CN101015553A - Medicinal composition for treating skin superficial fungal infection and preparation process thereof - Google Patents
Medicinal composition for treating skin superficial fungal infection and preparation process thereof Download PDFInfo
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Abstract
The invention discloses a Chinese medicinal composition for treating mycotic infection on shallow skin and its preparation method. The Chinese medicinal composition comprises ketoconazole clobetasolpropionate, and substrate; has the advantages of good therapeutic effect, wide application, and convenient administration; and can be used for treating tinea manuum, athlete's foot, tinea corporis, tinea cruris due to mycotic infection.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of superficial fungous infection of skin, specifically relate to a kind of pharmaceutical composition that is used for the treatment of diseases such as the tinea manuum due to the superficial fungous infection of skin, tinea pedis, tinea corporis, tinea cruris.The present invention also relates to the preparation method of aforementioned pharmaceutical compositions.
Background technology
The tinea manuum due to the superficial fungous infection of skin, tinea pedis, tinea corporis, tinea cruris show as water kitchen, keratinization and scaling patch, and main pathogenic bacterium are trichophyton.-as can be divided into three kinds of immersion-type, vesicle type and squama keratinization types.Immersion-type-as for referring to that skin flood, turns white, rubs with the hands and remove epidermis between toe, expose red rotten to the corn face, easy secondary infection; The vesicle type often is the big phlysis of syringe needle, can be fused into bulla sometimes; The squama keratinization type thickens based on desquamation, and boundary clear has vesicle.At present still there is not effectively to treat the medicine of this type of disease on the market.
Publication number is CN1130065A, denomination of invention is that the application for a patent for invention of compound ketoconazole external-use preparation discloses a kind of dermopathic compound external-use preparation of treatment with broad-spectrum antiseptic, antiinflammatory and antipruritic effect, and this external preparation is made up of ketoconazole 0.5-2%, clobetasol propionate 0.01-0.05%, antibiotic 0.1-2%, azone 0.1-3% and substrate.Owing to contain antibiotic in the prescription, human body is produced toxic and side effects, make its suitable crowd limited greatly.
Summary of the invention
The purpose of this invention is to provide a kind of good effect, be suitable for crowd's pharmaceutical composition that is used for the treatment of superficial fungous infection of skin wide, easy to use.
Another object of the present invention provides the preparation method of aforementioned pharmaceutical compositions.
For achieving the above object, the inventor has carried out a large amount of research, and paid performing creative labour, filter out good effect from numerous medical materials, be suitable for crowd's pharmaceutical composition that is used for the treatment of superficial fungous infection of skin wide, easy to use, described pharmaceutical composition is made up of ketoconazole, clobetasol propionate and substrate.
The every 1000g of described pharmaceutical composition contains ketoconazole 8-13g, clobetasol propionate 0.3-0.7g, surplus is a substrate.
The every 1000g of described pharmaceutical composition contains ketoconazole 10g, clobetasol propionate 0.5g, surplus is a substrate.
Described substrate be 16-18 mixed alcohol 40-55g, light liquid petrolatum 100-135g, stearic acid 70-8g,, laurocapram 15-21g, disodiumedetate 0.2-0.5g, triethanolamine 2.6-5.1ml, ethyl hydroxybenzoate 0.3-0.5g, glycerol 250-320g, anhydrous sodium sulfite 0.8-1.1g, 2, the mixture of 6-dibutyl paracresol 0.4-0.7g and water.
Described substrate is 16-18 mixed alcohol 50g, light liquid petrolatum 125g, stearic acid 7 5g, laurocapram 20g, disodiumedetate 0.5g, triethanolamine 4.5ml, ethyl hydroxybenzoate 0.5g, glycerol 300g, anhydrous sodium sulfite 1g, 2, the mixture of 6-dibutyl paracresol 0.5g and water.
A kind of method for preparing described pharmaceutical composition is characterized in that comprising the steps:
(1) with 16-18 mixed alcohols, light liquid petrolatum, stearic acid, the ethyl hydroxybenzoate Hybrid Heating makes fusion, crosses 150 mesh sieves, and is standby to 80～85 ℃ of insulations, adds 2 before the emulsifying, and the 6-dibutyl paracresol stirs and makes dissolving, gets oil phase;
(2) with water, glycerol, disodiumedetate, the triethanolamine Hybrid Heating makes dissolving, crosses 150 mesh sieves, and is standby to 80～85 ℃ of insulations, adds anhydrous sodium sulfite before the emulsifying, stirs and makes dissolving, gets water;
(3) clobetasol propionate, ketoconazole are dissolved in the laurocapram of recipe quantity, cross 150 mesh sieves, standby;
(4) water that makes of oil phase that step (1) is made and step (2) is cooled to 70～75 ℃ respectively, and water slowly to going in the oil phase, when being stirred to 60 ℃, is added the mixed liquor that step (3) makes, and continues to stir to be cooled to nearly room temperature, promptly.
