CN103417557A - Compound ketoconazole cream - Google Patents
Compound ketoconazole cream Download PDFInfo
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- CN103417557A CN103417557A CN2013103530058A CN201310353005A CN103417557A CN 103417557 A CN103417557 A CN 103417557A CN 2013103530058 A CN2013103530058 A CN 2013103530058A CN 201310353005 A CN201310353005 A CN 201310353005A CN 103417557 A CN103417557 A CN 103417557A
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- Prior art keywords
- ketoconazole
- cream
- compound
- compound ketoconazole
- tinea
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- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 title claims abstract description 43
- 229960004125 ketoconazole Drugs 0.000 title claims abstract description 43
- 239000006071 cream Substances 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 claims abstract description 17
- 229960004703 clobetasol propionate Drugs 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 229940057995 liquid paraffin Drugs 0.000 claims abstract description 12
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008213 purified water Substances 0.000 claims abstract description 12
- 239000003871 white petrolatum Substances 0.000 claims abstract description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- 108010019657 polymyxin drug combination nystatin neomycin dimethicone acetarsol Proteins 0.000 claims description 13
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 11
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 11
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 8
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 8
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 8
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 8
- 230000002421 anti-septic effect Effects 0.000 claims description 7
- 239000003230 hygroscopic agent Substances 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- 229960002152 chlorhexidine acetate Drugs 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 208000002474 Tinea Diseases 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 8
- 206010017533 Fungal infection Diseases 0.000 abstract description 7
- 208000031888 Mycoses Diseases 0.000 abstract description 7
- 201000010618 Tinea cruris Diseases 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 241000130764 Tinea Species 0.000 abstract 2
- 230000002745 absorbent Effects 0.000 abstract 1
- 239000002250 absorbent Substances 0.000 abstract 1
- 229940081733 cetearyl alcohol Drugs 0.000 abstract 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical group N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 abstract 1
- 229940053050 neomycin sulfate Drugs 0.000 abstract 1
- 239000003755 preservative agent Substances 0.000 abstract 1
- 230000002335 preservative effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 18
- 239000012071 phase Substances 0.000 description 15
- 241000233866 Fungi Species 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000012360 testing method Methods 0.000 description 11
- 238000011282 treatment Methods 0.000 description 10
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- 231100000444 skin lesion Toxicity 0.000 description 7
- 206010005913 Body tinea Diseases 0.000 description 6
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- 239000000463 material Substances 0.000 description 6
- 201000003875 tinea corporis Diseases 0.000 description 6
- 241000555676 Malassezia Species 0.000 description 5
- 208000007712 Tinea Versicolor Diseases 0.000 description 5
- 206010067197 Tinea manuum Diseases 0.000 description 5
- 206010056131 Tinea versicolour Diseases 0.000 description 5
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- 238000002360 preparation method Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 201000004647 tinea pedis Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 229940121375 antifungal agent Drugs 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
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- 238000000386 microscopy Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 206010015150 Erythema Diseases 0.000 description 3
- 241000283898 Ovis Species 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 230000003628 erosive effect Effects 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 201000009862 superficial mycosis Diseases 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 206010007134 Candida infections Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012504 Dermatophytosis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001460074 Microsporum distortum Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 201000003984 candidiasis Diseases 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
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- 230000014759 maintenance of location Effects 0.000 description 2
- 231100000017 mucous membrane irritation Toxicity 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- 101100025412 Arabidopsis thaliana XI-A gene Proteins 0.000 description 1
- 101100515520 Arabidopsis thaliana XI-J gene Proteins 0.000 description 1
- QYILKUYLKGLORV-UHFFFAOYSA-N C(CCC)O.O.C1(C(C(C2=CC=CC=C12)=O)=O)=O Chemical compound C(CCC)O.O.C1(C(C(C2=CC=CC=C12)=O)=O)=O QYILKUYLKGLORV-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 210000002615 epidermis Anatomy 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000004362 fungal culture Methods 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- -1 imidazoles dioxane derivative Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 230000003780 keratinization Effects 0.000 description 1
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- 210000004877 mucosa Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical pharmaceutics and particularly relates to externally applied drug, compound ketoconazole cream, for treating superficial fungal infections. Each 10g of the cream comprises 0.05-0.2g of ketoconazole, 2.0-3.0mg of clobetasol propionate, 2-8 ten thousands of units of neomycin sulfate, 1.0-1.5g of cetearyl alcohol, 500-1000mg of white Vaseline, 200-500mg of liquid paraffin, 100-200mg of leveling agent O, 300-700mg of absorbent, 15-25mg of preservative, 150-200mg of dimethyl sulfoxide, 2-8mg of essence, and the balance of purified water. The compound ketoconazole cream is mainly used for superficial skin fungal infections such as fungal infection of the hand, tinea of the feet, tinea of the body, and tinea cruris.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of medicine for external use-Compound Ketoconazole Cream for the treatment of mycotic infection of superficial part.
