CN1481797A - Composition comprising ketoconazole and sultifen - Google Patents
Composition comprising ketoconazole and sultifen Download PDFInfo
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- CN1481797A CN1481797A CNA021293929A CN02129392A CN1481797A CN 1481797 A CN1481797 A CN 1481797A CN A021293929 A CNA021293929 A CN A021293929A CN 02129392 A CN02129392 A CN 02129392A CN 1481797 A CN1481797 A CN 1481797A
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Abstract
The present invention relates to one kind of medicine composition containing Ketoconazole and Naftifine hydrochloride for treating fungus dermatosis. The medicine composition contains Ketoconazole and Naftifine hydrochloride in 0.625-5 wt% as its effective component and medicinal acceptable supplementary material, including excipient, etc. In the effective component, Ketoconazole accounts four 20-70 wt% and Naftifine hydrochloride 30-80 wt%. The pharmacodynamical experiment shows that the medicine composition has excellent medicinal activity on skin tinea fungus and candida albicans.
Description
Technical field:
The present invention relates to treat the pharmaceutical preparation of dermatomycosis, particularly a kind of pharmaceutical composition that contains ketoconazole and naftifine.
Background technology:
Dermatomycosis is a kind of commonly encountered diseases, frequently-occurring disease, and especially the geographic sickness rate of the moist high temperature in subtropical zone is higher.The medicine for external use majority of treatment dermatomycosis belongs to single current system effect preparation at present, and curative effect is not satisfactory.
Imidazoles and propylene amine drug are the antifungal drugs of novel, efficient, safety commonly used in recent years, low toxicity.They all can suppress the synthetic of fungal cell membrane ergosterol, thereby make membrane structure destroy the growth that suppresses the fungal cell.But it is different that the two influences the synthetic mechanism of ergosterol.On behalf of medicine, imidazoles ketoconazole, fluconazol, miconazole etc. are arranged, act on the C-14 demethylase of Pilus Caprae seu Ovis steroid, suppress of the conversion of Pilus Caprae seu Ovis steroid to 14-demethyl Pilus Caprae seu Ovis steroid, thereby suppress the synthetic of ergosterol, dermatophytosis and yeast etc. is all had stronger antibacterial and bactericidal action.But according to relevant, pathogen increases gradually to the drug resistance of imidazoles, single unsatisfactory curative effect occurs when treating with imidazoles, is easy to situation such as recurrence.The propylene amine mainly contains terbinafine and naftifine hydrochloride, and target site is the Squalene Cycloxygenase, suppresses Squalene and is converted into squalene epoxide, finally suppresses the biosynthesis of ergosterol.In addition, the accumulation of Squalene can cause cell membrane fragility to increase and break.The propylene amine is strong to the dermatophytosis sterilizing power, but relatively poor to saccharomycetic effect.
Summary of the invention:
The objective of the invention is to develop the preparation of a kind of propylene amine drug and imidazoles use in conjunction, by the different mechanism of action, provide to have synergism the pharmaceutical preparation of the novel fungitype dermatoses of antifungal good effect, tool anti-drug resistance.
The invention provides a kind of hydrochloric naftifine and ketoconazole as the pharmaceutical composition of active component, be used for the treatment of dermatomycosis.
Above-mentioned active ingredient hydrochloric acid naftifine and ketoconazole account for 0.625%～5% of composition total weight, and other composition is the acceptable adjuvant of medicine, as excipient etc.
The percentage composition of naftifine hydrochloride in active component is 30%～80% (weight), and the percentage composition of ketoconazole in active component is 20%～70% (weight).
Wherein, the preferred percentage composition of two kinds of compositions in active component is naftifine hydrochloride 80%, ketoconazole 20%.It is that preferred proportion (weight) is a naftifine hydrochloride: ketoconazole=4: 1.
Wherein, described active ingredient hydrochloric acid naftifine and ketoconazole preferably exist with the alcoholic solution form in pharmaceutical composition.Preferred solvent is a propylene glycol; Preferred solvent is a benzyl alcohol.
Confirm that through pharmacodynamic experiment pharmaceutical composition of the present invention all has the excellent drug activity to inside and outside dermatophytosis and Candida albicans, confirm that naftifine hydrochloride and ketoconazole use in conjunction have collaborative or summation action, promptly its drug effect obviously is better than single usefulness.
The dosage form of pharmaceutical composition of the present invention can be external-use drug forms such as solution, oil preparation, ointment, cream, powder.
