CN103432148B - A kind of preparation method of Compound Ketoconazole Cream - Google Patents
A kind of preparation method of Compound Ketoconazole Cream Download PDFInfo
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Abstract
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of preparation method for the treatment of the medicine for external use-Compound Ketoconazole Cream of mycotic infection of superficial part, does every 10g emulsifiable paste adopt following raw material when preparing: ketoconazole 0.05-0.2g, clobetasol propionate 2.0-3.0mg, polygynax 2-8 ten thousand unit, 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.The Compound Ketoconazole Cream that the present invention obtains is mainly used in superficial part cutaneous fungal infection, as the tinea manuum, tinea pedis, tinea corporis, tinea cruris etc.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of preparation method for the treatment of the medicine for external use-Compound Ketoconazole Cream 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 about 1/4 according to statistics.
Ketoconazole is the imidazoles dioxane derivative of synthetic in 1976.Act on the Pilus Caprae seu Ovis steroid 14 α-demethylase in fungal cell membrane forming process, suppress Pilus Caprae seu Ovis steroid to the conversion of 14 α-demethyl Pilus Caprae seu Ovis steroid, thus the biosynthesis of Antifungi cell membrane ergosterol and Antifungi growth.Ketoconazole has broad-spectrum antifungal effect, especially has obvious inhibitory action to dermatophytosis, candidiasis and chlosma.
Summary of the invention
The object of the present invention is to provide a kind of preparation method for the treatment of the Compound Ketoconazole Cream of mycotic infection of superficial part.
The present invention is by the following technical solutions:
A kind of preparation method of Compound Ketoconazole Cream, often prepare 10g emulsifiable paste and adopt following raw material: ketoconazole 0.05-0.2g, clobetasol propionate 2.0-3.0mg, polygynax 2-8 ten thousand unit, 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, the purified water of surplus;
Comprise the steps: during preparation
1) aqueous phase is prepared: drop in aqueous phase tank by hygroscopic agent, leveling agent o, polygynax, antiseptic and purified water in proportion, stir 20-30min in 85 ± 5 DEG C, for subsequent use;
2) prepare oil phase: add in oil phase tank by cetostearyl alcohol, white vaseline and liquid Paraffin in proportion, stir 20-30min in 83 ± 5 DEG C, for subsequent use;
3) emulsifiable paste is prepared: proceed in emulsion tank by above-mentioned aqueous phase substance, oil phase substance, in emulsion tank, vacuum is stir 20-30min under the condition of 0.03 ± 0.02Mpa, then homogenizing 10-25min, cools the temperature to 67 ± 5 DEG C, adds by the clobetasol propionate of appropriate dmso solution; Stirring is cooled to 50 ± 5 DEG C, adds the ketoconazole of surplus dmso solution, and homogenizing stirs 15-25min, is cooled to 40 ± 5 DEG C, then adds essence, continues to stir 20-50 minute, embedding and get final product.
The raw materials used preferred consumption further of preparation 10g emulsifiable paste is: ketoconazole 0.1g, clobetasol propionate 2.5mg, polygynax 50,000 unit, 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 the one in ethyl hydroxybenzoate, sorbic acid, sodium benzoate, benzalkonium bromide or chlorhexidine acetate.
The Compound Ketoconazole Cream that the present invention obtains is mainly used in superficial part cutaneous fungal infection, as the tinea manuum, tinea pedis, tinea corporis, tinea cruris etc., best to the curative effect of tinea corporis and cruris, is secondly pityriasis versicolor and Malassezia folliculits, and treating six weeks is 94.6% to 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 clinic application.
Detailed description of the invention
embodiment 1
A kind of preparation method of Compound Ketoconazole Cream, often prepare in 10g emulsifiable paste and adopt following weight raw material: ketoconazole 0.1g, clobetasol propionate 2.5mg, polygynax 50,000 unit, 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.
Following steps are adopted during preparation:
1) aqueous phase is prepared: drop in aqueous phase tank by aqueous phase material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water in proportion, stir 25min in 85 DEG C, for subsequent use;
2) prepare oil phase: add in oil phase tank by oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin in proportion, stir 25min in 83 DEG C, for subsequent use;
3) emulsifiable paste is prepared: proceed in emulsion tank by above-mentioned aqueous phase substance, oil phase substance, in emulsion tank, vacuum is stir 25min under the condition of 0.03Mpa, then homogenizing 20min, cools the temperature to 67 DEG C, adds by the clobetasol propionate of appropriate dmso solution; Stirring is cooled to 50 DEG C, adds the ketoconazole of surplus dmso solution, and homogenizing stirs 20min, is cooled to 40 DEG C, then adds essence, continues stirring 30 minutes, embedding and get final product.
embodiment 2
A kind of preparation method of Compound Ketoconazole Cream, often prepare in 10g emulsifiable paste and adopt following weight raw material: ketoconazole 0.05g, clobetasol propionate 2.0mg, polygynax 20,000 unit, 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.
