CN110051629A - A kind of atomization albuterol solution and preparation method thereof for treating respiratory disorder - Google Patents
A kind of atomization albuterol solution and preparation method thereof for treating respiratory disorder Download PDFInfo
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- CN110051629A CN110051629A CN201910412882.5A CN201910412882A CN110051629A CN 110051629 A CN110051629 A CN 110051629A CN 201910412882 A CN201910412882 A CN 201910412882A CN 110051629 A CN110051629 A CN 110051629A
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- Prior art keywords
- atomization
- parts
- solution
- respiratory disorder
- treating
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- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960002052 salbutamol Drugs 0.000 title claims abstract description 63
- 208000023504 respiratory system disease Diseases 0.000 title claims abstract description 30
- 238000000889 atomisation Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000011782 vitamin Substances 0.000 claims abstract description 24
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 21
- 229940088594 vitamin Drugs 0.000 claims abstract description 19
- 229930003231 vitamin Natural products 0.000 claims abstract description 19
- 235000013343 vitamin Nutrition 0.000 claims abstract description 19
- 150000003722 vitamin derivatives Chemical class 0.000 claims abstract description 19
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 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 claims abstract description 13
- 229960004436 budesonide Drugs 0.000 claims abstract description 13
- 229960000195 terbutaline Drugs 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 30
- 230000001954 sterilising effect Effects 0.000 claims description 25
- 238000004659 sterilization and disinfection Methods 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 239000007789 gas Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 10
- 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 claims description 10
- 230000001681 protective effect Effects 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 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 claims description 5
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 5
- 239000007832 Na2SO4 Substances 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 claims description 5
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 229960002061 ergocalciferol Drugs 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000001307 helium Substances 0.000 claims description 5
- 229910052734 helium Inorganic materials 0.000 claims description 5
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000012376 hot air sterilization Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 5
- 238000006386 neutralization reaction Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000001508 potassium citrate Substances 0.000 claims description 5
- 229960002635 potassium citrate Drugs 0.000 claims description 5
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 5
- 235000011082 potassium citrates Nutrition 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 235000020944 retinol Nutrition 0.000 claims description 5
- 239000011607 retinol Substances 0.000 claims description 5
- 229960003471 retinol Drugs 0.000 claims description 5
- 235000019192 riboflavin Nutrition 0.000 claims description 5
- 239000002151 riboflavin Substances 0.000 claims description 5
- 229960002477 riboflavin Drugs 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 238000013517 stratification Methods 0.000 claims description 5
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 5
- 235000001892 vitamin D2 Nutrition 0.000 claims description 5
- 239000011653 vitamin D2 Substances 0.000 claims description 5
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims description 5
- 239000011709 vitamin E Substances 0.000 claims description 5
- 235000019165 vitamin E Nutrition 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-M chlorosulfate Chemical compound [O-]S(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-M 0.000 claims 1
- 238000004064 recycling Methods 0.000 claims 1
- 229940041682 inhalant solution Drugs 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 210000004072 lung Anatomy 0.000 abstract description 5
- 238000012423 maintenance Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 239000000443 aerosol Substances 0.000 abstract description 4
- 210000004400 mucous membrane Anatomy 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000004615 ingredient Substances 0.000 abstract 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 4
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000007792 addition Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 description 1
- 101710152983 Beta-2 adrenergic receptor Proteins 0.000 description 1
- 102100034159 Beta-3 adrenergic receptor Human genes 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000003694 hair properties Effects 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Otolaryngology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of atomization albuterol solution and preparation method thereof for treating respiratory disorder, it is related to being atomized albuterol solution preparation field.This is used to treat the atomization albuterol solution of respiratory disorder, is made of raw material from the following weight: 45.0~54.5 parts of salbutamol, 35.2~48.0 parts of pH adjusting agent, 15.6~24.0 parts of budesonide, 14.3~18.5 parts of Terbutaline, 20.6~32.0 parts of vitamin and 85.6~96.5 parts of pure water.Compared with prior art; the beneficial effects of the present invention are: while not influencing to treat respiratory disorder, realizing the maintenance and protection to mucous membrane in lung using budesonide, Terbutaline and vitamin; furthermore; salbutamol aerosol inhalation solution of the invention has excellent stability, and related content of material is few, and ingredient is simple; reduce the risk of clinical application; drug safety is improved, while its preparation process is simple, has a vast market foreground.
