CN1524531A - Compound terbinafine hydrochloride composition of skin antibacterial drugs - Google Patents
Compound terbinafine hydrochloride composition of skin antibacterial drugs Download PDFInfo
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- CN1524531A CN1524531A CNA031052134A CN03105213A CN1524531A CN 1524531 A CN1524531 A CN 1524531A CN A031052134 A CNA031052134 A CN A031052134A CN 03105213 A CN03105213 A CN 03105213A CN 1524531 A CN1524531 A CN 1524531A
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Abstract
The invention relates to Terbinafine Hydrochloride, a compound medicinal composition for skin antibiosis, in particular a medicinal composition comprising Terbinafine Hydrochloride, Chlorhexidine Acetate, Triamcinolone Acetonide Acetate, the composition can be made into various dosage forms, overcoming the drawbacks of single-component being not able for effectively treating diseases as result of dermatophyte infection, bacterial infection or fungus, bacteria mixed infection.
Description
Technical field
The present invention relates to a kind of skin antibacterials compound hydrochloric acid terbinafine compositions, relate in particular to the pharmaceutical composition of a kind of hydrochloric terbinafine, chlorhexidine acetate, triamcinolone acetonide acetate component.
Background technology
Terbinafine HCl (is called for short terbinafine, Terbinafine) be propylene amine antifungal drug, it is characterized in that higher antifungal cure rate and lower in a short time relapse rate are arranged, but undesirable to treatment bacterial skin infections or fungus, the two mixed infection effect of antibacterial; Chlorhexidine acetate (the former name chlorhexidine acetate is called for short chlorhexidine, Chlorhexidine) be anti-bacterial drug, but to treat cutaneous fungal infection or fungus, the two mixed infection effect of antibacterial is undesirable; Triamcinolone acetonide acetate (be called for short triamcinolone acetonide, Triamcinoloni), Aeroseb-Dex has antiinflammatory action, no bacteriostasis, and general and aforementioned component merges uses better efficacy.
Summary of the invention
The purpose of this invention is to provide a kind of skin antibacterials compound hydrochloric acid terbinafine compositions, the pharmaceutical composition of a kind of hydrochloric terbinafine, chlorhexidine acetate, triamcinolone acetonide acetate component especially is provided, has overcome the shortcoming that above-mentioned one-component can not effectively be treated the disease that cutaneous fungal infection or fungus, the two mixed infection of antibacterial causes.
The present invention is achieved through the following technical solutions:
A kind of skin antibacterials compound hydrochloric acid terbinafine compositions comprises component terbinafine HCl, chlorhexidine acetate, triamcinolone acetonide acetate, in (0.8～1.5): (0.3～1): the formulated preparation of (0.01～0.05) proportioning ratio (weight portion).
The best proportioning ratio (weight portion) of described pharmaceutical composition component is 1: 0.5: 0.025;
Described medicament is meant said percutaneous drug delivery dosage form on any pharmaceutics, refers in particular to ointment, ointment, solution, tincture, ear oil preparation.
Pharmaceutical composition of the present invention can be made by following method:
Take by weighing terbinafine HCl, chlorhexidine acetate, triamcinolone acetonide acetate in described ratio, and add the adjuvant agent, be prepared from according to conventional dermatologic preparation method again.
The present invention has following effect and advantage:
1) invention has obvious synergistic effect and potentiation.Utilize three kinds of drug component effects separately, make up the back and find that composition medicine has obvious synergistic effect and potentiation aspect antifungal, and it is unaffected to have kept its antibacterium effect.
2) good effect, toxicity is low.Through the screening of variable concentrations prescription antibacterial action, find that also terbinafine HCl and the chlorhexidine acetate proportion about 1: 0.5: 0.025 is proper, its antifungic action is stronger, does not also influence its antibacterium effect.With three kinds of medicine aforementioned proportions is main constituent, adds adjuvant and makes compositions ointment, and the treatment guinea pig skin infects the sick good effect of trichophyton gypseum.Relevant toxicity is also lower.
3) can be used for developing new compound external-use local application (as compositions ointment, solution and ear oil preparation etc.), treatment dermatophytes, bacterial infection or the two mixed infection.Clinically some cutaneous fungal infection are merged the patient of bacterial infection, unique curative effect is arranged, do not influence simple fungus or bacterial infection treating for skin disease effect.Clinical principium test above-mentioned composition ointment, treatment numerical example dermatophytes or antibacterial, or fungus and antibacterial the two infect the patient of mixed infection, all obtain satisfied curative effect (auspicious see below case report).
Advantage of the present invention and effect can illustrate by following experiment.
One, following experiment can illustrate the synergism and the potentiation of pharmaceutical composition of the present invention, and toxic action is lower.
1. experiment in vitro---the external antibacterial action to common pathomycete of 109 strains and part antibacterial (representing bacterium) of pharmaceutical composition of the present invention and component thereof compares, purpose is to filter out each set of dispense of compositions of mycostasis than ratio, proves fungus bactericidal action of the present invention and bacteriostasis and measures its minimal inhibitory concentration (MIC).
1.1 materials and methods
1.1.1 strain
Fungus is drawn from Nanjing institute of internal medicine, Beijing Medical University's attached First Academy department of dermatologry and air force general hospital department of dermatologry, and antibacterial is drawn from preventive medicine academy of science institute of Antibiotics and air force general hospital clinical laboratory.
