CN110339168B - Nanometer preparation loaded with anti-pulmonary fibrosis drug and immunomodulator and preparation method thereof - Google Patents
Nanometer preparation loaded with anti-pulmonary fibrosis drug and immunomodulator and preparation method thereof Download PDFInfo
- Publication number
- CN110339168B CN110339168B CN201910682539.2A CN201910682539A CN110339168B CN 110339168 B CN110339168 B CN 110339168B CN 201910682539 A CN201910682539 A CN 201910682539A CN 110339168 B CN110339168 B CN 110339168B
- Authority
- CN
- China
- Prior art keywords
- pulmonary fibrosis
- preparation
- drug
- nano
- immunomodulator
- 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.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 170
- 238000002360 preparation method Methods 0.000 title claims abstract description 139
- 229940079593 drug Drugs 0.000 title claims abstract description 138
- 208000005069 pulmonary fibrosis Diseases 0.000 title claims abstract description 99
- 239000002955 immunomodulating agent Substances 0.000 title claims abstract description 55
- 229940121354 immunomodulator Drugs 0.000 title claims abstract description 55
- 230000002584 immunomodulator Effects 0.000 title claims abstract description 41
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 49
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 68
- 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 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 229960001338 colchicine Drugs 0.000 claims description 34
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 claims description 34
- 229960004378 nintedanib Drugs 0.000 claims description 34
- 239000002105 nanoparticle Substances 0.000 claims description 33
- 235000012000 cholesterol Nutrition 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 28
- 239000002245 particle Substances 0.000 claims description 27
- 239000012071 phase Substances 0.000 claims description 27
- 150000003904 phospholipids Chemical class 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 22
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 18
- 238000009472 formulation Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 206010016654 Fibrosis Diseases 0.000 claims description 14
- 230000004761 fibrosis Effects 0.000 claims description 14
- 239000006185 dispersion Substances 0.000 claims description 11
- 230000002209 hydrophobic effect Effects 0.000 claims description 11
- -1 DMPE Chemical compound 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical group CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 8
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 8
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 8
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 8
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 8
- 229960001967 tacrolimus Drugs 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 239000002502 liposome Substances 0.000 claims description 7
- 230000002441 reversible effect Effects 0.000 claims description 7
- 239000010409 thin film Substances 0.000 claims description 7
- 238000001132 ultrasonic dispersion Methods 0.000 claims description 7
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 5
- 229960002170 azathioprine Drugs 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 claims description 5
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 4
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 4
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 4
- 108010036949 Cyclosporine Proteins 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- 229960001265 ciclosporin Drugs 0.000 claims description 4
- 229960004544 cortisone Drugs 0.000 claims description 4
- 229960004397 cyclophosphamide Drugs 0.000 claims description 4
- 229930182912 cyclosporin Natural products 0.000 claims description 4
- 229960001428 mercaptopurine Drugs 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims description 4
- 229960004866 mycophenolate mofetil Drugs 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 229960003073 pirfenidone Drugs 0.000 claims description 4
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 4
- 229960004618 prednisone Drugs 0.000 claims description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 4
- 229960002930 sirolimus Drugs 0.000 claims description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 4
- MWRBNPKJOOWZPW-GPADLTIESA-N 1,2-di-[(9E)-octadecenoyl]-sn-glycero-3-phosphoethanolamine Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C\CCCCCCCC MWRBNPKJOOWZPW-GPADLTIESA-N 0.000 claims description 3
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 3
- DSNRWDQKZIEDDB-SQYFZQSCSA-N 1,2-dioleoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-SQYFZQSCSA-N 0.000 claims description 3
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 claims description 3
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 3
- PAZGBAOHGQRCBP-DDDNOICHSA-N 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-DDDNOICHSA-N 0.000 claims description 3
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 3
- UTGQNNCQYDRXCH-UHFFFAOYSA-N N,N'-diphenyl-1,4-phenylenediamine Chemical compound C=1C=C(NC=2C=CC=CC=2)C=CC=1NC1=CC=CC=C1 UTGQNNCQYDRXCH-UHFFFAOYSA-N 0.000 claims description 3
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 claims description 3
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims description 3
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 claims description 3
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 claims description 3
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 claims description 3
- 229940124644 immune regulator Drugs 0.000 claims description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 3
- 239000008347 soybean phospholipid Substances 0.000 claims description 3
- 102000006395 Globulins Human genes 0.000 claims description 2
- 108010044091 Globulins Proteins 0.000 claims description 2
- 230000000781 anti-lymphocytic effect Effects 0.000 claims description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims description 2
- 102100026802 72 kDa type IV collagenase Human genes 0.000 claims 3
- 101710151806 72 kDa type IV collagenase Proteins 0.000 claims 3
- 239000011159 matrix material Substances 0.000 abstract description 6
- 101710180316 Protease 2 Proteins 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 229940126585 therapeutic drug Drugs 0.000 abstract description 2
- 238000005728 strengthening Methods 0.000 abstract 1
- 239000010408 film Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 210000000651 myofibroblast Anatomy 0.000 description 11
- 210000002950 fibroblast Anatomy 0.000 description 10
- 230000010355 oscillation Effects 0.000 description 10
- 238000002390 rotary evaporation Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000000108 ultra-filtration Methods 0.000 description 10
- 230000004913 activation Effects 0.000 description 9
- 210000003712 lysosome Anatomy 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 229940083466 soybean lecithin Drugs 0.000 description 8
- 102000008186 Collagen Human genes 0.000 description 7
- 108010035532 Collagen Proteins 0.000 description 7
- 229920001436 collagen Polymers 0.000 description 7
- 108010033276 Peptide Fragments Proteins 0.000 description 5
- 102000007079 Peptide Fragments Human genes 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 230000001868 lysosomic effect Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108010091175 Matriptase Proteins 0.000 description 3
- 102100037942 Suppressor of tumorigenicity 14 protein Human genes 0.000 description 3
- 239000003470 adrenal cortex hormone Substances 0.000 description 3
- VBVAVBCYMYWNOU-UHFFFAOYSA-N coumarin 6 Chemical compound C1=CC=C2SC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 VBVAVBCYMYWNOU-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 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 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002300 anti-fibrosis Effects 0.000 description 2
- 230000003510 anti-fibrotic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101000713575 Homo sapiens Tubulin beta-3 chain Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 102100036790 Tubulin beta-3 chain Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000005931 immune cell recruitment Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Pulmonology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a nano preparation loaded with anti-pulmonary fibrosis drugs and an immunomodulator and a preparation method thereof. On the other hand, by utilizing the nano preparation modified by the metal matrix protease-2 (MMP-2) specific sensitive peptide segment and the carrier thereof, the rapid and large-scale release of therapeutic drugs including immunomodulators and anti-pulmonary fibrosis drugs is realized by means of the MMP-2 specific sensitive peptide segment, thereby providing a new way and strategy for strengthening the treatment of pulmonary fibrosis.