In development process, the inventor studies one by one to the composition of substrate and the combination matching of adjuvant, and has carried out necessary screening, by the suitable adjusting to various adjuvant use amounts, makes the mastic of developing reach perfectly effect.
The present invention is the white or the off-white color ointment of emulsion-type substrate, the quality quality of the shaping of its mastic and appearance character, mastic prescription mesostroma composition and combination are the screening key factors, will directly have influence on the quality of pharmaceutical composition of the present invention, comprise check, storage, use, stability etc.Therefore, screening a next and principal agent compatibility of substrate prescription preferably, make quality ointment preferably, is the committed step in the development process.At first, substrate must not produce whole detection and disturb; Secondly, the necessary denseness of the appearance character of mastic is moderate, fine and smooth.Have certain reflecting feel, and will satisfy the condition of big production.According to above-mentioned requirements, and with reference to the commercially available compound ketoconazole ointment of the multiple star morning sunlight Pharmaceutical limited company in Shanghai production, prescription and technology are studied and groped, having passed through one is that the routine finally selected substrate prescription with the principal agent compatibility of experiment is 16-18 mixed alcohol 40-55g, light liquid petrolatum 100-135g, stearic acid 70-80g, laurocapram 15-21g, disodiumedetate 0.2-0.5g, triethanolamine 2.6-5.1ml, ethyl hydroxybenzoate 0.3-0.5g, glycerol 250-320g, anhydrous sodium sulfite 0.8-1.1g, 2,6-dibutyl paracresol 0.4-0.7g and water are made ointment.Matrix optimization is 16-18 mixed alcohol 50g, light liquid petrolatum 125g, stearic acid 75g, laurocapram 20g, disodiumedetate 0.5g, triethanolamine 4.5ml, ethyl hydroxybenzoate 0.5g, glycerol 300g, anhydrous sodium sulfite 1g, 2,6-dibutyl paracresol 0.5g and water.
In by screening process to the substrate prescription, while is also studied the ointment preparation technology of emulsion-type substrate, according to the theoretical of pharmaceutics and combination junior middle school's experience for many years, and detect through the strictness to the sample developed and declaration sample, proved the preparation technology's of this product feasibility.
This product is the white or the off-white color ointment of emulsion-type substrate.Oil phase adjuvant in this prescription, 16-18 mixed alcohols, as auxiliary emulsifying and thickening agent, play improve emulsifying capacity and under the not enough situation of pasty consistence the increase denseness make mastic be tending towards more stable; A stearic acid part is a thickening agent, and another part and triethanolamine generate newborn soap and play the emulsifying agent effect; Liquid Paraffin is mainly regulated the denseness and increase gloss of mastic.Triethanolamine in the water adjuvant and oil phase adjuvant part of stearic acid be as emulsifying agent, makes oil, water under certain condition biphase, closely in conjunction with and mastic is shaped; Ethyl hydroxybenzoate keeps mastic not become sour before the deadline, never degenerate as antiseptic; Glycerol keeps not dehydration of mastic as wetting agent, and not atrophy makes cream keep stable before the deadline; Anhydrous sodium sulfite is an antioxidant; Disodiumedetate is the antioxygen synergist; 2, the 6-dibutyl paracresol is an antioxidant; Laurocapram is both as solvent, make ketoconazole, clobetasol propionate dissolving, again as transdermal enhancer, can make cutin softening, solidified structure albumen strengthens permeability, make medicine see through skin barrier, improve local blood drug level, improve bioavailability of medicament, to reach best therapeutic effect.
The inventor has also carried out layering, heat-resisting, low temperature resistant test to the stability of substrate.Wherein the layering test is substrate 10g to be packed into be with in the graduated centrifuge tube centrifugal half an hour on 2500 rev/mins centrifuge.Result: no lamination.Heat-resisting, low temperature resistant test is that ointment base is loaded in the aluminum pipe of commercially available ointment packing, places 55 ℃ of baking oven constant temperature 6 hours to place 24 hours with-15 ℃ respectively.Result: no oil-water separation phenomenon.
The inventor has also carried out the interference factor test of substrate, and selected substrate is detected by content assaying method in the compound ketoconazole ointment quality standard.Result: noiseless to principal agent.The test itemized record are as follows:
The assay method of substrate: high performance liquid chromatography
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, are mobile phase (75:25) with methanol-0.02mol/L potassium phosphate buffer (PH7.40), and the detection wavelength is 239nm.