1.1.2 culture medium
Fungi culture medium is the Sha Shi broth bouillon, is made up of 1% peptone and 2% glucose etc., and pH is 6--6.5; Bacteria culture media is an ordinary broth, and pH is 7.
1.1.3 the preparation of medicinal liquid culture medium
In the various ratio preparation of terbinafine, chlorhexidine and triamcinolone acetonide.
Each prescription adds sterile distilled water to 5ml more earlier with 1ml 95% dissolve with ethanol medicine; Respectively draw above-mentioned dosing 0.2ml then, be added to respectively in the culture medium of 1.8ml, shake up the medicinal liquid culture medium that the back two-fold dilution goes out variable concentrations.During experiment, add bacterium liquid 0.02ml among every pipe medicinal liquid culture medium 1ml; 1ml contains trichophyton 10
5-10
6Individual or yeast-like fungi 10
3-10
4Individual.Be put in after shaking up in 28 ℃ of incubators and cultivated 120-168 hour, wherein yeast-like fungi is 48 hours, observed result.
1.1.4 drug effect criterion
The limpid medicine blank pipe that is same as of meat soup is for there being the bactericidal action of pressing down; Meat soup is obviously muddy, or the Mycoderma growth is arranged, then for there not being the bactericidal action of pressing down.
1.1.5 the mensuration of bacteriocidal concentration
This method is used the agar tilt-pour process.Earlier pharmaceutical composition of the present invention is made into and contains variable concentrations medicinal liquid culture medium, 1 μ g/ml, 10 μ g/ml, 100 μ g/ml and 200 μ g/ml; Every again ml adds the test bacterium respectively, and the bacterium amount is 10
3-10
6Individual (ml), behind the effect different time, the 0.1ml that takes a sample respectively is inoculated in plate, pours sabouraud's agar into, fully shakes up, and cultivates 5-10 days; Count plate and statistical result.
1.2 experimental result
1.2.1 the screening of compound terbinafine component: compositions is shown by the external bacteriostatic test to the common fungus of 8 strains of terbinafine, chlorhexidine and triamcinolone acetonide different proportion compatibility, terbinafine, chlorhexidine and triamcinolone acetonide are in (0.8～1.5): (0.3～1): the compositions minimal inhibitory concentration (MIC) under the ratio of (0.01～0.05) is lower, and effect better; Especially the compositions under 1: 0.5: 0.025 ratio, (MIC) is low for minimal inhibitory concentration, bacteriostasis strong (seeing Table 1).
1.2.2 the external bacteriostasis to the common pathomycete effect of 21 strains of compositions and component thereof: compositions and its component terbinafine, chlorhexidine and triamcinolone acetonide comparison shows that to the bacteriostatic test of 21 strains experiment fungus, terbinafine, chlorhexidine and the triamcinolone acetonide compositions (this ratio is all used in following experiment) under 1: 0.5: 0.025 ratio all (sees Table 2) to the minimal inhibitory concentration of most bacterium between 0.002-1.25 μ g/ml; To most bacterium, its component terbinafine and chlorhexidine two medicines are all higher, and another component medicine triamcinolone acetonide does not have antifungal effect (MIC＞100 μ g/ml).
1.2.3 compositions and component thereof are to the common pathomycete bactericidal action of 21 strains: after measuring compositions and the MIC of component thereof to the common pathomycete of 21 strains, to not see that successively conk medicine bacterium liquid base subcultivation is in new liquid base, cultivated 5-7 days, and observed minimum bactericidal concentration (MBC).The result shows that compositions has bactericidal action preferably (seeing Table 3).
1.2.4 compositions and component thereof are external to 88 strain trichophyton, trichophyton gypseum, Sabouraudites lanosus and Candida albicans clinical separation strain 90% bacterial strain minimal inhibitory concentration (MIC
90) mensuration: from the clinical isolating 42 strain trichophyton of unit, 18 strain trichophyton gypseums, 12 strain Sabouraudites lanosuss and 22 strain Candida albicans (these 4 kinds of bacterial strains are that this institute's dermatomycosis is than the common pathogenic bacteria bacterial strain) such as attached institutes of Beijing Medical University, show that through bacteriostatic test compositions is to the bacterial strain minimal inhibitory concentration (MIC of these 4 kinds of test organismss (totally 88 strains) 90%
90) be respectively 0.004 μ g/ml, 0.032 μ g/ml, 0.002 μ g/ml and 2.5 μ g/ml; And its component terbinafine and chlorhexidine are obviously relatively poor, Candida albicans particularly, its MIC
90(see Table 4) than compositions up to several times, significant difference (P＜0.05).
