution at a pH between about 7.0 and about 7.2
- In another embodiment, the thermo-gelling solution is a solution maintained at a temperature below about 5° C. In a currently preferred embodiment, the thermo-gelling solution is maintained at a temperature between about 0° C. and about 4° C.
- In a further embodiment, the thermo-gelling solution forms a gel as the temperature rises to within a temperature range from about 35° C. to about 45° C. In a more preferred embodiment, the thermo-gelling solution forms a gel within a temperature range from about 35° C. to about 40° C. In a most preferred embodiment, the thermo-gelling solution forms a gel at a temperature of about 37° C.
- The invention further encompasses chitosan of varied molecular weights. In one aspect, chitosan from about 20,000 to about 250,000 is encompassed within the methods described herein.
- In accordance with the present invention, there is also provided a pharmaceutical composition comprising a thermo-gelling solution of chitosan and inorganic salts and insoluble solid particulates or water-soluble substances. There is also provided a method for administering the pharmaceutical composition comprising injecting or applying the pharmaceutical composition.
- In accordance with the present invention, there is also provided a method of preparing a thermo-gelling solution of the present invention, which comprises the steps of (a) dissolving chitosan within an acidic aqueous solution to obtain an aqueous chitosan solution; (b) maintaining the aqueous chitosan solution at a temperature below about 10° C.; and (c) dissolving an inorganic salt in the aqueous chitosan solution to obtain a thermo-gelling solution, wherein the thermo-gelling solution is a solution at pH between about 6.0 and about 8.0 and forms a gel within a temperature range of about 30° C. to about 50° C.
- In one embodiment, an inorganic salt includes inorganic phosphate and/or sulfate salts. In a preferred embodiment, an inorganic salt is ammonium hydrogen phosphate.
- In another preferred embodiment, the aqueous chitosan solution comprises between about 0.5 weight % and about 3.5 weight % chitosan.
- In another preferred embodiment, the thermo-gelling solution is a solution having a concentration between about 0.5 weight % and about 2.8 weight % ammonium hydrogen phosphate. In still another preferred embodiment steps (a), (b), and (c) yield a thermo-gelling solution having a ratio of chitosan to ammonium hydrogen phosphate between about 1 and about 3.5.
- In a further embodiment, steps (a), (b), and (c) yield a thermo-gelling solution at pH between about 6.5 and about 7.5. In a more preferred embodiment, steps (a), (b), and (c) yield a thermo-gelling solution at pH between about 6.8 and about 7.3. In a most preferred embodiment, steps (a), (b), and (c) yield a thermo-gelling solution at pH between about 7.0 and about 7.2.
- In a further embodiment, the aqueous chitosan solution is maintained below about 5° C. In a currently preferred embodiment, the aqueous chitosan solution is maintained between about 0° C. and about 4° C.
- In a still further embodiment, the thermo-gelling solution formed by steps (a), (b), and (c) forms a gel as the temperature rises to within a temperature range from about 35° C. to about 45° C. In a more preferred embodiment, the thermo-gelling solution forms a gel within a temperature range from about 35° C. to about 40° C. In a most preferred embodiment, the thermo-gelling solution forms a gel at a temperature of about 37° C.
- In accordance with the present invention there are also provided methods of using the thermo-gelling solution of the present invention. The invention provides a method of delivering the thermo-gelling solution as an injectable scaffold for tissue engineering comprising injecting an effective amount of the thermo-gelling solution.
- The invention further provides a method for delivering one or more substances from the group consisting of cells, fibroblasts, chondrocytes, osteogenic cells, stem cells, genes, drugs, proteins, chemicals, bioactive molecules, growth factors, and therapeutic proteins and peptides comprising administering the thermo-gelling solution as an injectable matrix for the delivery of these substances.
- The invention still further provides a method for providing the thermo-gelling solution as an injectable plug for therapeutic embolization and chemoembolization comprising injecting the thermo-gelling solution as an injectable plug for therapeutic embolization and chemoembolization.
- Therapeutics
- The embodiments of the invention can be useful for therapeutic purposes based on the properties of the metal nanoparticles, the silver comprising surfaces, substrates, and compositions themselves, or when additional therapeutic agents are used. For example, several preferred embodiments include use of any therapeutic molecule including, without limitation, any pharmaceutical or drug. These can be added separately to the substrate or composition or in conjunction with the metal being added to the substrate or composition. One of ordinary skill in the art will appreciate that additional therapeutic agents can also be administered to a subject in need thereof separately from the metal nanoparticle comprising surfaces and compositions of the invention.
- Additional Therapeutic Agents and Ingredients
- The composition of the invention can further comprise additional therapeutic additives, alone or in combination (e.g., 2, 3, or 4 additional additives). Examples of additional additives include but are not limited to: (a) antimicrobials, (b) steroids (e.g., hydrocortisone, triamcinolone); (c) pain medications (e.g., aspirin, an NSAID, and a local anesthetic); (d) anti-inflammatory agents; (e) growth factors; (f) cytokines; (g) hormones; and (h) combinations thereof.
- In one embodiment, a formulation of the invention contains an antimicrobial agent. The antimicrobial agent may be provided at, for example, a standard therapeutically effective amount. A standard therapeutically effective amount is an amount that is typically used by one of ordinary skill in the art or an amount approved by a regulatory agency (e.g., the FDA or its European counterpart). Antimicrobial agents useful for the invention include those directed against the spectrums of gram positive organisms, gram negative organisms, fungi, and viruses.
- According to the topical anesthetic embodiment of the present invention, in one aspect, suitable local anesthetic agents having a melting point of 30° to 70° C. are prilocaine, tetracaine, butanilcaine, trimecaine, benzocaine, lidocaine, bupivocaine, dibucaine, mepivocaine, and etidocaine.
- Examples of pharmaceuticals include, but are not limited to, anesthetics, hypnotics, sedatives and sleep inducers, antipsychotics, antidepressants, antiallergics, antianginals, antiarthritics, antiasthmatics, antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs, antihistamines, antipruritics, emetics, antiemetics, antispasmodics, appetite suppressants, neuroactive substances, neurotransmitter agonists, antagonists, receptor blockers and reuptake modulators, beta-adrenergic blockers, calcium channel blockers, disulfuram and disulfuram-like drugs, muscle relaxants, analgesics, antipyretics, stimulants, anticholinesterase agents, parasympathomimetic agents, hormones, anticoagulants, antithrombotics, thrombolytics, immunoglobulins, immunosuppressants, hormone agonists/antagonists, vitamins, antimicrobial agents, antineoplastics, antacids, digestants, laxatives, cathartics, antiseptics, diuretics, disinfectants, fungicides, ectoparasiticides, antiparasitics, heavy metals, heavy metal antagonists, chelating agents, gases and vapors, alkaloids, salts, ions, autacoids, digitalis, cardiac glycosides, antiarrhythmics, antihypertensives, vasodilators, vasoconstrictors, antimuscarinics, ganglionic stimulating agents, ganglionic blocking agents, neuromuscular blocking agents, adrenergic nerve inhibitors, anti-oxidants, vitamins, cosmetics, anti-inflammatories, wound care products, antithrombogenic agents, antitumoral agents, antiangiogenic agents, anesthetics, antigenic agents, wound healing agents, plant extracts, growth factors, emollients, humectants, rejection/anti-rejection drugs, spermicides, conditioners, antibacterial agents, antifungal agents, antiviral agents, antibiotics, tranquilizers, cholesterol-reducing drugs, antitussives, histamine-blocking drugs, monoamine oxidase inhibitor. All substances listed by the U.S. Pharmacopeia are also included within the substances of the present invention.
- A list of the types of drugs, and specific drugs within categories which are encompassed within the invention is provided below and are intended be non-limiting examples.
- Antimicrobial agents include: silver sulfadiazine, Nystatin, Nystatin/triamcinolone, Bacitracin, nitrofurazone, nitrofurantoin, a polymyxin (e.g., Colistin, Surfactin, Polymyxin E, and Polymyxin B), doxycycline, antimicrobial peptides (e.g., natural and synthetic origin), Neosporin (i.e., Bacitracin, Polymyxin B, and Neomycin), Polysporin (i.e., Bacitracin and Polymyxin B). Additional antimicrobials include topical antimicrobials (i.e., antiseptics), examples of which include silver salts, iodine, benzalkonium chloride, alcohol, hydrogen peroxide, and chlorhexidine.
- Analgesic: Acetaminophen; Alfentanil Hydrochloride; Aminobenzoate Potassium; Aminobenzoate Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; Antipyrine; Aspirin; Benoxaprofen; Benzydamine Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride; Butacetin; Butixirate; Butorphanol; Butorphanol Tartrate; Carbamazepine; Carbaspirin Calcium; Carbiphene Hydrochloride; Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol Hydrochloride; Clonixeril; Clonixin; Codeine; Codeine Phosphate; Codeine Sulfate; Conorphone Hydrochloride; Cyclazocine; Dexoxadrol Hydrochloride; Dexpemedolac; Dezocine; Diflunisal; Dihydrocodeine Bitartrate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floctafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupirtine Maleate; Fluproquazone; Fluradoline Hydrochloride; Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac; Indoprofen; Ketazocine; Ketorfanol; Ketorolac Tromethamine; Letimide Hydrochloride; Levomethadyl Acetate; Levomethadyl Acetate Hydrochloride; Levonantradol Hydrochloride; Levorphanol Tartrate; Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lomoxicam; Magnesium Salicylate; Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Methadone Hydrochloride; Methadyl Acetate; Methopholine; Methotrimeprazine; Metkephamid Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochloride; Molinazone; Morphine Sulfate; Moxazocine; Nabitan Hydrochloride; Nalbuphine Hydrochloride; Nalmexone Hydrochloride; Namoxyrate; Nantradol Hydrochloride; Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydrochloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Ocfentanil Hydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride; Oxycodone Terephthalate; Oxymorphone Hydrochloride; Pemedolac; Pentamorphone; Pentazocine; Pentazocine Hydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride; Phenyramidol Hydrochloride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline Maleate; Prodilidine Hydrochloride; Profadol Hydrochloride; Propirarn Fumarate; Propoxyphene Hydrochloride; Propoxyphene Napsylate; Proxazole; Proxazole Citrate; Proxorphan Tartrate; Pyrroliphene Hydrochloride; Remifentanil Hydrochloride; Salcolex; Salethamide Maleate; Salicylamide; Salicylate Meglumine; Salsalate; Sodium Salicylate; Spiradoline Mesylate; Sufentanil; Sufentanil Citrate; Talmetacin; Talniflumate; Talosalate; Tazadolene Succinate; Tebufelone; Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride; Tiopinac; Tonazocine Mesylate; Tramadol Hydrochloride; Trefentanil Hydrochloride; Trolamine; Veradoline Hydrochloride; Verilopam Hydrochloride; Volazocine; Xorphanol Mesylate; Xylazine Hydrochloride; Zenazocine Mesylate; Zomepirac Sodium; Zucapsaicin.