Description
Technical Field
The invention discloses a nano preparation loaded with anti-pulmonary fibrosis drugs and an immunomodulator and a preparation method thereof.
Background
Pulmonary fibrosis is a progressive interstitial lung disease with extremely high lethality, and the survival period is 3-5 years. In recent years, with the intensive research, the occurrence and the development of pulmonary fibrosis are closely related to the over-activation of the immune system. When AT2 is damaged, damaged or apoptotic epithelial cells secrete large amounts of inflammatory factors and peroxides that recruit bone marrow-derived immune cells to migrate into the damaged lung. At this time, a large number of immune cells are accumulated in the lung, proliferate in a large amount, secrete proinflammatory factors, activate fibroblasts to transform into myofibroblasts, and the activated myofibroblasts secrete excessive collagen to fill damaged parts in the alveoli, so that the lung parenchyma is destroyed, and the intercellular spaces are squeezed and filled with collagen, thereby forming pulmonary fibrosis. At present, two oral drugs for resisting pulmonary fibrosis, namely pirfenidone and nintedanib, are approved by the FDA. The main treatment mechanism is that the activation of myofibroblasts is inhibited so as to reduce the accumulation of collagen, but the aim of treating the initial stage of fibrosis is not fulfilled, so that the two marketed drugs can only delay the development of the disease, but cannot radically treat the pulmonary fibrosis.
In the development process of pulmonary fibrosis, a large number of proliferated macrophages can secrete a large number of inflammatory factors under the stimulation of a pulmonary fibrosis microenvironment, including TNF- β -4, IL-13, IL-1 β and the like, inflammatory response is further aggravated, lung fibroblasts are transformed into myofibroblasts, and activated myofibroblasts secrete a large number of collagens and accumulate, so that the fibrosis process is accelerated.
Despite the growing interest in disease treatment, the nano-formulations still lack effective therapeutic drugs or therapeutic systems for the treatment of pulmonary fibrosis.
Disclosure of Invention
The purpose is as follows: in order to overcome the defects in the existing pulmonary fibrosis treatment, the invention discloses a nano preparation loaded with anti-pulmonary fibrosis drugs and an immunomodulator and a preparation method thereof.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
according to a first aspect of the present invention, there is provided a nano-formulation vehicle for loading an anti-pulmonary fibrosis drug (M) and an immunomodulator (N), the nano-formulation vehicle comprising a phospholipid X-PEG-MAL, a phospholipid Y, cholesterol B and a sensitive peptide segment Z;
wherein X is a hydrophobic segment, X is selected from the group consisting of DSPE, DPPE, DMPE, DOPE; MAL is a maleimide group;
y is phospholipid including egg yolk lecithin, hydrogenated soybean lecithin and various synthetic phospholipids (DPPD, DOPS, DEPE, DMPE, DSPE, DPPE, DOPE, DOPG, EPG, POPG, DPPG, DSPG, DMPG, DPPA, DEPC, DOPC, DMPC, POPC, DSPC, DPPC);
the sensitive peptide segment Z contains a hydrophilic amino acid segment Z1 and a hydrophobic segment Z2, and Z1 comprises peptide segments and proteins containing PLGIAG; z2 is a C10 or higher linear or branched saturated/unsaturated alkane.
Further, the anti-pulmonary fibrosis drug comprises a hydrophobic anti-pulmonary fibrosis drug and/or a hydrophilic and hydrophobic anti-pulmonary fibrosis drug;
the immunomodulator is a drug or a bioactive molecule for regulating and controlling the secretion of proinflammatory factors, and the anti-pulmonary fibrosis drug is a drug or a bioactive molecule for inhibiting the activation of myofibroblasts and the accumulation of collagen;
wherein the anti-pulmonary fibrosis drug is selected from one or more of pirfenidone and nintedanib;
the immunomodulator is selected from one or more of cortisone, prednisone, cyclosporine, tacrolimus, azathioprine, 6-mercaptopurine, anti-lymphocyte globulin, OKT3, cyclophosphamide, tacrolimus, rapamycin, adrenocortical hormone, glucocorticoid, methotrexate, and mycophenolate mofetil. The long circulation of the polymer micelle in vivo is realized through PEG, more preferably, the rapid release of the anti-pulmonary fibrosis drug M and the immunomodulator N is realized through the MMP-2 sensitive peptide segment, and the efficient treatment of pulmonary fibrosis is realized.
Further, the sensitive peptide segment Z of the nano-preparation carrier is a sensitive peptide segment DPZ modified with MMP-2 or a sensitive peptide segment DP unmodified with MMP-2.