Below in conjunction with embodiment and test example the present invention is further illustrated, but it should be understood that the present invention is not restricted to these embodiment and test example.
The specific embodiment:
One, preparation of compositions
The preparation method of the present composition may further comprise the steps:
(1) naftifine hydrochloride, ketoconazole are dissolved in respectively in propylene glycol and the benzyl alcohol.
(2) preparation carrier of exterior-applied medicines or excipient.
(3) with (1) and (2) mix homogeneously.
Preparation process with embodiment 1 is an example:
(1) naftifine hydrochloride 1g, ketoconazole 0.25g are dissolved in respectively in 3g propylene glycol and the 1g benzyl alcohol.(ketoconazole (KCZ) and naftifine hydrochloride (NTF) standard substance are provided ketoconazole lot number 20001202 by Huabang Pharmaceutical Co., Ltd., Chongqing; Naftifine hydrochloride lot number 010208.)。
(2) white vaseline 7g, liquid paraffin 4g, glyceryl monostearate 3g, hexadecanol 3g are added in the container, are heated to 70～75 ℃, stir fusion.
(3) (1) is poured in (2) stirred.
(4) tween 80 and distilled water are joined in the container, are heated to 70～75 ℃, stir, temperature is remained on 70～75 ℃, stir and to add down in (3), emulsifying homogenizing 30 minutes, after the condensation promptly.
Embodiment naftifine hydrochloride (g) ketoconazole (g)
1????????????1????????????0.25
2????????????3????????????7
3????????????5????????????5
9????????????-????????????1
5????????????8????????????2
6????????????7????????????3
7????????????1????????????-
Two, biological experiment
Test 1 external pharmacodynamics test
Test objective
Compare the external antifungic action that ketoconazole, naftifine hydrochloride and two medicines are united, filter out the optimal drug proportioning of ketoconazole, naftifine hydrochloride two medicines.
The following method of test reference:
The standard of American National clinical trial standardization committee (NCCLS) in 1997 proposition
1.National Committee forclinical laboratory standards reference method for broth clilution antifungal susceptibility testingofyeast:approved Stancland M2fA.National Committee for clinical Laboratony Standards.Villanova.Pa, 1996 (M27-A schemes) are used constant liquid base dilution method and micro-dilution method respectively.
Cao Yongbing, Jiang Yuanying, Wang Ning trace liquid base dilution method are measured the extracorporeal antifungal activity of the special benzyl health of chemical compound azoles, Chinese antibiotic magazine 2000,3,183-187.
Zheng Weiqing, Wang Wenli, Li Ruoyu, 6 kinds of antifungal drug perception of micromethod detection of skin tinea bacterium, Chinese journal of dermatology 1999,5,350-352.
Liu Weijie, Wang Xingyan, Wu Jianming, micro-dilution method is measured the experimentation of dermatophytosis minimum inhibitory concentration (MIC), clinical department of dermatologry magazine 1997,4,228-229.
Trial drug and material 1) medicine
The pharmaceutical composition 2 of embodiment 1-7) test strain: 18 strain dermatophytosises and 30 strain Candida albicanss, specific as follows:
(1) Epidermophyton: acrothesium floccosum * 2 strains
(2) Microsporon: microsporum canis * 2 strains
Microsporon gypseum * 2 strains
(3) trichophyton: trichophyton * 5 strains
Alpha fungus * 5 strains
Trichophyton violaceum * 2 strains
(4) Candida: Candida albicans * 30 strains
Above bacterial strain provides by Long March hospital dermatology department fungus preservation administrative center cryptococcus specialty test chamber, is the clinical separation strain of identifying, and to select Candida albicans type strain ATCC76615 be the Quality Control bacterium.3) culture medium
The RPMI1640 culture fluid: RPMI1640 powder 10.4g MOPS powder 34.53g distilled water 900ml NaOH regulates PH to 7.0 and is settled to 1000ml; Filter filters so that remove and degerms.-20 ℃ of refrigerators are preserved.
Improve husky Bao Shi culture medium (SDA): water in culture dish behind glucose 2% peptone 1% agar 2% chloromycetin 0.05% autoclaving and in vitro, cryogenic refrigerator is preserved.