- Antihypertensive: Aflyzosin Hydrochloride; Alipamide; Althiazide; Amiquinsin Hydrochloride; Amlodipine Besylate; Amlodipine Maleate; Anaritide Acetate; Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflumethiazide; Benzthiazide; Betaxolol Hydrochloride; Bethanidine Sulfate; Bevantolol Hydrochloride; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril; Candoxatrilat; Captopril; Carvedilol; Ceronapril; Chlorothiazide Sodium; Cicletanine; Cilazapril; Clonidine; Clonidine Hydrochloride; Clopamide; Cyclopenthiazide; Cyclothiazide; Darodipine; Debrisoquin Sulfate; Delapril Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydrochloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril Maleate; Enalaprilat; Enalkiren; Endralazine Mesylate; Epithiazide; Eprosartan; Eprosartan Mesylate; Fenoldopam Mesylate; Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril Sodium; Fosinoprilat; Guanabenz; Guanabenz Acetate; Guanacline Sulfate; Guanadrel Sulfate; Guancydine; Guanethidine Monosulfate; Guanethidine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydrochloride; Hydralazine Polistirex; Hydroflumethiazide; Indacrinone; Indapamide; Indolaprif Hydrochloride; Indoramin; Indoramin Hydrochloride; Indorenate Hydrochloride; Lacidipine; Leniquinsin; Levcromakalim; Lisinopril; Lofexidine Hydrochloride; Losartan Potassium; Losulazine Hydrochloride; Mebutamate; Mecamylamine Hydrochloride; Medroxalol; Medroxalol Hydrochloride; Methalthiazide; Methyclothiazide; Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone; Metoprolol Fumarate; Metoprolol Succinate; Metyrosine; Minoxidil; Monatepil Maleate; Muzolimine; Nebivolol; Nitrendipine; Oformine; Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride; Perindopril Erbumine; Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide; Prazosin Hydrochloride; Primidolol; Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinaprilat; Quinazosin Hydrochloride; Quinelorane Hydrochloride; Quinpirole Hydrochloride; Quinuclium Bromide; Ramipril; Rauwolfia Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride; Temocapril Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide; Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxamine Hydrochloride; Tripamide; Xipamide; Zankiren Hydrochloride; Zofenoprilat Arginine.
- Anti-inflammatory: Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lornoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.
- Growth Factors
- In one embodiment, an effective amount of at least one growth factor, cytokine, hormone, or extracellular matrix compound or protein useful for enhancing wound healing is administered. In one aspect, a combination of these agents is used. In one aspect, growth factors useful in the practice of the invention include, but are not limited to, EGF, PDGF, GCSF, IL6, IL8, IL10, MCP1, MCP2, Tissue Factor, FGFb, KGF, VEGF, PLGF, MMP1, MMP9, TIMP1, TIMP2, TGFβ, and HGF. One of ordinary skill in the art will appreciate that the choice of growth factor, cytokine, hormone, or extracellular matrix protein used will vary depending on criteria such as the type of injury, disease, or disorder being treated, the age, health, sex, and weight of the subject, etc. In one aspect, the growth factors, cytokines, hormones, and extracellular matrix compounds and proteins are human.
- Proteins and other biologically active compounds that can be incorporated into, or included as an additive within, a composition comprising compounds of the present invention include, but are not limited to, collagen (including cross-linked collagen), fibronectin, laminin, elastin (including cross-linked elastin), osteopontin, osteonectin, bone sialoproteins (Bsp), alpha-2HS-glycoproteins, bone Gla-protein (Bgp), matrix Gla-protein, bone phosphoglycoprotein, bone phosphoprotein, bone proteoglycan, protolipids, bone morphogenetic protein, cartilage induction factor, skeletal growth factor, enzymes, or combinations and biologically active fragments thereof. Adjuvants that diminish an immune response can also be used in conjunction with the composite of the subject invention.
- Other molecules useful as compounds or substances in the present invention include, but are not limited to, growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, angiostatin, thrombospondin, osteogenic protein-1,
bone morphogenetic proteins 2 and 7, osteonectin, somatomedin-like peptide, osteocalcin, interferon alpha, interferon alpha A, interferon beta, interferon gamma,interferon 1 alpha, andinterleukins - The present invention encompasses treatment of various injuries, diseases, and disorders. These include, but are not limited to, thermal injury, skin injury, soft tissue injury, non-healing skin wound, burns, acute wound, chronic wound, scrape, cut, incision, laceration, decubitis, pressure ulcer, chronic venous ulcer, venous stasis ulcer, diabetic ulcer, arterial ulcer, radiation ulcer, traumatic wound, open complicated non-healing wound, body piercing, bite wound, insect bite, insect sting, stab wound, gunshot wound, stretch injury, crush wound, compression wound, fracture, sprain, strain, stroke, infarction, aneurism, herniation, ischemia, fistula, dislocation, radiation, surgery, cell, tissue or organ grafting, and cancer.
- In one embodiment, the invention provides novel delivery systems. In one aspect, the present invention provides methods and composition for delivering cells, chondrocytes, stem cells, genes, matrix materials, drugs, proteins, and chemicals. Delivery of bioactive molecules such as nucleic acid molecules encoding a protein can be significantly enhanced by immobilization of the bioactive molecule in a composition of the invention adjacent to the cells where delivery is desired.
- In one embodiment, the invention provides methods for administering novel delivery systems. In one aspect, the novel delivery systems are administered to treat diseases, disorders, and conditions in subjects in need thereof. In one aspect, the invention is useful for treating a musculoskeletal-associated disease or disorder. Musculoskeletal-associated diseases or disorders are described herein or are known in the art. In one aspect, the method is useful for enhancing bone repair. In another aspect, the method is useful for treating a bone-associated disease or disorder. In one aspect, treatment of a bone-associated disease or disorder can be done in conjunction with a surgical procedure. In one embodiment, the present invention provides methods and compositions for fabricating three-dimensional structures. In one aspect, the present invention provides various fabrication techniques. One of ordinary skill in the art would appreciate that various fabrication techniques are available to practice the methods of the invention.
- In one embodiment, the present invention provides compositions and methods for tissue regeneration. In one aspect, the tissues are selected from the group consisting of bone and spine.
- In one embodiment, the compositions and methods of the invention are useful for tissue engineering.
- In one embodiment, the compositions and methods of the invention are useful for preparing composites with organic or inorganic components.
- In one embodiment, the compositions and methods of the invention are useful in cell and tissue culture systems. In one aspect, the invention provides methods for encapsulating cells.
- Pharmaceutical Compositions and Delivery Form
- The formulations of the invention may be prepared in a variety of forms known in the art, such as liquids, aerosols, or gels. Topical administration of the present formulation can be performed by, for example, hand, mechanically (e.g., extrusion and spray delivery) or as a component of a dressing (e.g., gauze or other wound covering). The administration of the formulation directly by hand to a tissue or biomaterial surface is preformed so as to achieve a therapeutic coating, which may be uniform, alone or in combination with an overlying dressing.
- In one embodiment, the administration of the formulation mechanically is performed by using a device that physically pushes the composition onto a tissue or biomaterial surface so as to achieve a therapeutic coating, which may be uniform, alone or in combination with an overlying dressing.
- In another embodiment, the formulation can be sprayed onto a tissue or biomaterial surface so as to achieve a therapeutic coating, which may be uniform, alone or in combination with an overlying dressing. When part of a dressing, the formulation is applied so as to achieve a therapeutic coating of the surface, which may be uniform.
- Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 70% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- Those of ordinary skill in the art will be able to identify readily those pharmaceutical agents that have utility with the present invention. Those of ordinary skill in the art will also recognize numerous other compounds that fall within the categories and that are useful according to the invention for treating injuries where reduced blood flow occurs.
- The invention encompasses the preparation and use of pharmaceutical compositions comprising a compound useful for treatment of various skin related injuries, trauma, diseases, disorders, or conditions described herein, including burns, wounds, surgical incisions, etc. The invention also encompasses other injuries, trauma, associated diseases and disorders other than those of the skin, including, but not limited to, gum diseases and disorders. Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
- An obstacle for topical administration of pharmaceuticals to the skin is the stratum corneum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells. One of the factors that limits the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance which can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal.
- The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
- The compounds of the invention may be administered to, for example, a cell, a tissue, or a subject by any of several methods described herein and by others which are known to those of skill in the art.
- The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, sex, age, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
- In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active or therapeutic agents. Particularly contemplated additional agents include anti-emetics and scavengers such as cyanide and cyanate scavengers.
- Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
- Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- Additionally, formulations for topical administration may include liquids, ointments, lotions, creams, gels (e.g., poloxamer gel), drops, suppositories, sprays, aerosols, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The disclosed compositions can be administered, for example, in a microfiber, polymer (e.g., collagen), nanosphere, aerosol, lotion, cream, fabric, plastic, tissue engineered scaffold, matrix material, tablet, implanted container, powder, oil, resin, wound dressing, bead, microbead, slow release bead, capsule, injectables, intravenous drips, pump device, silicone implants, or any bio-engineered materials.
- Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone.
- One acceptable vehicle for topical delivery of some of the compositions of the invention may contain liposomes. The composition of the liposomes and their use are known in the art (for example, see Constanza, U.S. Pat. No. 6,323,219).
- The source of active compound to be formulated will generally depend upon the particular form of the compound. Small organic molecules and peptidyl or oligo fragments can be chemically synthesized and provided in a pure form suitable for pharmaceutical/cosmetic usage. Products of natural extracts can be purified according to techniques known in the art. Recombinant sources of compounds are also available to those of ordinary skill in the art.
- In alternative embodiments, the topically active pharmaceutical composition may be optionally combined with other ingredients such as moisturizers, cosmetic adjuvants, anti-oxidants, chelating agents, bleaching agents, tyrosinase inhibitors, and other known depigmentation agents, surfactants, foaming agents, conditioners, humectants, wetting agents, emulsifying agents, fragrances, viscosifiers, buffering agents, preservatives, sunscreens, and the like. In another embodiment, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, are known to those of skill in the art. In another aspect, the composition may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum. Various hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art.
- The compositions of this invention may also contain active amounts of retinoids (i.e., compounds that bind to any members of the family of retinoid receptors), including, for example, tretinoin, retinol, esters of tretinoin and/or retinol and the like.
- Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
- The present invention encompasses biologically active analogs, homologs, derivatives, and modifications of the compounds of the invention. Methods for the preparation of such compounds are known in the art.
- Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
- Liquid derivatives and natural extracts made directly from biological sources may be employed in the compositions of this invention in a concentration (w/w) from about 1 to about 99%. Fractions of natural extracts and protease inhibitors may have a different preferred rage, from about 0.01% to about 20% and, more preferably, from about 1% to about 10% of the composition. Of course, mixtures of the active agents of this invention may be combined and used together in the same formulation, or in serial applications of different formulations.
- The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of an aqueous gel because of repeated patient use when it is exposed to contaminants in the environment from, for example, exposure to air or the patient's skin, including contact with the fingers used for applying a composition of the invention such as a therapeutic gel or cream. Examples of preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea, and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.
- The composition may include an antioxidant and a chelating agent which inhibit the degradation of the compound for use in the invention in the aqueous gel formulation. Preferred antioxidants for some compounds are BHT, BHA, alphatocopherol, and ascorbic acid in the preferred range of about 0.01% to 0.3% and more preferably BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. Preferably, the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Particularly preferred chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20% and more preferably in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition which may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefor as would be known to those skilled in the art.