Algoscopy is got the about 4g of substrate No. 3, and accurate the title decides, and puts in the 50ml measuring bottle, add the about 30ml of dehydrated alcohol, put in 80 ℃ of water-baths and heat jolting, be cooled to room temperature, add dehydrated alcohol and be diluted to scale, shake up, put and cool off in the ice bath after 2 hours, filter, discard filtrate just, precision is measured subsequent filtrate 10 μ l, injects chromatograph of liquid, the record chromatogram.
Conclusion: in chromatogram, except that the substrate peak, find no other peaks, noiseless to the detection of ketoconazole, clobetasol propionate.
By above-mentioned one is that routine experiment draws: the substrate prescription that the present invention selectes is suitable makes ointment with ketoconazole, clobetasol propionate compatibility.The inventor has prepared three batches of samples (every batch 500 gram) according to the process characteristic of emulsion-type ointment, further understands and has determined this product prescription and grasp the preparation technology who makes this product from the process for preparation of three batches of samples.
The prescription of three batches of samples and technology
A. write out a prescription
Clobetasol propionate 0.5g
Ketoconazole 1g
16-18 mixed alcohol 50g
Light liquid petrolatum 125g
Stearic acid 75g
Laurocapram 20g
Disodiumedetate 0.5g
Triethanolamine 4.5ml
Ethyl hydroxybenzoate 0.5g
Glycerol 300g
Anhydrous sodium sulfite 1g
2,6-dibutyl paracresol 0.5g
Purified water adds to 1000g
B. technology: three crowdes of substrate preparation technologies by above-mentioned research, worked out the preparing process of three batches of samples, every crowd of 500g.The production technology that works up pharmaceutical composition of the present invention is as follows:
(1) oil phase: take by weighing 16-18 required mixed alcohols of recipe quantity, light liquid petrolatum, stearic acid, the ethyl hydroxybenzoate Hybrid Heating makes fusion, crosses 150 mesh sieves, and is standby to 80～85 ℃ of insulations, adds 2 before the emulsifying, and the 6-dibutyl paracresol stirs and makes dissolving, and is standby.
(2) water: take by weighing the required purified water of recipe quantity, glycerol, disodiumedetate, the triethanolamine Hybrid Heating makes dissolving, crosses 150 mesh sieves, and is standby to 80～85 ℃ of insulations, adds anhydrous sodium sulfite before the emulsifying, stirs and makes dissolving, standby.
(3) get in the laurocapram that the required clobetasol propionate of recipe quantity, ketoconazole be dissolved in recipe quantity (heating in water bath stirring and dissolving in case of necessity), cross 150 mesh sieves, standby.
(4) when profit phase temperature during, water slowly to going in the oil phase, when being stirred to 60 ℃, is added the mixed liquor of clobetasol propionate, ketoconazole/laurocapram all at 70～75 ℃.Continue to stir and be cooled to nearly room temperature.
By above-mentioned prescription and technology, pass through layering and heat-resisting, low temperature resistant test and assay after the preparation of the three batches of samples again, the result reaches experiment purpose fully.(seeing Table 1, table 2)
Three batches of sample trial results of table 1
| The test grouping | 1 | 2 | 3 |
| Character | The simple ointment of emulsion-type substrate | The simple ointment of emulsion-type substrate | The simple ointment of emulsion-type substrate |
| Denseness | Suitable | Suitable | Suitable |
| The layering test | No layering | No layering | No layering |
| Heat-resisting cold-resistant | No oil-water separation | No oil-water separation | No oil-water separation |
Three batches of sample assays of table 2 result
| Lot number | 1 | 2 | 3 | |||
| Clobetasol propionate | Ketoconazole | Clobetasol propionate | Ketoconazole | Clobetasol propionate | Ketoconazole | |
| Content (%) 1 | ||||||
| Content (%) 2 | ||||||
| Average content (%) | ||||||
Result by above-mentioned three batches of samples trial-production amplifies sample continuously and prepares three batch samples.Every crowd of 30kg, theoretical yield are 3000.Lot number is: 040801,040802,040803.See its whole process of preparation and be shaped, meet the technological requirement of formulation fully until mastic.Pasty consistence is suitable, and exquisiteness has certain gloss.Qualified after testing, fill is in the medicinal flexible pipe of aluminum matter.