More preferably, the anti-pulmonary fibrosis drug M is nintedanib, and the immunomodulator N is colchicine. The nano preparation loaded with the anti-pulmonary fibrosis drug and the immunomodulator is simultaneously loaded with the nintedanib and the colchicine. The colchicine is adopted to regulate the activation state of an immune system in a pulmonary fibrosis microenvironment, and the strategy of inhibiting the sustained activation of myofibroblasts by the nintedanib provides a new way and strategy for designing the medicine for treating pulmonary fibrosis.
According to another aspect of the present invention, there is provided a nano-formulation loaded with anti-pulmonary fibrosis drugs and immunomodulators, wherein the nano-formulation is loaded with anti-pulmonary fibrosis drugs and immunomodulators, which comprises DPZ/MN, DPZ/M, DPZ/N, DP/MN, DP/M, DP/N. The anti-pulmonary fibrosis drug can also comprise an antioxidant and an inhibitor at the same time, or one selected from the antioxidant and the inhibitor. The anti-pulmonary fibrosis drug is a drug or a biomolecule for inhibiting the activation of myofibroblasts, and the immunomodulator is a drug or a biomolecule for regulating the activation state of immune cells.
1) Immunomodulators:
cortisone, prednisone, cyclosporin, tacrolimus, 6-mercaptopurine, antilymphoglobulin, OKT3, cyclophosphamide, tacrolimus, rapamycin, adrenocortical hormone, glucocorticoid, azathioprine, methotrexate, mycophenolate mofetil, etc
2) Anti-pulmonary fibrosis drugs: pirfenidone, nintedanib.
The anti-pulmonary fibrosis drug comprises drugs or biomolecules for inhibiting myofibroblast activation and reducing collagen generation, and the immunomodulator is a drug or a biomolecule for regulating and controlling immune cell activation state.
Specifically, the preparation method of DPZ/MN is as follows:
dissolving hydrophobic anti-pulmonary fibrosis drug M/immunomodulator N, X-PEG-MAL, phospholipid Y, cholesterol and sensitive peptide DPZ modified with MMP-2 in an organic solvent, and mixing to form an organic phase;
dissolving hydrophilic anti-pulmonary fibrosis drug M/immunomodulator N in water phase,
preparing nanoparticles loaded with anti-pulmonary fibrosis drugs and immune modulators by a thin film dispersion method, an injection method, an ultrasonic dispersion method or a reverse evaporation method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
In the reaction, the mass ratio of the added X-PEG-MAL, the phospholipid Y, the cholesterol and the sensitive peptide segment Z is 1 (10-50) to (5-10).
DPZ/M
Firstly, dissolving an anti-pulmonary fibrosis drug M in an organic solvent/water phase, and dissolving X-PEG-MAL, phospholipid Y, cholesterol and a sensitive peptide segment DPZ modified with MMP-2 in the organic solvent;
preparing nanoparticles loaded with anti-pulmonary fibrosis drugs by a film dispersion method, an injection method, an ultrasonic dispersion method and a reverse evaporation method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
DPZ/N
Dissolving X-PEG-MAL, phospholipid Y, sensitive peptide DPZ and cholesterol in an organic solvent;
dissolving an immunomodulator N in a water phase/an organic phase, and preparing nanoparticles loaded with the immunomodulator by a thin film dispersion method, an injection method, an ultrasonic dispersion method and a reverse evaporation method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
The invention also prepares DP/MN which is not modified with sensitive peptide segment DP of MMP-2 and contains anti-pulmonary fibrosis drug M and immunomodulator N, DP/M which is not modified with sensitive peptide segment DP of MMP-2 and only contains anti-pulmonary fibrosis drug M and DP/N which is not modified with sensitive peptide segment DP of MMP-2 and only contains immunomodulator N, and the preparation method of the carrier materials is the same as the method.
The preparation method of DP/MN is as follows:
dissolving hydrophobic anti-pulmonary fibrosis drug M/immunomodulator N, X-PEG-MAL, phospholipid Y, cholesterol and sensitive peptide DP which is not modified with MMP-2 in an organic solvent, and mixing to form an organic phase;
dissolving hydrophilic anti-pulmonary fibrosis drug M/immunomodulator N in water phase,
preparing nanoparticles loaded with anti-pulmonary fibrosis drugs and immune modulators by a thin film dispersion method, an injection method, an ultrasonic dispersion method and a reverse evaporation method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
In addition, the invention also provides a preparation method of DPZ/M and DPZ/N, which comprises the following steps:
the DP/M and DP/N were prepared as follows:
DP/M
firstly, dissolving an anti-pulmonary fibrosis drug M in an organic solvent/water phase, and dissolving X-PEG-MAL, phospholipid Y and cholesterol in the organic solvent;
and (2) preparing the nanoparticles loaded with the anti-pulmonary fibrosis drug by a film dispersion method, an injection method, an ultrasonic dispersion method and a reverse evaporation method.
DP/N
Dissolving X-PEG-MAL, phospholipid Y and cholesterol in an organic solvent;
and (2) dissolving the immunomodulator N in a water phase or an organic solvent, and preparing the immunomodulator-loaded nanoparticles by a thin film dispersion method, an injection method, an ultrasonic dispersion method and a reverse evaporation method.
Preferably, the nano preparation loaded with the anti-pulmonary fibrosis drug and the immunomodulator is X-PEG-MAL, wherein the molecular weight range of X is 1000-50000, and the molecular weight range of PEG is 200-10000. More preferably, PEG with a molecular weight of 2000 is used.
Preferably, in the nano preparation, the drug loading rate of the loaded anti-pulmonary fibrosis drug M is between 2% and 30%, the drug loading rate of the loaded immune regulator N is between 1% and 40%, and the particle size of the nano preparation is between 20 nm and 600 nm.
