JPH0219089B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a novel antifungal composition containing pyrrolenitrin and an imidazole antifungal substance as active ingredients, and is used in the medical field. [Prior Art] Pyrrolenitrine is 3-(2-nitro-3-chlorophenyl)-4-chloropyrrole, which is represented by the following chemical structural formula and is widely known as a drug with antifungal effects. . Various imidazole antifungal substances are also known, and each of these is used alone as an antifungal agent. [Problems to be Solved by the Invention] The present invention uses pyrrolenitrin and imidazole antifungal substances in combination to achieve superior antifungal activity at lower concentrations than when each of them is used alone. This was done with the aim of obtaining a new drug. [Means for Solving the Problems] The imidazole antifungal substances in the present invention include, for example, 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole, known as clotrimazole, and migonazole, known as migonazole. 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole, known as econazole 4-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, also known as isoconazole, 1-[2-(2,4-dichlorophenyl)-2-[( 1-acetyl-4-, also known as 2.6-dichlorophenyl)methoxy]ethyl]-1H-imidazole, ketoconazole
[4-[[2-(2,4-dichlorophenyl)-2-
(1H-imidazol-1-ylmethyl)-1,3
-dioxolan-4-yl]methoxy]phenyl]piperazine, 1-[2-(2,4-dichlorophenyl)-, also known as enilconazole
1-[(1,1'-biphenyl)-4-ylphenylmethyl]-1H-imidazole, known as sulconazole 1-[2-[(4-chlorophenylmethyl)thio]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, also known as tioconazole −
1-[2-
(4-chlorophenyl)-2-[2,4-dichlorophenyl)methoxyimino]ethyl]-1H-imidazole and the like. These imidazole antifungal substances may be used in the form of their salts, and examples of such salts include, but are not limited to, hydrochlorides, sulfates, nitrates, phosphates, acetates, etc. Can be mentioned. The antifungal composition of the present invention contains pyrrolenitrin and the above-mentioned imidazole antifungal substance as active ingredients, and the content ratio of both is not particularly limited, but is preferably 1:10 by weight. or 10:1, more preferably 1:3 or 3:1
More preferably, the ratio is 1:2 to 2:1, but the ratio may be increased or decreased as appropriate depending on the target pathogenic bacteria, etc. The dosage form of the antifungal composition of this invention is not particularly limited, and it can be used in various dosage forms and usage methods similar to those of known antifungal agents, such as liquid, aerosol, gel, cream, powder, and ointment. It can be used as a vaginal suppository, etc., and is preferably used in a dosage form for external use. The content of the active ingredient, ie, a mixture of pyrrolenitrin and imidazole antifungal substance, in these preparations is about 0.01 to 50% by weight, preferably about 0.01 to 10% by weight. In addition, the dosage of the active ingredient in the antifungal composition of the present invention is appropriately selected depending on the dosage form, the content ratio of both active ingredients, the type of causative bacteria to be treated, the symptoms, etc., but in general, , 1-500mg/Kg/day,
It is preferably administered in a range of 1 to 50 mg/Kg/day. Furthermore, in addition to pyrrolenitrin and imidazole antifungal substances as active ingredients, the antifungal composition of the present invention includes, for example, crotamiton,
diphenhydramine, diphenylpyraline hydrochloride,
lidocaine, tesit, ethyl aminobenzoate,
Anti-pruritic, anti-inflammatory drugs such as dibucaine, methyl salicylate, menthol, camphor, lauromacrogol, glycyrrhetinic acid, azulene or its salts,
Analgesics or local anesthetics, disinfectants such as benzalkonium chloride, chlorhexidine, dequalinium chloride, resorcinol, phenol, Tego-51, chlorobutanol, iodine, boric acid, trimethylcetylammonium pentachlorophenate or its salts, salicylic acid, diethyl A keratin softening and penetrating agent such as sebacate, urea, and sulfur, an astringent or restorative agent such as zinc chloride, allantoin, dihydroxyaluminum or its salt, etc. may be blended as appropriate. The antifungal composition of the present invention can be formulated into various dosage forms as described above by blending it with various bases and carriers by conventional methods. For example, carriers for liquid preparations include water, lower alcohols, ethylene glycol, glycerin, and others.