- As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.), which is incorporated herein by reference.
- Other components such as preservatives, antioxidants, surfactants, absorption enhancers, viscosity enhancers or film forming polymers, bulking agents, diluents, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable coloring agents include red, black, and yellow iron oxides and FD&C dyes such as FD&C Blue No. 2, FD&C Red No. 40, and the like. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry grape flavors, combinations thereof, and the like. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide, and the like. Suitable sweeteners include aspartame, acesulfame K, thaumatic, and the like. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates, and the like.
- Absorption enhancers for use in accordance with the present invention include, for example, polysorbates, sorbitan esters, poloxamer block copolymers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric glycerides, sodium lauryl sulfate, dioctyl sulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids, oleic acid, linoleic acid, glyceryl caprylate/caprate, glyceryl monooleate, glyceryl monolaurate, caprylic/capric triglycerides, ethoxylated nonylphenols, PEG-(8-50) stearates, olive oil PEG-6 esters, triolein PEG-6 esters, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, cyclodextrins, citric acid, sodium citrate, triacetin, combinations thereof, and the like. In certain preferred embodiments, the absorption enhancer is triacetin. In certain preferred embodiments wherein an absorption enhancer is included in the formulation, the absorption enhancer is included in an amount of from about 0.001% to about 10% by weight of the formulation, preferably in an amount of about 0.01% to about 5% by weight of the formulation.
- The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
- Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs, and birds including commercially relevant birds such as chickens, ducks, geese, and turkeys.
- The pharmaceutical compositions of the invention can be administered in any suitable formulation, by any suitable means, and by any suitable route of administration. Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil in water or water in oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- Topical administration of compositions of the invention may include transdermal application. Transdermal application can be performed either passively or using iontophoresis or electroporation.
- Compositions of the invention may be applied using transdermal patches. Transdermal patches are adhesive backed patches laced with an effective amount of compounds of the invention. The pressure-sensitive adhesive of the matrix will normally be a solution of polyacrylate, a silicone, or polyisobutylene (PIB). Such adhesives are well known in the transdermal art. See, for instance, the Handbook of Pressure Sensitive Adhesive Technology, 2nd Edition (1989) Van Nostrand, Reinhold.
- Pressure sensitive solution polyacrylate adhesives for transdermal patches are made by copolymerizing one or more acrylate monomers (“acrylate” is intended to include both acrylates and methacrylates), one or more modifying monomers, and one or more functional group-containing monomers in an organic solvent. The acrylate monomers used to make these polymers are normally alkyl acrylates of 4-17 carbon atoms, with 2-ethylhexyl acrylate, butyl acrylate, and isooctyl acrylate being preferred. Modifying monomers are typically included to alter the Tg of the polymer. Such monomers as vinyl acetate, ethyl acrylate and methacrylate, and methyl methacrylate are useful for this purpose. The functional group-containing monomer provides sites for crosslinking The functional groups of these monomers are preferably carboxyl, hydroxy or combinations thereof. Examples of monomers that provide such groups are acrylic acid, methacrylic acid and hydroxy-containing monomers such as hydroxyethyl acrylate. The polyacrylate adhesives are preferably crosslinked using a crosslinking agent to improve their physical properties, (e.g., creep and shear resistance). The crosslinking density should be low since high degrees of crosslinking may affect the adhesive properties of the copolymer adversely. Examples of crosslinking agents are disclosed in U.S. Pat. No. 5,393,529. Solution polyacrylate pressure sensitive adhesives are commercially available under tradenames such as GELVA™ and DURO-TAK™ from 3M.
- Polyisobutylene adhesives are mixtures of high molecular weight (HMW) PIB and low molecular weight (LMW) PIB. Such mixtures are described in the art, e.g., PCT/US91/02516. The molecular weight of the HMW PIB will usually be in the range of about 700,000 to 2,000,000 Da, whereas that of the LMW PIB will typically range between 35,000 to 60,000. The molecular weights referred to herein are weight average molecular weight. The weight ratio of HMW PIB to LMW PIB in the adhesive will normally range between 1:1 to 1:10. The PIB adhesive will also normally include a tackifier such as polybutene oil and high Tg, low molecular weight aliphatic resins such as the ESCOREZ™ resins available from Exxon Chemical. Polyisobutylene polymers are available commercially under the tradename VISTANEX™ from Exxon Chemical.
- The silicone adhesives that may be used in forming the matrix are typically high molecular weight polydimethyl siloxanes or polydimethyldiphenyl siloxanes. Formulations of silicone adhesives that are useful in transdermal patches are described in U.S. Pat. Nos. 5,232,702, 4,906,169, and 4,951,622.
- Dosage forms for topical or transdermal administration of a compound of this invention include liquids, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, aerosols, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound(s) in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- The ointments, pastes, creams, and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Topical administration may also be performed using iontophoresis devices. Such delivery systems eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin. The process of iontophoresis has found commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine, and dexamethasone. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
- The present invention provides a system for the direct application of compounds of the invention, including additional therapeutic agents such as anesthetic agents, by iontophoresis for the treatment of decreased blood flow and concurrent pain associated with injuries, diseases, and disorders. While many compounds may be useful with the invention, as will be discussed below, it is particularly useful for the delivery of anesthetic agents such as lidocaine, bupivicaine, ropivicaine, and mepivicaine to damaged skin.
- In one embodiment, the methods of the invention provide a patch device with a donor or delivery chamber that is designed to be applied directly over an injury, incision, or wound site and utilizes an electric field to stimulate delivery of the active compound or additional therapeutic agents(s). The patch is sterilized so that risk of infection is minimal. Additionally, the system delivers medication in a constant manner over an extended period of time. Generally, such time periods are at least 30 minutes and may extend to as many as 96 hours.
- A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. Preferably, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
- Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally, the propellant may constitute about 50% to about 99.9% (w/w) of the composition, and the active ingredient may constitute about 0.1% to about 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
- Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
- The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.
- Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to about 500 micrometers. Such a formulation is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
- Formulations suitable for nasal administration may, for example, comprise from about as little as about 0.1% (w/w) and as much as about 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.
- A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, comprise about 0.1% to about 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or atomized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. Additionally, the formulation taken orally can be prepared as a pharmaceutical composition, including, but not limited to, a paste, a gel, a toothpaste, a mouthwash, a solution, an oral rinse, a suspension, an ointment, a cream, and a coating.
- A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1% to 1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.
- A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for intramucosal administration. The present invention provides for intramucosal administration of compounds to allow passage or absorption of the compounds across mucosa. Such type of administration is useful for absorption orally (gingival, sublingual, buccal, etc.), rectally, vaginally, pulmonary, nasally, etc.
- In some aspects, sublingual administration has an advantage for active ingredients, as well as additional therapeutic agents, which in some cases, when given orally, are subject to a substantial first pass metabolism and enzymatic degradation through the liver, resulting in rapid metabolization and a loss of therapeutic activity related to the activity of the liver enzymes that convert the molecule into inactive metabolites, or the activity of which is decreased because of this bioconversion.
- In some cases, a sublingual route of administration is capable of producing a rapid onset of action due to the considerable permeability and vascularization of the buccal mucosa. Moreover, sublingual administration can also allow the administration of active ingredients which are not normally absorbed at the level of the stomach mucosa or digestive mucosa after oral administration, or alternatively which are partially or completely degraded in acidic medium after ingestion of, for example, a tablet.
- The compounds of the invention can be prepared in a formulation or pharmaceutical composition appropriate for administration that allows or enhances absorption across mucosa. Mucosal absorption enhancers include, but are not limited to, a bile salt, fatty acid, surfactant, or alcohol. In specific embodiments, the permeation enhancer can be sodium cholate, sodium dodecyl sulphate, sodium deoxycholate, taurodeoxycholate, sodium glycocholate, dimethylsulfoxide, or ethanol. In a further embodiment, a compound of the invention can be formulated with a mucosal penetration enhancer to facilitate delivery of the compound. The formulation can also be prepared with pH optimized for solubility, drug stability, and absorption through mucosa such as nasal mucosa, oral mucosa, vaginal mucosa, respiratory, and intestinal mucosa.
- To further enhance mucosal delivery of pharmaceutical agents within the invention, formulations comprising the active agent may also contain a hydrophilic low molecular weight compound as a base or excipient. Such hydrophilic low molecular weight compounds provide a passage medium through which a water-soluble active agent, such as a physiologically active peptide or protein, may diffuse through the base to the body surface where the active agent is absorbed. The hydrophilic low molecular weight compound optionally absorbs moisture from the mucosa or the administration atmosphere and dissolves the water-soluble active peptide. The molecular weight of the hydrophilic low molecular weight compound is generally not more than 10000 and preferably not more than 3000. Exemplary hydrophilic low molecular weight compounds include polyol compounds, such as oligo-, di- and monosaccharides such as sucrose, mannitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, D-galactose, lactulose, cellobiose, gentibiose, glycerin, and polyethylene glycol. Other examples of hydrophilic low molecular weight compounds useful as carriers within the invention include N-methylpyrrolidone, and alcohols (e.g., oligovinyl alcohol, ethanol, ethylene glycol, propylene glycol, etc.). These hydrophilic low molecular weight compounds can be used alone or in combination with one another or with other active or inactive components of the intranasal formulation.
- When a controlled-release pharmaceutical preparation of the present invention further contains a hydrophilic base, many options are available for inclusion. Hydrophilic polymers such as a polyethylene glycol and polyvinyl pyrrolidone, sugar alcohols such as D-sorbitol and xylitol, saccharides such as sucrose, maltose, lactulose, D-fructose, dextran, and glucose, surfactants such as polyoxyethylene-hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene sorbitan higher fatty acid esters, salts such as sodium chloride and magnesium chloride, organic acids such as citric acid and tartaric acid, amino acids such as glycine, beta-alanine, and lysine hydrochloride, and aminosaccharides such as meglumine are given as examples of the hydrophilic base. Polyethylene glycol, sucrose, and polyvinyl pyrrolidone are preferred and polyethylene glycol are further preferred. One or a combination of two or more hydrophilic bases can be used in the present invention.
- The present invention contemplates pulmonary, nasal, or oral administration through an inhaler. In one embodiment, delivery from an inhaler can be a metered dose.
- An inhaler is a device for patient self-administration of at least one compound of the invention comprising a spray inhaler (e.g., a nasal, oral, or pulmonary spray inhaler) containing an aerosol spray formulation of at least one compound of the invention and a pharmaceutically acceptable dispersant. In one aspect, the device is metered to disperse an amount of the aerosol formulation by forming a spray that contains a dose of at least one compound of the invention effective to treat a disease or disorder encompassed by the invention. The dispersant may be a surfactant, such as, but not limited to, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohols, and polyoxyethylene sorbitan fatty acid esters. Phospholipid-based surfactants also may be used.
- In other embodiments, the aerosol formulation is provided as a dry powder aerosol formulation in which a compound of the invention is present as a finely divided powder. The dry powder formulation can further comprise a bulking agent, such as, but not limited to, lactose, sorbitol, sucrose, and mannitol.