Test procedure 1) constant liquid base dilution method
(1) preparation of bacteria suspension: the dermatophytosis that will be tried is inoculated in SDA and cultivated 10 days for last 27 ℃.Peek group (containing vegetative hyphae) is tried bacterium in the 0.8ml distilled water, evenly grinds through dismembyator.With the numeration of blood cell counts plate, comprise spore and mycelia, its concentration is transferred to 1-5 * 10
6CFU/ml (being equivalent to 0.5 Maxwell unit); Be 0.5-2.5 * 10 with the RPMI1640 culture fluid with the bacteria suspension concentration dilution then
5CFU/ml (final concentration).
(2) preparation of antifungal drug
Medicine is dissolved as the mother liquid medicine of 51200 μ g/ml with DMSO, and then dilution is 320 μ g/ml (10 times of working concentrations) respectively, after mixing by the different quality proportioning more successively doubling dilution become 10 concentration.
(3) liquid base dilution method:
Get in the test tube that 900 μ l bacterial suspension inoculation to 100 μ l contain the variable concentrations medicine (two-fold dilution).27 ℃ of filamentous fungis were cultivated 6～7 days, measured the absorbance of each test tube at 630nm place with spectrophotometer, with growth control pipe comparison 〉=pairing lowest concentration of drug of 80% growth inhibited be the MIC value that ketoconazole, naftifine hydrochloride and two medicines are united.
The mensuration of MBC (minimal bactericidal concentration): culture medium that will not have conk is distinguished transferred species again on the SDA culture medium, continues to cultivate 10-12 days, and the least concentration of asepsis growth is the MBC value of this medicine to this bacterium.2) micro-dilution method
(1) preparation of bacteria suspension: will be tried the Candida albicans inoculation and make bacteria suspension with the 2ml normal saline in the last 35 ℃ of cultivations of SDA after 48 hours, and be adjusted into 0.5 Maxwell unit with the Maxwell opacity tube, it is 1 * 10 that suspension is counted on blood cell counting plate
6-5 * 10
6CFU/ml is 1-5 * 10 with the RPMI1640 culture medium with the bacteria suspension concentration dilution then
3CFU/ml (diluting 1000 times) (2 times of working concentrations).
(2) preparation of medicinal liquid: medicine is dissolved as the mother liquid medicine of 51200 μ g/ml with DMSO, and then to dilute respectively with the RPMI1640 culture medium be 256 μ g/ml (2 times of working concentrations), after mixing by the different quality proportioning more successively doubling dilution be 10 concentration.
(3) drug sensitive reaction plate preparation: get aseptic 96 hole micro-reaction plates, add 100 μ l bacteria suspension and medicinal liquids in the 1-10 hole respectively, make the final drug level in each hole be respectively 128,64,32,16,8,4,2,1,0.5 and 0.25 μ g/ml; It is growth control that 11 holes add 200 μ l bacteria suspensions; It is blank that 12 holes add 200 μ l fluid mediums.Drug sensitive plate is placed 35 ℃ of calorstats and is cultivated.
(4) the judgement Candida albicans of MIC value and MBC value is surveyed each hole OD value with enzyme micro-plate reader in 620nm in 35 ℃ of cultivations after 48 hours.In the growth control boring ratio, be the MIC value with the drug level in the least concentration hole of OD value decline more than 80%.To not have the culture medium of conk then and distinguish transferred species again on the SDA culture medium, and continue to cultivate 10-12 days, the least concentration of asepsis growth is the MBC value of this medicine to this bacterium.
When the MIC of medicine value and MBC value surpass when measuring concentration range, add up by the following method: when MIC value and MBC value are higher than maximum concentration 128, count " 〉=128 ": MIC value and MBC value are not distinguished for least concentration or when least concentration is following, all count "≤0.03 ".
The equal operation repetitive of above-mentioned experiment 2-3 time just is accepted when MIC value and MBC value all can accurately repeat or only differ from a concentration, and with higher concentration as MIC value and MBC value; When MIC value or MBC value differ two concentration when above, then need experiment again, till meeting the requirements.3) time-kill curve experiment OscarM, Philippe M, Milippem, Michel PG, et al potent synergism of theCombination of flnconazole and cyclosporine in candida albicans Antimicrobial Agants andchemotherapy by 2000; 44,2373-0381.
(1) preparation of bacteria suspension: selecting two strain Candida albicans CZ3288 and CZ3087 is test strain. Candida albicans is made 1 Maxwell unit (1-10 * 10 with normal saline in 35 ℃ of cultivations on the SDA culture medium after 48 hours
6Cfu/ml) bacteria suspension.With the RPMI1640 culture fluid it being diluted to concentration then is 1-10 * 10
4The bacteria suspension of cfu/ml.