According to another aspect of the invention, the invention also claims the application of the nano preparation carrier and the nano preparation loaded with the anti-pulmonary fibrosis drug and the immunomodulator in the preparation of the drug for treating pulmonary fibrosis diseases.
The invention discloses a nano preparation loaded with anti-pulmonary fibrosis drugs and an immunomodulator and a preparation method thereof, and relates to a nano preparation modified by a metal matrix protease-2 (MMP-2) specific sensitive synthetic peptide segment and a carrier thereof. The nano preparation can responsively release a large amount of immunomodulators and anti-pulmonary fibrosis drugs in the nano preparation in a fibrosis microenvironment, and rapidly block the progress of fibrosis under immune overactivation. Characterized in that the carrier comprises a chemical drug loading component, an MMP-2 response release part. The chemical drug loading component is amphiphilic polymer with PEG modification at the tail end, long circulation can be realized in vivo, and the sensitive peptide segment DPZ can rapidly release a large amount of drugs at the fibrosis part to achieve the treatment purpose.
Has the advantages that: the invention discloses a nano preparation loaded with anti-pulmonary fibrosis drugs and immunomodulators and a preparation method thereof, and the nano preparation has the following advantages: (1) the nano-preparation carrier for loading the anti-pulmonary fibrosis drug (M) and the immunomodulator (N) is a nano-carrier with a double-layer structure, so that the entrapment of fat-soluble and water-soluble drugs can be well realized, and the PEG in the carrier can prolong the circulation time of the carrier in blood. (2) MMP-2 in the carrier can be efficiently and rapidly released in a pulmonary fibrosis microenvironment. The carrier can realize the high-efficiency release of the nano-drug and quickly reach the drug effect concentration for treatment. The anti-pulmonary fibrosis drug can effectively inhibit the activation of fibroblasts, and the immune activation state of the pulmonary fibrosis microenvironment can be efficiently regulated and controlled by the immune regulator, so that the aim of efficiently treating pulmonary fibrosis is fulfilled. MMP-2 specifically shears the sensitive peptide segment to realize sensitive release of the drug, thereby achieving the purpose of treating pulmonary fibrosis. The nanometer preparation contains anti-pulmonary fibrosis drugs and immunomodulators, and the purpose of effectively treating pulmonary fibrosis is achieved by respectively regulating the proliferation condition of immune cells and inhibiting the activation of myofibroblasts so as to reduce collagen secretion. Furthermore, the invention utilizes the characteristic of high MMP-2 expression in the lung microenvironment, realizes the strategy of effective drug release by specifically identifying and decomposing sensitive peptide fragments, and simultaneously adopts double drugs to cooperatively regulate and control the pulmonary fibrosis microenvironment, thereby providing a new way and strategy for effective release and effective treatment of anti-pulmonary fibrosis drugs. At present, the amphiphilic block phospholipid is widely applied by simultaneously loading hydrophilic and hydrophobic drugs by utilizing the amphiphilic characteristics of the amphiphilic block phospholipid, and the functionalized phospholipid comprises DSPE and DPPE; the natural phospholipids include egg yolk lecithin, hydrogenated soybean lecithin and soybean phospholipid and various synthetic phospholipids (DPPD, DOPS, DEPE, DMPE, DSPE, DPPE, DOPE, DOPG, EPG, POPG, DPPG, DSPG, DMPG, DPPA, DEPC, DOPC, DMPC, POPC, DSPC, DPPC).
The invention relates to a nanometer preparation loaded with anti-pulmonary fibrosis drugs and immunomodulators by utilizing functionalized phospholipids DSPE, DPPE, yolk lecithin, hydrogenated soybean lecithin, various functionalized phospholipids and the like, and a preparation method thereof, and relates to a nanometer preparation modified by synthetic polypeptide-metal matrix protease-2 (MMP-2) specific sensitive peptide and a carrier thereof. The nano preparation can responsively release a large amount of immunomodulators and anti-pulmonary fibrosis drugs in the nano preparation in a fibrosis microenvironment, and rapidly block the progress of fibrosis under immune overactivation.
Drawings
FIG. 1 is a schematic flow chart of the preparation of optimal formulation (DPZ/MN) nano-formulation in the present invention;
FIG. 2 shows the optimum ratio of each component of the nano-preparation prepared from the optimum preparation (DPZ/MN) of the present invention;
FIG. 3 is a UV full wavelength scan of the best formulation (DPZ/MN) encapsulated dual drug of the present invention;
FIG. 4 is a particle size distribution of the best preparation of the present invention (DPZ/MN);
FIG. 5 is a graph of the nanoparticle size and potential distribution of other formulations of the present invention (DP/MN, DPZ/M, DPZ/N);
FIG. 6 is a graph showing the responsive release of the best preparation (DPZ/MN) of the present invention under conditions of high MMP-2 expression;
FIG. 7 is a graph of the lysosomal escape of the best preparation of the invention (DPZ/MN);
FIG. 8 is a graph showing the anti-fibrotic effect of the nano-preparations prepared by the present invention at the cellular level (using the expression of α -SMA as the determination index).
Detailed Description
The invention will be further described with reference to the following drawings and specific embodiments.