Pharmacodynamic study of the present invention shows, medicine of the present invention is consistent with the control drug compound ketoconazole ointment to the curative effect of tinea corporis model, and effective percentage all reaches 100%, 2 weeks of drug withdrawal, fungus smear, cultivation negative rate reach 100%, the obvious model group of its anti-mycotic efficiency (P＜0.01).Said preparation can significantly alleviate the ear swelling degree of chronic dermatitis mice, alleviates the chronic inflammatory disease performance of animal pattern ear epidermis and corium, reduces and soaks into the inflammatory cell number.Point out medicine of the present invention that the mice chronic dermatitis is had significant inhibitory effect.Antifungal drug is killed fungus, and for condition has been created in the healing of skin infection, and a certain amount of hormone promotes to make antifungal drug kill fungus better by fungal spore mycelia inversion of phases in opposite directions, has embodied the advantage of compound preparation.And the medication number of times is few, and is more convenient, and toxic and side effects is low.Thereby for the treatment superficial fungous infection of skin provides the pharmacodynamics foundation.
Pharmacodynamic study
Medicine of the present invention is the dermopathic compound preparation of treatment, and main component is ketoconazole and clobetasol propionate, is mainly used in superficial fungous infection of skin, as: the tinea manuum, tinea pedis, tinea corporis, tinea cruris etc.Have characteristics such as determined curative effect, toxicity be lower, easy to use.95109576.5), and open by retrieval, (application number:, its main component also contains a certain amount of antibiotic except that ketoconazole, clobetasol propionate to have " compound ketoconazole external-use preparation " to declare national inventing patent at present.
This research is verified the drug effect of medicine of the present invention by to the influence of tinea corporis guinea pig model, to the research of mice ear and pathological change influence, and (application number: drug effect 95109576.5) contrasts with patent of invention " compound ketoconazole external-use preparation ".
1 experiment material
Animal: 4～5 age in week 20 of healthy guinea pigs, male and female half and half, body constitution amount (212.4 ± 18.7) g.36 of Kunming mouses, body weight 22 ± 2g, male and female half and half.Provide the quality certification number by The Fourth Military Medical University's Experimental Animal Center: SYXK-2006-044.
Medicine and reagent: the used preparation of test group is the ointment according to the embodiment of the invention 4 preparation, i.e. lab scale medicine, lot number 060812.Control drug: according to national inventing patent " compound ketoconazole external-use preparation " (application number: the 95109576.5) compound ketoconazole ointment of embodiment 1 (ketoconazole 1%, polygynax 0.5%, clobetasol propionate 0.025%, azone 1.0%) preparation, lot number 060812.Above medicine is produced by Jiangxi Yaodu Renhe Pharmaceutical Co., Ltd.Dinitrochlorobenzene (DNCB), Xing Jin chemical plant, Beijing, lot number: 20060402.
2 experimental techniques and result
2.1 influence to the tinea corporis guinea pig model
Animal model preparation: adopt puncture method, guinea pig back inoculation alpha fungus (2 * 10
5CFU/ml) preparation tinea corporis model.
Grouping and administration: 20 on tinea corporis model is divided into model group, lab scale medicine group and control drug group totally 3 groups (n=5) at random by body weight.Respectively at back inoculation district coating, lab scale medicine group is coated with the lab scale medicine, 1 time/2d; Control drug group part is coated with control drug, 1 time/2d; Not administration of model group.
Observation index: the tinea corporis symptom score, inoculate the 11st day and respectively pimple (0～4 minute), vesicle (0～2 minute), squama (0～1 minute) were marked in 2 weeks with treating; Smear is cultivated and is surveyed positive rate before the treatment; Drug withdrawal 2 all smears are cultivated and are surveyed negative rate.
Therapeutic outcome: according to skin lesion scoring before and after the medication relatively, carry out curative effect and judge.Cure: after the medication skin lesion disappear 〉=90%; Produce effects: skin lesion disappears 〉=and 70%; Effectively: skin lesion disappears 〉=and 30%; Invalid: skin lesion disappears＜and 30%.The result shows that lab scale medicine group effect is consistent with matched group, obviously is better than model group (P＜0.01, the x2 check of multisample rate sees Table 3).Respectively organize positive for fungi culture rate difference 80%, 80%, 100% and 80% before the treatment, drug withdrawal is during 2 weeks, and lab scale medicine group and control drug group fungal culture negative rate are 100%, and the model group negative rate is 50%, and the fungus smear also obtains similar result.
Table 3 tinea corporis guinea pig model 2 all curative effects (n=5)
| Group | Cure | Produce effects | Effectively | Invalid | Effective percentage (%) |
| Model group lab scale medicine group | 0 4 | 0 0 | 1 1 | 4 0 | 20 100 ** |
| The control drug group | 3 | 1 | 1 | 0 | 100 ** |
Annotate: with model control group ratio, * P＜0.05, * * P＜0.01.