- In another specific embodiment, the aerosol formulation is a liquid aerosol formulation further comprising a pharmaceutically acceptable diluent, such as, but not limited to, sterile water, saline, buffered saline and dextrose solution.
- In further embodiments, the aerosol formulation further comprises at least one additional compound of the invention in a concentration such that the metered amount of the aerosol formulation dispersed by the device contains a dose of the additional compound in a metered amount that is effective to ameliorate the symptoms of disease or disorder disclosed herein when used in combination with at least a first or second compound of the invention.
- Compounds of the invention will be prepared in a formulation or pharmaceutical composition appropriate for nasal administration. In a further embodiment, the compounds of the invention can be formulated with a mucosal penetration enhancer to facilitate delivery of the drug. The formulation can also be prepared with pH optimized for solubility, drug stability, absorption through nasal mucosa, and other considerations.
- Capsules, blisters, and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.
- For administration by inhalation, the compounds for use according to the methods of the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the drugs and a suitable powder base such as lactose or starch.
- As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., which is incorporated herein by reference.
- Typically, dosages of the compounds of the invention which may be administered to an animal, preferably a human, range in amount from about 1.0 μg to about 100 g per kilogram of body weight of the animal. The precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal and the route of administration. Preferably, the dosage of the compound will vary from about 1 mg to about 10 g per kilogram of body weight of the animal. More preferably, the dosage will vary from about 10 mg to about 1 g per kilogram of body weight of the animal.
- The compounds may be administered to a subject as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.
- Biosensors, Chemical Sensors, and Data Display
- Compositions of the invention comprising metal nanoparticles are also useful for other methods, including, for example, as sensors and for data display. In one embodiment, the method of present invention employs nanosize particles for detection of molecular structures of interest. It is appreciated that the method of present invention is not bound to any particular assumption or theory of the mechanism of interaction of the chemical groups present on the substrate surface and said nano-particles. The method of present invention can be practiced by many different ways. Various other embodiments and variations to the preferred embodiments will be apparent to those skilled in the art and may be made without departing from the spirit and scope of the following claims.
- Nucleic acid hybridization has become an increasingly important technology for DNA analysis and gene expression studies. For example, DNA and RNA hybridization techniques are very useful for detecting, identifying, fingerprinting, and mapping molecular structures. Recently developed combinatorial DNA chips, which rely on the specific hybridization of target and probe DNA on a solid surface, are also encompassed by the present invention. Proteomics has also introduced a very valuable complimentary approach to study the biological functions of a cell. Proteomics involves the qualitative and quantitative measurement of gene activity by detecting and quantifying expressions at the protein level, rather than at the messenger RNA level. Multianalyte assays, also known in the art as “protein chips”, involve the use of multiple antibodies and are directed towards assaying for multiple analytes. The approach enables rapid, simultaneous processing of thousands of proteins employing automation and miniaturization strategy introduced by DNA microarrays.
- Currently, the most common approach to detect DNA bound to a microarray is to label it with a reporter molecule that identifies DNA presence. The reporter molecules emits detectable light when excited by an external light source. Light emitted by a reporter molecule has a characteristic wavelength, which is different from the wavelength of the excitation light, and therefore a detector such as a Charge-Coupled Device (CCD) or a confocal microscope can selectively detect a reporter's emission. Although the use of optical detection methods increases the throughput of the sequencing experiments, the disadvantages are serious. Incorporation of a fluorescent label into a nucleic acid sequence increases the complexity and cost of the entire process. Although the chemistry is commonplace, it necessitates additional steps and reagents for fluorescent labeling, and can be accomplished only with specialized expensive equipment for detection of weak fluorescent signals.
- Autoradiography is another common technique for the detection of molecular structures. For DNA sequence analysis applications, oligonucleotide fragments are end labeled, for example, with 32P or 35S. These end labeled fragments are then exposed to X-ray film for a specified amount of time. The amount of film exposure is determined by densitometry and is directly related to the amount of radioactivity of the labeled fragments adjacent to a region of film.
- The use of any radioactive label has several disadvantages. First, the use of radioactive isotopes increases the risk of workers acquiring mutation-related diseases. As such, precautions must be implemented when using radioactive markers or labels. Second, the need of an additional processing step and the use of additional chemical reagents and short-lived radioisotopes increases the cost and complexity of this detection technique.
- A method of using metal nanoparticles, as an alternative detection agent for detection of nucleic acids on microarrays without using specialized expensive equipment for detection is taught in U.S. Pat. Nos. 6,495,324 and 6,682,895. The nucleotides having sequence complimentary to the target nucleic acid first are attached to the surface of gold nano-particles (nanoparticle-oligonucleotide conjugates). The gold nano-particles conjugates that hybridized with target molecules hybridized to the probes on microarray surface. In this method the hybridization of gold conjugates marks array spots where target molecules are located. However, the method required a large number of sequence-specific oligonucleotides for manufacturing nano-particle conjugates, which seen as the significant disadvantage of the oligonucleotide-conjugate method. In addition, oligonucleotides-gold conjugates are often unstable under the typical hybridization conditions, which further complicates the use of gold-oligonucleotides conjugates (see Li et al., “Multiple thiol-anchor capped DNA-gold nanoparticle conjugates”, Nuc. Acids Res., 30(7), 1558-1562 (2202)).
- Yguerabide et al., U.S. Pat. No. 6,586,193, describes a method of using light scattering for sensitive detection of target biopolymers. In this method another type of metal-conjugate particles described, which conjugates provides specific binding component to bind target molecules through hapten pairs, such as biotin/streptavidin or digoxigenin/antidigoxigenin and the similar binding systems. In some embodiments of the method the particles are coated with, for instance, streptavidin wherein biotin is incorporated into the structure of target molecules during the steps of analyte preparation. Yet, the modification of target molecules by incorporating labeling group(s) (e.g., biotin and the similar) for detection often introduces bias, reduces accuracy and increases the cost and complexity of microarray analysis.
- Remacle et al., US App. No. 2003/0096321, describes a method for identification of a labeled target compound on a surface of solid support. In one embodiment, the use of non-modified target molecules is described by employing a sandwich type assay, in which the target is hybridized with an additional labeled nucleotide sequence, which labeled nucleotide allows attachment of gold-conjugates to the target compound. Yet, once again, the method requires the use of a large number of labeled sequence-specific oligonucleotides, which makes the method unpractical. The modification of this approach for reducing the number of various labeled sequence-specific oligonucleotides, in which universal binding sequences such as polyT and polyA nucleotides are used, has a limited utility and cannot be used for analysis of partially degraded mRNA, which lost partially or completely the polyA tail or for analysis of microbial mRNA, which do not have polyA tail.
- While a large number of detection methods for use with nucleic acids and protein arrays have been described in patents and in the scientific literature, virtually all methods set forth in prior art contain one or more inherent weaknesses. Some lack the sensitivity necessary to accomplish certain tasks. Other methods lack the recognition specificity due to imposing non-optimal conditions for forming probe-target duplexes. Still others are expensive and difficult to implement due to complexity of sample preparation and often have drawbacks due to bias introduced by labeling groups incorporated into the structure of target molecules.
- Thus, there is a need for an improved method for visualization of molecular structures, which method is quantitative, sensitive, and simple to implement.
- For quantification of the hybridized target molecules, the surface of the solid support (i.e., microarray) covered by nanoparticles can be analyzed and density of the bound nanoparticles can be measured using conventional optical techniques and a suitable image-capturing apparatus. A suitable image-capturing apparatus can include any device of plurality of devices capable of acquiring absorbance on the surface and reflectance from the surface of interest, and most preferably, includes flatbed scanners. The resolution of the image-capturing device must be sufficient to identify optical response from individual test sites on the surface of the substrate. Most preferably, the image-capturing device must be able to digitize the captured image and transfer the image to a computer for storage and further analysis. It is appreciated that images of the same area of the substrate can be captured multiple times for averaging, reducing noise, color manipulations, filtering and performing other image-processing operations known to one skilled in the art. Specialized software can be implemented for obtaining quantitative characteristics of the optical response from each individual test site on the substrate. These quantitative parameters can be used to quantify the distribution of nano-particles bound to the substrate and accordingly to measure the quantity of molecular structure of interest in corresponded site(s) of the substrate.
- The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the different aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
- The examples provided throughout his application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.
- The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.
- Surface Modification of Titanium Metal by Surface Etching Followed by Silver Nanoparticle Formation
- Titanium thin films were procured from Good Fellow Inc. The metal film was cut into 1×1 cm. square samples for surface modification. The samples were washed with acetone, 1% triton followed by mild sonication in distilled water.
- The morphology of the metal surfaces, both before and after surface modifications, was evaluated using secondary electron imaging (SEI) in a JEOL 6700F scanning electron microscope (SEM). The elemental composition of the modified surface was evaluated using energy dispersive spectroscopy (PGT Light Element Detector running Spirit software).
-
FIG. 1 shows images of scanning electron micrographs of unmodified titanium sample indicating the morphology.FIG. 2 shows the elemental composition of the unmodified metal film indicating that the surface is composed solely of titanium metal. - Surface Etching of Titanium Thin Films:
- The washed samples were incubated in 5 M sodium hydroxide solution at 40° C. for 24 h. After the incubation time the samples were washed with water twice and dried under vacuum.
FIGS. 3 and 4 represent scanning electron micrographs of base etched titanium sample showing the morphology. Under the present etching conditions, the surface of the metal showed a uniform nanofibrous structure. The gross morphology of the structure was found to be highly reproducible. The fibrous structure on the surface was found to have an average diameter of less than ˜100 nm. -
FIG. 5 shows the EDS spectra of surface etched titanium films. The surface mainly shows the presence of titanium metal on the surface. The absence of sodium peak on the surface can be attributed to washing the surface with water. - Surface Functionalization of Etched Titanium Films Using Silver Nitrate Solution
- The etched titanium films were incubated in 50 mM silver nitrate solution in water at 40° C. for 24 h. After the incubation time the samples were washed with water twice and dried under vacuum.
FIGS. 6 and 7 represent scanning electron micrographs showing the morphology of base etched titanium films incubated in silver nitrate solution. Again the gross morphology of the structure was found to be highly reproducible (n=3).FIGS. 7 and 8 clearly demonstrate the presence of silver on the surface of base etched titanium surfaces. However, contrary to what was expected, high magnified image (FIG. 7 b) clearly shows the formation of few nanoparticles (˜10 nm) on the surface of the metal even though no reducing agents have been used.FIGS. 9 and 10 shows the surface of alkali etched titanium surface treated with silver ions after reduction using sodium borohydride. As shown in the figure, reduction of silver ions significantly increased. The size of the silver particles were found to range from ˜5-10 nm. The formation of silver nanoparticles was further confirmed by EDS spectra (FIG. 10 ). The nanofibrous structure present on the surface due to titanium has been found to have very small diameter in the range of 10-20 nm. This unique structure results in the formation of unique color change to the metal.FIG. 11 shows the photographs of surface modified and unmodified titanium films. The formation of silver nanoparticles changed the color of the film to brown-blue color with a metallic luster. Further studies showed significant reduction of bacteria on the surface comprising metallic nanoparticles and showed the use for the metal substrates for growing mammalian cells (see Example 4 andFIG. 32 ). - For polymeric substrates, we have developed an unique surface coating technique to modify the surfaces of polymeric biomaterials and devices with silver nanoparticles. The process is based on the photochemistry of azides. Briefly polymeric substrates either carboxylated, aminated or hydroxylated (any reactive functional groups) polymers can be functionalized with aromatic or aliphatic azides to make them photoactive. The photoactive polymers can be permanently coated on any substrates by photoirradiation. In the case of aromatic azides, the absorption occurs in the range of ˜275 nm and therefore irradiation of the coated surface with UV radiation result in immobilization of the polymer on the surface due to an azide insertion reaction.