Various organic solvents can be mentioned. As an aerosol carrier, for example, a liquid carrier as described above and Freon gas can be used in combination. As the gel base material, for example, a combination of a liquid carrier and a gel forming agent as described above can be used, and the gel forming agent is, for example, a combination of a carboxyvinyl polymer and an organic amine or a base such as an aqueous sodium hydroxide solution. combinations or cellulose ethers such as hydroxypropylcellulose, sodium alginate, propylene glycol alginate, and the like. As cream bases, emulsifiers such as nonionic surfactants can be used in combination with gel bases, ointment bases and/or aqueous bases. Examples of powder bases include calcium carbonate,
Calcium phosphate, lactose, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium stearate,
Inert diluents such as aluminum stearate, talc, silicone, granulating agents, dispersants, binders, etc. can be used alone or in combination. Ointment bases include peanut oil, olive oil, sesame oil, coconut oil, paraffin oil, lanolin, petrolatum, zinc oxide, beeswax, macrogol,
Stearyl alcohol, propylene glycol, etc. can be used alone or in combination. Furthermore, the antifungal composition of the present invention can also be formulated with conventional solubilizers, stabilizers, humectants, preservatives, etc. in addition to the bases and additives mentioned above. These various preparations can be manufactured by conventional methods, such as the method described in the Japanese Pharmacopoeia, 10th edition. The antifungal composition of the present invention is suitable for use in dermatophytosis such as ringworm, ringworm, ringworm, tinea profundus, tinea versicolor, tinea rubrum, tinea, sporotrichosis, chromomycosis, and cryptococcus dermatosis. mucocutaneous Candida, including cutaneous aspergillosis, cutaneous mucormycosis, cutaneous coccidioidomycosis, histoplasmosis, infantile parasitic erythema, candidal intertrigo, candidal interdigital erosion, candidal oral erosion, and chronic mucocutaneous Candida. It can be used to treat fungal infections such as candidiasis and deep-seated candidiasis. [Operations and Effects of the Invention] Next, the effects of the antifungal composition of the present invention will be explained using test examples. Test Example 1: Pyrrolnitrin PY alone, clotrimazole CL alone, virolnitrin PY and clotrimazole CL at a ratio of 2:1 against various bacterial strains
The antibacterial activity of the mixture, 1:1 mixture and 1:2 mixture was investigated and the results are shown in Table 1. Test bacteria: a: Candida albicans YU-1200 b: Candida albicans FP578 c: Candida albicans FP579 d: Candida albicans FP580 e: Candida albicans FP581 f: Aspergillus oryzae IFO ⁵²³⁹ g: Stahylococcus epidermidis 91 Test Drug Preparation Composition A: PY (10 mg) was dissolved in 1 ml of ethanol, and then mixed with 9 ml of sterile water to produce a milky white suspension A. Composition B: CL (10 mg) was dissolved in 1 ml of N,N-dimethylformamide and then mixed with 9 ml of sterile water to produce a milky white suspension B. Composition C: Suspension C is prepared by mixing Suspensions A and B obtained above at a volume ratio of 2:1. Composition D: Suspension D is prepared by mixing equal volumes of suspensions A and B obtained above. Composition E: Suspension E is prepared by mixing Suspensions A and B obtained above at a volume ratio of 1:2. Test method Suspensions A to E obtained as above were placed on Sabouraud agar medium for test strains a to f;
If the test strain is g, Mueller-Hinton (M
-ueller Hinton) Prepare agar plates of various concentrations by mixing and diluting with agar medium. Test strains a to g were inoculated onto the agar plates at various concentrations and cultured under the following conditions, and then the minimum inhibitory concentration (MIC; μg/ml) at which the growth of each test strain was inhibited was determined. Culture Conditions Test strains a to e were cultured at 30°C for 24 hours after inoculation. Test strain f was cultured at 30°C for one week after inoculation. Test strain g was cultured at 37°C for 20 hours after inoculation. Test results:

[Table] Test Example 2: Antibacterial activities of PY alone, miconazole alone, econazole alone, oxiconazole alone, and 1:1 mixtures of PY and miconazole, PY and econazole, and PY and oxiconazole against various bacterial strains were investigated and the results were obtained. are listed in Table 2. Test bacteria a: Candida albicans YU-1200 b: Candida albicans FP580 Preparation composition of test drug A: Compositions F, G and H manufactured by the same method as described in Test Example 1: Composition B of Test Example 1 Miconazole (10 mg) was substituted for the listed CL (10 mg).
mg), econazole (10 mg) and oxiconazole (10 mg) to produce a milky white suspension (composition F), a clear liquid (composition G) and a milky white suspension (composition H), respectively.