Background technology
Mycotic infection of superficial part refers to be limited to the fungal infection of skin outermost layer (epidermis), deck, hair and mucosa, and its main pathogenic fungi is dermatophytosis, chlosma, candidiasis etc.This type of disease is the modal infectious disease of department of dermatologry, and its sickness rate can account for all dermopathic 1/4 left and right according to statistics.
Ketoconazole is the imidazoles dioxane derivative of synthetic in 1976.Act on Pilus Caprae seu Ovis steroid 14 α in the fungal cell membrane forming process-demethylase, suppress the conversion of Pilus Caprae seu Ovis steroid to 14 α-demethyl Pilus Caprae seu Ovis steroid, thus the biosynthesis of Antifungi cell membrane ergosterol and Antifungi growth.Ketoconazole has the broad-spectrum antifungal effect, especially dermatophytosis, candidiasis and chlosma is had to obvious inhibitory action.
Summary of the invention
The object of the present invention is to provide a kind of Compound Ketoconazole Cream for the treatment of mycotic infection of superficial part.
The present invention is by the following technical solutions:
A kind of Compound Ketoconazole Cream, contain following raw material in every 10g emulsifiable paste: ketoconazole 0.05-0.2g, clobetasol propionate 2.0-3.0mg, polygynax 2-8 ten thousand units, cetostearyl alcohol 1.0-1.5g, white vaseline 500-1000mg, liquid Paraffin 200-500mg, leveling agent o 100-200mg, hygroscopic agent 300-700mg, antiseptic 15-25mg, dimethyl sulfoxide 150-200mg, essence 2-8mg, surplus is purified water.
Further preferably, contain following raw material in every 10g emulsifiable paste: ketoconazole 0.1g, clobetasol propionate 2.5mg, polygynax 50,000 units, cetostearyl alcohol 1.27g, white vaseline 666.7mg, liquid Paraffin 333.3mg, leveling agent o 166.7mg, hygroscopic agent 466.7mg, antiseptic 20mg, dimethyl sulfoxide 186.7mg, essence 5mg, surplus is purified water.
Described hygroscopic agent is one or more in glycerol, polyoxyethylene sorbitan monoleate or propylene glycol.
Described antiseptic is a kind of in ethyl hydroxybenzoate, sorbic acid, sodium benzoate, benzalkonium bromide or chlorhexidine acetate.
Compound Ketoconazole Cream of the present invention comprises the steps: while preparing
1) prepare water: in proportion hygroscopic agent, leveling agent o, polygynax, antiseptic and purified water are dropped in the water tank, in 85 ± 5 ℃ of stirring 20-30min, standby;
2) prepare oil phase: in proportion cetostearyl alcohol, white vaseline and liquid Paraffin are added in the oil phase tank, in 83 ± 5 ℃ of stirring 20-30min, standby;
3) prepare emulsifiable paste: above-mentioned aqueous phase substance, oil phase substance are proceeded in emulsion tank, stir 20-30min under the condition that vacuum is 0.03 ± 0.02Mpa in emulsion tank, then homogenizing 10-25 min, cool the temperature to 67 ± 5 ℃, add the clobetasol propionate by appropriate dmso solution; Stirring is cooled to 50 ± 5 ℃, adds the ketoconazole of surplus dmso solution, and homogenizing stirs 15-25min, is cooled to 40 ± 5 ℃, then adds essence, continues to stir 20-50 minute, embedding and get final product.