2.2 influence to mice ear
Get 36 of body weight 22 ± 2g mices, male and female half and half are divided into model group, lab scale medicine group and control drug group at random, 12 every group.Be applied to back sensitization outward with 7%DNCBl00 μ l, smearing 0.1%DNCB5 μ 1 in the mouse right ear inboard after 5 days excites, excite back 24h, 48h, 72h to use slide gauge (production of Wuxi stannum measuring tool company limited) to survey the mice ear degree respectively, repeat to survey 3 times at every turn, average, every 3M: excite 1 time.Lab scale medicine group and control drug group excite back 24h, 48h, 72h in the inboard coating of mouse right ear, every day 2 times at every turn.Each is organized in the 4th and excites back 72h, gets 6 mouse right ears respectively and does the pathology section, and HE dyeing is calculated corium and soaked into the inflammatory cell number.The result with
Expression is relatively checked with t between two groups.
Influence table 4 couple mice ear mm) (
, n=12)
| Group | Before exciting | Excite for the 1st time | Excite for the 2nd time | ||||||
| oh | 24h(d1) | 48h(d2) | 72h(d3) | 24h(d4) | 48h(d5) | 72h(d6) | |||
| Model group | 0.27±0.033 | 0.30±0. 039 | 0.32± 0.046 1 | 0.33± 0.058 1 | 0.32± 0.040 1 | 0.34± 0.056 2 | 0.36± 0.057 2 | ||
| Lab scale medicine group | 0.26±0. 038 | 0.30±0. 033 | 0.28±0. 043 | 0.26± 0.041 4 | 0.29±0. 033 | 0.32±0.47 | 0.32± 0.036 | ||
| The control drug group | 0.27±0. 044 | 0.27±0. 047 | 0.28±0. 059 | 0.29±0. 052 | 0.30±0. 043 | 0.32±0. 047 | 0.32± 0.063 | ||
| Group | Excite for the 3rd time | The 4th excites | |||||||
| 24h(d7) | 48h(d8) | 72h(d9) | 24h(d10) | 48h(d11) | 72h(d12) | ||||
| Model group | 0.44±0. 0742 | 0.45±0. 056 2 | 0.49±0. 045 2 | 0.47±0.061 2 | 0.51±0.055 2 | 0.55±0.049 2 | |||
| Lab scale medicine group | 0.36±0. 0444 | 0.38±0. 037 4 | 0.39±0. 057 4 | 0.40±0.061 4 | 0.41±0.061 4 | 0.41±0.053 4 | |||
| The control drug group | 0.38±0. 0503 | 0.39±0. 43 4 | 0.40±0. 048 4 | 0.39±0.031 4 | 0.39±0.031 4 | 0.40±0.066 4 | |||
Annotate: 1.P＜0.05, compare with the control drug group 2.P＜0.05; 3.P＜0.05, compare with model group 4.P＜0.01.
2.3 influence to the variation of mouse ear histopathology
Model group mouse ear epidermis thickens, and has vesicle to form in the epidermis shallow-layer, visible a large amount of monocyte infiltrations in intradermal vasodilation, the edema, a matter.Lab scale medicine group epidermis thickens slightly, and the intradermal congestion and edema is alleviated, and inflammatory cell infiltration obviously reduces.The pathological change of control drug group is similar to lab scale medicine group.Each is organized mouse ear corium infiltration number of inflammatory cells and sees Table 5.
Table 5 mouse ear corium soaks into number of inflammatory cells
| Group | Number of animals (only) | Cell number | The P value |
| Model group lab scale medicine group | 6 6 | 93.4±8.95 31.9±6.80 | ＜0.01 |
| The control drug group | 6 | 49.3±7.24 | ＜0.01 |
3 discuss:
Ketoconazole belongs to the imidazoles antifungal agent.Have antibacterial and bactericidal action to dermophyte, yeast (Candida, Pityrosporum, Torulopsis, Cryptococcus), two-phase fungus and Mycophytes; The mechanism of action of ketoconazole is mainly the activity that high selectivity disturbs the cytochrome P-450 of fungus, thereby suppresses the biosynthesis of ergosterol on the fungal cell membrane.Clobetasol propionate belongs to the potent 17-hydroxy-11-dehydrocorticosterone of external.Effect has stronger blood capillary contraction and antiinflammatory action rapidly.Both share not only has stronger antifungic action, and antiinflammatory, antiallergic, itching-relieving action are arranged again.Experimentation by pharmacodynamics shows, medicine of the present invention is consistent with the control drug compound ketoconazole ointment to the curative effect of tinea corporis model, and effective percentage all reaches 100%, 2 weeks of drug withdrawal, fungus smear, cultivation negative rate reach 100%, the obvious model group of its anti-mycotic efficiency (P＜0.01).Said preparation can significantly alleviate the ear swelling degree of chronic dermatitis mice, alleviates the chronic inflammatory disease performance of animal pattern ear epidermis and corium, reduces and soaks into the inflammatory cell number.Point out medicine of the present invention that the mice chronic dermatitis is had significant inhibitory effect.Antifungal drug is killed fungus, and for condition has been created in the healing of skin infection, and a certain amount of hormone promotes to make antifungal drug kill fungus better by fungal spore mycelia inversion of phases in opposite directions, has embodied the advantage of compound preparation.And the medication number of times is few, and is more convenient, and toxic and side effects is low.Thereby for the treatment superficial fungous infection of skin provides the pharmacodynamics foundation.