Example 1 synthesis and preparation of nano-formulation components, as shown in fig. 1, a flow diagram for DPZ/MN nano-formulation preparation is shown, and the ratio of each formulation feed is shown in fig. 2:
preparation of nanoparticles containing sensitive peptide segment DPZ entrapped dual drugs and containing DSPE-PEG-MAL, soybean lecithin (PC) and cholesterol
1. Preparation of sensitive peptide segment DPZ entrapped dual-drug nanoparticle
Firstly, dissolving the anti-hydrophobic pulmonary fibrosis drug M, the X-PEG-MAL, the phospholipid Y, the sensitive peptide segment DPZ and the cholesterol in an organic solvent and then mixing. Dissolving a hydrophilic drug N in a water phase, and preparing nanoparticles loaded with anti-pulmonary fibrosis drugs and immune modulators by a thin film dispersion method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
The invention preferably adopts a film dispersion method to prepare the nanoparticles coated with the anti-pulmonary fibrosis drug (nintedanib/colchicine). The preparation method comprises the following steps:
80 mg of PC, 10mg of DSPE-PEG-MAL, 15mg of cholesterol, 2mg of sensitive peptide fragment DPZ and 5mg of nintedanib are weighed and dissolved in 10 mL of CH2Cl2In the solution, the nanometer preparation containing 5mg of colchicine needs to be dissolved in water phase. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
1) Immunomodulators:
cortisone, prednisone, cyclosporin, tacrolimus, azathioprine, 6-mercaptopurine, antilymphoglobulin, OKT3, cyclophosphamide, tacrolimus, rapamycin, adrenocortical hormone, glucocorticoid, azathioprine, methotrexate, mycophenolate mofetil, etc
2) Anti-pulmonary fibrosis drugs: nintedanib.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2% -30%, the drug loading of the immunomodulator N in the nano preparation is 1% -40%, and the particle size of the nano preparation is 20 nm-600 nm. The optimal preparation (DPZ/(nintedanib/colchicine)) in this example has uniform particle size distribution and uniform morphology. The successful entrapment of the nano preparation for double drugs is shown in fig. 3, which proves that the preparation DPZ can entrap the anti-pulmonary fibrosis drug M and the immunomodulator N for treating diseases. The particle size distribution of the optimal preparation is shown in fig. 4, and the particle size distribution of the nano preparation is proved to be uniform and the shape is uniform. The particle size of other preparations is shown in FIG. 5, and all groups of nano preparations have uniform particle size distribution and uniform shape.
2. Preparation of sensitive peptide segment DPZ entrapped single drug (nintedanib) or entrapped single drug (colchicine) nanoparticle
Packing single medicine (Nidamib)
80 mg of PC, 10mg of DSPE-PEG-MAL, 15mg of cholesterol, 2mg of sensitive peptide fragment DPZ and 5mg of nintedanib are weighed and dissolved in 10 mL of CH2Cl2In solution. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2% -30%, and the particle size of the nano preparation is 20 nm-600 nm. The optimal preparation (DPZ/(nintedanib)) of the invention has the advantages of uniform particle size distribution and uniform shape of the nano preparation.
Packing single medicine (colchicine)
Weighing 80 mg PC, 10mg DSPE-PEG-MAL, 15mg cholesterol, 2mg sensitive peptide DPZ, and dissolving in 10 mLCH2Cl2In solution. Dissolving colchicine 5mg in water phase, and dissolving in water bath. And (3) carrying out rotary evaporation on the volatile organic solvent at the temperature of 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading rate of the immunomodulator N in the nano preparation is 1-40%, and the particle size of the nano preparation is 20-600 nm. The optimal preparation (DPZ/(colchicine)) of the invention has the advantages of nano preparation particle size distribution, uniform particle size distribution and uniform shape.
Secondly, preparing nanoparticles containing sensitive peptide fragments DP and containing DSPE-PEG-MAL, soybean lecithin (PC) and cholesterol entrapped with double drugs/single drugs
1. Preparation of DP-entrapped double-drug (Nintedanib and colchicine) nanoparticle containing sensitive peptide segment
Firstly, dissolving the anti-hydrophobic pulmonary fibrosis drug M, the X-PEG-MAL, the phospholipid Y, the cholesterol and the sensitive peptide DP in an organic solvent and then mixing. Dissolving a hydrophilic drug N in a water phase, and preparing nanoparticles loaded with anti-pulmonary fibrosis drugs and immune modulators by a thin film dispersion method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
The invention preferably adopts a film dispersion method to prepare PLGA-PEG-MAL nanoparticles coated with anti-pulmonary fibrosis drug (Nintedanib/colchicine). The preparation method comprises the following steps:
80 mg of PC, 10mg of DSPE-PEG-MAL, 15mg of cholesterol, 5mg of nintedanib dissolved in 10 mL of CH are weighed2Cl2In the solution, the nanometer preparation containing 5mg of colchicine needs to be dissolved in water phase. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
2. Preparation of sensitive peptide DP entrapped single drug (nintedanib) or entrapped single drug (colchicine) nanoparticle
Packing single medicine (Nidamib)
80 mg of PC, 10mg of DSPE-PEG-MAL, 15mg of cholesterol, sensitive peptide fragment DP and 5mg of nintedanib are weighed and dissolved in 10 mL of CH2Cl2In solution. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
Packing single medicine (colchicine)
80 mg of PC, 10mg of DSPE-PEG-MAL and 15mg of cholesterol were dissolved in 10 mL of CH2Cl2In solution. Dissolving colchicine 5mg in water phase, and dissolving in water bath. And (3) carrying out rotary evaporation on the volatile organic solvent at the temperature of 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2-30%, the drug loading of the immunomodulator N in the nano preparation is 1-40%, and the particle size of the nano preparation is 20-600 nm. The optimal preparation (DPZ/(nintedanib/colchicine)) of the invention has uniform particle size distribution and uniform shape of the nano preparation.
Preparation of nanoparticles containing sensitive peptide DPZ/sensitive peptide DP entrapped with double drugs/single drug and containing DSPE-PEG, egg yolk lecithin and cholesterol
Weighing 80 mg egg yolk lecithin, 10mg DSPE-PEG-MAL, 15mg cholesterol, 2mg sensitive peptide DPZ/sensitive peptide DP and 5mg nintedanib, and dissolving in 10 mL CH2Cl2In the solution, the nanometer preparation containing 5mg of colchicine needs to be dissolved in water phase. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2-30%, the drug loading of the immunomodulator N in the nano preparation is 1-40%, and the particle size of the nano preparation is 20-600 nm. The optimal preparation (DPZ/(nintedanib/colchicine)) of the invention has uniform particle size distribution and uniform shape of the nano preparation.
