CN111743853A - External pharmaceutical composition of near-neutral hydrocortisone butyrate - Google Patents
External pharmaceutical composition of near-neutral hydrocortisone butyrate Download PDFInfo
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- CN111743853A CN111743853A CN201910247341.1A CN201910247341A CN111743853A CN 111743853 A CN111743853 A CN 111743853A CN 201910247341 A CN201910247341 A CN 201910247341A CN 111743853 A CN111743853 A CN 111743853A
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- Prior art keywords
- hydrocortisone butyrate
- pharmaceutical composition
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- water
- temperature
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- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound 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 45
- 229960001524 hydrocortisone butyrate Drugs 0.000 title claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 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 16
- 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
- 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
- 239000000203 mixture Substances 0.000 claims description 6
- 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
- 230000002421 anti-septic effect Effects 0.000 claims description 3
- 239000011159 matrix material Substances 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 2
- 239000006071 cream Substances 0.000 abstract description 31
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000007794 irritation Effects 0.000 abstract description 4
- 239000012071 phase Substances 0.000 description 27
- 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 206010040880 Skin irritation Diseases 0.000 description 5
- 239000003862 glucocorticoid Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 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
- 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 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
- 230000007774 longterm Effects 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
- 208000002193 Pain Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 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
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002674 ointment 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
- 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
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000010812 external standard method 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
- 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
- 238000004519 manufacturing process Methods 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
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 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
- 239000012088 reference solution Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an external pharmaceutical composition of hydrocortisone butyrate, in particular to a near-neutral hydrocortisone butyrate cream, which avoids irritation of medicines and ensures stability of products at the same time by optimizing a prescription under the condition that the pH value is more than 6.
Description
Technical Field
The invention relates to an external pharmaceutical composition of hydrocortisone butyrate, in particular to a near-neutral hydrocortisone butyrate cream.
Background
Glucocorticoids, which are one of the steroidal corticosteroids, have a steroidal compound structure and inhibit inflammatory and allergic skin reactions, and also inhibit the reactions associated with accelerated cell regeneration, which lead to symptoms such as erythema, edema, pachynsis, and a decrease in rough skin surface, and alleviate itching, burning sensation, and pain. Due to the introduction of ester groups on the compounds, particularly the 21 and/or 17 positions of the pregnane compounds, the fat solubility of the compounds is better, so that better curative effect can be achieved in external treatment. The glucocorticoid contains hydrocortisone butyrate, methylprednisolone aceponate, dexamethasone acetate, hydrocortisone acetate, mometasone furoate, prednisone acetate, prednisolone acetate, fluticasone propionate, fluticasone furoate, desonide, triamcinolone acetonide and other medicaments, and the structure of the glucocorticoid is similar, the action mechanism is consistent, so the medicaments have strong similarity in the aspect of anti-inflammation, and the difference is only the strength of the curative effect. The glucocorticoid has strong curative effect and also has adverse reactions such as skin atrophy and thinning, capillary vessel dilatation, pigmentation, secondary infection and the like.
Hydrocortisone butyrate (CAS: 13609-67-1), a type of glucocorticoid, inhibits inflammatory and allergic skin reactions, and also inhibits the reactions associated with accelerated cell regeneration that lead to symptoms such as erythema, edema, thickening of the skin, and a decrease in rough skin surface, and alleviates itching, burning sensation, and pain. Due to the fact that 17-butyrate is introduced into the hydrocortisone molecule, the fat solubility of hydrocortisone butyrate is better, the better curative effect can be achieved during external treatment, and the advantage of lighter side effects of hydrocortisone is retained, so that the hydrocortisone butyrate is an external steroid corticosteroid for children. The prior external preparation mainly comprises hydrocortisone butyrate cream (trade name: Utrel, product of Tianjin pharmaceutical industry group Co., Ltd., marketed in China in 1994), and the specification of the hydrocortisone butyrate cream (http:// www.kingyork.biz/2009/0312/446.html) discloses that the used auxiliary materials comprise glycerol, propylene glycol, vaseline, octadecanol, liquid paraffin, peregal A-20, citric acid, sodium citrate, ethylparaben (preservative) and purified water.
We have found through our experiments that the impurity generated during storage in the hydrocortisone butyrate cream is mainly 21-hydrocortisone butyrate, and the main reason for generating the impurity is that the 17-ester group is hydrolyzed during storage and undergoes similar ester exchange reaction with the 21-hydroxyl group to become hydrocortisone-21-butyrate. In the specification of US20040152682a1, second page table 3 also discloses hydrocortisone-21-butyrate (HCB-21) produced by transesterification of main impurities in a hydrocortisone butyrate preparation stability experiment, and under the existing preparation process and formula, the transesterification reaction has a higher speed, more impurities are produced, and the product stability is greatly interfered, and meanwhile, the curative effect of the product is also influenced to a certain extent due to the production of the impurities.