(2) preparation of medicinal liquid: with the RPMI1640 culture fluid medicine is made into the medicinal liquid that concentration is MBC, wherein the concentration of ketoconazole, naftifine hydrochloride and two medicine use in conjunction (2/8) is 128 μ g/ml.
(3) getting the 1ml bacteria suspension mixes with 9ml medicinal liquid (matched group is the 9mlRPMI1640 fluid medium) and puts 35 ℃ and cultivated 48 hours.Got the 10 times of level dilutions successively of 100 μ l mixed liquors respectively at 0,12,24,36,48 hour: 1/10,1/10
2, 1/10
3, 1/10
4, 1/10
5And then the diluent of getting an amount of concentration of 100 μ l evenly is coated with inoculation (3 parts), 35 ℃ of cultivation calculating its colony countings (getting the meansigma methods of 3 values) after 48 hours on the SDA culture medium.Draw time-kill curve according to counting.See time one killing curve figure.
Result of the test
1, dermatophytosis and Candida albicans see Table 1,2,3 to ketoconazole, naftifine hydrochloride and the MIC value of two medicines associating and the geometric mean and the distribution of MBC value, and the result of the test of Quality Control bacterium is all in normal range.Show that through rank test dermatophytosis is to naftifine hydrochloride: the sensitivity differences of ketoconazole=4: 1 proportioning group and other several groups of medicines has statistical significance (P＜0.01).It can be seen from the table, naftifine hydrochloride: ketoconazole=proportioning had good drug activity to dermatophytosis in 4: 1, its MIC peak value between 0.03-0.063 μ g/ml (dermatophytosis), its MBC peak value also between 0.03-0.063 μ g/ml, MIC
50And MIC
90Be minimum, and its geometric mean all is starkly lower than other several groups of medicines.Naftifine hydrochloride: ketoconazole=3: 7,4: 1,5: 5 and 0: 1 oidiomycetic fungistatic effect of proportioning group dialogue are all better, show mutual no statistical discrepancy through rank test, and all effective than 2: 8,7: 3 and 1: 0 has statistical significance (P＜0.01).
2, naftifine hydrochloride: ketoconazole=4: 1 groups all demonstrates collaborative or summation action to dermatophytosis and Candida albicans.
Finding in the test that 3, ketoconazole and the oidiomycetic MIC value of naftifine hydrochloride dialogue scope are all bigger, is 0.125-64 μ g/ml as the MIC value scope of ketoconazole, and the MIC value scope of naftifine hydrochloride is 0.5-128 μ g/ml.
4, time-kill curve as a result naftifine hydrochloride, ketoconazole and use in conjunction thereof Candida albicans is mainly shown as bacteriostasis, and two medicine use in conjunction can strengthen its bacteriostasis.
Conclusion
Experiment in vitro proof naftifine hydrochloride and its drug effect of ketoconazole use in conjunction obviously are better than single usefulness, and the best matched proportion density of two medicines is: naftifine hydrochloride: ketoconazole=4: 1.Test the pharmacodynamics test of 2 guinea pig skin fungal infection
Test objective
How estimate compound hydrochloric acid for antifungic action in the fragrant body, filter out optimum medicine concentration.
Material and method
Trial drug
Compound hydrochloric acid naftifine emulsifiable paste (CNTF), constitute by naftifine hydrochloride and ketoconazole and substrate, its height (2.5%), in (1.25%) and low (0.625%) concentration naftifine hydrochloride content be respectively 2%, 1% and 0.5%, ketoconazole content is respectively 0.5%, 0.25% and 0.125%.Lot number is respectively 010802,010803,010804,2% ketoconazole cream (KCZ) and 1% naftifine hydrochloride emulsifiable paste (NTF) lot number are respectively 010810 and 010808, blank emulsifiable paste (substrate M) lot number is 010805, provides by Huabang Pharmaceutical Co., Ltd., Chongqing.
Test strain
Trichophyton (Trichophyton rubrum, Trichophyton purputeatum), C21251;
Candida albicans (Candida albicans), C2ATCC76615.
Provide by The 2nd Army Medical College Long March hospital dermatology department.
Recover its pathogenicity before the inoculation earlier, and be inoculated in husky fort agar (Sabrouraud dextrose agar SDA) slant tube, cultivated about 10 days in 26 ℃ of culture medium, it is standby to get bacterium colony.