Manufacture. Composition I: Suspension I is prepared by mixing equal volumes of suspensions A and F obtained above. Composition J: Suspension J is prepared by mixing equal volumes of Suspension A and Clear Liquid G obtained above. Composition K: Suspension K is prepared by mixing equal volumes of suspensions A and H obtained above. Test results:

【table】

[Table] The FIC index value of the antifungal composition according to the present invention was determined using the following formula, and the results are also shown in parentheses. -Calculation formula for calculating FIC index- For composition C FIC = MIC of composition C x 2 / MIC of composition A x 3
+ MIC of composition C / MIC of composition B × 3 For composition D FIC = MIC of composition D / MIC of composition A × 2 + MIC of composition D / MIC of composition B × 2 For composition E FIC = MIC of composition E / MIC of composition A × 3 + MIC of composition E × 2 / MIC of composition B × 3 For composition I FIC = MIC of composition I / MIC of composition A × 2 + MIC of composition I / MIC of composition F × 2 Composition J In the case of FIC = MIC of composition J / MIC of composition A × 2 + MIC of composition J / MIC of composition G × 2 In case of composition K FIC = MIC of composition K / MIC of composition A × 2 + MIC of composition K / composition H MIC×2 It is generally accepted that there is a synergistic effect if the FIC index is 1.0 or less, but the FIC index of the antifungal composition containing PY and imidazole antifungal substance according to the present invention is It was also 0.50 or less for the test bacterial strain, and it is clear that the combination of PY and imidazole antifungal substance according to the present invention has a strong synergistic effect. As is clear from the above test results, the composition of the present invention is useful as an antifungal agent, and is useful as a therapeutic agent for mycosis, particularly effective against candidiasis. Next, preferred embodiments of formulations of the present invention will be described as examples, but the present invention is not limited thereto, and may be applied to various formulation techniques, such as addition of a third ingredient, improvement of manufacturing process, etc. Included in this invention. Example 1 Pyrrolenitrile 2.5g Clotrimazole 5.0g Olive oil 100.0g Refined lanolin 80.0g White petrolatum 812.5g Pyrrolenitrine 2.5g and clotrimazole 5.0g
An oil-based ointment is produced by heating and dissolving g in 100.0 g of olive oil, 80.0 g of purified lanolin, and 812.5 g of white petrolatum, and stirring to homogenize. Example 2 Pyrrolenitrine 5.0g Clotrimazole 2.5g Zinc oxide 200.0g Refined lanolin 105.0g White beeswax 40.0g White petrolatum 647.5g 200.0g of zinc oxide is mixed with 105.0g of purified lanolin to make it homogeneous. Meanwhile, add 5.0g of pyrrole nitrine and 2.5g of clotrimazole to 40.0g of white beeswax.
and 647.5 g of white petrolatum, stirred to make it homogeneous, add the above-mentioned triglyceride of zinc oxide and purified lanolin, and stir and mix evenly to produce an oil-based ointment. do. Example 3 Pyrrolenitrine 2.5g Clotrimazole 5.0g Macrogol 4000 496.25g Macrogol 400 496.25g Pyrrolenitrine 2.5g and clotrimazole 5.0
g is macro goal 4000 496.25 g and macro goal
An aqueous ointment is prepared by heating and dissolving 496.25 g of 400 and stirring to make it homogeneous. Example 4 Pyrrolenitrine 2.50g Clotrimazole 5.00g White petrolatum 250.00g Stearyl alcohol 220.00g Propylene glycol 120.00g Sodium lauryl sulfate 15.00g Methylparaben 0.25g Propylparaben 0.15g Purified water 387.10g Pyrrolenitrine 2.50g and Clotrimazole sol
5.00g white petrolatum 250.00g, stearyl alcohol 220.00g, propylene glycol 120.00g
Heat and dissolve in 0.15 g of propylparaben and stir to homogenize. On the other hand, 15.00 g of sodium lauryl sulfate and 0.25 g of methylparaben are heated and dissolved in 387.10 g of purified water, mixed uniformly, and then the above-mentioned main ingredient solution is added and stirred to emulsify, and mixed uniformly to form an emulsion. Manufactures a sex ointment. Example 5 Pyrrolenitrine 2.5g Clotrimazole 5.0g White petrolatum 400.0g Setanol 180.0g Sorbitan sesquioleate 50.0g Lauromacrogol 5.0g Methylparaben 1.0g Provilparaben 1.0g Purified water 355.5g Pyrrolenitrine 2.5g and Clotrimazole 2.5g trimazole 5.0