- A typical procedure for the modification of polymeric substrates with azide group is as follows:
- Preparation of Photoactive Carboxylated Polymers: the Carboxylated polymers [poly(acrylic acid), alginica acid, heparin and chondroitin sulfate) were treated with 4-azidoaniline hydrochloride in the presence of water soluble carbodiimide and N-hydroxysuccinimide in distilled water. N-hydroxysuccinimide is commonly used as an activating reagent for carboxylic acids. The pH of the solution was adjusted to ˜4 using sodium hydroxide solution and the resulting solution was stirred overnight at 4° C. in dark. The ratios of the reagents was varied to get a substitution of 10, 30, and 50% of carboxyl groups with azidoaniline groups. The chemically modified polymer was purified by dialysis against water at 4° C. in dark for 48 h. The resulting purified polymer solution was lyophilized for 72 h and the dry polymer powder was kept at −20° C. (
FIG. 20 ).FIG. 12 shows the UV spectra of azidated polymer showing strong absorbance in the 275-280 nm due to the aromatic azide groups. - Surface Immobilization of Azidated Polymers
- The azidated polymers was dissolved in double distilled water and coated onto polymeric substrates. Commercially available polystyrene cover slips were commonly used, however feasibility to coat on other polymers have also been demonstrated. Different polymer concentrations were used for coating including 10 mg/ml, 5.0 mg/ml, 1.0 mg/ml, and 0.05 mg/ml. The coating was allowed to dry over night in the dark. The coated surface was then irradiated with UV radiation at a wave length of 275 nm for 2-3 minutes for azidated polymer immobilization on the substrate (
FIG. 20 ). The coated substrate was then sonicated in water for 1-2 min to wash off the unattached polymer. The coated substrate was then dried under vacuum. - Incorporation of Silver Ions on the Surface by Ion Exchange Method
- The Photomodified Polymeric Substrates were Incubated in Silver Nitrate solution (10-50 μM) at 37° C. for various periods of time (5 h-24 h). The silver ion complexed surfaces were washed with distilled water and dried under vacuum. The reduction of silver ions to silver metal can be performed using various reducing agents. This includes, for example, 5-10 μM solution of sodium borohydride in water, solution of dextrose in water. In other cases, a basic ammoniacal silver nitrate solution can be used for ion exchange method for direct reduction of ions to metal. The modified polymeric substrates shows unique colors depending on the method of reduction and will be extensively washed with water and dried under vacuum.
FIG. 13 shows silver nanoparticles formed on polystyrene surface coated with silver nanoparticles. The coated surfaces were incubated in silver nanoparticles for 24 h before reduction. The white spots have been identified as silver nanoparticles uniformly distributed in the surface of the polymer coating.FIG. 14 demonstrates the different sizes and distribution of silver nanoparticles formed on azidated alginic acid on polystyrene cover slips after ion exchanging with silver followed by reduction. - Spot EDS spectra has identified the elemental composition of the surface (
FIG. 14E ). The arrows (and regions with similar color) indicates silver on the surface. The dark background indicated by the arrow on the far right indicates regions rich in carbon and oxygen and is therefore presumably the alginic acid substrate. - During this process, we demonstrated the feasibility of developing silver nanoparticles by treating silver nitrate solution in the presence of sodium hydroxide and ammonium hydroxide in a polysaccharide solution. Feasibility of developing silver nanoparticles without using reducing agents: Silver nanoparticles have been shown to be formed in the presence of reducing sugars at above neutral pHs. We have found that ammoniacal solution of azidated polymers such as heparin sulfate at appropriate concentrations can directly form silver nanoparticles without the use of strong reducing agents such as sodium borohydride.
FIGS. 17 a & b show the nanoparticles formed in solution and its UV absorption spectra. This will be further investigated in the proposed study as a single step Green Synthetic route for making nanoparticles on substrates. - We are currently investigating this reduction method as the novel environmentally friendly reducing process compared to using strong reducing agents such as sodium borohydride in forming the silver nanoparticles. We are also currently investigating polymeric aldehyde as a substrate for direct reduction of metals to form stable nanoparticles. We are using natural polymeric aldehydes (which are prepared by the sodiumperiodate reduction of polysaccharides) as a template for the direct reduction of nanoparticles based on a reaction similar to Tollen's reaction [13]. The same azide chemistry described earlier can be used to immobilize these aldehyde substituted polymers on the surface for various applications. Feasibility of developing silver nanoparticle coatings on nanofibers: Photografting process can also be used to form nanoparticles on a variety of structures.
FIGS. 18 a and 18 b shows nanoparticles formed on polymeric nanofiber matrices using two different concentrations of the azidated polymer coating solutions. - Feasibility of Patterning Surfaces with Metal Particles
- We have also demonstrated the feasibility of patterning metal nanoparticles on the surface by using azidated polymers.
FIG. 19A shows poly(acrylic azide) coated and shined with UV light through a photomask. The yellow region (appears as a lighter shade in a black and white photograph) shows polyacrylic acid grafted on polystyrene surface.FIG. 19B shows silver nanoparticles formed on the polyacrylic acid patterns on polystyrene.FIG. 20 schematically illustrates the preparation and photo-immobilization of azidated polymers.FIG. 21 schematically illustrates the formation of silver nanoparticles on polymeric substrates. - Procedure 1: 30 mg of Silver in 9.5 mL of Neat PluroGel.
- 2 mL of PluroGel was aliquoted and stirred using a magnetic stirrer at 4° C. in an icebath. 0.01 gm of silver nitrate powder was then added to PluroGel. The color of the solution instantly turned to yellow. The solution was stirred for another 2-5 minutes to form the silver nanoparticle-PluroGel composite mixture. The solution showed phase transition (liquid to solid) when heated to 37° C. in a water bath.
- Procedure 2: 30 mg of Silver Solution in 9.5 mL of Neat PluroGel
- 2 mL of PluroGel was aliquoted and stirred using a magnetic stirrer at 4° C. in an icebath. 10 μL of 10% solution of silver nitrate in water was then added to PluroGel. The color of the solution instantly turned to yellow. The solution was stirred for another 2-5 minutes to form the silver particle-PluroGel composite mixture. The solution showed phase transition (liquid to solid) when heated to 37° C. in a water bath.
- Procedure 3: 30 mg of Silver Solution in 9.5 mL of Neat PluroGel
- 2 mL of PluroGel was aliquoted and stirred using a magnetic stirrer at 4° C. in an icebath. 20 μL of 5% solution of silver nitrate in water was then added to PluroGel. The color of the solution instantly turned to yellow. The solution was stirred for another 2-5 minutes to form the silver particle-PluroGel composite mixture. The solution showed phase transition (liquid to solid) when heated to 37° C. in a water bath.
- Procedure 4: 30 mg of Silver Solution in 9.5 ml of Neat PluroGel
- 2 mL of PluroGel was aliquoted and stirred using a magnetic stirrer at 4° C. in an icebath. 40 μL of 2.5% solution of silver nitrate in water was then added to PluroGel. The color of the solution instantly turned to yellow. The solution was stirred for another 2-5 minutes to form the silver particle-PluroGel composite mixture. The solution did not show phase transition (liquid to solid) when heated to 37° C. in a water bath.
- For 2 mL of PluroGel, addition of ˜200 μL of silver nitrate solution retained the solution's temperature induced transition.
- The procedure was also performed using a diluted formulation of PluroGel which is less viscous at room temperature. Using the diluted formulation, the above procedures were performed at room temperature rather than 4° C.
- The present invention further encompasses methods for preparing and using surface active polymers, including PluroGel and variations thereof as described in International Application No. PCT/US2008/066094 (Katz and Rodeheaver), filed Jun. 6, 2008, the contents of which are hereby incorporated in their entirety herein.
- Characterizations: Silver nanoparticles exhibited a golden yellow to blue color due to its unique surface plasmon resonance (see
FIGS. 22-25 ).FIG. 22 photographically illustrates silver particles formed usingProcedure 1 as described above. Three vials, labeled A, B, and C are depicted. The photograph ofFIG. 22 also demonstrates visually the difference between PluroGel (FIG. 22A ), PluroGel plus silver particles at 4° C. (22B), and PluroGel plus silver particles at 37° C. (22C). The phase transition is also apparent (note that the vial labeled C is upside down and the composition had gelled).FIG. 23 illustrates the solutions ofFIG. 22 (A and B) after 4 days at 4° C. -
FIG. 24 photographically illustrates silver particles formed usingProcedure 2 described above. The photograph ofFIG. 24 also demonstrates visually the difference between PluroGel (FIG. 24A ), PluroGel plus silver particles at 4° C. (24B), and PluroGel plus silver particles at 37° C. (24C). The phase transition is also apparent.FIG. 25 illustrates the solutions ofFIG. 24 (A and B) after 4 days at 4° C. -
FIG. 26 provides transmission electron micrographic evidence of the silver nanoparticles prepared according toProcedure 1. It can be seen inFIG. 26A that there are silver nanoparticles and that the general size ranges are about 10-15 nm. -
FIG. 26B represents a higher magnification image of silver nanoparticles and demonstrates the partially crystalline structure.FIG. 26C represents an x-ray diffraction pattern which confirms the partially crystalline structure of the particles. The PluroGel™ composition comprising metallic nanoparticles maintains the physical characteristics of PluroGel without the metallic nanoparticles, e.g., the liquid or gel states temperature dependent. - UV Absorption Spectra:
- Even though TEM demonstrated the formation of silver nanoparticles with average size less than 20 nm, the UV visible spectrum of the composite system showed unique peaks. It showed a broad absorption peak covering 275-310 nm presumably due to multivalent silver ions (Ag4 2+ and Ag2 + species), broad peak between 300-350 nm well below the plasmon resonance of silver nanoparticles and has been attributed to atomic clusters of silver and a broad beak with maxima around 430-450 nm indicating the presence of silver nanoparticles. Current research is focused to evaluate the antibacterial efficacy of the composite system as well as to develop methods to control the size of the silver species formed within PluroGel.
- Composite films created with nanoparticles evenly dispersed throughout the polymer can have very interesting properties. Layer by layer casting of polyelectrolytes (Chitosan and carboxymethyl chitosan (CMC)) were used to create thin films to form silver nanoparticles in situ.