The method reference literature:
New drug (Western medicine) preclinical study guideline compilation, Ministry of Health of the People's Republic of China issues, in May, 1994
Bao Yanyan, reach the clouds, naftifine hydrochloride such as Chen Mupu is to the mould observation of curative effect of guinea pig skin magnesium tinea, Chinese antibiotic magazine
2000，25(2)，145；
Special curative effect such as Guo Ningru, Wu Shaoxi, Shen Yongzhuo than naftifine treatment guinea pig skin trichophyton mentagrophytes infection, new drug and clinical 1996,
15(6)，339。
Choose 140 of healthy qualified one-level Cavia porcelluss, body weight 240～270g, the male and female dual-purpose is provided by Medical University Of Chongqing's Experimental Animal Center, No. the 310101019th, the moving word of laboratory animal quality certification doctor, No. the 310103002nd, the moving word of the environmental facility quality certification number doctor.Feed earlier and observe a week, remove then spinal column both sides, back hair (8 * 4cm), be about 1/4 of whole body area.With 2# sand paper damage by friction skin repeatedly, there is slight exudate to be as the criterion.The skin injury Cavia porcellus is divided into two parts (each part is 70), and a part of animal is smeared trichophyton suspension 1ml repeatedly in cutaneous lesion, and another part animal is smeared Candida albicans suspension 1ml repeatedly in cutaneous lesion, and repeated friction 1～2min.The animal that infects trichophyton or Candida albicans is isolated nursing 7～10 days respectively, keep room temperature at 28～30 ℃.After feeding 7～10 days, detect every animal skin fungal infection model respectively.Erythra or squama occur with skin, have fungal mycelia then to infect for trichophyton through microscopy; There is fungal spore then to be candida albicans infection mould.
70 trichophyton or 70 Candida albicans animal patterns are divided into the large, medium and small dosage group of compound hydrochloric acid naftifine, 2% ketoconazole group, 1% naftifine hydrochloride group and matrix group and blank group (B) respectively at random, every group is infected 10 of Cavia porcelluss, trichophyton infection model animal amounts to 7 groups, and the candida albicans infection mould animal amounts to 7 groups.Each treated animal is isolated nursing respectively.Each treated animal is smeared relative medicine respectively, and every animal dosage every day 1g uses at twice, at 9 in the morning and afternoons 4 point, continuous use 14 days.Began in 4 days to detect drug effect in medication by an animal.
Therapeutic evaluation is in smearing medicine beginning in the 4th day, and every day, mirror detected fungal infection skin place erythra, scurf, crust fungal mycelia or spore down, and the negative animal of double microscopy is then scraped the bark fetching bits or crust carries out fungal culture.Criterion of cure is that skin lesion disappears, twice microscopy feminine gender and fungal culture negative patient.Invalidly then do not move back fungus microscope examination positive person for skin lesion.
Add up and calculate the cure rate of each treated animal respectively.
We at first use uniting of ketoconazole and naftifine hydrochloride and study, tests such as a series of general pharmacologies, pharmacodynamics, anxious poison, long poison, pharmacokinetics, local irritation have been carried out, we find that the two unites use and can reach good fungistatic effect, following description of test the present invention.
The compound hydrochloric acid naftifine shows the result: naftifine hydrochloride: ketoconazole=the proportioning group had the excellent drug activity to dermatophytosis in 4: 1, was better than other proportioning groups; Naftifine hydrochloride: ketoconazole=3: 7,4: 1,5: 5 and 0: 1 proportioning group are all better to the oidiomycetic fungistatic effect of white, all effective than 2: 8,7: 3 and 1: 0.Naftifine hydrochloride and its drug effect of ketoconazole use in conjunction obviously are better than single usefulness, and the best matched proportion density of two medicines is a naftifine hydrochloride: ketoconazole=4: 1.
Skin tinea bacterium and Candida albicans all demonstrate collaborative or summation action.
Finding in the test that 3, ketoconazole and the oidiomycetic MIC value of naftifine hydrochloride dialogue scope are all bigger, is 0.125-64 μ g/ml as the MIC value scope of ketoconazole, and the MIC value scope of naftifine hydrochloride is 0.5-12 μ g/ml.
4, time-kill curve as a result naftifine hydrochloride, ketoconazole and use in conjunction thereof Candida albicans is mainly shown as bacteriostasis, and two medicine use in conjunction can strengthen its bacteriostasis.