Description
Technical field
The present invention relates to atomization albuterol solution technical fields more particularly to a kind of for treating the atomization of respiratory disorder
Albuterol solution and preparation method thereof.
Background technique
Salbutamol sulfate aerosol inhalation solution salbutamol sulfate aerosol inhalation solution, chemical name: 1-(4- hydroxyl-
3- hydroxymethyl phenyl) the tertiary fourth amino of -2-() ethyl alcohol Hemisulphate, molecular formula are as follows: C13H21NO3.1/2H2SO4, this product be choosing
The beta-2-adrenoreceptor agonists of selecting property, mechanism of action are irritated into the cell by the effect to Beta-3 adrenergic receptor
Adenyl cyclase, it is horizontal to improve adenosine cyclophosphate, keeps bronchial smooth muscle loose, and inhibit speed hair property hypersensitivity cell
The medium of (especially mast cell) discharges.The clinical test of most of strict controls shows salbutamol to the work of respiratory tract
It is better than the comparable isoprel of dosage with (relaxation bronchial smooth muscle), and it is less on cardiovascular influence.
Currently, having had already appeared the salbutamol sulfate of several formulations form on the market, wherein the sulphur of inhalation solution form
Sour salbutamol can directly reach diseased region, and effect is directly, rapid-action, can effectively avoid oral administration as caused by liver
First pass effect substantially increases bioavilability, and drug dose used is fewer than systemic administration amount, avoids or reduces Formulations for systemic administration
Issuable side effect.But as solution, salbutamol sulfate stability is poor, the structure and pharmacology of catabolite
Property is unclear, affects the safety of medication.Therefore, how to improve its stability is that those skilled in the art thirst for chasing after always
The target asked.And in order to make solution show preferable long-time stability, it will usually preservative, stabilizer, anti-oxidant be added
Auxiliary materials, the additions of above-mentioned auxiliary material such as agent, osmotic pressure regulator, metal ion network mixture (natrium adetate) play raising sulfuric acid
The effect of salbutamol aerosol inhalation solution stability, but the addition of many auxiliary materials affects the quality of product, increases and faces
The risk of bed medication, in addition, existing atomization albuterol solution is difficult to carry out maintenance and protection to mucous membrane in lung.
Summary of the invention
How the technical problem to be solved by the present invention is to guaranteeing while treating respiratory disorder, gluing in lung
Film carries out maintenance and protection.
In order to solve the above technical problems, the atomization salbutamol that the present invention provides a kind of for treating respiratory disorder is molten
Liquid and preparation method thereof is guaranteeing while treating respiratory disorder, realizes the maintenance and protection to mucous membrane in lung.
It is a kind of for treating the atomization albuterol solution of respiratory disorder, it is characterised in that: by the raw material of following parts by weight
It is made: 45.0~54.5 parts of salbutamol, 35.2~48.0 parts of pH adjusting agent, 15.6~24.0 parts of budesonide, Terbutaline
14.3~18.5 parts, 20.6~32.0 parts of vitamin and 85.6~96.5 parts of pure water.
Further, the preparation process of the salbutamol is that salicylide, tert-butylamine and ethyl alcohol are put into reaction kettle first
In, solvent is recovered under reduced pressure after heating stirring reflux, benzene and thionyl chloride are then added in a solvent, and continue to stir, later mistake
Filter washs to obtain N with benzene, and monoxone and two chloroethenes are then added in N- dimethyl chloride thiosulfuric acid base methene ammonium solid into its solid again
Alkane is stirred at room temperature, and water stratification is then added, with saturated sodium chloride solution and water washing, anhydrous Na2SO4Dry filter, later
Aluminum trichloride (anhydrous) stirring is being added into filtrate, and reactant is being poured into ice water, is separating organic phase, successively with saturation chlorination
Sodium solution and water washing, are dried by anhydrous sodium sulfate again later, are filtered, cooling, then again through neutralization, reduction and again at
Salt obtains salbutamol.
Further, the pH adjusting agent is one in sulfuric acid, hydrochloric acid, acetic acid, citric acid, potassium citrate and amion acetic acid
Kind is several.
Further, the vitamin is retinol, riboflavin, vitamin D2, Vitamin E, vitamine T and Wei Sheng
One or more of plain U.
Further, described a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder, it is special
Sign is, specific steps are as follows:
A 75~85% pure water of synthesis reactor volume) is added first in synthesis reactor, is subsequently charged with protective gas, husky butylamine is added later
Alcohol, pH adjusting agent, budesonide, Terbutaline and vitamin, are sufficiently stirred, and until all raw materials are completely dissolved
B) with the section pH value of solution carries out constant volume, then to 3.0~5.0 later in synthesis reactor in pH adjusting agent regulating step A)
Successively pass through coarse filtration and refined filtration again, finally obtains albuterol solution；
C) albuterol solution obtained in step B) is detected, subsequent encapsulating, and carries out sterilization treatment, finally storage envelope
It deposits.
Further, the step A) in protective gas be one of nitrogen, argon gas and helium.
Further, the step B) in coarse filtration and refined filtration be respectively 0.55 μm of coarse filtration and 0.18 μm of refined filtration.
Further, the step C) in sterilization treatment be hot air sterilization or moist heat sterilization.
Further, the sterilising temp is 65~80 DEG C, and sterilization time is 12~16min.
Compared with prior art, the beneficial effects of the present invention are: using budesonide, Terbutaline and vitamin, not
While influencing treatment respiratory disorder, the maintenance and protection to mucous membrane in lung are realized, in addition, salbutamol of the invention is atomized
Inhalation solution has excellent stability, and related content of material is few, and ingredient is simple, reduces the risk of clinical application, improves
Drug safety, while its preparation process is simple, has a vast market foreground.
Specific embodiment
With reference to embodiment, the present invention is furture elucidated, it should be understood that following specific embodiments are only used for
It is bright the present invention rather than limit the scope of the invention.
Embodiment 1
It is a kind of for treating the atomization albuterol solution of respiratory disorder, be made of raw material from the following weight: salbutamol
45.0 parts, 48.0 parts of pH adjusting agent, 15.6 parts of budesonide, 18.5 parts of Terbutaline, 20.6 parts of vitamin and 96.5 parts of pure water.
The present invention is a kind of for treating the atomization albuterol solution of respiratory disorder, the preparation process of the salbutamol
For salicylide, tert-butylamine and ethyl alcohol are put into reaction kettle first, solvent is recovered under reduced pressure after heating stirring reflux, then molten
Benzene and thionyl chloride are added in agent, and continues to stir, filtering later washs to obtain N, N- dimethyl chloride thiosulfuric acid base methene ammonium with benzene
Solid is then added monoxone and dichloroethanes into its solid again, is stirred at room temperature, water stratification is then added, with saturation chlorine
Change sodium solution and water washing, anhydrous Na2SO4Aluminum trichloride (anhydrous) stirring is being added into filtrate later for dry filter, and will be anti-
It answers object to pour into ice water, separates organic phase, successively use saturated sodium chloride solution and water washing, done again by anhydrous sodium sulfate later
It is dry, it filters, it is cooling, then again through neutralization, reduction and again salbutamol is obtained at salt.
In the present embodiment, the pH adjusting agent is in sulfuric acid, hydrochloric acid, acetic acid, citric acid, potassium citrate and amion acetic acid
One or more.
In the present embodiment, the vitamin be retinol, riboflavin, vitamin D2, Vitamin E, vitamine T and
One or more of vitamin.
It is of the present invention a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder, specific steps
Are as follows:
A) first in synthesis reactor be added 75% pure water of synthesis reactor volume, be subsequently charged with protective gas, later be added salbutamol,
PH adjusting agent, budesonide, Terbutaline and vitamin, are sufficiently stirred, and until all raw materials are completely dissolved；
B) with the section pH value of solution carries out constant volume, then again successively to 5.0 later in synthesis reactor in pH adjusting agent regulating step A)
By coarse filtration and refined filtration, albuterol solution is finally obtained；
C) albuterol solution obtained in step B) is detected, subsequent encapsulating, and carries out sterilization treatment, finally storage envelope
It deposits.
In the present embodiment, the step A) in protective gas be one of nitrogen, argon gas and helium.
In the present embodiment, the step B) in coarse filtration and refined filtration be respectively 0.55 μm of coarse filtration and 0.18 μm of refined filtration.
In the present embodiment, the step C) in sterilization treatment be hot air sterilization or moist heat sterilization.
In the present embodiment, the sterilising temp is 65 DEG C, sterilization time 16min.
Embodiment 2
It is a kind of for treating the atomization albuterol solution of respiratory disorder, be made of raw material from the following weight: salbutamol
54.5 parts, 35.2 parts of pH adjusting agent, 24.0 parts of budesonide, 14.3 parts of Terbutaline, 32.0 parts of vitamin and 85.6 parts of pure water.