Compound Ketoconazole Cream of the present invention is mainly used in the superficial part cutaneous fungal infection, as the tinea manuum, tinea pedis, tinea corporis, tinea cruris etc., to curative effect the best of tinea corporis and cruris, is secondly pityriasis versicolor and Malassezia folliculits, and treating six weeks is 94.6% to the fungus clearance rate.Test and Fungus examination result show that Compound Ketoconazole Cream finds no toxic and side effects and untoward reaction in using, without skin, mucous membrane irritation, and the clinic application.
The specific embodiment
Embodiment 1
A kind of Compound Ketoconazole Cream, contain the following weight raw material in every 10g emulsifiable paste: ketoconazole 0.1g, clobetasol propionate 2.5mg, polygynax 50,000 units, cetostearyl alcohol 1.27g, white vaseline 666.7mg, liquid Paraffin 333.3mg, glycerol 333.3mg, leveling agent o 166.7mg, polyoxyethylene sorbitan monoleate 133.3mg, ethyl hydroxybenzoate 20mg, dimethyl sulfoxide 186.7mg, essence 5mg, surplus is purified water.
Adopt following steps during preparation:
1) prepare water: in proportion water material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water are dropped in the water tank, in 85 ℃ of stirring 25min, standby;
2) prepare oil phase: in proportion oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin are added in the oil phase tank, in 83 ℃ of stirring 25min, standby;
3) prepare emulsifiable paste: above-mentioned aqueous phase substance, oil phase substance are proceeded in emulsion tank, stir 25min under the condition that vacuum is 0.03Mpa in emulsion tank, then homogenizing 20min, cool the temperature to 67 ℃, adds the clobetasol propionate by appropriate dmso solution; Stirring is cooled to 50 ℃, adds the ketoconazole of surplus dmso solution, and homogenizing stirs 20min, is cooled to 40 ℃, then adds essence, continues to stir 30 minutes embedding and get final product.
Embodiment 2
A kind of Compound Ketoconazole Cream, contain the following weight raw material in every 10g emulsifiable paste: ketoconazole 0.05g, clobetasol propionate 2.0mg, polygynax 20,000 units, cetostearyl alcohol 1.0g, white vaseline 500mg, liquid Paraffin 200mg, glycerol 200mg, leveling agent o 100mg, polyoxyethylene sorbitan monoleate 100mg, ethyl hydroxybenzoate 15mg, dimethyl sulfoxide 150mg, essence 2mg, surplus is purified water.
Adopt following steps during preparation:
1) prepare water: in proportion water material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water are dropped in the water tank, in 80 ℃ of stirring 30min, standby;
2) prepare oil phase: in proportion oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin are added in the oil phase tank, in 78 ℃ of stirring 30min, standby;
3) prepare emulsifiable paste: above-mentioned aqueous phase substance, oil phase substance are proceeded in emulsion tank, stir 30min under the condition that vacuum is 0.01Mpa in emulsion tank, then homogenizing 25 min, cool the temperature to 62 ℃, adds the clobetasol propionate by appropriate dmso solution; Stirring is cooled to 45 ℃, adds the ketoconazole of dmso solution, and homogenizing stirs 25min, is cooled to 35 ℃, then adds essence, continues to stir 50 minutes embedding and get final product.
Embodiment 3
A kind of Compound Ketoconazole Cream, contain the following weight raw material in every 10g emulsifiable paste: ketoconazole 0.2g, clobetasol propionate 3.0mg, polygynax 80,000 units, cetostearyl alcohol 1.5g, white vaseline 1000mg, liquid Paraffin 500mg, glycerol 500mg, leveling agent o 200mg, polyoxyethylene sorbitan monoleate 200mg, ethyl hydroxybenzoate 25mg, dimethyl sulfoxide 200mg, essence 8mg, surplus is purified water.
Adopt following steps during preparation:
1) prepare water: in proportion water material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water are dropped in the water tank, in 90 ℃ of stirring 20min, standby;
2) prepare oil phase: in proportion oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin are added in the oil phase tank, in 88 ℃ of stirring 20min, standby;
3) prepare emulsifiable paste: above-mentioned aqueous phase substance, oil phase substance are proceeded in emulsion tank, stir 20min under the condition that vacuum is 0.05Mpa in emulsion tank, then homogenizing 10min, cool the temperature to 72 ℃, adds the clobetasol propionate by appropriate dmso solution; Stirring is cooled to 55 ℃, adds the ketoconazole of dmso solution, and homogenizing stirs 15min, is cooled to 45 ℃, then adds essence, continues to stir 20 minutes embedding and get final product.