Conclusion
Experiment in vitro proof naftifine hydrochloride and its drug effect of ketoconazole use in conjunction obviously are better than single usefulness, and the best matched proportion density of two medicines is: naftifine hydrochloride: ketoconazole=8: 2.
Compound hydrochloric acid naftifine emulsifiable paste is to the observation of curative effect result of Cavia porcellus trichophyton or candida albicans infection mould, the big or middle dosage group of compound hydrochloric acid naftifine is better than single with 1% naftifine hydrochloride emulsifiable paste (P＜0.05) to 7 days curative effects of Cavia porcellus trichophyton infection model, how curative effect was compared also variant for sweet smell with 1% hydrochloric acid with 2% ketoconazole in 14 days; 8 days curative effects of Cavia porcellus candida albicans infection mould are better than single with 1% naftifine hydrochloride and 2% ketoconazole cream (P＜0.05), how curative effect replaced sweet smell to compare variant with 1% hydrochloric acid in 14 days.Experimental result shows that the compound hydrochloric acid naftifine all has obvious curative effects to trichophyton or candida albicans infection.
The compound hydrochloric acid naftifine is treated Candida albicans, and large, medium and small dosage group and substrate and blank group compare, and cure rate all has significant difference after treating the 7th day.Dosage group therapeutic equivalence big or middle reaches 80%, the 12nd day cure rate at the 8th day cure rate and reaches 100%, with 1% naftifine hydrochloride or 2% ketoconazole group significant difference is arranged relatively; Cure rate was 100% in the 14th day, and is more variant with 1% naftifine group.Small dose group and 1% naftifine hydrochloride and 2% ketoconazole group relatively, in whole treatment stage cure rate there are no significant difference.Result of the test shows: the big or middle dosage group treatment of compound hydrochloric acid naftifine candida albicans infection obviously is better than 1% naftifine hydrochloride and 2% ketoconazole, small dose group and 1% naftifine hydrochloride and 2% ketoconazole therapeutic equivalence.The compound hydrochloric acid naftifine is treated trichophyton, and large, medium and small dosage group and substrate and blank group compare, and cure rate all has significant difference after treating the 6th day.Dosage group therapeutic equivalence big or middle, it is 100% that the 7th day cure rate reaches 80%, the 11 day cure rate, with 1% naftifine hydrochloride group or 2% ketoconazole group significant difference is arranged relatively; Cure rate was 100% in the 14th day, and is more variant with 1% naftifine hydrochloride and 2% ketoconazole group.Small dose group and 1% naftifine and 2% ketoconazole group relatively, in whole treatment stage cure rate there are no significant difference.Result of the test shows: the big or middle dosage group treatment of compound hydrochloric acid naftifine trichophyton infects and obviously is better than 1% naftifine hydrochloride and 2% ketoconazole, small dose group and 1% naftifine and 2% ketoconazole therapeutic equivalence.In addition, how reach identical curative effect compound hydrochloric acid replaces fragrant used time ratio list how shorter for sweet smell and 2% ketoconazole with 1% hydrochloric acid.
Above result of the test prompting, dosage in the naftifine hydrochloride (1.25%) group antifungal curative effect obviously is better than 1% naftifine hydrochloride and 2% ketoconazole (being clinical application concentration), and concentration belongs to the junior, therefore, the 1.25%th, compound hydrochloric acid naftifine optium concentration is the drug level that we recommend to be used for clinical research.
The compound hydrochloric acid naftifine all has significant curative effect to Candida albicans or trichophyton infection guinea pig model, is better than single with 1% Naftifine Hydrochloride Ointment and 2% ketoconazole 2.