Following steps are adopted during preparation:
1) aqueous phase is prepared: drop in aqueous phase tank by aqueous phase material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water in proportion, stir 30min in 80 DEG C, for subsequent use;
2) prepare oil phase: add in oil phase tank by oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin in proportion, stir 30min in 78 DEG C, for subsequent use;
3) emulsifiable paste is prepared: proceed in emulsion tank by above-mentioned aqueous phase substance, oil phase substance, in emulsion tank, vacuum is stir 30min under the condition of 0.01Mpa, then homogenizing 25min, cools the temperature to 62 DEG C, adds by the clobetasol propionate of appropriate dmso solution; Stirring is cooled to 45 DEG C, adds the ketoconazole of dmso solution, and homogenizing stirs 25min, is cooled to 35 DEG C, then adds essence, continues stirring 50 minutes, embedding and get final product.
embodiment 3
A kind of preparation method of Compound Ketoconazole Cream, often prepare in 10g emulsifiable paste and adopt following weight raw material: ketoconazole 0.2g, clobetasol propionate 3.0mg, polygynax 80,000 unit, 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.
Following steps are adopted during preparation:
1) aqueous phase is prepared: drop in aqueous phase tank by aqueous phase material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water in proportion, stir 20min in 90 DEG C, for subsequent use;
2) prepare oil phase: add in oil phase tank by oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin in proportion, stir 20min in 88 DEG C, for subsequent use;
3) emulsifiable paste is prepared: proceed in emulsion tank by above-mentioned aqueous phase substance, oil phase substance, in emulsion tank, vacuum is stir 20min under the condition of 0.05Mpa, then homogenizing 10min, cools the temperature to 72 DEG C, adds by the clobetasol propionate of appropriate dmso solution; Stirring is cooled to 55 DEG C, adds the ketoconazole of dmso solution, and homogenizing stirs 15min, is cooled to 45 DEG C, then adds essence, continues stirring 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 peak should be consistent with the retention time of reference substance solution two main peak.
(2) get this product to be about 1.5g(and to be equivalent to polygynax 7500 unit), put in tool plug centrifuge tube, add chloroform 10ml and water 5ml, strong jolting, centrifugal, get the supernatant, as need testing solution; Separately get polygynax standard substance, add water make every 1ml about containing the solution of 2mg as standard solution, test according to thin layer chromatography (Chinese Pharmacopoeia version in 2010 two annex V B), draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with methanol-chloroform-ammonia (13.5mol/L) (60:20:40) for developing solvent, launch, dry, spray is with 1% 1,2,3-indantrione monohydrate butanol solution, 105 DEG C 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 test sample 5, removing enclosing cover, its outer wall clean respectively, after to be dried, its weight accurately weighed respectively, removing content, container is cleaned and after drying, then the weight of respectively accurately weighed empty, obtains the loading amount of each container contents and average loading amount, the loading amount of each container is no less than 93% of sign loading amount, and average loading amount is no less than sign loading amount.
limit test of microbe: check according to microbial limit test (Chinese Pharmacopoeia version in 2010 two annex Ⅺ J), bacterial population, yeast and mold number all must not cross 100cfu/g; The all every 1g of staphylococcus aureus, Pseudomonas aeruginosa must not detect.
polygynaxget this product and be about 2g, accurately weighed, put in 100ml tool plug conical flask, add petroleum ether (boiling range 90 ~ 120 DEG C) 50ml, 80 DEG C of heating in water bath make stromatolysis or disperse rear supersound process about 30 minutes, let cool, be transferred in separatory funnel, 4 times are extracted, each 20ml, merge extractive liquid, with the phosphate buffer (pH7.8) containing 3% sodium chloride, put in 100ml measuring bottle, add above-mentioned buffer and be diluted to scale, shake up, measure according to antibiotic-microbial assays (Chinese Pharmacopoeia version in 2010 two annex Ⅺ A).
assay:
Ketoconazole, clobetasol propionate measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Algoscopy is got this product and is about 4g, accurately weighed, adds dehydrated alcohol appropriate, put in 80 DEG C of water-baths and ketoconazole and clobetasol propionate are dissolved, move in right amount in 50ml measuring bottle with dehydrated alcohol, let cool, scale is diluted to dehydrated alcohol, shake up, in ice bath, cool 2 hours, filter, get subsequent filtrate room temperature and place 15 minutes, precision measures subsequent filtrate 10 μ l, injection liquid chromatography, record chromatogram; Separately get ketoconazole reference substance and clobetasol propionate reference substance appropriate, accurately weighed, add anhydrous alcohol solution and quantitatively the solution about containing ketoconazole 0.8mg and clobetasol propionate 20 μ g in every 1ml is made in dilution, shake up, be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
In order to verify that medicine of the present invention has good therapeutic effect, carry out correlation test research, specific as follows:
1 case selection
219 routine patients all from Dermatology Outpatient Department, male 126 example, women 93 example, 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 of fungus is positive, is diagnosed as tinea corporis and cruris, tinea manus and pedis, pityriasis versicolor, Malassezia folliculits person; Sex, age are not limit; Non-whole body application antifungal agent in nearly 1 month, non-local topical antifungal preparation person in 1 week; Patient's informed consent.
Exclusion standard local merges bacteriological infection, eczema; Merge deep fungal infection, eczema; Merging deep fungal infection or tinea unguium need whole body application antifungal agent; Known to imidazoles allergy sufferers; Trimester of pregnancy, women breast-feeding their children.
Rejecting standard finds the person that meets exclusion standard after entering group; 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 Cream is applied in 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, Keratotic tinea hand or pedis medication 6 weeks, and advise patient to sterilize medicated clothing.
observational technique
(1) clinical observation on the therapeutic effect: before treatment, treatment observes and evaluate clinical symptoms and sign for 3 weeks, 6 weeks, does the evaluation of clinical symptoms and sign respectively, by 0-3 level point system, that is: 0=without, gently, in 2=, 3=weighs 1=.Sings and symptoms comprises erythema, pimple, vesicle, erosion, squama, pruritus etc.; And carry out the direct microscopy of fungus, record 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 is marked: clinical symptoms and sign are observed and comprised erythema, pruritus, pimple, vesicle, squama and erosion 6, respectively by without (0 point), light (1 point), in (2 points), heavy (3 points) score, wherein erythema, pruritus are light, and during pimple, vesicle, squama be, erosion is attached most importance to; Calculating all patients is treated that front and back skin lesion is marked and is skin lesion integration.
Comprehensive therapeutic effect criterion: recovery from illness: skin lesion all disappears or only stays pigmentation, negative fungal examination; Effective: 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%; Fungus microscope examination is positive.Effective percentage adds effective calculating by recovery from illness.Mycology curative effect is removed (negative fungal examination) according to fungus and is not removed (fungus microscope examination is positive) statistics.
therapeutic effect
In 219 routine patients, complete clinical investigators 204 people, reject 15 people, wherein 14 people reject because not 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 by regulation.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 treats 204 routine superficial mycosis curative effect examples (%)
(2) mycology curative effect: before 204 routine patient treatments, the direct microscopy of fungus is the positive, fungal culture 193 example is 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 observations result: only 1 routine patient applies Compound Ketoconazole Cream appearance local pruritus, uses the treatment of other antifungal preparations after exiting instead.Do not observe other untoward reaction.
Conclusion: this test application Compound Ketoconazole Cream treats 219 routine superficial mycosis, and its cure rate is 56.9%, and effective percentage reaches 92.6%, wherein best to the curative effect of tinea corporis and cruris, be secondly pityriasis versicolor and Malassezia folliculits.From fungus removing situation, find that treatment three weeks clearance rate 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 clinic application.
Claims (1)
1. the preparation method of a Compound Ketoconazole Cream, it is characterized in that: often prepare in 10g emulsifiable paste adopting following weight raw material: ketoconazole 0.2g, clobetasol propionate 3.0mg, polygynax 80,000 unit, 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;
Following steps are adopted during preparation:
1) aqueous phase is prepared: drop in aqueous phase tank by aqueous phase material glycerol, leveling agent o, polygynax, polyoxyethylene sorbitan monoleate, ethyl hydroxybenzoate and purified water in proportion, stir 20min in 90 DEG C, for subsequent use;
2) prepare oil phase: add in oil phase tank by oil phase material cetostearyl alcohol, white vaseline and liquid Paraffin in proportion, stir 20min in 88 DEG C, for subsequent use;
3) emulsifiable paste is prepared: proceed in emulsion tank by above-mentioned aqueous phase substance, oil phase substance, in emulsion tank, vacuum is stir 20min under the condition of 0.05Mpa, then homogenizing 10min, cools the temperature to 72 DEG C, adds by the clobetasol propionate of appropriate dmso solution; Stirring is cooled to 55 DEG C, adds the ketoconazole of dmso solution, and homogenizing stirs 15min, is cooled to 45 DEG C, then adds essence, continues stirring 20 minutes, embedding and get final product.
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| CN104146950A (en) * | 2014-07-30 | 2014-11-19 | 上海新亚药业闵行有限公司 | Compound ketoconazole ointment and preparation method thereof |
| CN105169462B (en) * | 2015-10-22 | 2017-10-17 | 江苏科技大学 | Improve the mixed method of neomycinsulphate dispersing uniformity in vaseline |
| CN106018614A (en) * | 2016-06-23 | 2016-10-12 | 湖北人福成田药业有限公司 | Method for detecting related substances in ketoconazole sample and method for preparing ketoconazole preparation |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129409A (en) * | 2007-08-30 | 2008-02-27 | 程贵昌 | Antimycotic externally used drug |
| CN102058777A (en) * | 2009-11-17 | 2011-05-18 | 费小平 | Traditional Chinese medicine and western medicine-combined formula for radically treating chloasma and preparation process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101129409A (en) * | 2007-08-30 | 2008-02-27 | 程贵昌 | Antimycotic externally used drug |
| CN102058777A (en) * | 2009-11-17 | 2011-05-18 | 费小平 | Traditional Chinese medicine and western medicine-combined formula for radically treating chloasma and preparation process thereof |
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| Title |
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| 复方酮康唑乳膏的制备及质量控制;于西全等;《海峡药学》;20010930;第13卷(第03期);第15-16页 * |
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