Compound Ketoconazole Cream of the present invention is tested by following quality standard:
Character: this product is white or off-white color emulsifiable paste.Concrete discriminating is as follows:
(1), in the chromatogram recorded under ketoconazole, clobetasol propionate assay item, the retention time of need testing solution two main peaks should be consistent with the retention time of reference substance solution two main peaks.
(2) get the about 1.5g(of this product and be equivalent to polygynax 7500 units), put in tool plug centrifuge tube, add chloroform 10ml and water 5ml, strong jolting, centrifugal, get the supernatant, as need testing solution; Separately get the polygynax standard substance, add water make every 1ml approximately containing the solution of 2mg as standard solution, according to thin layer chromatography (two appendix V B of Chinese Pharmacopoeia version in 2010), test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, methanol-chloroform-the ammonia (13.5mol/L) of take is (60:20:40) developing solvent, launch, dry, spray is with 1% 1,2,3-indantrione monohydrate butanol solution, 105 ℃ of heating 2 minutes, need testing solution the position of aobvious principal spot should be identical with the principal spot of standard solution with color.
Loading quantity inspection: get 5 of test samples, remove enclosing cover, clean its outer wall respectively, to be dried after, accurately weighed its weight respectively, remove content, container clean and drying after, then distinguish the weight of accurately weighed empty, obtain the loading amount and average loading amount of each container contents, the loading amount of each container is no less than 93% of sign loading amount, and average loading amount is no less than the sign loading amount.
Limit test of microbe: according to microbial limit test (two appendix XI J of Chinese Pharmacopoeia version in 2010), check, bacterial population, yeast and mold number all must not be crossed 100cfu/g; Staphylococcus aureus, Pseudomonas aeruginosa all every 1g must not detect.
PolygynaxGet the about 2g of this product, accurately weighed, put in 100ml tool plug conical flask, add petroleum ether (90 ~ 120 ℃ of boiling ranges) 50ml, 80 ℃ of heating in water bath make stromatolysis or disperse rear supersound process approximately 30 minutes, let cool, be transferred in separatory funnel, extract 4 times each 20ml, merge extractive liquid, with the phosphate buffer (pH7.8) containing 3% sodium chloride, put in the 100ml measuring bottle, add above-mentioned buffer and be diluted to scale, shake up, measure according to antibiotic-microbial assays (two appendix XI A of Chinese Pharmacopoeia version in 2010).
Assay:
Ketoconazole, clobetasol propionate are measured according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010).
Algoscopy is got the about 4g of this product, accurately weighed, adds dehydrated alcohol appropriate, put in 80 ℃ of water-baths ketoconazole and clobetasol propionate are dissolved, move in right amount in the 50ml measuring bottle with dehydrated alcohol, let cool, be diluted to scale with dehydrated alcohol, shake up, in ice bath cooling 2 hours, filter, getting the subsequent filtrate room temperature places 15 minutes, precision measures subsequent filtrate 10 μ l, and the injection liquid chromatography, record chromatogram; Separately get the ketoconazole reference substance and the clobetasol propionate reference substance is appropriate, accurately weighed, add anhydrous alcohol solution and quantitatively dilution make in every 1ml approximately containing the solution of ketoconazole 0.8mg and clobetasol propionate 20 μ g, shake up, be measured in the same method.By external standard method, with calculated by peak area, obtain.
In order to verify that medicine of the present invention has good therapeutic effect, carried out correlation test research, specific as follows:
1 case is selected
219 routine patients are all from Dermatology Outpatient Department, male's 126 examples, women's 93 examples, age 10-75 year; Course of disease 2d-8a.
Inclusion criteria has clinical symptoms, the sign of mycotic infection of superficial part, and the direct microscopy positive of fungus, be diagnosed as tinea corporis and cruris, tinea manus and pedis, pityriasis versicolor, Malassezia folliculits person; Sex, age are not limit; Not whole body application antifungal agent, local topical antifungal preparation person not in 1 week in nearly 1 month; Patient's informed consent.