- Methods:
- 2% solution of chitosan in 0.5% acetic acid and 2% solution of carboxymethyl chitosan in distilled water were used to prepare the layer by layer casted films. Briefly, 6 mL of chitosan was poured into 100 mL petri dish and allowed to dry at 80° C. for 1.5 h. Then 6 mL of carboxymethyl chitosan solution was added and allowed to dry at 80° C. for 1.5 h. After than 6 mL of chitosan was added on top of it and allowed to dry at 80° C. for 1.5 h.
- Crosslinking the films: Some of the films were further heated to 110° C. for 1 h to crosslink the different polymer layers. All the films were then subjected to neutralization using 0.4N sodium hydroxide solution.
- Preparation of Silver Nanoparticles: we have Demonstrated the Feasibility of forming silver nanoparticles in the presence of CMC and sodium hydroxide. However, the stability of the particles were found to be very low leading to particle aggregation. There fore trilayer polymer films were used to develop silver particles in situ. After sodium hydroxide treatment, the films were immersed in silver nitrate solution for various periods of time. We have found that after 24 hours the films show characteristic Plasmon resonance of silver nanoparticles indicating the formation of silver particles in situ.
FIGS. 27A (1 hour), 27B (3 hours), 27C (5 hours), and 27D (24 hours) provide UV absorption spectra for these experiments. It can be seen that by 3 hours (FIG. 27B ), a characteristic peak of silver nanoparticles is present at 410-450 nm, and that by 24 hours (FIG. 27D ) there is a significant increase in the peak. -
FIG. 28 photographically illustrates a side by side comparison of a film with silver particles (left film; appears brown in a color photograph) and the control film on the right (no color change). - The formation of particles was further confirmed by transmission electron microscopy. The films were sectioned using a cryomicrotome and the cross-section of the film was observed using a transmission electron microscope (see
FIG. 29 ). The study demonstrated the formation of large number of particles in the middle layer, however the chitosan layer also found to have particles and the particles in the chitosan layer was found to be less aggregated compared to the middle layer. Further studies are currently underway to optimize the size and distribution of the particles. - A trilayer film was also subjected to energy-dispersive x-ray microanalysis. The results (
FIG. 30 ) indicate the elemental contents of the particles in the film.FIG. 30 graphically represents an EDS spectrum of the particles within the trilayer film. The presence of the silver peaks (Ag) confirms the composition of the particles. -
FIG. 31 represents a photomicrographic image illustrating the distribution of the particles within a trilayer film. More particle aggregates are found along the CMC later compared to the chitosan layer. The marker in the photograph represents 50 μm. - Other methods for forming and using compositions comprising chitosan are known in the art and such methods and compositions are encompassed by the present application. Such methods and compositions are described in, for example, International Patent Publication WO 2007/087350 (Laurencin et al.) published Aug. 2, 2007, the contents of which are hereby incorporated by reference in their entirety.
- Materials and Methods: Titanium metal foil (0.25 mm) was procured from Good Fellow, Cambridge Ltd. Sodium hydroxide, silver nitrate, sodium borohydride and ethanol were procured from Sigma Aldrich (St, Louis USA). Human bone marrow-derived mesenchymal stem cells (hMSCs) were obtained from Cambrex and E. coli from ATCC.
- Titanium samples (1×1 cm) were then incubated in 5 M sodium hydroxide solution at 40° C. for 24 h. hMSCs were cultured for 14 days on modified titanium surfaces using basal growth media. Cell proliferation was determined using MTS colorimetric assay and alkaline phosphatase activity using standard alkaline phosphatase kit.
- The base etched films were incubated in 50 mM aqueous silver nitrate solution at 40° C. for 24 h. The films were then washed with a mild reducing agent such as 70% ethanol and then exposed to 10 mM aqueous sodium borohydride solution for 2-3 minutes. A fast reaction occurred and the color of the metal foil changed to dark brown. The modified substrates were further washed with 70% ethanol, twice with distilled water and dried under vacuum.
- Results
- The morphology of the metal surfaces, both before and after surface modifications, was evaluated using secondary electron imaging (SEI) in a JEOL 6700F scanning electron microscope (SEM). The elemental composition of the modified surface was evaluated using energy dispersive spectroscopy (PGT Light Element Detector running Spirit software).
- The base etched titanium films were found to be cytocompatible as evidenced by the proliferation of human mesenchymal stem cells on the surface (
FIG. 32A ). The cells on nanostructured film showed higher alkaline phosphatase activity compared to control film.FIG. 32B shows the presence of near spherical shaped silver nanoparticles on the nanofibrous structures with a mean diameter of ˜10 nm. This is highly significant since previous studies have demonstrated that the shape and size of the silver nanoparticles plays a significant role in its antibacterial activity with highest activity found for particles with sizes ranging from 1-10 nm. The composition of the silver nanoparticles was further confirmed by EDS. The high antibacterial property of surfaces containing silver nanoparticles was demonstrated using E. coli. - Conclusions: The development of nanostructured implants can be considered as one of the promising strategies to increase osseointegration and provides matrices to be used to deliver cells such as hMSCs to an osseous defect and reduce implant associated infection. The study shows a versatile technique to develop nanostructured titanium containing silver nanoparticles as a potential biomaterial.
- The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference herein in their entirety.
- Headings are included herein for reference and to aid in locating certain sections. These headings are not intended to limit the scope of the concepts described therein under, and these concepts may have applicability in other sections throughout the entire specification.
- The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Accordingly, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
-
- 1. R. J. Gehr, R. W. Boyd, Chem. Mater. 8 (1996) 1807.
- 2. R. Patakfalvi, Z. Viranyi, I. Dekany. Colloid Polym Sci. 283 (2004) 299.
- 3. Shon Y S, Colorado R, Williams C T, Bain C D, Lee T R. Langmuir, 2000, 16: 541.
- 4. Limsavarn L, Sritaveesinsub V, Dubas S T. Materials Letters 61: 2007, 3048-51.
- 5. Zhao S, Zhang K. An J, Sun Y, Sun C. Mater Lett 60; 2006; 1215.
- 6. Dokoutchaev A, James J T, Koene S C, Pathak S, Surya prakash G K, Thompson M E. Chem Mater 1999; 11: 2389.
- 7. Kobayashi Y, Salguerino-Maceira V, Liz-Marzan Chem Mater 2001; 13: 1630.
- 8. Wang D, Salgueirino-Maceira, Liz-Marzan L M, Caruso F. Adv Mater 2002; 14: 908
- 9. Pol V G, Grisaru H, Gedanken A. Langmuir, 2005; 21: 3635
- 10. Sant S B, K. S. Gill b, R. E. Burrell c g Acta Biomaterialia 2007; 3: 341
- 11. Wright J B, Lam K, Buret A G, Olson M E, Burrell R E. Wound Repair Regeneration. 2002; 10: 141.
- 12. Masuka K, Ishihara M, Asazuma T, Hattori H et al Biomaterials 26 (2005) 3277-3284
- 13. Yin Y, Li Z, Zhong Z, Gates B, Xia Y, Venkataeswaran S. J Mater Chem 2002; 12: 522-527.
Claims (72)
1. A method for making a metal substrate comprising metallic nanoparticles, said method comprising:
obtaining a metal substrate and optionally etching said surface;
contacting said metal substrate with a composition comprising a metal for forming metallic nanoparticles;
and optionally washing said metal substrate following said contact, thereby making a metal substrate comprising metallic nanoparticles.
2. The method of claim 1 , wherein said metal substrate comprises a metal film.
3. The method of claim 2 , wherein said metal substrate comprises titanium.
4. The method of claim 2 , wherein said metal substrate is etched.
5. The method of claim 4 , wherein said metal substrate is etched with NaOH.
6. The method of claim 2 , wherein said metal substrate is contacted with a composition comprising silver.
7. The method of claim 6 , wherein said composition comprises silver nitrate.
8. The method of claim 6 , wherein said metallic nanoparticles are silver nanoparticles.
9. The method of claim 4 , wherein said metal substrate is washed after etching.
10. The method of claim 2 , wherein said metal substrate is washed after contact with said composition.
11. The method of claim 2 , wherein the nanoparticles range in size from about 1.0 nm to about 100 nm.
12. The method of claim 11 , wherein the nanoparticles range in size from about 2.0 nm to about 75 nm.
13. The method of claim 12 , wherein the nanoparticles range in size from about 3.0 nm to about 50 nm.
14. The method of claim 13 , wherein the nanoparticles range in size from about 4.0 nm to about 25 nm.
15. The method of claim 14 , wherein the nanoparticles range in size from about 5.0 nm to about 10.0 nm.
16. The method of claim 4 , wherein said metal substrate is etched for up to 48 hours.
17. The method of claim 16 , wherein said metal substrate is etched for up to 24 hours.
18. The method of claim 2 , wherein said metal substrate is contacted with said composition for up to 48 hours.
19. The method of claim 18 , wherein said metal substrate is contacted with said composition for up to 24 hours.
20. The method of claim 2 , wherein said method immobilizes said metallic nanoparticles on said metallic substrate.
21. A metal substrate comprising immobilized metallic nanoparticles made according to claim 1 .
22. The method of claim 2 , wherein said metallic nanoparticles are useful as a therapeutic agent or as a biosensor.
23. The method of claim 22 , wherein said metal substrate comprising metallic nanoparticles comprises at least one additional therapeutic agent.
24. The method of claim 22 , wherein said metallic nanoparticle is useful as an antimicrobial.
25. A method of making polymeric substrates comprising metallic nanoparticles, said method comprising;
forming a photoactive polymer by contacting a polymer comprising a reactive group with an aromatic azide or aliphatic azide;
contacting said photoactive polymer with said polymeric substrate;
immobilizing said photoactive polymer to said polymeric substrate by irradiation;
contacting said polymeric substrate comprising immobilized photoactivated polymers with a composition comprising a metal for forming metallic nanoparticles and optionally washing said substrate after said contact;
thereby making polymeric substrates comprising metallic nanoparticles.
26. The method of claim 25 , wherein said polymeric substrate is polystyrene.
27. The method of claim 25 , wherein said polymer comprising a reactive group is selected from the group consisting of poly(acrylic acid), alginica acid, heparin, and chondroitin sulfate.
28. The method of claim 25 , wherein said azidated polymer is purified following azidation.
29. The method of claim 28 , wherein said purified azidated polymer is dried.
30. The method of claim 29 , wherein before contacting said polymeric substrate said dried purified azidated polymer is resuspended at concentrations selected from the group consisting of 10 mg/ml, 5.0 mg/ml, 1.0 mg/ml, and 0.05 mg/ml.
31. The method of claim 25 , wherein said irradiation is ultraviolet irradiation.
32. The method of claim 31 , wherein the wavelength of said ultraviolet irradiation is about 275 nm.
33. The method of claim 25 , wherein the composition comprises silver.
34. The method of claim 33 , wherein the immobilized silver is reduced from silver ion to silver metal.
35. The method of claim 33 , wherein the silver nanoparticles are made using ammoniacal polysaccharides.
36. The method of claim 25 , wherein said polymers are applied in patterns.
37. A polymeric substrate comprising metallic nanoparticles made by the method of claim 25 .
38. The method of claim 25 , wherein the nanoparticles range in size from about 1.0 nm to about 100 nm.
39. The method of claim 38 , wherein the nanoparticles range in size from about 2.0 nm to about 75 nm.
40. The method of claim 39 , wherein the nanoparticles range in size from about 3.0 nm to about 50 nm.
41. The method of claim 40 , wherein the nanoparticles range in size from about 4.0 nm to about 25 nm.
42. The method of claim 41 , wherein the nanoparticles range in size from about 5.0 nm to about 10.0 nm.
43. A pharmaceutical composition comprising at least on surface active copolymer and metallic nanoparticles, wherein said composition has the same transition phase characteristics as an otherwise identical pharmaceutical composition without metallic particles.