Table 1 terbinafine and chlorhexidine, triamcinolone acetonide variable concentrations compatibility are external
Bacteriostasis to 8 strain pathomycetes
--------------------------------------------------------------------
Terbinafine and chlorhexidine, triamcinolone acetonide proportion compatibility and minimal inhibitory concentration (MIC, μ g/ml)
Strain name--------------------------------------------------------
1: 0.5: 0.1 1: 0.5: 0.025 1: 0.5: 0.01 terbinafine (contrast)
--------------------------------------------------------------------
Trichophyton 0.003 0.0015 0.003 0.003
(A9534)
Trichophyton 0.0015 0.003 0.003 0.003
(k950408)
Trichophyton gypseum 0.003 0.0015 0.003 0.003
(k950415)
Sabouraudites lanosus 0.006 0.003 0.003 0.006
(k950401)
Ferrum is embroidered color sporidiole bacteria 0.006 0.003 0.006 0.006
(k950416)
White is read bacterial strain 1.56 1.56 1.56 6.25
(A9468)
White is read bacterial strain 1.56 1.56 1.56 6.25
(B68561)
Cryptococcus histolyticus 0.39 0.39 0.39 0.78
(Changhai mutation)
--------------------------------------------------------------------
Annotate: data are for cultivating 120-168 hour (yeast-like fungi 48 hours) observed result in the table
The external inhibitory action of table 2 compositions and component thereof to the common pathomycete of 21 strains (14 kinds)
--------------------------------------------------------------------
Minimal inhibitory concentration (MIC, μ g/ml)
Strain name----------------------------------------------------------
Compositions terbinafine chlorhexidine triamcinolone acetonide
--------------------------------------------------------------------
Trichophyton A9435 0.003 0.003 1.25＞100
Trichophyton k950408 0.0015 0.003 0.62＞100
Trichophyton B12500 0.0015 0.003 1.25＞100
Trichophyton B1279 0.003 0.003 2.50＞100
Trichophyton gypseum k950415 0.006 0.006 2.50＞100
Trichophyton gypseum B19503 0.003 0.003 1.25＞100
Sabouraudites lanosus k950401 0.006 0.003 1.25＞100
Ferrum is embroidered color sporidiole bacteria k950416 0.006 0.006 0.62＞100
Trichophyton tonsurans k950515 0.003 0.003 2.50＞100
Acrothesium floccosum B002 0.003 0.003 1.25＞100
Du Yang Shi sporidiole bacteria B002 0.006 0.003 2.50＞100 difficult to understand
Fonsecaea dermatitidis B001 1.25 2.50 5.00＞100
Aspergillus flavus B002 1.25 2.50 2.50＞100
Aspergillus niger B002 1.25 2.50 5.00＞100
Pink auspicious spore B001 1.25 5.00 5.00＞100
Torulopsis glabrata B002 0.62 1.25 1.25＞100
Candida albicans A9468 1.25 2.50 2.50＞100
Candida albicans B68561 1.25 5.00 2.50＞100
Candida albicans B318 0.62 5.00 2.50＞100
Candida albicans B6853 1.25 5.00 2.50＞100
Neogenesis cryptococcus (Changhai mutation) 0.62 1.25 2.50＞100
--------------------------------------------------------------------
Annotate: after data are the new culture fluid of transferred species in the table, cultivate 10 days (yeast-like fungi 5 days) observed results
The external bactericidal action--------------------------------------------------------------------of table 3 compositions and component thereof to the common pathomycete of 21 strains (14 kinds)
Minimal bactericidal concentration (MBC, μ g/ml)
Strain name------------------------------------------------------
Compositions terbinafine chlorhexidine triamcinolone acetonide--------------------------------------------------------------------
Trichophyton A9534 0.003 0.006 2.50＞100
Trichophyton k950408 0.006 0.006 1.25＞100
Trichophyton B12500 0.003 0.006 5.00＞100
Trichophyton B1279 0.003 0.003 5.00＞100
Trichophyton gypseum k950415 0.012 0.012 2.50＞100
Trichophyton gypseum B19503 0.006 0.008 5.00＞100
Sabouraudites lanosus k950401 0.012 0.006 2.50＞100
Ferrum is embroidered color sporidiole bacteria k950416 0.006 0.012 2.50＞100
Trichophyton tonsurans k950515 0.006 0.006 5.00＞100
Acrothesium floccosum B002 0.006 0.012 2.50＞100
Du Yang Shi sporidiole bacteria B002 0.012 0.024 5.00＞100 difficult to understand
Fonsecaea dermatitidis B001 2.50 5.00 10.0＞100
Aspergillus flavus B002 2.50 5.50 10.0＞100
Aspergillus niger B002 2.50 5.50 10.0＞100
Pink auspicious spore B001 5.00 10.0 5.00＞100
Torulopsis glabrata B002 1.25 2.50 2.50＞100
Candida albicans A9468 2.50 5.00 2.50＞100
Candida albicans B68561 2.50 5.00 2.50＞100
Candida albicans B318 2.50 5.00 5.00＞100
Candida albicans B6853 2.50 5.00 2.50＞100
Neogenesis cryptococcus (Changhai mutation) 1.25 2.50 5.00＞100--------------------------------------------------------------------
Annotate: data are 120-168 hour (yeast-like fungi 48 hours) observed result in the table
Table 4 compositions and component thereof are external to the common pathomycete of clinical separation 94 strains (4 kinds)
Mensuration (the MIC of 50% and 90% bacterial strain minimum inhibitory concentration
50Or MIC
90, μ g/ml) and--------------------------------------------------------------------
Strain name (strain number) medicine scope of restraining fungi MIC
50MIC
90--------------------------------------------------------------------
Trichophyton (42) compositions 0.0005-0.016 0.002 0.004
Terbinafine 0.001-0.016 0.004 0.008
Chlorhexidine 0.31-2.5 0.62 2.50
Triamcinolone acetonide＞100＞100＞100
Trichophyton gypseum (18) compositions 0.001-0.032 0.004 0.008
Terbinafine 0.002-0.016 0.008 0.016
Chlorhexidine 0.62-2.50 1.25 2.50
Triamcinolone acetonide＞100＞100＞100
Sabouraudites lanosus (12) compositions 0.0001-0.002 0.002 0.002
Terbinafine 0.002-0.008 0.004 0.008
Chlorhexidine 0.62-2.50 0.62 2.50
Triamcinolone acetonide＞100＞100＞100
White is read bacterial strain (22) compositions 0.32-2.50 1.25 2.50
Terbinafine 0.62-10.0 5.00 10.0
Chlorhexidine 0.62-5.00 5.00 5.00
Triamcinolone acetonide＞100＞100＞100
--------------------------------------------------------------------
1.2.5 compositions and component thereof are to the mensuration of trichophyton and Candida albicans bacteriocidal concentration
Carry out parallel laboratory test with compositions and its component, when drug level 10 μ g/ml, medicine bacterium effect 4 hours, compositions and component terbinafine and chlorhexidine, trichophyton (A9534) sterilizing rate is respectively 99.72%, 83.31% and 97.19% (seeing Table 5), and its result shows that compositions is better than its component.To the bactericidal action of Candida albicans (A9468), compositions and chlorhexidine obviously are better than terbinafine (seeing Table 6), and triamcinolone acetonide is all invalid to this two bacterium.