Local antibacterial infection, the eczema of merging of exclusion standard; Merge deep fungal infection, eczema; Merge deep fungal infection or tinea unguium and need whole body application antifungal agent; Known to the imidazoles allergy sufferers; Trimester of pregnancy, women breast-feeding their children.
The rejecting standard enters after group to find to meet the exclusion standard person; Violate testing program person; Do not complete person's course for the treatment of (drug withdrawal person is not counted in curative effect because of untoward reaction, but counts untoward reaction); Only have clinical efficacy and lack mycology curative effect person.
Therapeutic Method
Clean affected part, the embodiment of the present invention 3 Compound Ketoconazole Creams are applied in to affected part equably, gently rub a moment, medication every day 1 time, tinea corporis and cruris, pityriasis versicolor medication 2 weeks, tinea manus and pedis, Malassezia folliculits medication 4 weeks, keratinization type tinea manus and pedis medication 6 weeks, and advise patient's medicated clothing of sterilizing.
Observational technique
(1) clinical observation on the therapeutic effect: before treatment, treat and within 3 weeks, 6 weeks, observe to estimate clinical symptoms and sign, do respectively the evaluation of clinical symptoms and sign, press 0-3 level point system, that is: 0=without, 1=is light, in 2=, the 3=weight.Sings and symptoms comprises erythema, pimple, vesicle, erosion, squama, pruritus etc.; And carry out the direct microscopy of fungus, record the untoward reaction situation;
2) mycology observation of curative effect: before and after treatment, all do the direct microscopy of fungus;
(3) untoward reaction after recording medicine.
Curative effect judging standard
Skin lesion scoring: clinical symptoms and sign are observed and are comprised 6 of erythema, pruritus, pimple, vesicle, squama and erosions, respectively by without (0 minute), light (1 minute), in (2 minutes), heavy (3 minutes) score, wherein erythema, pruritus are light, and during pimple, vesicle, squama be, erosion is attached most importance to; The calculating all patients is treated that the front and back skin lesion is marked and is the skin lesion integration.
The comprehensive therapeutic effect criterion: recovery from illness: skin lesion all disappears or only stays pigmentation, negative fungal examination; Produce effects: 60%≤skin lesion integration decline ﹤ 100%; Negative fungal examination; Take a turn for the better: 20%≤skin lesion integration decline ﹤ 60%; Negative fungal examination or the positive; Invalid: skin lesion integration decline ﹤ 20%; The fungus microscope examination positive.Effective percentage adds produce effects by recovery from illness and calculates.The mycology curative effect is removed (negative fungal examination) and is not removed (the fungus microscope examination positive) statistics according to fungus.
Therapeutic effect
In 219 routine patients, complete clinical research person 204 people, reject 15 people, wherein 14 people do not reject because completing the course for the treatment of, and another people drops by the wayside because of untoward reaction.Enter in 204 people of final therapeutic evaluation tinea manus and pedis 41 people; Tinea corporis and cruris 80 people; Pityriasis versicolor 59 people; Malassezia folliculits 24 people.
(1) clinical efficacy: all cases all complete the course for the treatment of in accordance with regulations.Treat three weeks and treat six weeks cure rates and be respectively 33.8% and 56.9%, total effective rate is respectively 64.7% and 92.6%, and concrete outcome is in Table 1.
Table 1 Compound Ketoconazole Cream is treated 204 routine superficial mycosis curative effect examples (%)
(2) mycology curative effect: before 204 routine patient treatments, the direct microscopy of fungus is all positive, and fungal culture 193 examples are positive, positive rate 94.6%.Treat three weeks and six weeks fungus clearance rate in Table 2.
Table 2 Compound Ketoconazole Cream is treated 204 routine superficial mycosis funguses and is removed situation example (%)
(3) safety observed result: only 1 routine patient applies Compound Ketoconazole Cream and local pruritus occurs, uses other antifungal preparations treatments after exiting instead.Do not observe other untoward reaction.