Table 1 drug sensitive experiment is summed up catalog
Annotate: how much=geometric mean
| Bacterial strain | The strain number | ??N∶K＝0∶1????????N∶K＝2∶8????????N∶K＝3∶7????????N∶K＝5∶5??????N∶K＝7∶3???????N∶K＝8∶2????????N∶K＝1∶0 | |
| How much of mean geometric mean geometric mean geometric mean geometric mean geometric mean geometric means | |||
| MIC | Dermatophytosis | 18 | ??0.555????0.174????0.088????0.07?????0.111????0.103????0.281???0.138???0.117???0.073????0.043????0.038????0.4?????0.162 |
| Candida albicans | 30 | ??15.17????6.96?????105.2????78.79????31.03????5.16?????13.57???5.79????82.40???73.52????27.07????5.28?????92.98???45.25 | |
| MBC | The tinea castor | 18 | ??3.6??????0.96?????0.215????0.145????0.188????0.17?????1.07????0.61????0.63????0.158????0.067????0.045????0.63????0.33 |
| Candida albicans | 30 | ??67.33????43.21????125.9????125.1????50.94????27.86????53.33???36.76???125.9???125.1????56.53????35.92????128?????128 | |
| The big minispread of geometric mean | Dermatophytosis | MIC：2∶8＜8∶2＜3∶7＜7∶3＜5∶5＜0∶1＜1∶0 | |
| MBC：2∶8＜8∶2＜3∶7＜7∶3＜5∶5＜0∶1＜1∶0 | |||
| Candida albicans | MIC：7∶3＜2∶8＜5∶5＜1∶0＜0∶1＜3∶7＜8∶2 | ||
| MBC：7∶3＜2∶8＜5∶5＜1∶0＜3∶7＜8∶2＜0∶1 | |||
N=naftifine hydrochloride K=ketoconazole
Table 2 ketoconazole, naftifine hydrochloride and two medicine couplings distribute to the MIC of test strain
Annotate: N=naftifine hydrochloride, K=ketoconazole, NTF=naftifine hydrochloride, KCZ=ketoconazole
| Medicine | Strain | The strain number | MIC scope (μ g/ml) | Geometric mean | MIC＞(μ g/ml) distribute (bacterial strain number) |
| ≥128?64???32???16????8????4????2????1????0.5??0.25???0.125????0.063??≤0.03 | |||||
| ??KCZ | Dermatophytosis | ??18 | ??0.03-4 | ??0.174 | ???????????????????????????1????1????1????4????2??????2????????1????????6 |
| Candida albicans | ??30 | ??0.125-64 | ??6.96 | ??????1????7????8?????2????3????4????2????2????0??????1????????0????????0 | |
| ??NTF | Dermatophytosis | ??18 | ??0.03-2 | ??0.162 | ????????????????????????????????1????3????2????3??????1????????3????????5 |
| Candida albicans | ??30 | ??0.5-128 | ??45.25 | ??21??1????0????1?????1????2????2????1????1 | |
| ??N/K＝5/5 | Dermatophytosis | ??18 | ??0.03-1 | ??0.138 | ?????????????????????????????????????2????4????1??????5????????0????????6 |
| Candida albicans | ??30 | ??0.125-64 | ??5.79 | ??????1????6????5?????7????1????4????1????4????0??????1????????0????????0 | |
| ??N/K＝3/7 | Dermatophytosis | ??18 | ??0.063-0.25 | ??0.103 | ???????????????????????????????????????????????1??????11???????6????????0 |
| Candida albicans | ??30 | ??0.125-128 | ??5.16 | ??6???0????1????4?????5????6????1????0????0????1??????6????????0????????0 | |
| ??N/K＝7/3 | Dermatophytosis | ??18 | ??0.03-1 | ??0.073 | ?????????????????????????????????????1????0????0??????1????????15???????1 |
| Candida albicans | ??30 | ??8-128 | ??73.52 | ??10??18???1????0?????1 | |
| ??N/K＝2/8 | Dermatophytosis | ??18 | ??0.03-0.25 | ??0.07 | ???????????????????????????????????????????????2??????4?????????7???????5 |
| Candida albicans | ??30 | ??4-128 | ??78.79 | ??24??0????2????1?????2????1 | |
| ??N/K＝8/2 | Dermatophytosis | ??18 | ??0.03-0.125 | ??0.038 | ??????????????????????????????????????????????????????1?????????4???????13 |
| Candida albicans | ??30 | ??0.125-128 | ??5.28 | ??8???1????1????8?????2????0????2????2????2????0??????4?????????0???????0 |
Table 3 ketoconazole, naftifine hydrochloride and uniting uses the MBC to test strain to distribute
Annotate: N=naftifine hydrochloride, K=ketoconazole, NTF=naftifine hydrochloride, KCZ=ketoconazole
| Medicine | Strain | The strain number | MBC scope (μ g/ml) | Geometric mean | MBC＞(μ g/ml) distribute (bacterial strain number) |
| ≥128?64??32????16????8????4????2????1????0.5???0.25??0.125??0.063??≤0.03 | |||||
| ??KCZ | Dermatophytosis | ????18 | ????0.125-32 | ????0.96 | ??????????1?????1?????0????1????3????5????2?????2?????3??????????????0 |