It is known that (Marylang, type and influence factor of carboxylic ester hydrolysis, Proc. Nature science edition, 9 Vol. 11 of 1998, 417-.
In chinese patent CN200910228788.0, a hydrocortisone butyrate cream is described. The technical scheme is that the emulsion contains hydrocortisone butyrate 0.05-0.2% as an active ingredient, the solid used as an oil phase ingredient accounts for 3% -20%, and the solid is selected from one or more of higher alcohols; the dosage of the consistency regulator is 5 to 20 percent. One or more selected from vaseline and liquid paraffin; the dosage of the humectant is 3% -10%, and the humectant is selected from polyalcohol compounds; the dosage of the emulsifier is 1-10%, and the emulsifier is selected from polyoxyethylene ether derivatives; the dosage of the preservative is 0.05-0.2%, and the preservative is selected from a nipagin preservative; the pH regulator is preferably citric acid/sodium citrate buffer. The pH of the cream is between 5.2 and 5.8.
Disclosure of Invention
In the prior art, the pH value of the medicine has to be reduced to be below 6 in order to maintain the stability of the medicine, but the skin irritation is increased, and the medicine is particularly obvious for children. In order to overcome the problems in the prior art, the invention provides hydrocortisone butyrate cream with a new formula, which avoids the irritation of medicines and ensures the stability of products at the same time by optimizing the formula under the condition that the pH is more than 6.
An external pharmaceutical composition of hydrocortisone butyrate comprises 0.05-0.2% of hydrocortisone butyrate as an active ingredient, 10-25% of white vaseline, 10-25% of cetostearyl alcohol, 10-20% of liquid paraffin, 2-10% of ceteareth-20 and 0.1-0.5% of preservative as pharmaceutical excipients, citric acid and sodium citrate are used for adjusting the pH value of the composition to be more than 6.0 and less than 6.5, and the balance of water.
The external pharmaceutical composition is characterized in that the preservative is one or more of methylparaben and ethylparaben.
The external medicine composition is characterized in that the hydrocortisone butyrate content is 0.05-0.1%.
The external pharmaceutical composition is prepared by the following steps:
(1) preparing an oil phase: heating white vaseline, cetostearyl alcohol, part of liquid paraffin and ceteareth-20 in oil phase matrix to melt into solution, and maintaining the temperature at 70-90 deg.C;
(2) preparing a water phase: mixing with water with pH value adjusted by citric acid and sodium citrate, adding antiseptic, heating, stirring, and maintaining at 70-90 deg.C;
(3) uniformly dispersing hydrocortisone butyrate micropowder in the rest part of liquid paraffin, and keeping the temperature at 50-60 ℃;
(4) phase combination: slowly adding the oil phase prepared in the step (1) and the active ingredient phase prepared in the step (3) into the water phase prepared in the step (2), stirring, keeping the temperature at 70-90 ℃, stirring, and cooling to form paste.
Due to the fact that the pH value and the formula of the cream are optimized, the brand-new hydrocortisone butyrate cream provided by the invention is good in quality stability. In addition, the cream provided by the present invention is under the influence of a preferred pH range and recipe.
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
All the creams prepared in the examples were packed in 10 g/aluminium tube portions for further use. The hydrocortisone butyrate is micropowder with particle size of 5-50 μm.
The method for measuring the pH value of the cream paste comprises the following steps: accurately weighing 5g of paste sample, adding 25ml of boiled and cooled purified water, heating to 40 ℃, stirring to completely dissolve, cooling to room temperature, and measuring by using a pH value meter.
The preparation of the examples and the preparation of the comparative examples are prepared according to the total amount of 1000g, and various auxiliary materials in the prescription are prepared according to the corresponding percentages.
Example 1
The components are accurately weighed according to the mixture ratio, and the preparation method of the composition is as follows:
(1) preparing an oil phase: heating white vaseline, cetostearyl alcohol, part of liquid paraffin and ceteareth-20 in oil phase matrix to melt into solution, and maintaining the temperature at 70-90 deg.C;
(2) preparing a water phase: mixing with citric acid and sodium citrate, adjusting pH, adding antiseptic, heating, stirring, and maintaining at 70-90 deg.C;
(3) uniformly dispersing hydrocortisone butyrate micropowder in the rest part of liquid paraffin, and keeping the temperature at 50-60 ℃;
(4) phase combination: slowly adding the oil phase prepared in the step (1) and the active ingredient phase prepared in the step (3) into the water phase prepared in the step (2), stirring, keeping the temperature at 70-90 ℃, stirring, and cooling to form paste.
Example 2
The preparation method is the same as example 1.