Table 5 compositions is to the bactericidal action of trichophyton (A9534)
--------------------------------------------------------------------
Action time and sterilizing rate (%)
Medicine name drug level----------------------------------------
(μg/ml) 1h 4h 8h 24h
--------------------------------------------------------------------
Compositions 1 59.94 70.31 79.27 82.63
10 99.72 100.0 100.0 100.0
100 100.0 100.0 1000 100.0
Terbinafine 1 54.62 63.31 65.27 72.83
10 83.31 98.31 100.0 100.0
100 95.04 100.0 100.0 100.0
Chlorhexidine 1 49.78 66.11 62.47 67.51
10 97.19 97.76 100.0 100.0
100 100.0 100.0 100.0 100.0
Triamcinolone acetonide 200 0.00 0.00 0.00 0.00
Contrast no medicine 0.00 0.00 0.00 0.00
--------------------------------------------------------------------
Table 6 compositions is to the bactericidal action of Candida albicans (A9468)
--------------------------------------------------------------------
Action time and sterilizing rate (%)
The medicine name drug level-----------------------------------------
(μg/ml) 1h 4h 8h 24h
--------------------------------------------------------------------
Compositions 1 0.00 0.00 3.45 6.89
10 90.72 93.10 100.0 100.0
100 100.0 100.0 100.0 100.0
Terbinafine 200 0.00 6.89 0.00 17.24
Chlorhexidine 1 3.45 44.82 41.34 27.58
10 93.10 96.55 100.0 100.0
100 100.0 100.0 100.0 100.0
Triamcinolone acetonide 200 0.00 0.00 0.00 0.00
Contrast no medicine 0.00 0.00 0.00 0.00
--------------------------------------------------------------------
1.2.6 compositions is to the antibacterial and killing action of some common malignant bacteria (representing bacterium): compositions is also better to the bacteriostasis of antibacterial, 19 kinds of common pathogens and represent bacterium, minimal inhibitory concentration (sees Table 7) between 0.156-5.00 μ g/ml, to common malignant bacteria of clinical separation 59 strains external 50% and 90% bacterial strain minimal inhibitory concentration (MIC
50And MIC
90) between 0.039-5.0 μ g/ml, (see Table 8).Bactericidal action is also better, and when the drug level of 10 μ g/ml, with staphylococcus aureus effect 10 minutes, killing rate can reach more than 99.99% and (see Table 9), and was similar with single medicine chlorhexidine.Thereby after showing chlorhexidine and terbinafine and triamcinolone acetonide compatibility, do not influence inhibition and the killing action of chlorhexidine to antibacterial.Terbinafine and triamcinolone acetonide are to antibacterial invalid (MIC＞100 μ g/ml).
Table 7 compositions and component thereof are to the inhibitory action--------------------------------------------------------------------of some common malignant bacterias (or representing bacterium)
Minimal inhibitory concentration (MIC, μ g/ml)
Strain name-----------------------------------------------------
Compositions terbinafine chlorhexidine triamcinolone acetonide--------------------------------------------------------------------
Staphylococcus aureus A923 0.312＞100 0.156＞100
Staphylococcus aureus 09 0.312＞100 0.312＞100
Staphylococcus aureus 18 0.312＞100 0.156＞100
Staphylococcus aureus 37 0.078＞100 0.078＞100
Staphylococcus epidermidis A108 0.625＞100 0.625＞100
Staphylococcus epidermidis 99 0.156＞100 0.312＞100
Bacillus subtilis A6633 0.625＞100 0.625＞100
Escherichia coli 07 0.156＞100 0.156＞100
Escherichia coli 10 0.625＞100 0.625＞100
Enterobacter cloacae 68 5.00＞100 2.50＞100
Bacillus pyocyaneus 30 2.50＞100 2.50＞100
Bacillus pyocyaneus 31 5.00＞100 5.00＞100
Pneumobacillus 15 2.50＞100 2.50＞100
Bacillus proteus 05 5.00＞100 5.00＞100
Aerobacteria 20 5.00＞100 5.00＞100
Song Shi dysentery bacterium 977 0.625＞100 0.312＞100
Shigella flexneri 973 0.625＞100 0.312＞100
Bacillus typhi 20 0.625＞100 0.625＞100
Bacillus typhi murium 05 1.25＞100 1.25＞100
--------------------------------------------------------------------
Annotate: data are 24-48 hour observed result in the table.This concentration is only accomplished in "＞" expression experiment, does not further up do.