Dissolve g in a mixture of 400.0 g of white petrolatum, 180.0 g of cetanol, 50.0 g of sorbitan sesquioleate and 1.0 g of propylparaben by heating, and mix uniformly. On the other hand, 5.0 g of lauromacrogol and 1.0 g of methylparaben are heated and dissolved in purified water, mixed uniformly, and then the above-mentioned active ingredient solution is added to emulsify and mixed uniformly to form an emulsion ointment. Manufacture. Example 6 Pyrrolenitrine 2.5g Clotrimazole 5.0g Polyethylene glycol monolaurate (10E.O) 100.0g Propylene glycol 60.0g Diisopropyl adipate 20.0g Ethanol 400.0g Carbopol 940 12.0g Diisopropanolamine 1.5g Purified water 399.0 g pyrrolenitrine 2.5g and clotrimazole 5.0g
g to polyethylene glycol monolaurate (10E.O) 100.0g, propylene glycol 60.0g
Dissolve in 20.0 g of diisopropyl adipate and 400.0 g of ethanol, add 240 g of a 5% aqueous solution of Carbopol 940, and stir. A gel preparation for external use is produced by adding 1.5 g of diisopropanolamine dissolved in 150 g of purified water, then adding purified water to make a total volume of 1000, and stirring to make it homogeneous. Example 7 Pyrrolenitrine 2.5g Clotrimazole 5.0g Stearyl alcohol 250.0g Stearic acid 50.0g Macrogol 6000 50.0g Hexanetriol 50.0g Propylene glycol 400.0g Macrogol 400 192.5g Pyrrolenitrine 2.5g and clotrimazole 5.0
Heat g to 400.0 g of propylene glycol, dissolve it, and stir to make it homogeneous. On the other hand, 250.0 g of stearyl alcohol, 50.0 g of stearic acid, 50.0 g of Macrogol 6000, 50.0 g of hexatriol, and 192.5 g of Macrogol 400 are dissolved and mixed by heating to make them uniform. A gel preparation for external use is produced by adding the above-mentioned main drug solution and stirring to make it uniform. Example 8 Pyrrolenitrine 2.5g Clotrimazole 5.0g Glycerin 30.0g Ethanol 700ml Purified water Appropriate amount Pyrrolenitrine 2.5g and clotrimazole 5.0g
A tincture for external use is prepared by dissolving 10 g in 30.0 g of glycerin and 700 ml of ethanol, adding purified water to make 1000 ml, and stirring to make it homogeneous. Example 9 Pyrrolenitrine 5.0g Clotrimazole 2.5g Zinc oxide, fine powder 100.0g Starch 142.5g Talc 750.0g A dusting agent for external use is produced by uniformly mixing the above components passed through a No. 100 sieve. Example 10 Pyrrolenitrine 2.5g Clotrimazole 5.0g Ethanol 325.5g Freon (1:1 mixture of Freon-11 and Freon-12) 64.0g Pyrrolenitrine 2.5g and Clotrimazole 5.0
g is dissolved in 352.5 g of ethanol, 64 g of Freon is added thereto, and the mixture is filled into an aerosol container to produce an aerosol formulation. Example 11 Pyrrolenitrine 2.5g Clotrimazole 5.0g Wax 15.0g Ethanol 547.5g Borivinylpyrrolidone 20.0g Ion exchange water 330.0g Freon (1:1 mixture of Freon-11 and Freon-12) 8.0g Pyrrolenitrine 2.5 g and clotrimazole 5.0
After dissolving g in 547.5 g of ethanol, the wax was 15.0 g.
g, 20.0 g of polyvinylpyrrolidone, and 330.0 g of ion-exchanged water were uniformly dissolved and mixed.
An aerosol formulation is produced by adding 8.0 g and filling it into an aerosol container. Example 12 Pyrrolenitrine 5.0g Clotrimazole 2.5g Olive oil 100.0g Refined lanolin 80.0g White petrolatum 812.5g The above components are treated in the same manner as in Example 1 to produce an oily ointment. Example 13 Pyrrolnitrine 5.0g Clotrimazole 2.5g Glycerin 30.0g Ethanol 700ml Purified water Appropriate amount The above components are treated in the same manner as in Example 8 to produce a tincture for external use. Example 14 Pyrrolenitrine 3.75g Clotrimazole 3.75g Zinc oxide 200.0g Refined lanolin 105.0g White beeswax 40.0g White petrolatum 647.5g The above components are treated in the same manner as in Example 2 to produce an oily ointment. Example 15 Pyrrolnitrine 2.5g Clotrimazole 5.0g Crotamiton 20.0g Ethyl alcohol 400.0g 4% aqueous solution of carboxyvinyl polymer
400.0g 20% aqueous solution of monoethanolamine 80.0g Purified water 92.5g Dissolve pyrrolenitrin and clotrimazole in crotamiton at 80°C, then add ethanol to make a homogeneous solution. A 4% aqueous solution of carboxyvinyl polymer and a 20% aqueous solution of monoethanolamine are sequentially added to this solution with stirring. Next, add purified water to this solution to bring the total amount to 1000g.