The specific embodiment
Embodiment 1
Prescription: ketoconazole 8g, clobetasol propionate 0.6g, 16-18 mixed alcohol 42g, light liquid petrolatum 135g, stearic acid 70g, laurocapram 17g, disodiumedetate 0.2g, triethanolamine 5.1ml, ethyl hydroxybenzoate 0.3g, glycerol 280g, anhydrous sodium sulfite 1.1g, 2,6-dibutyl paracresol 0.6g and pure water;
Preparation method
(1) with 16-18 mixed alcohols, light liquid petrolatum, stearic acid, the ethyl hydroxybenzoate Hybrid Heating makes fusion, crosses 150 mesh sieves, and is standby to 80 ℃ of insulations, adds 2 before the emulsifying, and the 6-dibutyl paracresol stirs and makes dissolving, gets oil phase;
(2) with water, glycerol, disodiumedetate, the triethanolamine Hybrid Heating makes dissolving, crosses 150 mesh sieves, and is standby to 83 ℃ of insulations, adds anhydrous sodium sulfite before the emulsifying, stirs and makes dissolving, gets water;
(3) clobetasol propionate, ketoconazole are dissolved in the laurocapram of recipe quantity, cross 150 mesh sieves, standby;
(4) water that makes of oil phase that step (1) is made and step (2) is cooled to 70 ℃ respectively, and water slowly to going in the oil phase, when being stirred to 60 ℃, is added the mixed liquor that step (3) makes, and continues to stir to be cooled to nearly room temperature, promptly.
Embodiment 2
Prescription: ketoconazole 12g, clobetasol propionate 0.4g, 16-18 mixed alcohol 55g, light liquid petrolatum 110g, stearic acid 73g, laurocapram 21g, disodiumedetate 0.4g, triethanolamine 3.0ml, ethyl hydroxybenzoate 0.4g, glycerol 250g, anhydrous sodium sulfite 0.8g, 2,6-dibutyl paracresol 0.4g and pure water;
Preparation method
(1) with 16-18 mixed alcohols, light liquid petrolatum, stearic acid, the ethyl hydroxybenzoate Hybrid Heating makes fusion, crosses 150 mesh sieves, and is standby to 83 ℃ of insulations, adds 2 before the emulsifying, and the 6-dibutyl paracresol stirs and makes dissolving, gets oil phase;
(2) with water, glycerol, disodiumedetate, the triethanolamine Hybrid Heating makes dissolving, crosses 150 mesh sieves, and is standby to 80 ℃ of insulations, adds anhydrous sodium sulfite before the emulsifying, stirs and makes dissolving, gets water;
(3) clobetasol propionate, ketoconazole are dissolved in the laurocapram of recipe quantity, cross 150 mesh sieves, standby;
(4) water that makes of oil phase that step (1) is made and step (2) is cooled to 72 ℃ respectively, and water slowly to going in the oil phase, when being stirred to 60 ℃, is added the mixed liquor that step (3) makes, and continues to stir to be cooled to nearly room temperature, promptly.