44. The composition of claim 43 , wherein said metallic nanoparticles are silver nanoparticles.
45. The composition of claim 44 , wherein said surface active copolymers are selected from the group consisting of poloxamer, meroxapol, and poloxamine.
46. The method of claim 43 , wherein said composition comprises PluroGel™.
47. A pharmaceutical composition comprising PluroGel™ and metallic nanoparticles.
48. The pharmaceutical composition of claim 47 wherein said metallic nanoparticles are silver nanoparticles.
49. A thermo-gelling solution comprising chitosan and an inorganic salt, wherein said thermo-gelling solution is a solution at a pH between about 6.0 and about 8.0 and at a temperature below about 20° C., further wherein said solution forms a gel within a temperature range from about 20° C. to about 50° C., further wherein said solution comprises metallic nanoparticles.
50. The thermo-gelling solution of claim 49 , wherein said metallic nanoparticles are silver nanoparticles.
51. A method of making a tri-layer membrane comprising metallic nanoparticles for use as a therapeutic agent or a biosensor, said method comprising:
preparing a chitosan solution;
preparing a carboxymethyl chitosan solution;
applying a first layer of solution to a surface and allowing said solution to dry;
applying a second layer comprising the other solution to the dried first layer and allowing said second layer to dry;
applying a third layer of the same solution as applied for the first layer over the second layer and allowing the third layer to dry;
optionally heating the dried layers;
neutralizing the dried layers;
contacting the three layers with a composition comprising a metal for forming metallic nanoparticles;
thereby making a tri-layer membrane comprising metallic nanoparticles.
52. The method of claim 51 , wherein said composition comprising a metal is silver nitrate.
53. The method of claim 51 , wherein said metal is sliver.
54. The method of claim 51 , wherein said composition comprising a metal is contacted with said three layers for at least about 48 hour.
55. The method of claim 54 , wherein said composition is contacted with said three layers for at least about 24 hours.
56. The method of claim 55 , wherein said composition is contacted with said three layers for at least about 12 hours.
57. The method of claim 56 , wherein said composition is contacted with said three layers for at least about 6 hours.
58. The method of claim 57 , wherein said composition is contacted with said three layers for at least 3 hours.
59. The method of claim 58 , wherein said composition is contacted with said three layers for at least about 1 hour.
60. The method of claim 51 , wherein said composition is contacted with said three layers for about 24 hours or less.
61. The method of claim 51 , wherein said three layers are neutralized with NaOH.
62. The method of claim 51 , wherein said second layer comprises carboxymethyl cellulose.
63. The method of claim 51 , wherein each layer is dried at about 80° C.
64. The method of claim 51 , wherein said chitosan solution comprises about 2% chitosan.
65. The method of claim 51 , wherein said carboxymethyl chitosan solution comprises about 2% carboxymethyl chitosan.
66. A method for culturing mammalian cells on a metal substrate made according to claim 1 , said method comprising contacting said metal substrate with a composition comprising at least one mammalian cell type, allowing the cells to attach, and maintaining said cells in culture.
67. The method of claim 66 , wherein said metal substrate is a titanium substrate.
68. The method of claim 67 , wherein said titanium substrate comprises metallic nanoparticles.
69. The method of claim 68 , wherein said metallic nanoparticles are silver nanoparticles.
70. The method of claim 66 , wherein said mammalian cells are selected from the group consisting of stem cells, pluripotent stem cells, committed stem cells, embryonic stem cells, adult stem cells, bone marrow stem cells, bone marrow-derived stem cells, adipose stem cells, umbilical cord stem cells, dura mater stem cells, precursor cells, differentiated cells, osteoblasts, osteoclasts, myoblasts, neuroblasts, fibroblasts, glioblasts, germ cells, hepatocytes, chondrocytes, keratinocytes, smooth muscle cells, cardiac muscle cells, connective tissue cells, glial cells, epithelial cells, endothelial cells, hormone-secreting cells, cells of the immune system, normal cells, cancer cells, Schwann cells, and neurons.
71. The method of claim 70 , wherein said cells are human cells.
72. The method of claim 71 , wherein said human cells are bone marrow-derived mesenchymal stem cells.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/669,981 US20100203144A1 (en) | 2007-08-23 | 2008-07-23 | Immobilized Metallic Nanoparticles as Unique Materials for Therapeutic and Biosensor Applications |
US13/741,591 US8927018B2 (en) | 2007-08-23 | 2013-01-15 | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US96158707P | 2007-08-23 | 2007-08-23 | |
US12/669,981 US20100203144A1 (en) | 2007-08-23 | 2008-07-23 | Immobilized Metallic Nanoparticles as Unique Materials for Therapeutic and Biosensor Applications |
PCT/US2008/070875 WO2009025955A1 (en) | 2007-08-23 | 2008-07-23 | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2008/070875 A-371-Of-International WO2009025955A1 (en) | 2007-08-23 | 2008-07-23 | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/741,591 Division US8927018B2 (en) | 2007-08-23 | 2013-01-15 | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications |
Publications (1)
Publication Number | Publication Date |
---|---|
US20100203144A1 true US20100203144A1 (en) | 2010-08-12 |
Family
ID=40378512
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/669,981 Abandoned US20100203144A1 (en) | 2007-08-23 | 2008-07-23 | Immobilized Metallic Nanoparticles as Unique Materials for Therapeutic and Biosensor Applications |
US13/741,591 Active US8927018B2 (en) | 2007-08-23 | 2013-01-15 | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/741,591 Active US8927018B2 (en) | 2007-08-23 | 2013-01-15 | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications |
Country Status (2)
Country | Link |
---|---|
US (2) | US20100203144A1 (en) |
WO (1) | WO2009025955A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120107405A1 (en) * | 2008-07-22 | 2012-05-03 | Consejo Superior De Investigaciones Cient¿¿Ficas | Method for the dry dispersion of nanoparticles and the production of hierarchical structures and coatings |
WO2012135422A3 (en) * | 2011-04-01 | 2012-12-27 | University Of Florida Research Foundation, Inc. | Thermo-sensitive, mucoadhesive or dermoadhesive, and penetration-enhancing formulations for topical delivery of therapeutics |
US20140377331A1 (en) * | 2012-01-19 | 2014-12-25 | Cg Bio Co., Ltd. | Antimicrobial wound-covering material and method for manufacturing same |
WO2014126570A3 (en) * | 2013-02-14 | 2015-07-30 | California Institute Of Technology | Crosslinked polymer electrolyte |
US9345803B2 (en) | 2009-12-24 | 2016-05-24 | Advanced Medical Solutions Limited | Absorbent material |
US9730679B1 (en) * | 2012-12-21 | 2017-08-15 | University Of South Florida | Device for sterile uterine sampling and drug delivery |
CN110333216A (en) * | 2018-12-29 | 2019-10-15 | 厦门市普识纳米科技有限公司 | The detection method of xacin-series antibiotic in a kind of animal foodstuff |
WO2019235755A1 (en) * | 2018-06-08 | 2019-12-12 | 주식회사 아이센스 | Crosslinker comprising genipin for use in preparation of sensing film or diffusion control film of electrochemical sensor |
WO2021098892A1 (en) | 2019-11-23 | 2021-05-27 | Grade Medical s.r.o. | Device for the preparation of functionalised substances |
US20220104733A1 (en) * | 2020-10-06 | 2022-04-07 | Zense-Life Inc. | Working wire for a continuous biological sensor with an enzyme immobilization network |
CN114514293A (en) * | 2019-08-29 | 2022-05-17 | 法国比克公司 | Method for preparing aqueous gel ink with variable colour comprising silver nanoparticles |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10500564B2 (en) | 2011-03-17 | 2019-12-10 | Perma-Fix Environmental Services, Inc. | Preparation of chitosan-based microporous composite material and its applications |
US9849512B2 (en) | 2011-07-01 | 2017-12-26 | Attostat, Inc. | Method and apparatus for production of uniformly sized nanoparticles |
CN105051864B (en) * | 2013-03-13 | 2017-09-12 | 学校法人冲绳科学技术大学院大学学园 | The metal inducement nano-crystallization of amorphous semiconductor quantum dot |
WO2015148726A1 (en) * | 2014-03-26 | 2015-10-01 | Beth Israel Deaconess Medical Center, Inc. | Activation of antimicrobial agents |
US20160081346A1 (en) | 2014-09-23 | 2016-03-24 | Attostat, Inc. | Antimicrobial compositions and methods |
JP6827960B2 (en) | 2015-03-03 | 2021-02-10 | ティーアールエス ホールディングス リミテッド ライアビリティ カンパニー | Coating scaffold |
US9839652B2 (en) | 2015-04-01 | 2017-12-12 | Attostat, Inc. | Nanoparticle compositions and methods for treating or preventing tissue infections and diseases |
US10774429B2 (en) | 2015-04-13 | 2020-09-15 | Attostat, Inc. | Anti-corrosion nanoparticle compositions |
US11473202B2 (en) | 2015-04-13 | 2022-10-18 | Attostat, Inc. | Anti-corrosion nanoparticle compositions |
US10201571B2 (en) | 2016-01-25 | 2019-02-12 | Attostat, Inc. | Nanoparticle compositions and methods for treating onychomychosis |
US10398732B2 (en) | 2016-10-13 | 2019-09-03 | Marshall University Research Corporation | Compositions and methods for treating striated muscle injury, treating striated muscle atrophy and/or for promoting striated muscle growth |
EP3544644A1 (en) * | 2016-11-25 | 2019-10-02 | Stimos GmbH | Material for a bone implant and method for producing the same |
US11018376B2 (en) | 2017-11-28 | 2021-05-25 | Attostat, Inc. | Nanoparticle compositions and methods for enhancing lead-acid batteries |
US11646453B2 (en) | 2017-11-28 | 2023-05-09 | Attostat, Inc. | Nanoparticle compositions and methods for enhancing lead-acid batteries |
EP3774024A1 (en) * | 2018-03-26 | 2021-02-17 | Perma-Fix Environmental Services, Inc. | Preparation of chitosan-based microporous composite material and its applications |
CN109675100B (en) * | 2019-01-31 | 2021-04-06 | 济南大学 | Polylactic acid-zinc oxide micron nano multilevel structure composite microsphere material and application thereof |
US12115250B2 (en) | 2019-07-12 | 2024-10-15 | Evoq Nano, Inc. | Use of nanoparticles for treating respiratory infections associated with cystic fibrosis |