Conclusion: this test application Compound Ketoconazole Cream is treated 219 routine superficial mycosis, and its cure rate is 56.9%, and effective percentage reaches 92.6%,, to curative effect the best of tinea corporis and cruris, is secondly wherein pityriasis versicolor and Malassezia folliculits.Find that from fungus removing situation three weeks clearance rate for the treatment of are 64.7%, treating six weeks clearance rate is 94.6%.Test and Fungus examination result show that Compound Ketoconazole Cream finds no toxic and side effects and untoward reaction in using, without skin, mucous membrane irritation, and the clinic application.
Claims (4)
1. a Compound Ketoconazole Cream, it is characterized in that in every 10g emulsifiable paste containing following raw material: ketoconazole 0.05-0.2g, clobetasol propionate 2.0-3.0mg, polygynax 2-8 ten thousand units, cetostearyl alcohol 1.0-1.5g, white vaseline 500-1000mg, liquid Paraffin 200-500mg, leveling agent o 100-200mg, hygroscopic agent 300-700mg, antiseptic 15-25mg, dimethyl sulfoxide 150-200mg, essence 2-8mg, surplus is purified water.
2. Compound Ketoconazole Cream as claimed in claim 1, it is characterized in that, contain following raw material in every 10g emulsifiable paste: ketoconazole 0.1g, clobetasol propionate 2.5mg, polygynax 50,000 units, cetostearyl alcohol 1.27g, white vaseline 666.7mg, liquid Paraffin 333.3mg, leveling agent o 166.7mg, hygroscopic agent 466.7mg, antiseptic 20mg, dimethyl sulfoxide 186.7mg, essence 5mg, surplus is purified water.
3. Compound Ketoconazole Cream as claimed in claim 1 or 2, is characterized in that, described hygroscopic agent is one or more in glycerol, polyoxyethylene sorbitan monoleate or propylene glycol.
4. Compound Ketoconazole Cream as claimed in claim 1 or 2, is characterized in that, described antiseptic is a kind of in ethyl hydroxybenzoate, sorbic acid, sodium benzoate, benzalkonium bromide or chlorhexidine acetate.
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| CN103768079A (en) * | 2014-02-24 | 2014-05-07 | 周建国 | External drug or ointment for treating psoriasis and preparation method thereof |
| GB2518826A (en) * | 2013-09-27 | 2015-04-08 | Thanasis Athanasiou | Composition |
| CN108169154A (en) * | 2017-12-27 | 2018-06-15 | 佛山市南海东方澳龙制药有限公司 | The method for detecting Determination of Ketoconazole in compound ketoconazole ointment |
| CN111821256A (en) * | 2020-08-17 | 2020-10-27 | 北京安德普泰医疗科技有限公司 | Self-emulsifying cream matrix and application thereof |
| CN113440477A (en) * | 2021-08-12 | 2021-09-28 | 海南海神同洲制药有限公司 | Low-viscosity ketoconazole cream and preparation method thereof |
| CN113876799A (en) * | 2021-11-15 | 2022-01-04 | 安徽云讯生物技术有限公司 | A biochemical composition for treating refractory dermatopathy |
| CN116327776A (en) * | 2022-12-12 | 2023-06-27 | 石中顺 | Ketoconazole ointment and application of Ketoconazole ointment analogue in treating recurrent stomatitis |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2518826A (en) * | 2013-09-27 | 2015-04-08 | Thanasis Athanasiou | Composition |
| CN103768079A (en) * | 2014-02-24 | 2014-05-07 | 周建国 | External drug or ointment for treating psoriasis and preparation method thereof |
| CN108169154A (en) * | 2017-12-27 | 2018-06-15 | 佛山市南海东方澳龙制药有限公司 | The method for detecting Determination of Ketoconazole in compound ketoconazole ointment |
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| CN113440477A (en) * | 2021-08-12 | 2021-09-28 | 海南海神同洲制药有限公司 | Low-viscosity ketoconazole cream and preparation method thereof |
| CN113876799A (en) * | 2021-11-15 | 2022-01-04 | 安徽云讯生物技术有限公司 | A biochemical composition for treating refractory dermatopathy |
| CN116327776A (en) * | 2022-12-12 | 2023-06-27 | 石中顺 | Ketoconazole ointment and application of Ketoconazole ointment analogue in treating recurrent stomatitis |
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