Embodiment 3
Prescription: ketoconazole 13g, clobetasol propionate 0.7g, 16-18 mixed alcohol 40g, light liquid petrolatum 105g, stearic acid 80g, laurocapram 16g, disodiumedetate 0.3g, triethanolamine 3.5ml, ethyl hydroxybenzoate 0.35g, glycerol 270g, anhydrous sodium sulfite 0.9g, 2,6-dibutyl paracresol 0.7g and pure water;
Preparation method
(1) with 16-18 mixed alcohols, light liquid petrolatum, stearic acid, the ethyl hydroxybenzoate Hybrid Heating makes fusion, crosses 150 mesh sieves, and is standby to 85 ℃ of insulations, adds 2 before the emulsifying, and the 6-dibutyl paracresol stirs and makes dissolving, gets oil phase;
(2) with water, glycerol, disodiumedetate, the triethanolamine Hybrid Heating makes dissolving, crosses 150 mesh sieves, and is standby to 85 ℃ of insulations, adds anhydrous sodium sulfite before the emulsifying, stirs and makes dissolving, gets water;
(3) clobetasol propionate, ketoconazole are dissolved in the laurocapram of recipe quantity, cross 150 mesh sieves, standby;
(4) water that makes of oil phase that step (1) is made and step (2) is cooled to 75 ℃ respectively, and water slowly to going in the oil phase, when being stirred to 60 ℃, is added the mixed liquor that step (3) makes, and continues to stir to be cooled to nearly room temperature, promptly.
Embodiment 4
Prescription: ketoconazole 10g, clobetasol propionate 0.5g, 16-18 mixed alcohol 50g, light liquid petrolatum 125g, stearic acid 75g, laurocapram 20g, disodiumedetate 0.5g, triethanolamine 4.5ml, ethyl hydroxybenzoate 0.5g, glycerol 300g, anhydrous sodium sulfite 1.0g, 2,6-dibutyl paracresol 0.5g and pure water;
Preparation method is with embodiment 1.
Embodiment 5
Prescription: ketoconazole 11g, clobetasol propionate 0.3g, 16-18 mixed alcohol 46g, light liquid petrolatum 100g, stearic acid 77g, laurocapram 15g, disodiumedetate 0.35g, triethanolamine 2.6ml, ethyl hydroxybenzoate 0.45g, glycerol 320g, anhydrous sodium sulfite 0.85g, 2,6-dibutyl paracresol 0.45g and pure water;
Preparation method is with embodiment 2.
Embodiment 6
Prescription: ketoconazole 9g, clobetasol propionate 0.5g, 16-18 mixed alcohol 52g, light liquid petrolatum 120g, stearic acid 72g, laurocapram 19g, disodiumedetate 0.45g, triethanolamine 4.0ml, ethyl hydroxybenzoate 0.4g, glycerol 260g, anhydrous sodium sulfite 0.95g, 2,6-dibutyl paracresol 0.55g and pure water;
Preparation method is with embodiment 3.
Embodiment 7
Prescription: ketoconazole 10.5g, clobetasol propionate 0.55g, 16-18 mixed alcohol 44g, light liquid petrolatum 130g, stearic acid 71g, laurocapram 18g, disodiumedetate 0.25g, triethanolamine 5.0ml, ethyl hydroxybenzoate 0.3g, glycerol 290g, anhydrous sodium sulfite 0.9g, 2,6-dibutyl paracresol 0.5g and pure water;
Preparation method is with embodiment 1.
Embodiment 8
Prescription: ketoconazole 10g, clobetasol propionate 0.45g, 16-18 mixed alcohol 48g, light liquid petrolatum 115g, stearic acid 76g, laurocapram 19g, disodiumedetate 0.4g, triethanolamine 3.2ml, ethyl hydroxybenzoate 0.4g, glycerol 310g, anhydrous sodium sulfite 0.9g, 2,6-dibutyl paracresol 0.6g and pure water;
Preparation method is with embodiment 2.
Claims (6)
1, a kind of pharmaceutical composition that is used for the treatment of superficial fungous infection of skin is characterized in that described pharmaceutical composition is made up of ketoconazole, clobetasol propionate and substrate.
2,, it is characterized in that the every 1000g of described pharmaceutical composition contains ketoconazole 8-13g, clobetasol propionate 0.3-0.7g, surplus is a substrate according to the described pharmaceutical composition of claim 1.
3,, it is characterized in that the every 1000g of described pharmaceutical composition contains ketoconazole 10g, clobetasol propionate 0.5g, surplus is a substrate according to the described pharmaceutical composition of claim 2.
4, according to the described pharmaceutical composition of claim 2, it is characterized in that described substrate is 16-18 mixed alcohol 40-55g, light liquid petrolatum 100-135g, stearic acid 70-80g, laurocapram 15-21g, disodiumedetate 0.2-0.5g, triethanolamine 2.6-5.1ml, ethyl hydroxybenzoate 0.3-0.5g, glycerol 250-320g, anhydrous sodium sulfite 0.8-1.1g, 2, the mixture of 6-dibutyl paracresol 0.4-0.7g and water.