| Candida albicans | ????30 | ????4-128 | ????43.21 | ??11??5????7????3?????1????3 | |
| ??NTF | Dermatophytosis | ????18 | ????0.063-2 | ????0.33 | ????????????????????????????????3????3????1?????6?????1??????4???????0 |
| Candida albicans | ????30 | ????≥128 | ????128 | ??30 | |
| ??N/K＝5/5 | Dermatophytosis | ????18 | ????0.25-4 | ????0.61 | ???????????????????????????2????3????2????2?????9?????0??????0???????0 |
| Candida albicans | ????30 | ????8-125 | ????36.76 | ??5??11????5????3?????6 | |
| ???N/K＝3/7 | Dermatophytosis | ????18 | ????0.125-0.5 | ????0.17 | ??????????????????????????????????????????1?????6?????11?????0???????0 |
| Candida albicans | ????30 | ????0.25-128 | ????27.86 | ??8??2?????7????7?????5????0????0????0????0?????1 | |
| ???N/K＝7/3 | Dermatophytosis | ????18 | ????0.63-8 | ????0.158 | ??????????????????????1????0????0????1????1?????4??????2?????9 |
| Candida albicans | ????30 | ????64-128 | ????125.08 | ??29?1 | |
| ???N/K＝2/8 | Dermatophytosis | ????18 | ????0.03-0.5 | ????0.145 | ??????????????????????????????????????????4?????5??????2?????5???????2 |
| Candida albicans | ????30 | ????64-128 | ????125.08 | ??29?1 | |
| ???N/K＝8/2 | Dermatophytosis | ????18 | ????0.03-0.5 | ????0.045 | ??????????????????????????????????????????1?????0??????0?????6???????11 |
| Candida albicans | ????30 | ????16-128 | ????35.92 | ??8??6?????5????5????6 |
Claims (4)
1, a kind of pharmaceutical composition that is used for the treatment of dermatomycosis is characterized as hydrochloric naftifine and ketoconazole as active component.
2, according to the pharmaceutical composition of claim 1, described active ingredient hydrochloric acid naftifine and ketoconazole account for 0.625%～5% of composition total weight, and other composition is the acceptable adjuvant of medicine.
3, according to the pharmaceutical composition of claim 1, wherein the percentage composition of naftifine hydrochloride in active component is 30%～80% (weight), and the percentage composition of ketoconazole in active component is 20%～70% (weight).
4, according to the pharmaceutical composition of claim 3, wherein, naftifine hydrochloride and the ketoconazole preferred percentage composition in active component is naftifine hydrochloride 80% (weight), ketoconazole 20% (weight).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021293929A CN1481797A (en) | 2002-09-09 | 2002-09-09 | Composition comprising ketoconazole and sultifen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021293929A CN1481797A (en) | 2002-09-09 | 2002-09-09 | Composition comprising ketoconazole and sultifen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1481797A true CN1481797A (en) | 2004-03-17 |
Family
ID=34144139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA021293929A Pending CN1481797A (en) | 2002-09-09 | 2002-09-09 | Composition comprising ketoconazole and sultifen |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1481797A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100998575B (en) * | 2006-01-11 | 2010-12-08 | 重庆华邦制药股份有限公司 | Finger nail coating agent of antifungal agent and its preparing method |
| CN114886839A (en) * | 2022-05-10 | 2022-08-12 | 上海博悦生物科技有限公司 | Naftifine ketoconazole gel composition and preparation method thereof |
| CN115212214A (en) * | 2022-07-01 | 2022-10-21 | 上海博悦生物科技有限公司 | Naftifine ketoconazole cream composition and preparation method thereof |
-
2002
- 2002-09-09 CN CNA021293929A patent/CN1481797A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100998575B (en) * | 2006-01-11 | 2010-12-08 | 重庆华邦制药股份有限公司 | Finger nail coating agent of antifungal agent and its preparing method |
| CN114886839A (en) * | 2022-05-10 | 2022-08-12 | 上海博悦生物科技有限公司 | Naftifine ketoconazole gel composition and preparation method thereof |
| CN115212214A (en) * | 2022-07-01 | 2022-10-21 | 上海博悦生物科技有限公司 | Naftifine ketoconazole cream composition and preparation method thereof |
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