and cool to produce a clear gel formulation. Example 16 Pyrrolenitrine 2.5g Clotrimazole 5.0g Crotamiton 20.0g Isopropyl myristate 100.0g Propylene glycol 100.0g Polyoxyethylene sorbitan monolaurate
10.0g 4% aqueous solution of carboxyvinyl polymer
170.0g Ethylenediaminetetraacetic acid 12.0g 1% aqueous solution of disodium 2% aqueous solution of sodium hydroxide 20.0g Purified water 560.5g Dissolve pyrrole nitrine and clotrimazole in crotamiton at 70°C, then add isopropyl myristate and propylene gellicol. , polyoxyethylene sorbitan monolaurate, a 4% aqueous solution of carboxyvinyl polymer, 530 g of purified water, and a 1% aqueous solution of disodium ethylenecyaminetetraacetate were sequentially added. A 2% aqueous solution of sodium hydroxide is gradually added to this solution while stirring at 70-80°C, and then purified water is added to bring the total amount to 1000 g, followed by cooling to produce a cream for external use. Example 17 Pyrrolenitrine 3.75g Oxiconazole 3.75g Olive oil 100.0g Refined lanolin 80.0g White petrolatum 812.5g Pyrrolenitrine and oxiconazole were dissolved in a mixture of olive oil, purified lanolin and white petrolatum under heating and stirred. An oily ointment is produced by homogenizing the mixture. Example 18 Pyrrolenitrine 2.0g Econazole 4.0g Glycerin 30.0g Ethanol 700ml Purified water Appropriate amount Pyrrolenitrin and econazole are dissolved in a mixture of glycerin and ethanol, and then purified water is added to bring the total volume to 1000ml. The solution is stirred until homogeneous to produce a tincture for external use. Example 19 Pyrrolenitrine 5.0g Miconazole 2.5g Crotamiton 20.0g Isopropyl myristate 100.0g Propylene glycol 100.0g Polyoxyethylene sorbitan monolaurate
10.0g 4% aqueous solution of carboxyvinyl polymer
170.0g 1% aqueous solution of disodium ethylenediaminetetraacetate 12.0g 2% aqueous solution of sodium hydroxide 20.0g Purified water 560.5g After dissolving pyrrolenitrin and miconazole in crotamiton at 70°C, add isopropyl myristate, propylene glycol to this solution. , polyoxyethylene sorbitan monolaurate, 4% aqueous solution of carboxyvinyl polymer, purified water 530
g and a 1% aqueous solution of disodium ethylenediaminetetraacetate are added sequentially. Additionally, add 70
After adding a 2% aqueous solution of sodium hydroxide at -80°C, add purified water to make a total amount of 1000 g, and cool to produce a cream for external use. Example 20 Pyrrolenitrin 2.0g Miconazole 4.0g Glycerin 30.0g Ethanol 700ml Purified water Appropriate amount Pyrrolenitrin and miconazole were dissolved in a mixture of glycerin and ethanol, then purified water was added to make the total volume 1000ml, and the solution was A tincture for external use is prepared by stirring until homogeneous.

Claims (1)

[Scope of Claims] 1. An antifungal composition containing pyrrolenitrine and an imidazole antifungal substance as active ingredients. 2. The antifungal composition according to claim 1, wherein the imidazole antifungal substance is clotrimazole. 3. The antifungal composition according to claim 1, wherein the imidazole antifungal substance is miconazole. 4. The antifungal composition according to claim 1, wherein the imidazole antifungal substance is econazole. 5. The antifungal composition according to claim 1, wherein the imidazole antifungal substance is oxiconazole. 6. The antifungal composition according to claim 1, which contains 1 to 3 parts by weight of pyrrolenitrin and 3 to 1 parts by weight of an imidazole antifungal substance as active ingredients. 7. The antifungal composition according to claim 6, wherein the imidazole antifungal substance is clotrimazole. 8. The antifungal composition according to claim 6, wherein the imidazole antifungal substance is miconazole. 9. The antifungal composition according to claim 6, wherein the imidazole antifungal substance is econazole. 10. The antifungal composition according to claim 6, wherein the imidazole antifungal substance is oxiconazole.