5, according to claim 2,3, the described pharmaceutical composition of 4 arbitrary claim, it is characterized in that described substrate is 16-18 mixed alcohol 50g, light liquid petrolatum 125g, stearic acid 75g, laurocapram 20g, disodiumedetate 0.5g, triethanolamine 4.5ml, ethyl hydroxybenzoate 0.5g, glycerol 300g, anhydrous sodium sulfite 1.0g, 2, the mixture of 6-dibutyl paracresol 0.5g and water.
6, a kind of method for preparing claim 3 or 4 described pharmaceutical compositions is characterized in that comprising the steps:
(1) with 16-18 mixed alcohols, light liquid petrolatum, stearic acid, the ethyl hydroxybenzoate Hybrid Heating makes fusion, crosses 150 mesh sieves, and is standby to 80～85 ℃ of insulations, adds 2 before the emulsifying, and the 6-dibutyl paracresol stirs and makes dissolving, gets oil phase;
(2) with water, glycerol, disodiumedetate, the triethanolamine Hybrid Heating makes dissolving, crosses 150 mesh sieves, and is standby to 80～85 ℃ of insulations, adds anhydrous sodium sulfite before the emulsifying, stirs and makes dissolving, gets water;
(3) clobetasol propionate, ketoconazole are dissolved in the laurocapram of recipe quantity, cross 150 mesh sieves, standby;
(4) water that makes of oil phase that step (1) is made and step (2) is cooled to 70～75 ℃ respectively, and water slowly to going in the oil phase, when being stirred to 60 ℃, is added the mixed liquor that step (3) makes, and continues to stir to be cooled to nearly room temperature, promptly.
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| CN 200710079724 CN101015553A (en) | 2007-03-06 | 2007-03-06 | Medicinal composition for treating skin superficial fungal infection and preparation process thereof |
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| CN 200710079724 CN101015553A (en) | 2007-03-06 | 2007-03-06 | Medicinal composition for treating skin superficial fungal infection and preparation process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102283850A (en) * | 2011-08-25 | 2011-12-21 | 西北农林科技大学 | Oil-in-water type compound ketoconazole nano-medicament and preparation method thereof |
| CN101762659B (en) * | 2010-01-05 | 2012-07-18 | 广东省汕头市药品检验所 | Quick screening method for illegally-added ketoconazole in scurf removing shampoo cosmetics |
| CN105434445A (en) * | 2015-12-08 | 2016-03-30 | 浙江鼎泰药业有限公司 | Hair lotion treating scalp superficial fungal infection and preparation method thereof |
| CN105456182A (en) * | 2015-12-08 | 2016-04-06 | 浙江鼎泰药业有限公司 | Topical cream for treating fungal infection and production method thereof |
| CN107132284A (en) * | 2017-04-26 | 2017-09-05 | 江苏知原药业有限公司 | Compound prescription Biejiarangan analysis method |
| CN107441127A (en) * | 2017-09-01 | 2017-12-08 | 骆凌翔 | The compound effacement emulsion of suppression oxygen orientation medicine transdermal chronic disease one again |
| CN108051514A (en) * | 2017-11-28 | 2018-05-18 | 江苏知原药业有限公司 | The preparation method of compound prescription Biejiarangan test liquid |
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- 2007-03-06 CN CN 200710079724 patent/CN101015553A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101762659B (en) * | 2010-01-05 | 2012-07-18 | 广东省汕头市药品检验所 | Quick screening method for illegally-added ketoconazole in scurf removing shampoo cosmetics |
| CN102283850A (en) * | 2011-08-25 | 2011-12-21 | 西北农林科技大学 | Oil-in-water type compound ketoconazole nano-medicament and preparation method thereof |
| CN105434445A (en) * | 2015-12-08 | 2016-03-30 | 浙江鼎泰药业有限公司 | Hair lotion treating scalp superficial fungal infection and preparation method thereof |
| CN105456182A (en) * | 2015-12-08 | 2016-04-06 | 浙江鼎泰药业有限公司 | Topical cream for treating fungal infection and production method thereof |
| CN105434445B (en) * | 2015-12-08 | 2018-04-13 | 浙江鼎泰药业股份有限公司 | A kind of hair lotion for treating scalp superficial part mycotic infection and preparation method thereof |
| CN107132284A (en) * | 2017-04-26 | 2017-09-05 | 江苏知原药业有限公司 | Compound prescription Biejiarangan analysis method |
| CN107441127A (en) * | 2017-09-01 | 2017-12-08 | 骆凌翔 | The compound effacement emulsion of suppression oxygen orientation medicine transdermal chronic disease one again |
| CN108051514A (en) * | 2017-11-28 | 2018-05-18 | 江苏知原药业有限公司 | The preparation method of compound prescription Biejiarangan test liquid |
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