COMPARATIVE EXAMPLE 1 (EXAMPLE 1 in CN 200910228788.0)
Hydrocortisone butyrate 1g, white vaseline 100g, octadecanol 30g, liquid paraffin 30g,
peregal A-2050 g, glycerin 50g, propylene glycol 20g, ethylparaben 1g, and citric acid (C)6H8O7·H2O)10g，
Sodium citrate (Na)3C6H5O7·2H2O)18g of water for injection to 1000g
Accurately weighing the components in the proportion, and preparing the emulsifiable paste as follows:
(1) preparing an oil phase: putting white vaseline, octadecanol, liquid paraffin and peregal A-20 into a container, heating to melt, and keeping the temperature at 90 ℃;
(2) preparing a water phase: dissolving citric acid and sodium citrate in water for injection, uniformly dispersing main drug in glycerol and propylene glycol, adding aqueous solution of citric acid and sodium citrate and ethylparaben, heating, stirring uniformly, and keeping the temperature at 90 deg.C;
(3) phase combination: slowly adding the oil phase prepared in step (1) into the water phase prepared in step (2), stirring, maintaining the temperature at 80 deg.C, stirring for 30min, cooling to obtain cream with content of 0.1% and pH of 5.5, 1000 g.
COMPARATIVE EXAMPLE 2 (EXAMPLE 2 in CN 200910228788.0)
Hydrocortisone butyrate 1g, white vaseline 30g, octadecanol 100g, liquid paraffin 100g,
peregal A-2010 g, glycerin 10g, propylene glycol 50g, ethylparaben 1g, and citric acid (C)6H8O7·H2O)4g，
Sodium citrate (Na)3C6H5O7·2H2O)6g of water for injection to 1000g
Accurately weighing the components in the proportion, and preparing the emulsifiable paste as follows:
(1) preparing an oil phase: putting white vaseline, octadecanol, liquid paraffin and peregal A-20 into a container, heating to melt, and keeping the temperature at 75 ℃;
(2) preparing a water phase: dissolving citric acid and sodium citrate in water for injection, uniformly dispersing main drug in glycerol and propylene glycol, adding aqueous solution of citric acid and sodium citrate and ethylparaben, heating, stirring uniformly, and keeping the temperature at 90 deg.C;
(3) phase combination: slowly adding the oil phase prepared in step (1) into the water phase prepared in step (2), stirring, maintaining the temperature at 90 deg.C, stirring for 30min, cooling to obtain cream with content of 0.1% and pH of 5.2, and making into cream with content of 1000 g.
Compared with the prescription of Chinese patent CN200910228788.0 and the commercially available hydrocortisone butyrate cream, the brand-new hydrocortisone butyrate cream provided by the invention has similar quality stability but lower irritation under the condition that the pH value is greater than 6.
Example stability
According to the stability investigation method of the ointment preparation of the second edition of Chinese pharmacopoeia 2005, the stability investigation of the homemade novel hydrocortisone butyrate cream for a long time is carried out, and compared with the data in CN200910228788.0, the method is consistent with that in CN 200910228788.0.
The sample amount of each group is 45, the specification is 10 g/count, the aluminum-plastic tube is packaged, the liquid phase content and the HCB-21 content are mainly detected, the detection method is carried out according to the method disclosed by Zhongwei height (determination of hydrocortisone butyrate in hydrocortisone butyrate ointment by HPLC (Huaihai medicine, Vol. 24, No. 5, No. 428-.
A detection instrument: shimadzu LC-IOA hplc; SPD-l0A ultraviolet detector
Chromatographic conditions are as follows: a chromatography column, Shimadzu CIS-ODS column (150 mm. times.4.6 mm, 5 μm); mobile phase, methanol: water: diethyl ether (62: 38: 2); the flow rate is 1.0 ml/min; sample size, 20 μ L; column temperature, room temperature; detection wavelength, UV240 nm. The theoretical plate number is not less than 2000 calculated by hydrocortisone butyrate. The separation degree of the peak of the hydrocortisone butyrate and the adjacent impurity peak meets the requirement.
Preparation of control solution, weighing hydrocortisone butyrate control (for content measurement, provided by China biological products assay) 12.0mg precisely, dissolving with mobile phase, metering to 100m1, and shaking up to obtain a solution with a concentration of about 0.120mg per 1 ml.
Preparation of sample solution: the sample cream was about 3.0 g. Accurately weighing, and placing in a 50ml measuring flask. Adding appropriate amount of methanol, dissolving in 80 deg.C water, heating to dissolve, cooling to room temperature, diluting with methanol to desired volume, and shaking. The mixture was cooled in an ice bath for 2 h. Taking out, quickly filtering, discarding the primary filtrate, and taking the secondary filtrate as a sample solution.