The present invention is a kind of for treating the atomization albuterol solution of respiratory disorder, the preparation process of the salbutamol
For salicylide, tert-butylamine and ethyl alcohol are put into reaction kettle first, solvent is recovered under reduced pressure after heating stirring reflux, then molten
Benzene and thionyl chloride are added in agent, and continues to stir, filtering later washs to obtain N, N- dimethyl chloride thiosulfuric acid base methene ammonium with benzene
Solid is then added monoxone and dichloroethanes into its solid again, is stirred at room temperature, water stratification is then added, with saturation chlorine
Change sodium solution and water washing, anhydrous Na2SO4Aluminum trichloride (anhydrous) stirring is being added into filtrate later for dry filter, and will be anti-
It answers object to pour into ice water, separates organic phase, successively use saturated sodium chloride solution and water washing, done again by anhydrous sodium sulfate later
It is dry, it filters, it is cooling, then again through neutralization, reduction and again salbutamol is obtained at salt.
In the present embodiment, the pH adjusting agent is in sulfuric acid, hydrochloric acid, acetic acid, citric acid, potassium citrate and amion acetic acid
One or more.
In the present embodiment, the vitamin be retinol, riboflavin, vitamin D2, Vitamin E, vitamine T and
One or more of vitamin.
It is of the present invention a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder, specific steps
Are as follows:
A) first in synthesis reactor be added 85% pure water of synthesis reactor volume, be subsequently charged with protective gas, later be added salbutamol,
PH adjusting agent, budesonide, Terbutaline and vitamin, are sufficiently stirred, and until all raw materials are completely dissolved；
B) with the section pH value of solution carries out constant volume, then again successively to 3.0 later in synthesis reactor in pH adjusting agent regulating step A)
By coarse filtration and refined filtration, albuterol solution is finally obtained；
C) albuterol solution obtained in step B) is detected, subsequent encapsulating, and carries out sterilization treatment, finally storage envelope
It deposits.
In the present embodiment, the step A) in protective gas be one of nitrogen, argon gas and helium.
In the present embodiment, the step B) in coarse filtration and refined filtration be respectively 0.55 μm of coarse filtration and 0.18 μm of refined filtration.
In the present embodiment, the step C) in sterilization treatment be hot air sterilization or moist heat sterilization.
In the present embodiment, the sterilising temp is 80 DEG C, sterilization time 12min.
Embodiment 3
It is a kind of for treating the atomization albuterol solution of respiratory disorder, be made of raw material from the following weight: salbutamol
48.5 parts, 38.0 parts of pH adjusting agent, 19.0 parts of budesonide, 16.5 parts of Terbutaline, 22.0 parts of vitamin and 86.5 parts of pure water.
The present invention is a kind of for treating the atomization albuterol solution of respiratory disorder, the preparation process of the salbutamol
For salicylide, tert-butylamine and ethyl alcohol are put into reaction kettle first, solvent is recovered under reduced pressure after heating stirring reflux, then molten
Benzene and thionyl chloride are added in agent, and continues to stir, filtering later washs to obtain N, N- dimethyl chloride thiosulfuric acid base methene ammonium with benzene
Solid is then added monoxone and dichloroethanes into its solid again, is stirred at room temperature, water stratification is then added, with saturation chlorine
Change sodium solution and water washing, anhydrous Na2SO4Aluminum trichloride (anhydrous) stirring is being added into filtrate later for dry filter, and will be anti-
It answers object to pour into ice water, separates organic phase, successively use saturated sodium chloride solution and water washing, done again by anhydrous sodium sulfate later
It is dry, it filters, it is cooling, then again through neutralization, reduction and again salbutamol is obtained at salt.
In the present embodiment, the pH adjusting agent is in sulfuric acid, hydrochloric acid, acetic acid, citric acid, potassium citrate and amion acetic acid
One or more.
In the present embodiment, the vitamin be retinol, riboflavin, vitamin D2, Vitamin E, vitamine T and
One or more of vitamin.
It is of the present invention a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder, specific steps
Are as follows:
A) first in synthesis reactor be added 78% pure water of synthesis reactor volume, be subsequently charged with protective gas, later be added salbutamol,
PH adjusting agent, budesonide, Terbutaline and vitamin, are sufficiently stirred, and until all raw materials are completely dissolved；
B) with the section pH value of solution carries out constant volume, then again successively to 4.0 later in synthesis reactor in pH adjusting agent regulating step A)
By coarse filtration and refined filtration, albuterol solution is finally obtained；
C) albuterol solution obtained in step B) is detected, subsequent encapsulating, and carries out sterilization treatment, finally storage envelope
It deposits.
In the present embodiment, the step A) in protective gas be one of nitrogen, argon gas and helium.
In the present embodiment, the step B) in coarse filtration and refined filtration be respectively 0.55 μm of coarse filtration and 0.18 μm of refined filtration.
In the present embodiment, the step C) in sterilization treatment be hot air sterilization or moist heat sterilization.
In the present embodiment, the sterilising temp is 69 DEG C, sterilization time 15min.
In addition to the implementation, the present invention can also have other embodiments.It is all to use equivalent substitution or equivalent transformation shape
At technical solution, fall within the scope of protection required by the present invention.
Claims (9)
1. a kind of for treating the atomization albuterol solution of respiratory disorder, it is characterised in that: by the raw material system of following parts by weight
At: 45.0~54.5 parts of salbutamol, 35.2~48.0 parts of pH adjusting agent, 15.6~24.0 parts of budesonide, Terbutaline
14.3~18.5 parts, 20.6~32.0 parts of vitamin and 85.6~96.5 parts of pure water.
2. according to claim 1 a kind of for treating the atomization albuterol solution of respiratory disorder, it is characterised in that: institute
The preparation process for stating salbutamol is that salicylide, tert-butylamine and ethyl alcohol are put into reaction kettle first, is subtracted after heating stirring reflux
Recycling design is pressed, benzene and thionyl chloride are then added in a solvent, and continue to stir, filtering later washs to obtain N, N- diformazan with benzene
Base chloro sulfate methene ammonium solid is then added monoxone and dichloroethanes into its solid again, is stirred at room temperature, then plus
Enter water stratification, with saturated sodium chloride solution and water washing, anhydrous Na2SO4Anhydrous three are being added into filtrate later for dry filter
Aluminium chloride stirring, and reactant is poured into ice water, organic phase is separated, successively uses saturated sodium chloride solution and water washing, later
It is dried, is filtered by anhydrous sodium sulfate again, it is cooling, then again through neutralization, reduction and again salbutamol is obtained at salt.
3. according to claim 1 a kind of for treating the atomization albuterol solution of respiratory disorder, it is characterised in that: institute
Stating pH adjusting agent is one or more of sulfuric acid, hydrochloric acid, acetic acid, citric acid, potassium citrate and amion acetic acid.
4. according to claim 1 a kind of for treating the atomization albuterol solution of respiratory disorder, it is characterised in that: institute
Stating vitamin is one or more of retinol, riboflavin, vitamin D2, Vitamin E, vitamine T and vitamin.
5. according to any one of claims 1-4 a kind of for treating the system of the atomization albuterol solution of respiratory disorder
Preparation Method, which is characterized in that specific steps are as follows:
A 75~85% pure water of synthesis reactor volume) is added first in synthesis reactor, is subsequently charged with protective gas, husky butylamine is added later
Alcohol, pH adjusting agent, budesonide, Terbutaline and vitamin, are sufficiently stirred, and until all raw materials are completely dissolved；
B) with the section pH value of solution carries out constant volume, then to 3.0~5.0 later in synthesis reactor in pH adjusting agent regulating step A)
Successively pass through coarse filtration and refined filtration again, finally obtains albuterol solution；
C) albuterol solution obtained in step B) is detected, subsequent encapsulating, and carries out sterilization treatment, finally storage envelope
It deposits.
6. it is according to claim 5 a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder,
Be characterized in that: the step A) in protective gas be one of nitrogen, argon gas and helium.
7. it is according to claim 5 a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder,
Be characterized in that: the step B) in coarse filtration and refined filtration be respectively 0.55 μm of coarse filtration and 0.18 μm of refined filtration.
8. it is according to claim 5 a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder,
Be characterized in that: the step C) in sterilization treatment be hot air sterilization or moist heat sterilization.
9. it is according to claim 8 a kind of for treating the preparation method of the atomization albuterol solution of respiratory disorder,
Be characterized in that: the sterilising temp is 65~80 DEG C, and sterilization time is 12~16min.
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Application publication date: 20190726 |