Table 8 compositions is to the common malignant bacteria of clinical separation 59 strains external 50% and 90%
Mensuration (the MIC of bacterial strain minimal inhibitory concentration
50And MIC
90, μ g/ml) and--------------------------------------------------------------------
Strain name (strain number) medicine scope of restraining fungi MIC
50MIC
90--------------------------------------------------------------------
Staphylococcus aureus (16) compositions 0.039-0.625 0.156 0.312
Terbinafine＞100＞100＞100
Chlorhexidine 0.039-0.625 0.078 0.312
Triamcinolone acetonide＞100＞100＞100
Other gram positive bacteria (4) compositions 1.56-1.25 0.625 1.250
Terbinafine＞100＞100＞100
Chlorhexidine 0.78-0.625 0.312 0.625
Triamcinolone acetonide＞100＞100＞100
Escherichia coli (13) compositions 0.156-1.2 0.625 1.25
Terbinafine＞00＞00＞100
Chlorhexidine 0.156-1.25 0.312 1.25
Triamcinolone acetonide＞100＞100＞100
Other gram negative bacteria (26) compositions 0.31-10.0 1.25 5.00
Terbinafine＞100＞100＞100
Chlorhexidine 0.31-10.0 0.625 5.00
Triamcinolone acetonide＞100＞100＞100--------------------------------------------------------------------
Table 9 compositions and component thereof are to the bactericidal action of staphylococcus aureus (A923)
--------------------------------------------------------------------
Action time and sterilizing rate (%)
Medicine name drug level----------------------------------------
(μ g/ml) 1 minute 5 minutes 10 minutes 30 minutes
--------------------------------------------------------------------
Compositions 1 23.81 36.73 87.25 89.12
10 96.96 97.97 100.0 100.0
100 100.0 100.0 100.0 100.0
Terbinafine 200 7.48 0.00 0.00 10.20
Chlorhexidine 1 78.23 92.52 95.23 91.84
10 99.32 98.64 100.0 100.0
100 100.0 100.0 100.0 100.0
Triamcinolone acetonide 200 0.00 0.00 0.00 0.00
Contrast no medicine 0.00 0.00 0.00 0.00
--------------------------------------------------------------------
2. animal is tested a compositions and component ointment thereof to guinea pig skin local infection fungus curative effect relatively at body, proves that further the antibacterial action of compositions is strong
2.1 materials and methods
Compositions and component terbinafine thereof and chlorhexidine are the medicine chamber preparation of this institute, and with O/W (oil/water) dosage form, excipient is preparations such as octadecanol, stearic acid, glyceryl monostearate, vaseline, G ﹠ W.Compositions ointment, terbinafine ointment, chlorhexidine ointment and Kin White.
It is infectious bacteria that strain is selected the most susceptible fungal bacterial strain trichophyton gypseum of Cavia porcellus (k950415) and Sabouraudites lanosus (k950401), is provided by the air force general hospital department of dermatologry.
Cavia porcellus (Dunkin-Hartley strain) white, male female half and half, about body weight 250g, provide by the air force general hospital Experimental Animal Center.27-32 ℃ of Animal House temperature, relative humidity 65-75%.Selecting the back side of Cavia porcellus is the infected area, and every group of 10-15 only uses various Drug therapys respectively.10 is blank frost contrast, promptly observes the natural growth and decline of infecting.About 3 * the 4cm2 of hair is shaved at every Cavia porcellus back side, and artificial challenge fungus according to a conventional method obviously forms to the 5th day local infection, and after fungus microscope examination (cultivate the back) confirmation, just carries out Drug therapy, every infection place dosage 0.15g, 1 time/day, continuous 2 weeks.Carrying out fungus microscope examination and skin lesion in per 2 days observes.The evaluation of clinical curative effect standard is a secondary standard, and 1. healing is disappeared continuous 2 the fungus feminine genders of microscopy for skin lesion; 2. invalidly do not disappear the microscopy fungus positive for skin lesion.
2.2 experimental result
2.2.1 compositions and component ointment thereof are to the curative effect of guinea pig skin local infection trichophyton gypseum
The Cavia porcellus of guinea pig skin local infection trichophyton gypseum is respectively with 1% compositions ointment, 1% terbinafine ointment, 0.5% chlorhexidine ointment and the treatment of 0.025% Kin White, 1% its therapeutic effect of compositions ointment best (seeing Table 10) as a result.One all cure rates are learned by statistics respectively and are handled, and compositions ointment is than 1% terbinafine ointment significant difference (P＜0.01).
2.2.2 compositions and component ointment thereof are to the curative effect of guinea pig skin local infection Sabouraudites lanosus
The Cavia porcellus of guinea pig skin local infection Sabouraudites lanosus is respectively with 1% compositions ointment, 1% terbinafine ointment, 0.5% chlorhexidine ointment and the treatment of 0.025% Kin White, 1% compositions Ointment in Treatment effect also best (seeing Table 11) as a result.One all cure rates are learned by statistics respectively and are handled the two significant difference (p＜0.01).