Determination of the linear relationship: hydrocortisone butyrate control (content 98.79%) 12.0mg was weighed out precisely, and made into a solution of about 0.120mg per 1ml with methanol solution. Precisely measuring 4 ml, 8 ml, 10 ml, 12 ml, 16 ml and 20ml, respectively placing into a 50m1 measuring flask, adding methanol to dilute to the scale, and shaking up. Under the chromatographic conditions, 20 mu L of sample is injected respectively, and the result shows that the concentration of hydrocortisone butyrate within the concentration range of 30-45mg/L has a good linear relation with the peak area. The regression equation Y is 4475.3X + 422.45. r is 0.9993.
And (3) sample determination: sampling 20 μ L of reference solution and sample solution, reading peak area value, and calculating content according to external standard method.
Stability examination stability tests were carried out in a long-term stability test (22 ℃ at 25 ℃, 65% relative humidity 25%) according to the method disclosed in the Chinese pharmacopoeia 2005 edition appendix 176 page of the guidelines for the stability tests of pharmaceutical preparations.
TABLE 1 Long-term stability test results (mean content) for hydrocortisone butyrate creams of different prescriptions
The content range of the active ingredients is 90-110% as specified under the project of 'hydrocortisone butyrate cream' on page 22 of the second edition of Chinese pharmacopoeia 2005. Comparison of the stability data of hydrocortisone butyrate cream samples prepared in examples 1-2 of Table 1 with the stability data of a control cream shows that: after 36 months of stability test, the content of the medicines in all experimental groups is reduced within 10 percent, but the effective component content of the samples provided by the embodiment of the invention is higher than that of the commercial cream at different sampling time points, and the effective component content at the end of the 36 months test is obviously higher than that of the commercial cream (P < 0.05) and is similar to that of the cream of the formula of CN 200910228788.0. This is a good indication that the creams made according to the examples of the present invention are more stable than commercially available creams. In addition, the cream prepared according to the scheme of the invention has no phenomena of layering and discoloration in long-term stability examination. Skin irritation test.
Irritation test
The skin irritation test was carried out with reference to the requirements in the skin irritation/corrosion test of the cosmetic hygiene code (2015 edition).
Experimental animals: each group of 3-month-old white rabbits had 5 rabbits.
The test method comprises the following steps: 24h before the test, the hairs on both sides of the spine of the animal are cut off, the hair removal ranges are respectively 3cm multiplied by 3cm, about 0.5ml (g) of the test object is taken and smeared on the skin of one side, the smearing range is 2.5cm multiplied by 2.5cm, smearing is carried out for 1 time/d, smearing is continuously carried out for 14 days, and the skin of the other side is used as a control group (when the test object is prepared by using a non-irritant solvent, the solvent is used as a control). The results were observed after 1 hour from day 2, before each application, and were scored according to Table 1 in the skin irritation/corrosion test of the cosmetic hygiene standards (2015 edition), the control and test areas were treated in the same manner, and the average score per animal per day was calculated after the test was completed, and the skin irritation intensity was determined.
And (3) test results:
TABLE 2 results of skin irritation examination of hydrocortisone butyrate creams of different prescriptions (mean)
Claims (4)
1. An external pharmaceutical composition of hydrocortisone butyrate comprises 0.05-0.2% of hydrocortisone butyrate as an active ingredient, 10-25% of white vaseline, 10-25% of cetostearyl alcohol, 10-20% of liquid paraffin, 2-10% of ceteareth-20 and 0.1-0.5% of preservative as pharmaceutical excipients, citric acid and sodium citrate are used for adjusting the pH value of the composition to be more than 6.0 and less than 6.5, and the balance of water.
2. The external pharmaceutical composition of claim 1, wherein the preservative is one or more of methylparaben and ethylparaben.
3. The topical pharmaceutical composition of claim 1, wherein the hydrocortisone butyrate is present in an amount of 0.05-0.1%.
4. The topical pharmaceutical composition of claim 1, formulated as follows:
(1) preparing an oil phase: heating white vaseline, cetostearyl alcohol, part of liquid paraffin and ceteareth-20 in oil phase matrix to melt into solution, and maintaining the temperature at 70-90 deg.C;
(2) preparing a water phase: mixing with water with pH value adjusted by citric acid and sodium citrate, adding antiseptic, heating, stirring, and maintaining at 70-90 deg.C;
(3) uniformly dispersing hydrocortisone butyrate micropowder in the rest part of liquid paraffin, and keeping the temperature at 50-60 ℃;
(4) phase combination: slowly adding the oil phase prepared in the step (1) and the active ingredient phase prepared in the step (3) into the water phase prepared in the step (2), stirring, keeping the temperature at 70-90 ℃, stirring, and cooling to form paste.
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| CN113413363A (en) * | 2021-08-12 | 2021-09-21 | 福元药业有限公司 | Desonide cream and preparation method thereof |
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