US20210100991A1 (en) * | 2019-09-17 | 2021-04-08 | Biointraface Inc. | Metal oxide and polymer-controlled delivery systems, sunscreens, treatments, and topical coating applicators for antifungal and antimicrobial agents |
CN111437431A (en) * | 2020-03-26 | 2020-07-24 | 吉林大学 | Exosome hydrogel wound dressing and preparation method thereof |
CN113125422B (en) * | 2021-04-16 | 2023-07-25 | 合肥工业大学 | Preparation method of chemiluminescent hydrogel microbead, prepared hydrogel microbead and application thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030170378A1 (en) * | 2002-02-20 | 2003-09-11 | University Of Southern California | Novel materials for dental and biomedical application |
US20050112544A1 (en) * | 2002-12-20 | 2005-05-26 | Xiao Xu | Impedance based devices and methods for use in assays |
US20060194037A1 (en) * | 2003-01-15 | 2006-08-31 | Dietmar Fink | Flexible, breathable polymer film and method for production thereof |
US20070190100A1 (en) * | 2002-09-20 | 2007-08-16 | Shastri Venkatram P | Engineering of material surfaces |
US20080206554A1 (en) * | 2005-01-04 | 2008-08-28 | Rutgers, The State University | Hydroxyapatite With Controllable Size And Morphology |
US20100047546A1 (en) * | 2006-05-22 | 2010-02-25 | Vinod Chintamani Malshe | Non-Metallic Nano/Micro Particles Coated with Metal, Process and Applications Thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE243049T1 (en) * | 1999-12-09 | 2003-07-15 | Biosyntech Canada Inc | MINERAL-POLYMER HYBRID COMPOSITION |
US20050220882A1 (en) * | 2004-03-04 | 2005-10-06 | Wilson Pritchard | Materials for medical implants and occlusive devices |
CA2628244A1 (en) * | 2005-11-04 | 2007-05-10 | Bio Syntech Canada Inc. | Gel formation of polyelectrolyte aqueous solutions by thermally induced changes in ionization state |
CN101184512B (en) * | 2006-04-07 | 2012-09-05 | 防菌公司 | Antimicrobial substrates and uses thereof |
-
2008
- 2008-07-23 US US12/669,981 patent/US20100203144A1/en not_active Abandoned
- 2008-07-23 WO PCT/US2008/070875 patent/WO2009025955A1/en active Application Filing
-
2013
- 2013-01-15 US US13/741,591 patent/US8927018B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030170378A1 (en) * | 2002-02-20 | 2003-09-11 | University Of Southern California | Novel materials for dental and biomedical application |
US20070190100A1 (en) * | 2002-09-20 | 2007-08-16 | Shastri Venkatram P | Engineering of material surfaces |
US20050112544A1 (en) * | 2002-12-20 | 2005-05-26 | Xiao Xu | Impedance based devices and methods for use in assays |
US20060194037A1 (en) * | 2003-01-15 | 2006-08-31 | Dietmar Fink | Flexible, breathable polymer film and method for production thereof |
US20080206554A1 (en) * | 2005-01-04 | 2008-08-28 | Rutgers, The State University | Hydroxyapatite With Controllable Size And Morphology |
US20100047546A1 (en) * | 2006-05-22 | 2010-02-25 | Vinod Chintamani Malshe | Non-Metallic Nano/Micro Particles Coated with Metal, Process and Applications Thereof |
Non-Patent Citations (1)
Title |
---|
Maitz, et al., Bioactivity of titanium following sodium plasma immersion ion implantation and deposition, 26 Biomaterials 5465 (2005). * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8859002B2 (en) * | 2008-07-22 | 2014-10-14 | Consejo Superior De Investigaciones Cientificas | Method for the dry dispersion of nanoparticles and the production of hierarchical structures and coatings |
US20120107405A1 (en) * | 2008-07-22 | 2012-05-03 | Consejo Superior De Investigaciones Cient¿¿Ficas | Method for the dry dispersion of nanoparticles and the production of hierarchical structures and coatings |
US9345803B2 (en) | 2009-12-24 | 2016-05-24 | Advanced Medical Solutions Limited | Absorbent material |
WO2012135422A3 (en) * | 2011-04-01 | 2012-12-27 | University Of Florida Research Foundation, Inc. | Thermo-sensitive, mucoadhesive or dermoadhesive, and penetration-enhancing formulations for topical delivery of therapeutics |
US9056137B2 (en) | 2011-04-01 | 2015-06-16 | University Of Florida Research Foundation, Incorporated | Thermo-sensitive, mucoadhesive or dermoadhesive, and penetration-enhancing formulations for topical delivery of therapeutics |
US9339548B2 (en) | 2011-04-01 | 2016-05-17 | University Of Florida Research Foundation, Incorporated | Thermo-sensitive, mucoadhesive or dermoadhesive, and penetration-enhancing formulations for topical delivery of therapeutics |
US9610378B2 (en) * | 2012-01-19 | 2017-04-04 | Cg Bio Co., Ltd. | Antimicrobial wound-covering material and method for manufacturing same |
US20140377331A1 (en) * | 2012-01-19 | 2014-12-25 | Cg Bio Co., Ltd. | Antimicrobial wound-covering material and method for manufacturing same |
US9730679B1 (en) * | 2012-12-21 | 2017-08-15 | University Of South Florida | Device for sterile uterine sampling and drug delivery |
WO2014126570A3 (en) * | 2013-02-14 | 2015-07-30 | California Institute Of Technology | Crosslinked polymer electrolyte |
US20150380767A1 (en) * | 2013-02-14 | 2015-12-31 | California Institute Of Technology | Crosslinked polymer electrolyte |
US10547082B2 (en) * | 2013-02-14 | 2020-01-28 | California Institute Of Technology | Crosslinked polymer electrolyte |
WO2019235755A1 (en) * | 2018-06-08 | 2019-12-12 | 주식회사 아이센스 | Crosslinker comprising genipin for use in preparation of sensing film or diffusion control film of electrochemical sensor |
JP2021525371A (en) * | 2018-06-08 | 2021-09-24 | アイセンス,インコーポレーテッド | Crosslinker for manufacturing sensing or diffusion control membranes of electrochemical sensors containing genipin |
EP3805304A4 (en) * | 2018-06-08 | 2022-03-02 | i-Sens, Inc. | Crosslinker comprising genipin for use in preparation of sensing film or diffusion control film of electrochemical sensor |
JP7160950B2 (en) | 2018-06-08 | 2022-10-25 | アイセンス,インコーポレーテッド | Cross-linking agent for the production of sensing membranes or diffusion control membranes of electrochemical sensors containing genipin |
CN110333216A (en) * | 2018-12-29 | 2019-10-15 | 厦门市普识纳米科技有限公司 | The detection method of xacin-series antibiotic in a kind of animal foodstuff |
CN114514293A (en) * | 2019-08-29 | 2022-05-17 | 法国比克公司 | Method for preparing aqueous gel ink with variable colour comprising silver nanoparticles |
WO2021098892A1 (en) | 2019-11-23 | 2021-05-27 | Grade Medical s.r.o. | Device for the preparation of functionalised substances |
US20220104733A1 (en) * | 2020-10-06 | 2022-04-07 | Zense-Life Inc. | Working wire for a continuous biological sensor with an enzyme immobilization network |
Also Published As
Publication number | Publication date |
---|---|
US8927018B2 (en) | 2015-01-06 |
US20130142885A1 (en) | 2013-06-06 |
WO2009025955A1 (en) | 2009-02-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8927018B2 (en) | Immobilized metallic nanoparticles as unique materials for therapeutic and biosensor applications | |
EP2167045B1 (en) | Topical poloxamer formulations for enhancing microvascular flow: compositions and uses thereof | |
Huang et al. | Gold nanoparticles-loaded polyvinylpyrrolidone/ethylcellulose coaxial electrospun nanofibers with enhanced osteogenic capability for bone tissue regeneration | |
EP2437755B1 (en) | Surface active agent compositions and methods for enhancing oxygenation, reducing bacteria and improving wound healing | |
US8623403B2 (en) | Methods for regulating gelation of hydrogel solutions and uses thereof | |
Tonglairoum et al. | Fabrication of mucoadhesive chitosan coated polyvinylpyrrolidone/cyclodextrin/clotrimazole sandwich patches for oral candidiasis | |
Wsoo et al. | Vitamin D3-loaded electrospun cellulose acetate/polycaprolactone nanofibers: Characterization, in-vitro drug release and cytotoxicity studies | |
Tonglairoum et al. | Fast-acting clotrimazole composited PVP/HPβCD nanofibers for oral candidiasis application | |
Wu et al. | Advancement of Near-infrared (NIR) laser interceded surface enactment of proline functionalized graphene oxide with silver nanoparticles for proficient antibacterial, antifungal and wound recuperating therapy in nursing care in hospitals | |
US11680143B2 (en) | Porous material with microscale features | |
Al-Baadani et al. | In situ preparation of alendronate-loaded ZIF-8 nanoparticles on electrospun nanofibers for accelerating early osteogenesis in osteoporosis | |
Tarawneh et al. | Characterization of Chlorhexidine‐Impregnated Cellulose‐Based Hydrogel Films Intended for the Treatment of Periodontitis | |
Deepak et al. | Development and characterization of novel medicated nanofiber for the treatment of periodontitis | |
US9682078B2 (en) | Compositions and methods for tissue engineering and cell based therapies | |
Takallu et al. | Development of antibacterial collagen membranes with optimal silver nanoparticle content for periodontal regeneration | |
Cesur | Combination techniques towards novel drug delivery systems manufacturing: 3D PCL scaffolds enriched with tetracycline-loaded PVP nanoparticles | |
Wang et al. | Novel design and development of Centella Asiatica extract-loaded poloxamer/ZnO nanocomposite wound closure material to improve anti-bacterial action and enhanced wound healing efficacy in diabetic foot ulcer | |
Khamene et al. | Fabrication and characterization of an innovative g-C3N4/calcium/aloe vera enriched PVA-bacterial cellulose wound dressing: A novel approach to diabetic wound management | |
Su et al. | Scalable Fabrication of Polymeric Composite Microspheres to Inhibit Oral Pathogens and Promote Osteogenic Differentiation of Periodontal Membrane Stem Cells | |
AU2015205871B2 (en) | Surface active agent compositions and methods for enhancing oxygenation, reducing bacteria and improving wound healing | |
US12121608B2 (en) | Biodegradable implant for sustained trans-nasal delivery of therapeutic agents to the brain | |
Shaloo et al. | Graphene and its composites used in research of dental and oral infection | |
Eren Boncu et al. | Formulation, characterization and evaluation of minocycline hydrochloride loaded polyurethane/collagen nanofibers via electrospinning as wound dressings | |
JP2024156651A (en) | Porous materials with microscale structures |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: UNIVERSITY OF VIRGINIA, VIRGINIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LAURENCIN, CATO T.;NAIR, LAKSHMI SREEDHARAN;SIGNING DATES FROM 20080605 TO 20080617;REEL/FRAME:021360/0402 |
|
AS | Assignment |
Owner name: UNIVERSITY OF VIRGINIA PATENT FOUNDATION, VIRGINIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:UNIVERSITY OF VIRGINIA;REEL/FRAME:021621/0436 Effective date: 20080826 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |