CN111743854A - 一种控制黏度的丁酸氢化可的松的外用药物组合物 - Google Patents
一种控制黏度的丁酸氢化可的松的外用药物组合物 Download PDFInfo
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- CN111743854A CN111743854A CN201910247432.5A CN201910247432A CN111743854A CN 111743854 A CN111743854 A CN 111743854A CN 201910247432 A CN201910247432 A CN 201910247432A CN 111743854 A CN111743854 A CN 111743854A
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- hydrocortisone butyrate
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- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical group C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 title claims abstract description 46
- 229960001524 hydrocortisone butyrate Drugs 0.000 title claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 20
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 15
- 229940057995 liquid paraffin Drugs 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000001509 sodium citrate Substances 0.000 claims description 12
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 9
- 239000003871 white petrolatum Substances 0.000 claims description 9
- 239000003755 preservative agent Substances 0.000 claims description 8
- 230000002335 preservative effect Effects 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 7
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 7
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 7
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 7
- 229940073669 ceteareth 20 Drugs 0.000 claims description 5
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 5
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 5
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 5
- 239000011159 matrix material Substances 0.000 claims description 4
- 230000002421 anti-septic effect Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 2
- 229960002216 methylparaben Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 claims 3
- 239000006071 cream Substances 0.000 abstract description 43
- 238000002360 preparation method Methods 0.000 abstract description 12
- 239000012071 phase Substances 0.000 description 27
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 239000003814 drug Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
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- 239000000243 solution Substances 0.000 description 6
- 239000003862 glucocorticoid Substances 0.000 description 5
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 4
- YZNQMPPBWQTLFJ-TUFAYURCSA-N [2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] butanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CCC)(O)[C@@]1(C)C[C@@H]2O YZNQMPPBWQTLFJ-TUFAYURCSA-N 0.000 description 4
- 150000001875 compounds Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 231100000475 skin irritation Toxicity 0.000 description 4
- 230000036556 skin irritation Effects 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960000890 hydrocortisone Drugs 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 206010006784 Burning sensation Diseases 0.000 description 2
- 206010012434 Dermatitis allergic Diseases 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
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- 239000003995 emulsifying agent Substances 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
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- 230000007803 itching Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 231100000022 skin irritation / corrosion Toxicity 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- 206010040799 Skin atrophy Diseases 0.000 description 1
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940069078 citric acid / sodium citrate Drugs 0.000 description 1
- MOVRKLZUVNCBIP-RFZYENFJSA-N cortancyl Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O MOVRKLZUVNCBIP-RFZYENFJSA-N 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- 229960003657 dexamethasone acetate Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
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- 150000002148 esters Chemical group 0.000 description 1
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- 238000010812 external standard method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 1
- 229960001469 fluticasone furoate Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- DALKLAYLIPSCQL-YPYQNWSCSA-N methylprednisolone aceponate Chemical compound C1([C@@H](C)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CC)[C@@]2(C)C[C@@H]1O DALKLAYLIPSCQL-YPYQNWSCSA-N 0.000 description 1
- 229960002037 methylprednisolone aceponate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane group Chemical group [C@@H]12CC[C@H](CC)[C@@]1(C)CC[C@H]1[C@H]2CCC2CCCC[C@]12C JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 230000000717 retained effect Effects 0.000 description 1
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- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- -1 vaseline Chemical compound 0.000 description 1
Classifications
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种新配方的丁酸氢化可的松乳膏,涉及一种在0‑30℃下的黏度在3000‑3900mPa.S之间的丁酸氢化可的松乳膏,在同等制备条件下,可以避免膏剂中产生较多的气泡,造成膏剂会自动从管中流出的情况。
Description
技术领域
本发明涉及一种丁酸氢化可的松外用药物组合物,尤其是涉及一种在0-30℃下的黏度在3000-3900mPa.S之间的丁酸氢化可的松乳膏。
背景技术
糖皮质激素是甾体皮质激素的一种,具有甾体的化合物结构,可抑制发炎及过敏皮肤的反应,同时亦抑制与细胞加速再生有关联的反应而导致症状,例如红斑、水肿、皮肤厚化、皮肤表面粗糙的减退,以及减轻瘙痒、灼热感和疼痛等问题。由于在这类化合物上引入了酯基,尤其是在孕甾类化合物的21和/或17位引入酯基,使得其脂溶性更好,从而在外用治疗时能够达到更好的疗效。糖皮质激素包含丁酸氢化可的松、醋丙甲泼尼龙、醋酸地塞米松、醋酸氢化可的松、糠酸莫米松、醋酸泼尼松、醋酸泼尼松龙、丙酸氟替卡松、糠酸氟替卡松、地奈德、曲安奈德等药物,其结构类似,作用机制一致,所以该类药物在抗炎方面具有极强的类似性啊,区别仅是疗效的强弱。糖皮质激素在具有较强的疗效的同时,也存在造成皮肤萎缩变薄、毛细血管扩张、色素沉着、继发感染等不良反应。
丁酸氢化可的松(Hydrocortisone-17-butyrate,CAS:13609-67-1)是糖皮质激素的一种,可抑制发炎及过敏皮肤的反应,同时亦抑制与细胞加速再生有关联的反应而导致症状,例如红斑、水肿、皮肤厚化、皮肤表面粗糙的减退,以及减轻瘙痒、灼热感和疼痛等问题。由于在氢化可的松分子上引入了17-丁酸酯,使得丁酸氢化可的松的脂溶性更好,从而在外用治疗时能够达到更好的疗效,同时保留了氢化可的松副作用较轻的优点,是一种可以用于儿童的外用甾体皮质激素。现有外用制剂主要丁酸氢化可的松乳膏(商品名:尤卓尔,天津药业集团有限公司生产,1994年在中国上市),在丁酸氢化可的松乳膏的说明书(http://www.kingyork.biz/2009/0312/446.html)中公开了其使用的辅料为,甘油、丙二醇、凡士林、十八醇、液状石蜡、平平加A-20、枸橼酸、枸橼酸钠、羟苯乙酯(防腐剂)、纯化水。
经过我们实验发现丁酸氢化可的松乳膏中在储存过程中所产生的杂质主要是21-丁酸氢化可的松,产生该杂质的主要原因是17位酯基在储存过程中发生了水解,并与21位羟基发生类似酯交换反应而成为氢化可的松-21-丁酸酯。美国专利申请US20040152682A1说明书第二页表3中也公开了丁酸氢化可的松制剂稳定性实验中主要的杂质酯交换产生的氢化可的松-21-丁酸酯(HCB-21),现有的制剂工艺与配方下,酯交换反应发生的速度较快,产生的杂质较多,对产品的稳定性产生加大的干扰,同时由于杂质的产生对产品的疗效也产生了一定的影响。
众所周知(马军营,羧酸酯水解的类型及影响因素,《信阳师范学院学报:自然科学版》,1998年11卷4期,417-421)叔醇酯丁酸氢化可的松在酸性或碱性条件下都可以进行水解,但是由于不同的PH值会对酯水解速度产生较大的影响。
中国专利CN 200910228788.0中介绍了一种丁酸氢化可的松乳膏。其技术方案是含有作为活性成分的丁酸氢化可的松0.05-0.2%,所述作为油相成分的固体的用量为3%~20%,选自高级醇中的一种或几种;所述稠度调节剂,用量为5%~20%。选自凡士林、液体石蜡中的一种或几种;所述保湿剂的用量为3%~10%,选自多元醇类化合物;所述乳化剂用量为1-10%,选自聚氧乙烯醚衍生物;所述的防腐剂用量为0.05-0.2%,选自尼泊金类防腐剂;所述的pH调节剂优选柠檬酸/柠檬酸钠缓冲剂。乳膏的PH在5.2-5.8之间。
甄少立(均匀设计探讨平平O乳膏基质的塑粘度,海峡药学2009年第21卷第1期,29-30)认为,平平O与十六醇组成的O/W,非离子型乳膏剂的适合的黏度为3200mPa.S。
发明内容
膏剂在生产中搅拌过程中会产生教导的气泡,导致膏剂管口打开后不需要挤压,膏剂会自动从管中流出,造成膏体的损失,甚至会造成对其他物品的污染。为克服现有技术中的问题,本发明提供了一种新配方的丁酸氢化可的松乳膏,通过优选处方,在同等制备条件下,可以避免膏剂中产生较多的气泡,造成膏剂会自动从管中流出的情况。
一种丁酸氢化可的松外用药物组合物,由作为活性成分的0.05-0.2%丁酸氢化可的松,作为药用辅料的10-25%白凡士林、10-25%十六醇十八醇、10-20%液体石蜡、2%~10%鲸蜡硬脂醇聚醚-20、0.1-0.5%防腐剂,用柠檬酸和柠檬酸钠调节组合物的pH值>6.0且≦6.5和余量的水组成,在0-30℃下的黏度在3000-3900mPa.S之间。
上述的外用药物组合物,其特征是所述10-30℃下的黏度在3200-3800mPa.S之间。
上述的外用药物组合物,其特征是所述的防腐剂为尼泊金甲酯、尼泊金乙酯中的一种或几种。
上述的外用药物组合物,其特征是所述的丁酸氢化可的松含量为0.05-0.1%。
上述的外用药物组合物,所述组合物的配制方法如下:
(1)油相配制:取用于油相基质的白凡士林、十六醇十八醇、部分液体石蜡、鲸蜡硬脂醇聚醚-20加热熔融成为溶液,温度保持在70-90℃;
(2)水相配制:用柠檬酸、柠檬酸钠调节好pH值的水混合,加入防腐剂、加热,搅拌均匀温度保持在70-90℃;
(3)将丁酸氢化可的松微粉均匀分散于剩余部分液体石蜡中,温度保持在50-60℃;
(4)合相:将步骤(1)配制的油相、步骤(3)中的活性成分相缓缓加入步骤(2)配制的水相中,搅拌,保持温度在70-90℃,搅拌,冷却成膏。
由于优选了所得乳膏剂的pH值与组方,使得本发明提供的全新的丁酸氢化可的松乳膏质量稳定性要好。此外,在优选的pH值范围和处方影响下,本发明提供的乳膏。
具体实施方式
下面将通过实施例对本发明作进一步的描述,这些描述并不是对本发明内容作进一步的限定。本领域的技术人员应理解,对本发明的技术特征所作的等同替换,或相应的改进,仍属于本发明的保护范围之内。
所有实施例制得的乳膏均用10g/支的铝管分包装备用。所用的丁酸氢化可的松为粒径范围5-50μm的微粉。
乳膏膏体测定PH值方法如下:精密称取膏体样品5g,加入经煮沸放冷的纯化水25ml,加热至40℃,搅拌,使其完全溶解,冷却至室温,用pH值计测定。
实施例、对照实施例配置按照总量1000g配置,处方中的各种辅料按相应的百分比准备。
实施例1
按以上配比精确称量,组合物的配制方法如下:
(1)油相配制:取用于油相基质的白凡士林、十六醇十八醇、部分液体石蜡、鲸蜡硬脂醇聚醚-20加热熔融成为溶液,温度保持在70-90℃;
(2)水相配制:用柠檬酸、柠檬酸钠调节好pH值的余量的水混合,加入防腐剂、加热,搅拌均匀温度保持在70-90℃;
(3)将丁酸氢化可的松微粉均匀分散于剩余部分液体石蜡中,温度保持在50-60℃;
(4)合相:将步骤(1)配制的油相、步骤(3)中的活性成分相缓缓加入步骤(2)配制的水相中,以合相搅拌速度搅拌,保持温度在70-90℃,搅拌30分钟后,冷却,成膏,灌装。
实施例2
制备方法同实施例1
对照实施例1(CN 200910228788.0中的实施例1)
丁酸氢化可的松1g,白凡士林100g,十八醇30g,液体石蜡30g,平平加A-20 50g,甘油50g,丙二醇20g,尼泊金乙酯1g,柠檬酸(C6H8O7·H2O)10g,
柠檬酸钠(Na3C6H5O7·2H2O)18g 注射用水加至1000g
按以上配比精确称量,乳膏配制过程如下:
(1)油相配制:取白凡士林,十八醇,液体石蜡,平平加A-20置于容器中,加热至熔融,温度保持在90℃;
(2)水相配制:将柠檬酸与柠檬酸钠溶于注射用水中,将主药均匀分散于甘油、丙二醇中,加入柠檬酸与柠檬酸钠的水溶液,尼泊金乙酯,加热,搅拌均匀温度保持在90℃;
(3)合相:将步骤(1)配制的油相缓缓加入步骤(2)配制的水相中,搅拌,保持温度在80℃,搅拌速度1000rmp,搅拌30min,冷却成膏,得到1000g乳膏,灌装,含量0.1%,测得膏体pH为5.5。
对照实施例2(CN 200910228788.0中的实施例2)
丁酸氢化可的松1g,白凡士林30g,十八醇100g,液体石蜡100g,平平加A-20 10g,甘油10g,丙二醇50g,尼泊金乙酯1g,柠檬酸(C6H8O7·H2O)4g,
柠檬酸钠(Na3C6H5O7·2H2O)6g 注射用水至1000g
按以上配比精确称量,乳膏配制过程如下:
(1)油相配制:,取白凡士林,十八醇,液体石蜡,平平加A-20置于容器中,加热至熔融,温度保持在75℃;
(2)水相配制:将柠檬酸与柠檬酸钠溶于注射用水中,将主药均匀分散于甘油、丙二醇中,加入柠檬酸与柠檬酸钠的水溶液,尼泊金乙酯,加热,搅拌均匀温度保持在90℃;
(3)合相:将步骤(1)配制的油相缓缓加入步骤(2)配制的水相中,搅拌,保持温度在90℃,搅拌速度1000rmp,搅拌30min,冷却成膏,得到1000g乳膏,灌装,含量0.1%,测得膏体pH为5.2。
本发明提供的全新的丁酸氢化可的松乳膏实施例与对照实施例1、2在PH值>6的情况下与中国专利CN 200910228788.0的处方、市售丁酸氢化可的松乳膏相比,质量稳定性近似,但刺激性较低。
膏体黏度试验:
在不同温度调节下按照按照《中国药典》2005年版二部方法测定动力黏度,采用NDJ-1型旋转式黏度计,以4号转子,转速为每分钟6转。同时将取每个实施例5支,扎破乳膏管口,观察膏体自动流出的支数,乳膏测试结果如下表:
表 丁酸氢化可的松乳膏黏度测试结果
通过上述数据说明全新的丁酸氢化可的松乳膏实施例与对照实施例1、2的黏度范围更加确定,不容易出现膏体自动流出的情况。
实施例稳定性
按照《中国药典》2005年版二部的软膏制剂的稳定性考察方法,对自制的全新的丁酸氢化可的松乳膏进行了长期的稳定性考察,与CN200910228788.0中的数据进行比较,方法与CN 200910228788.0中的一致。
每组样本量为45支,规格为10g/支,铝塑管包装,主要对液相含量和HCB-21含量进行检测,检测方法按照仲维高(HPLC法测定丁酸氢化可的松软膏中丁酸氢化可的松,(淮海医药,2006年9月第24卷第5期,428-429)公开的方法进行检测,每次取样量为5只。
检测仪器:日本岛津LC—IOA高效液相色谱仪;SPD-l0A紫外检测器
色谱条件:色谱柱,岛津CIS-ODS柱(150mm×4.6mm,5μm);流动相,甲醇:水:乙醚(62:38:2);流速1.0ml/min;进样量,20μL;柱温,室温;检测波长,UV240nm。理论塔板数按丁酸氢化可的松计算应不低于2 000。丁酸氢化可的松的峰与相邻杂质峰的分离度符合要求。
对照品溶液的制备,精密称取丁酸氢化可的松对照品((含量测定用,中国生物制品检定所提供)12.0mg,用流动相溶解,并定容至100m1,摇匀。即是浓度为每1ml约含0.120mg的溶液。
样品溶液的制备:取样品乳膏约3.0g。精密称定,置50ml量瓶中。加甲醇适量,置80℃水溶中,加热使溶解,放冷至室温,加甲醇稀释至刻度,摇匀。置冰浴中冷却2h。取出后迅速滤过,弃去初滤液,取续滤液作为样品溶液。
线性关系的确定:精密称取丁酸氢化可的松对照品(含量为98.79%)12.0mg,用甲醇溶液并制成每1ml约含0.120mg的溶液。精密量取4、8、10、12、16、20ml分别置50m1量瓶中,加甲醇稀释至刻度,摇匀。在上述色谱条件下,分别进样20μL,结果表明丁酸氢化可的松在30-45mg/L浓度范围内浓度与峰面积有良好的线性关系。回归方程Y=4475.3X+422.45。r=0.9993。
样品测定:取对照品溶液和供试品溶液各20μL进样,读取峰面积值,按外标法计算含量。
稳定性考查按照中国药典2005版附录176页中药物制剂稳定性试验指导原则公开方法进行长期稳定性试验(25℃22℃,相对湿度65%25%)下的稳定性试验。
表1不同处方丁酸氢化可的松乳膏长期稳定性考察结果(含量均值)
《中国药典》2005年版二部的22页“丁酸氢化可的松乳膏”项目下规定,活性成分含量范围为90%-110%。由表1的实施例1~2制得的丁酸氢化可的松乳膏样品和对照乳膏稳定性数据对比可以发现:经过36个月的稳定性实验后所有实验组药物含量降低都在10%以内,但本发明实施例提供的样品在不同取样时间点的有效成分含量均高于市售乳膏,而在36个月实验终了时的有效成分含量显著高于市售乳膏(P<0.05),而与CN 200910228788.0的处方的乳膏相比近似。这充分说明了按照本发明实施例制得的乳膏比市售乳膏稳定性要好。此外,按本发明方案制得的乳膏在长期稳定性考察中,均没有发生分层、变色现象。皮肤刺激性试验。
刺激性实验
参考《化妆品卫生规范》(2015年版)皮肤刺激性/腐蚀性试验中的要求开展皮肤刺激性试验。
实验动物:3月龄白色家兔每组5只。
试验方法:试验前24h,将动物背部脊柱两侧被毛剪掉,去毛范围各为3cm×3cm,取受试物约0.5ml(g)涂抹在一侧皮肤上,涂抹范围在2.5cm×2.5cm,涂抹1次/d,连续涂抹14天,另一侧皮肤作为对照组(当受试物使用无刺激性溶剂配制时,涂溶剂作为对照)。从第2天开始,每次涂抹前剪毛,1h后观察结果,按《化妆品卫生规范》(2015年版)皮肤刺激性/腐蚀性试验中表1评分,对照区和试验区作同样处理,试验结束后计算每天每只动物平均积分,判定皮肤刺激强度。
试验结果:
表2不同处方丁酸氢化可的松乳膏皮肤刺激性考察结果(均值)
Claims (5)
1.一种丁酸氢化可的松外用药物组合物,由作为活性成分的0.05-0.2%丁酸氢化可的松,作为药用辅料的10-25%白凡士林、10-25%十六醇十八醇、10-20%液体石蜡、2%~10%鲸蜡硬脂醇聚醚-20、0.1-0.5%防腐剂,用柠檬酸和柠檬酸钠调节组合物的pH值>6.0且≦6.5和余量的水组成,在0-30℃下的黏度在3000-3900mPa.S之间。
2.如权利要求1所述的外用药物组合物,其特征是所述10-30℃下的黏度在3200-3800mPa.S之间。
3.如权利要求1所述的外用药物组合物,其特征是所述的防腐剂为尼泊金甲酯、尼泊金乙酯中的一种或几种。
4.如权利要求1所述的外用药物组合物,其特征是所述的丁酸氢化可的松含量为0.05-0.1%。
5.如权利要求1所述的外用药物组合物,所述组合物的配制方法如下:
(1)油相配制:取用于油相基质的白凡士林、十六醇十八醇、部分液体石蜡、鲸蜡硬脂醇聚醚-20加热熔融成为溶液,温度保持在70-90℃;
(2)水相配制:用柠檬酸、柠檬酸钠调节好pH值的水混合,加入防腐剂、加热,搅拌均匀温度保持在70-90℃;
(3)将丁酸氢化可的松微粉均匀分散于剩余部分液体石蜡中,温度保持在50-60℃;
(4)合相:将步骤(1)配制的油相、步骤(3)中的活性成分相缓缓加入步骤(2)配制的水相中,搅拌,保持温度在70-90℃,搅拌,冷却成膏。
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CN113413363A (zh) * | 2021-08-12 | 2021-09-21 | 福元药业有限公司 | 一种地奈德乳膏及其制备方法 |
CN114504548A (zh) * | 2020-11-16 | 2022-05-17 | 湖北舒邦药业有限公司 | 软膏剂及其制备方法 |
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CN114504548A (zh) * | 2020-11-16 | 2022-05-17 | 湖北舒邦药业有限公司 | 软膏剂及其制备方法 |
CN114504548B (zh) * | 2020-11-16 | 2023-08-22 | 湖北舒邦药业有限公司 | 软膏剂及其制备方法 |
CN113413363A (zh) * | 2021-08-12 | 2021-09-21 | 福元药业有限公司 | 一种地奈德乳膏及其制备方法 |
CN113413363B (zh) * | 2021-08-12 | 2022-07-05 | 福元药业有限公司 | 一种地奈德乳膏及其制备方法 |
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