Table 10 compositions and component ointment thereof infect the curative effect of trichophyton gypseum to guinea pig skin
--------------------------------------------------------------------
The medicine number of animals is cured one week Tuesday of scope
(my god) healing (%) healing (%)
--------------------------------------------------------------------
1% compositions ointment, 15 2-10 80.00 100.00
1% terbinafine ointment, 15 4-12 53.33 100.00
0.5% chlorhexidine ointment, 15 6-20 13.33 60.00
0.025% Kin White, 10 18-34 0.00 0.00
Excipient (contrast) 10 10-28 0.00 30.00
--------------------------------------------------------------------
Table 11 compositions and component ointment thereof are to the curative effect of guinea pig skin infected dogs sporidiole bacteria
--------------------------------------------------------------------
The medicine number of animals is cured one week Tuesday of scope
(my god) healing (%) healing (%)
--------------------------------------------------------------------
1% compositions ointment, 15 2-10 80.00 100.00
1% terbinafine ointment, 15 4-12 60.00 100.00
0.5% chlorhexidine ointment, 15 6-18 26.67 66.67
0.025% Kin White, 10 16-36 0.00 0.00
Excipient (contrast) 10 12-30 0.00 30.00
--------------------------------------------------------------------
3. the oral acute toxicity (LD of compositions and component mice thereof
50) mensuration, purpose is that proof present composition toxicity is lower.
3.1 materials and methods
3.1.1 animal Kunming outbreeding system mice, body weight 18-22g is provided by Military Medical Science Institute's Experimental Animal Center.Animal Lab. is 23 ± 1 ℃ of constant temperature, and relative humidity is 50-70%, the artificial lighting (time mutually 12 hours bright, 12 hours are dark), divide cylinder to raise, 5 in every cylinder is fed with common mice piece material, freely drinks water.
3.1.2 experimental technique
The mice random assortment, every kind of medicine is established six groups, and 20 every group, male and female half and half.The compound terbinafine maximal dose is 4000mg/kg, and minimum dose is 464mg/kg; The terbinafine maximal dose is 6000mg/kg, and minimum dose is 696mg/kg; The chlorhexidine maximal dose is 3000mg/kg, and minimum dose is 348mg/kg; The triamcinolone acetonide maximal dose is 500mg/kg, and minimum dose is 58mg/kg.Group is apart from being 1: 0.65.Preceding jejunitas 14-16 hour of administration, drinking-water is not limit.Gastric infusion according to dosage, per 10 gram body weight are irritated stomach 0.3ml, and 2 hours feedings after the administration were observed 14 days.Performance and death condition that every day, the observed and recorded animal poisoned.Dead animal performs an autopsy on sb, and weighs once in per 7 days.
3.1.3 computational methods
Calculate following parameters, animal half lethal dose (LD with simplifying probit's general formula
50), 5% animal fatal dose (LD
5), 95% animal fatal dose (LD
95), LD
5095% average fiducial limit (L
95) and slope (b).
3.2 experimental result
Compositions is to the oral LD of mice
50Be 1585 (1347-1868) mg/kg, the LD of male and female mice
50No significant difference (table 12), mice poisoning manifestations are dysphoria, twitch, and most animals is dead (table 13) in 48 hours.Becoming thin, losing weight appears in the animal of lat theta-dead, dispirited.The visible liver blood stasis of postmortem, the gastrointestinal congestion and edema.Terbinafine, chlorhexidine and triamcinolone acetonide are to the oral LD of mice
50Be respectively 3195 (2669-3826) mg/kg, 1442 (1205-1727) mg/kg and 216 (190-244) mg/kg; The LD of male and female mice
50There is not significant difference (table 12) yet.According to the classification of chemical compound acute toxicity, compositions is the lower toxicity material.
The oral acute toxicity of table 12 compound and component thereof to mice
--------------------------------------------------------------------
Sex LD
50L
95LD
5LD
95b
(mg/kg) (mg/kg) (mg/kg) (mg/kg)
--------------------------------------------------------------------
Compositions
Mix 1585 1347-1868 656 3,836 4.278
Female 1691 1357-2106 680 4,130 4.224
Male 1485 1174-1880 627 3,519 4.380
Terbinafine
Mix 3195 2669-3826 901 11,331 2.983
Female 3044 2356-3934 936 9,899 3.203
Male 3354 2572-4373 1,273 7,632 4.593
Chlorhexidine
Mix 1442 1205-1727 374 5,557 2.702
Female 1382 1056-1807 356 3,988 2.786
Male 1589 1236-2044 459 5,501 3.041
Triamcinolone acetonide
Mix 216 190-244 74.3 626 3.542
Female 220 171-284 71.2 682 3.341
Male 222 174-280 80.2 607 3.733
--------------------------------------------------------------------
1.2.2 the compositions mice mixes the mensuration (calculating) of virulence
Measure the oral LD of mice of three single medicine terbinafines, chlorhexidine and triamcinolone acetonide of compositions and composition compound recipe earlier
50Formula according to Finney calculates then, and its formula is 1/ application of mixture theory LD
50Value=a/LD
50(A)+b/LD
50(B)+... (LD in the formula
50(A) and LD
50(B) be each single medicine actual measurement virulence value, a and b are the percentage composition of each single medicine in mixture), promptly obtain intermixture theoretical L D
50Value and intermixture actual measurement LD
50The ratio of value.If its ratio＞2.7, for increasing poison,＜0.4 is attenuation, and the person is the virulence summation action between 0.5-2.6.According to actual compositions, terbinafine, chlorhexidine and the triamcinolone acetonide of recording to the oral LD of mice
50Result's (table 12-16), press the Finney formula, calculation composition intermixture theoretical L D
50Value/mixture actual measurement LD
50Be 1.62, the mixing virulence that proves compositions only is a summation action, no potentiation.
Computational methods and result:
1/ theoretical L D
50Value=a/LD
50(A)+b/LD
50(B)+c/LD
50(C)
1/ theoretical L D
50Value=a/3195+b/1442+c/216
1/ theoretical L D
50Value=65.57%/3195+32.787%/1442+1.639%/216
1/ theoretical L D
50Value=65.57%x3195+32.787%x1442+1.639%x216
＝2094.96+472.79+3.54
＝2571.29mg/kg
Actual measurement LD
50Value=1585mg/kg
Press the Finney formula and calculate compound terbinafine intermixture theoretical L D
50Value/mixture actual measurement LD
50=1.62.
Pharmaceutical composition of the present invention is an antifungal compound medicines that screens from more than 20 DANFU sides.From external fungus bacteriostatic test data and animal skin mycosis therapeutic test data, and the animal toxicity test data shows, the compositions fungistatic effect is obviously more excellent than its component: 1. composition is outer shows the medical fungus bacteriostatic test of 109 strains, compositions is lower than its component terbinafine 2-10 doubly to most bacterium minimal inhibitory concentrations (MIC), be lower than hibitane 10-30 doubly, triamcinolone acetonide is to antibacterial invalid, and kept the inhibitory or killing effect of its component medicine chlorhexidine to antibacterial.2. the mycotic curative effect of guinea pig skin is shown, the Cavia porcellus of guinea pig skin local infection trichophyton gypseum and Sabouraudites lanosus, with 1% compositions ointment, 1% terbinafine ointment, 0.5% chlorhexidine ointment and the treatment of 0.025% Kin White, 1% its therapeutic effect of compositions ointment is best as a result respectively.One all cure rates are learned by statistics respectively and are handled the two significant difference (P＜0.01).3. toxicity aspect, according to actual compositions, terbinafine, chlorhexidine and the triamcinolone acetonide of recording to the oral LD of mice
50The result, be respectively 3195 (2669-3826) mg/kg, 1442 (1205-1727) mg/kg and 216 (190-244) mg/kg.Press the Finney formula, calculation composition intermixture theoretical L D
50Value/mixture actual measurement LD
50Be 1.62, the mixing virulence that proves the compound terbinafine drug combination only is a summation action, no potentiation.Acute toxicity rank groups compound by chemical substance belongs to the lower toxicity material.
When the present composition, especially terbinafine, chlorhexidine and triamcinolone acetonide formula proportion are 1: 0.5: 0.025 ointment formulation, the disease of treatment cutaneous fungal infection, bacterial infection and fungus, bacteria mixed infection had preferable therapeutic effect.
Two, clinical case report
Example 1. Liu * *, the male, 25 years old, because of skin lesion companion between the biped toe itched 2 years, to itch recently and scratch, the state of an illness increases the weight of, and mixes red and swollen the prescription on individual diagnosis, is diagnosed as between toe the type tinea pedis and mixes bacterial infection.Sings and symptoms is all heavier before the treatment, and microscopy is cultivated and is alpha fungus, and antibacterial culturing is golden yellow staphylococcus.Then give 1 week of compositions ointment logotype, sings and symptoms disappears substantially during drug withdrawal, and fungus microscope examination and antibacterial culturing are all negative; The 2nd week, clinical and fungus, bacteriology checking were all fully recovered.
Example 2. Huangs * *, the male, 28 years old, because of itching, preceding chest and back skin lesion companion went to a doctor in 1 year, be diagnosed as tinea versicolor.Sings and symptoms is obviously long-pending before the treatment, the fungus microscope examination positive.Then give compositions ointment, in 1 week of logotype, sings and symptoms disappears during the 2nd all drug withdrawal, negative fungal examination, clinical recovery.
Example is 3. old * *, the male, 50 years old, because of itching, bifilar inboard skin lesion companion go to a doctor February, be diagnosed as tinea cruris.Sings and symptoms is obvious before the treatment, and fungal culture is a trichophyton.Then give 1 week of compositions ointment logotype, the 2nd all sings and symptomses disappear, and fungus microscope examination and cultivation are all negative, clinical recovery.
Example 4. grandsons * *, the woman, 35 years old, because of itching, left neck skin lesion companion went to a doctor in 10 days, and the fungus microscope examination positive is diagnosed as tinea corporis, and sings and symptoms is obvious before the treatment, and fungal culture is a trichophyton.Then give the external of compositions ointment, 1 week of logotype, the clinical and mycology recovery from illness of the 2nd week.。
Example 5. week * *, the male, 20 years old, to suffer from furuncle and phyma because of left thigh and mix and went to a doctor in red and swollen 2 days, antibacterial culturing is golden yellow staphylococcus, is diagnosed as suppurative folliculitis.Sings and symptoms is obvious before the treatment, gives 1 week of compositions ointment logotype then, and the 2nd all sings and symptomses disappear antibacterial culturing feminine gender, clinical recovery.
The specific embodiment
Embodiment 1
Take by weighing terbinafine 1 gram, chlorhexidine 0.5 gram and triamcinolone acetonide 0.025 gram raw material by 1: 0.5: 0.025 formula proportion, above-mentioned raw materials is a top grade, use the O/W dosage form, excipient is octadecanol 4 grams, stearic acid 4 grams, glyceryl monostearate 3.5 grams, vaseline 10 grams, glycerol 10 grams, and soil temperature-80 2 gram and surplus distilled water are mixed with ointment 100 grams.
Embodiment 2
Take by weighing terbinafine 1 gram, chlorhexidine 0.7 gram and triamcinolone acetonide 0.05 gram raw material by 1: 0.7: 0.05 formula proportion, above-mentioned raw materials is a top grade, adds the 20ml dissolve with ethanol, adds the 20ml propylene glycol again, the formulated solution 100ml of 10ml glycerol and surplus distilled water.
Embodiment 3
Take by weighing terbinafine 0.8 gram, chlorhexidine 0.3 gram and triamcinolone acetonide 0.01 gram raw material by 0.8: 0.3: 0.01 formula proportion, above-mentioned raw materials is a top grade, use the O/W dosage form, excipient is octadecanol 4 grams, stearic acid 4 grams, glyceryl monostearate 15 grams, vaseline 6 grams, glycerol 10 grams, and soil temperature-80 2 gram and surplus distilled water are mixed with ointment 100 grams.
Claims (4)
1, a kind of skin antibacterials compound hydrochloric acid terbinafine compositions comprises component terbinafine HCl, chlorhexidine acetate, triamcinolone acetonide acetate, in (0.8～1.5): (0.3～1): the formulated medicament of (0.01～0.05) weight portion proportioning ratio.
2, skin antibacterials compound hydrochloric acid terbinafine compositions according to claim 1, the weight portion proportioning ratio of wherein said medicament component terbinafine HCl, chlorhexidine acetate, triamcinolone acetonide acetate is 1: 0.5: 0.025.
3, skin antibacterials compound hydrochloric acid terbinafine compositions according to claim 1 and 2, wherein said medicament is meant said percutaneous drug delivery dosage form on any pharmaceutics.
4, skin antibacterials compound hydrochloric acid terbinafine compositions according to claim 3, wherein said medicament is meant ointment, ointment, solution, tincture, ear oil preparation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031052134A CN1524531A (en) | 2003-02-24 | 2003-02-24 | Compound terbinafine hydrochloride composition of skin antibacterial drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031052134A CN1524531A (en) | 2003-02-24 | 2003-02-24 | Compound terbinafine hydrochloride composition of skin antibacterial drugs |
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| Publication Number | Publication Date |
|---|---|
| CN1524531A true CN1524531A (en) | 2004-09-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031052134A Pending CN1524531A (en) | 2003-02-24 | 2003-02-24 | Compound terbinafine hydrochloride composition of skin antibacterial drugs |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100443085C (en) * | 2006-03-16 | 2008-12-17 | 中国人民解放军第二军医大学 | Externally applied compound gel and its preparing method |
| CN100453082C (en) * | 2006-01-12 | 2009-01-21 | 张松 | Compound terbinafine and root of large flowered skullcap cream and its preparing method |
| CN104546885A (en) * | 2015-01-29 | 2015-04-29 | 成都乾坤动物药业有限公司 | Medicine composition for treating skin diseases as well as preparation method and application thereof |
| CN105311282A (en) * | 2015-11-26 | 2016-02-10 | 青岛海之源智能技术有限公司 | Terbinafine hydrochloride compound lotion and preparation method |
| CN105327034A (en) * | 2015-11-26 | 2016-02-17 | 青岛海之源智能技术有限公司 | Terbinafine hydrochloride compound ointment as well as preparation method and application thereof |
| CN105362504A (en) * | 2015-11-26 | 2016-03-02 | 青岛海之源智能技术有限公司 | Terbinafine hydrochloride compound tincture and preparation method and application |
| CN111067883A (en) * | 2020-01-15 | 2020-04-28 | 安徽汇喻科技服务有限公司 | Preparation method of terbinafine hydrochloride liniment |
| CN112004532A (en) * | 2018-05-03 | 2020-11-27 | 凯尔赛德株式会社 | Composition for preventing or treating skin infection |
-
2003
- 2003-02-24 CN CNA031052134A patent/CN1524531A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100453082C (en) * | 2006-01-12 | 2009-01-21 | 张松 | Compound terbinafine and root of large flowered skullcap cream and its preparing method |
| CN100443085C (en) * | 2006-03-16 | 2008-12-17 | 中国人民解放军第二军医大学 | Externally applied compound gel and its preparing method |
| CN104546885A (en) * | 2015-01-29 | 2015-04-29 | 成都乾坤动物药业有限公司 | Medicine composition for treating skin diseases as well as preparation method and application thereof |
| CN105311282A (en) * | 2015-11-26 | 2016-02-10 | 青岛海之源智能技术有限公司 | Terbinafine hydrochloride compound lotion and preparation method |
| CN105327034A (en) * | 2015-11-26 | 2016-02-17 | 青岛海之源智能技术有限公司 | Terbinafine hydrochloride compound ointment as well as preparation method and application thereof |
| CN105362504A (en) * | 2015-11-26 | 2016-03-02 | 青岛海之源智能技术有限公司 | Terbinafine hydrochloride compound tincture and preparation method and application |
| CN112004532A (en) * | 2018-05-03 | 2020-11-27 | 凯尔赛德株式会社 | Composition for preventing or treating skin infection |
| CN112004532B (en) * | 2018-05-03 | 2022-02-18 | 凯尔赛德株式会社 | Composition for preventing or treating skin infection |
| CN111067883A (en) * | 2020-01-15 | 2020-04-28 | 安徽汇喻科技服务有限公司 | Preparation method of terbinafine hydrochloride liniment |
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