Preparation of nanoparticles containing DSPE-PEG-MAL, soybean lecithin and cholesterol and containing sensitive peptide segment DPZ/sensitive peptide segment DP entrapped double drugs/single drug
Weighing 80 mg soybean phospholipid, 10mg DSPE-PEG, 15mg cholesterol, 2mg sensitive peptide DPZ/sensitive peptide DP and 5mg nintedanib, and dissolving in 10 mL CH2Cl2In the solution, the nanometer preparation containing 5mg of colchicine needs to be dissolved in water phase. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2-30%, the drug loading of the immunomodulator N in the nano preparation is 1-40%, and the particle size of the nano preparation is 20-600 nm. The optimal preparation (DPZ/(nintedanib/colchicine)) of the invention has uniform particle size distribution and uniform shape of the nano preparation.
Fifthly, preparation of nanoparticles containing DPPE-PEG-MAL, soybean lecithin and cholesterol and containing sensitive peptide segment DPZ/sensitive peptide segment DP entrapped double drugs/single drugs
Weighing 80 mg soybean lecithin, 10mg DPPE-PEG, 15mg cholesterol, 2mg sensitive peptide DPZ/sensitive peptide DP and 5mg nintedanib, and dissolving in 10 mL CH2Cl2In the solution, the nanometer preparation containing 5mg of colchicine needs to be dissolved in water phase. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2% -30%, the drug loading of the immunomodulator N in the nano preparation is 1% -40%, and the particle size of the nano preparation is 20 nm-600 nm. The optimal preparation (DPZ/(nintedanib/colchicine)) of the invention has uniform particle size distribution and uniform shape of the nano preparation.
Sixthly, preparation of nanoparticles containing DPPE-PEG-MAL, synthetic phospholipid and cholesterol with double drugs/single drugs encapsulated by sensitive peptide segment DPZ/sensitive peptide segment DP
80 mg of synthetic phospholipid, 10mg of DPPE-PEG, 15mg of cholesterol, 2mg of sensitive peptide DPZ/sensitive peptide DP) and 5mg of nintedanib were dissolved in 10 mL of CH2Cl2In the solution, the nanometer preparation containing 5mg of colchicine needs to be dissolved in water phase. And (3) carrying out rotary evaporation on the volatile organic solvent under the condition of water bath at 45 ℃, forming a film, adding the water phase into the flask, carrying out ultrasonic oscillation for 30min, and centrifuging at 2500rpm/min for 20 min to remove the free medicine which is not entrapped. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
The drug loading of the anti-pulmonary fibrosis drug M in the nano preparation is 2-30%, the drug loading of the immunomodulator N in the nano preparation is 1-40%, and the particle size of the nano preparation is 20-600 nm. The optimal preparation (DPZ/(nintedanib/colchicine)) of the invention has uniform particle size distribution and uniform shape of the nano preparation.
Example 2 Release of Nanodiormulations under conditions of high MMP-2 expression
Nanoparticulations of DPZ/(nintedanib/colchicine), DPZ/(nintedanib), DPZ/(colchicine), DP/(nintedanib/colchicine), DP/(nintedanib), DP/(colchicine) were prepared as described in example 1. After the nano preparation is concentrated to 500 mu L and 10 mu g/mL MMP-2 matriptase is added, the nano preparation is placed at 37 ℃ for 24h, and a particle size analyzer is used for measuring the drug release rate of the nano preparation under the stimulation of MMP-2 high expression condition.
(1) MMP-2 matriptase is added into the nano preparation containing MMP-2, the nano preparation without MMP-2 and the nano preparation containing MMP-2 through an ultraviolet spectrophotometer, the nano preparation without MMP-2 matriptase and colchicine are scanned at a full wavelength of 200nm-800nm, and the drug release rate under the action of MMP-2 is investigated.
The particle size data obtained in this example are shown in fig. 6, and the change in particle size of the nanoparticles was measured before and after the stimulation. Before the stimulation of matrix enzyme containing MMP-2 is not carried out, the release rate of colchicine is very slow, after the matrix enzyme containing MMP-2 is carried out, the nano preparation is destroyed to release a large amount of medicaments, and characteristic absorption peaks of the released colchicine in the nano preparation acted by the matrix enzyme containing MMP-2 can be observed at 245nm and 350 nm.
Example 3 examination of the escape ability of the Nanopropreparations in Primary fibroblasts Using coumarin 6 as a model drug
A nano-formulation of DP/coumarin 6 was prepared as described in example 1. Primary fibroblasts were plated at2 × 104Perml/mL in confocal Petri dish at 37 ℃ 5% C02After the cells grow for 24 hours in the cell incubator by adherence, the culture medium is aspirated, 1mL (10 mu g/mL) of coumarin 6 nanometer preparation is respectively added, and the cells are respectively incubated with the fibroblasts for 30min, 1 hour and 4 hours later. Washed three times with PBS, incubated for 10min with cell fixative, and washed three times with PBS. Then lysotraker red lysosomal dye was added at 37 ℃ with 5% CO2After washing with PBS three times, the escape of the nanopreparations in primary fibroblasts at different time points was determined using laser confocal (LSM-700).
The lysosome escape of the nano preparation measured in the embodiment is shown in fig. 7, and at 30min, the green fluorescence for marking the nano preparation is coincided with the red fluorescence marked by the cell lysosome, which proves that the nano preparation can be taken up by cells at 30min, but mainly stays in the lysosome of the cells; after 1h, the green fluorescence for marking the nano preparation is partially separated from the red fluorescence marked by the cell lysosome, and red and green bright spots appear in the cell, which proves that the nano preparation can escape from the lysosome in 1h, but a part of the nano preparation still exists in the lysosome; after 4h, the green fluorescence for marking the nano preparation is completely separated from the red fluorescence marked by the cell lysosome, and red and green bright spots appear in the cell, so that the nano preparation can completely escape from the lysosome in 4h, and the drug is released to the cytoplasm to play a role;
EXAMPLE 4 examination of the anti-fibrotic Effect of Nanodiazole DPZ/MN and other groups
DPZ/MN, DPZ/M, DPZ/N, DP/MN Nanormulations were prepared as described in example 1. First, 6-8 week-old male C57BL/6 mice were usedThe primary fibroblast cells of (1) are used as model cells with drug effect, the cells after TGF- β stimulation are used as positive control, the cells without treatment and normal culture are used as negative control, firstly, 1 × 106And (3) plating in each hole, changing the medium into an incomplete medium containing 5 mu g/mL TGF- β to act for 24h when the cells grow to be full of 80%, adding different nano preparations into each group, and observing the expression condition of the related pulmonary fibrosis protein α -SMA of the fibroblast after each hole acts for 24h with the dosage of 200nM of nintedanib and 50nM of colchicine.
The results of the drug effect at the cell level show that the anti-fibrosis effect of different preparation groups, namely DPZ/MN > DP/MN > DPZ/M and DPZ/N > DP/M and DP/N > TGF- β (lung fibrosis model) shows that the drug can be rapidly released by adding MMP-2 and the lung fibrosis is treated by the synergistic effect of the two drugs, the nano preparation DPZ/MN has better anti-fibrosis effect compared with other preparation groups, and consistent with the results of the example 3, the nano preparation DPZ/MN can inhibit the transformation of the fibroblast to the myofibroblast.
The functionalized phospholipid comprises DSPE and DPPE; the natural phosphatide comprises yolk lecithin, hydrogenated soybean lecithin, soybean lecithin and various synthetic phosphatides which are common hydrophobic blocks with good biocompatibility, are often used as hydrophobic cores in amphiphilic block copolymers, and have better affinity to most of medicines with certain hydrophobicity. In the above examples, it is clear to those skilled in the art that the DPPE-PEG-MAL block copolymer is used instead of the DSPE-PEG-MAL block copolymer, and the egg yolk lecithin and the soybean lecithin are used instead of the soybean lecithin to load the drug having a certain hydrophobicity, thereby forming the polymer micelle.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (8)
1. A nano-preparation carrier for loading anti-pulmonary fibrosis drugs and immunomodulators is characterized in that: the nano preparation carrier comprises X-PEG-MAL, phospholipid Y, cholesterol B and a sensitive peptide segment Z;
wherein X is a hydrophobic segment, X is selected from the group consisting of DSPE, DPPE, DMPE, DOPE; MAL is a maleimide group;
y is phospholipid selected from egg yolk lecithin, hydrogenated soybean lecithin and soybean phospholipid and various synthetic phospholipids DPPD, DOPS, DEPE, DMPE, DSPE, DPPE, DOPE, DOPG, EPG, POPG, DPPG, DSPG, DMPG, DPPA, DEPC, DOPC, DMPC, POPC, DSPC, DPPC;
the anti-pulmonary fibrosis drug is selected from one or more of pirfenidone and nintedanib;
the immunomodulator is selected from one or more of cortisone, prednisone, cyclosporine, tacrolimus, azathioprine, 6-mercaptopurine, anti-lymphocyte globulin, OKT3, cyclophosphamide, tacrolimus, rapamycin, methotrexate, and mycophenolate mofetil;
the sensitive peptide segment Z is a sensitive peptide segment DPZ modified with MMP-2.
2. A nanometer preparation loaded with anti-pulmonary fibrosis drugs and immunomodulators is characterized in that: the nano-preparation carrier of claim 1 is loaded with anti-pulmonary fibrosis drug M and immunomodulator N, comprising DPZ/MN.
3. The nano-formulation loaded with anti-pulmonary fibrosis drug and immune modulator of claim 2, wherein: the anti-pulmonary fibrosis drug M is nintedanib, and the immunomodulator N is colchicine.
4. The nano-formulation loaded with anti-pulmonary fibrosis drug and immune modulator of claim 2, wherein: DPZ/MN preparation method:
dissolving hydrophobic anti-pulmonary fibrosis drug M/immunomodulator N, X-PEG-MAL, phospholipid Y, cholesterol and sensitive peptide DPZ modified with MMP-2 in an organic solvent to form an organic phase;
dissolving hydrophilic anti-pulmonary fibrosis drug M/immunomodulator N in water phase,
preparing nanoparticles loaded with anti-pulmonary fibrosis drugs and immune modulators by a thin film dispersion method, an injection method, an ultrasonic dispersion method or a reverse evaporation method; wherein MMP-2 in the liposome can realize the rapid release of the medicament in a fibrosis microenvironment, so that the medicament can rapidly take effect to achieve the treatment purpose.
5. The Nanoproliferative formulation loaded with anti-pulmonary fibrosis drugs and immunomodulators according to any one of claims 2 to 4, wherein: in the X-PEG-MAL, the molecular weight range of X is 1000-30000, and the molecular weight range of PEG is 200-10000.
6. The Nanoproliferative formulation loaded with anti-pulmonary fibrosis drugs and immunomodulators according to any one of claims 2 to 4, wherein: in the nano preparation, the drug loading rate of the loaded anti-pulmonary fibrosis drug M is 2-30%, the drug loading rate of the loaded immune regulator N is 1-40%, and the particle size of the nano preparation is 20-600 nm.
7. The use of the nanoformulation carrier of claim 1 in the preparation of a medicament for the treatment of pulmonary fibrosis related diseases.
8. Use of the nano-formulation loaded with anti-pulmonary fibrosis drug and immunomodulator according to any of claims 2-6 in preparation of a medicament for treating pulmonary fibrosis related diseases.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910682539.2A CN110339168B (en) | 2019-07-26 | 2019-07-26 | Nanometer preparation loaded with anti-pulmonary fibrosis drug and immunomodulator and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910682539.2A CN110339168B (en) | 2019-07-26 | 2019-07-26 | Nanometer preparation loaded with anti-pulmonary fibrosis drug and immunomodulator and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110339168A CN110339168A (en) | 2019-10-18 |
CN110339168B true CN110339168B (en) | 2020-05-22 |
Family
ID=68180315
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910682539.2A Active CN110339168B (en) | 2019-07-26 | 2019-07-26 | Nanometer preparation loaded with anti-pulmonary fibrosis drug and immunomodulator and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110339168B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4308112A1 (en) * | 2021-03-18 | 2024-01-24 | Board of Regents, The University of Texas System | Compositions for delivery of drug combinations to treat lung disease |
CN113694213A (en) * | 2021-08-20 | 2021-11-26 | 锦州医科大学 | Nanometer preparation loaded with gene diagnosis probe and/or anti-pulmonary fibrosis drug and preparation method thereof |
CN113995855A (en) * | 2021-11-10 | 2022-02-01 | 中国药科大学 | Anti-fibrosis nano-carrier and nano-preparation and preparation method thereof |
CN115414492B (en) * | 2022-09-29 | 2024-05-28 | 中国药科大学 | Nanometer preparation for treating pancreatic fibrosis and preparation method thereof |
CN115708867B (en) * | 2022-10-10 | 2024-06-04 | 哈尔滨医科大学 | Pulmonary administration oxygen-carrying nano-drug combined preparation for idiopathic pulmonary fibrosis and preparation method thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109432047A (en) * | 2018-10-29 | 2019-03-08 | 中国药科大学 | A kind of reverse pulmonary fibrosis nanometer formulation and preparation method thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6426103B2 (en) * | 2013-10-15 | 2018-11-21 | 国立大学法人 東京大学 | c-Met protein agonist |
-
2019
- 2019-07-26 CN CN201910682539.2A patent/CN110339168B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109432047A (en) * | 2018-10-29 | 2019-03-08 | 中国药科大学 | A kind of reverse pulmonary fibrosis nanometer formulation and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CN110339168A (en) | 2019-10-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110339168B (en) | Nanometer preparation loaded with anti-pulmonary fibrosis drug and immunomodulator and preparation method thereof | |
JP6881877B2 (en) | Multilayer hydrogel capsule for cell encapsulation and cell assembly | |
US10675303B2 (en) | Extracellular matrix compositions for the treatment of cancer | |
US11692172B2 (en) | Formulation comprising extracellular vesicles, method for producing the same, and uses thereof | |
US8846099B2 (en) | Parenteral composition comprising microspheres with a diameter between 10 and 20 microns | |
WO2022111595A1 (en) | Core-shell microgel, oxygen sustained-release material, drug sustained-release formulation and multifunctional cell encapsulation system | |
DE69535305T2 (en) | MEANS TO REDUCE MOLECULAR FUNCTIONS | |
CN106693040A (en) | Preparation method of drug-loadable polyvinyl alcohol eluted microspheres | |
CN109432047B (en) | Reverse pulmonary fibrosis nano preparation and preparation method thereof | |
Shi et al. | Mesoporous polydopamine nanoparticles for sustained release of rapamycin and reactive oxygen species scavenging to synergistically accelerate neurogenesis after spinal cord injury | |
CN1197552C (en) | Preparations for the application of anti-inflammatory agents | |
CN113679670A (en) | Vesicle nano-drug loaded with chloroquine compound and preparation method and application thereof | |
CN115414492B (en) | Nanometer preparation for treating pancreatic fibrosis and preparation method thereof | |
Yabanoglu-Ciftci et al. | Transforming growth factor-β3 (TGF-β3) loaded PLGA-b-PEG nanoparticles: efficacy in preventing cardiac fibrosis induced by TGF-β1 | |
CN118059063A (en) | Mesenchymal stem cell bionic nano vesicle for targeted treatment of vascular endothelial cells, and preparation method and application thereof | |
CN116059400B (en) | Preparation method and application of hydrogel microsphere for regulating nucleus pulposus oxygen metabolism balance | |
CN110876734A (en) | Formulations comprising extracellular vesicles, methods for preparing the same, and uses thereof | |
Yuan et al. | Impact of physicochemical properties on biological effects of lipid nanoparticles: Are they completely safe | |
TWI763991B (en) | Novel ophthalmic gel and its preparation method | |
CN116327700A (en) | Methotrexate nano-drug-carrying system, preparation method thereof and application thereof in treating rheumatoid arthritis | |
CN118681003A (en) | Combined medicine for resisting hepatic fibrosis and application thereof | |
Raimondo | Biomaterial Directed Immune Modulation and Tissue Regeneration in the Context of Skeletal Muscle Injury | |
JP2023529545A (en) | Polypeptide albumin nanoparticles, and methods for their preparation and use | |
CN118576566A (en) | Preparation method and application of astaxanthin and perfluorooctyl bromide loaded liposome | |
CN114209890A (en) | Bone repair material with strong bone affinity and preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20210806 Address after: Room 814, block a, phase I, Zhongdan Life Science Industrial Park, no.3-1, xinjinhu Road, Jiangbei new district, Nanjing City, Jiangsu Province, 210046 Patentee after: Burning point (Nanjing) Biomedical Technology Co., Ltd Address before: No. 639 Jiangning longmian Road District of Nanjing City, Jiangsu province 211198 Patentee before: CHINA PHARMACEUTICAL University |