JPH09176014A - Antifungal topical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the above composition having a wide antimicrobial spectrum, having excellent antimycotic effect at low doses, and useful as a therapeutic agent for dermatophytosis such as serpigo on the hands, legs and/or body, containing, as active ingredients, a specific antimycotic substance and tolnaftate. SOLUTION: This antimycotic composition contains, as active ingredients, (A) an imidazole-based antimycotic substance or its salt (e.g. econazole, miconazole, tioconazole, isoconazole, hydrochloride, sulfate, nitrate, phosphate, acetate; esp. econazole) and (B) tolnaftate in the weight ratio A/B of pref. (1:20) to (10:1) [esp. (1:2) to (2:1)]. It is preferable that this composition be administered at 0.1-500 (esp. 1-50)mg/kg a day in terms of the active ingredients.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel antifungal external composition showing an excellent antibacterial activity against a wide range of fungi.

[0002]

BACKGROUND OF THE INVENTION athlete's foot is caused by athlete's foot fungus in the stratum corneum of the skin.
It is a skin disease that occurs because of proliferation. For athlete's foot, tinea pedis on the hands and feet between the toes and toes, tinea corporis known by the nickname "Tamushi", and other worms such as "Inkin tinea (tinea cruris)" and "Shirakumo (tinea capitis)" Also included. Generally speaking, athlete's foot fungus refers to yeast which is a unicellular fungus and mold which is a multicellular fungus. The former representative is Candida and the latter representative is Trichophyton (Trichophyton).
phyton) species, so-called ringworm. These athlete's foot fungus secretes an enzyme that decomposes the stratum corneum of the skin and grows with the degradation product as a nutrient source. Then, when athlete's foot fungus increases in the stratum corneum, it induces an inflammatory response as a biological defense mechanism, infiltration,
Many people still suffer from symptoms such as redness and itching.

One of the long-known external antifungal agents is tolnaphthalate, which has an antibacterial effect against Trichophyton but has little effect on other fungi such as Candida. Moreover, it is soluble in solvents such as acetone, chloroform, methyl ethyl ketone, etc., but is difficult to dissolve in water and other organic solvents, so it is difficult to make the drug concentration sufficient to penetrate the skin, or skin irritation caused by organic solvents. However, there is a drawback that it is difficult to use.

In recent years, miconazole, econazole, which are widely used as clinical antifungal agents in clinical settings,
There are imidazole antifungal agents such as isoconazole. Although imidazole antifungal agents have antibacterial activity across fungi, they have a weak antibacterial activity against Trichophyton and have a bacteriostatic effect. May recur, and no satisfactory effect has been obtained. On the other hand, when a drug is mixed in a high concentration in order to obtain a bactericidal effect, side effects such as irritation to the skin and toxicity occur. In order to improve the antibacterial activity of imidazole antifungal agents, a technology in combination with pyrrolenitrin (JP-A-61-56127) and a technology in combination with an arylmethylamine antifungal agent (JP-A-1-56127) 93525
However, these techniques are effective as a combination of both antifungal substances, except for fungi such as Candida albicans, Aspergillus oryzae, and Staphylococcus epidermidis. Only the effect on it is shown.

[0005]

Therefore, an object of the present invention is to eliminate the above-mentioned drawbacks of conventionally used imidazole antifungal agents and tolnaphthalate, that is, to retain the broad antibacterial spectrum of imidazole antifungal agents. At the same time, it is to provide a novel antifungal external composition having an excellent effect on Trichophyton at a low concentration.

[0006]

Under such circumstances, as a result of intensive investigations by the present inventors, it was found that a composition in which an imidazole antifungal substance and torunafate are used in combination exerts a remarkable synergistic effect based on the combination. They have found the present invention and completed the present invention.

That is, the present invention provides an antifungal external composition containing an imidazole antifungal substance or a salt thereof and tolnaphthalate as active ingredients.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the imidazole antifungal substance in the present invention include clotrimazole [Arzneim.-Forsh.
Vol. 2, p. 1280 (1972)], Miconazole [Arzneim. Horshrung (Arzneim.-Forsh.)]
21: 256 (1971)], Econazole [Arzneim.-Forsh.]
Vol. 25, p. 224 (1975)], Isoconazole [Arzneimtel Horschlung (Arzneim.-Fors
h.) 29: 1344 (1979)], thioconazole [Antimicrobial Agents Chemotherapy] 15: 597
~ 602 (1979)], sulconazole ["fungi and mycoses" 23: 314-317 (1982)],
Oxyconazole [Arzneim.-Forsh., Vol. 32, pages 17-24 (1982)
)], Croconazole [Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 26, 768-
770 (1983)], bifonazole [Arzneimitter-Horschlung (Arzneim.-Forsh.) 33: 517-524 (1983)], butonazole [Journal of Medicinal Chemistry (J.
Med. Chem.) 21: 840 (1978)], Fenticonazole [Arzneim.-Forsh.] 31: 2127 (1981).
)], Dinoconazole [Journal of Medicinal Chemistry (J. Med. Chem.) Vol.
445 (1983)], Ketoconazole [Journal of Medicinal Chemistry (J. Med. Che
m.) Vol. 22, 1003 to 1005 (1979)] and the like, and preferably is econazole, miconazole, thioconazole or isoconazole, more preferably econazole. In addition, these imidazole antifungal substances may be used in the form of their salts,
Such salt is not particularly limited, for example,
Hydrochloride, sulfate, nitrate, phosphate, acetate and the like can be mentioned.

In the composition of the present invention, the compounding ratio of the imidazole antifungal substance or its salt and tolnaphthalate is not particularly limited, but is preferably 1:20 to 1 by weight.
The ratio is 0: 1, more preferably 1:10 to 4: 1 and further preferably 1: 2 to 2: 1, but can be increased or decreased as appropriate depending on the target pathogen and the like.

The dosage form of the composition of the present invention is not particularly limited, and can be used in various dosage forms and methods of use similar to known antifungal agents for external use, such as liquids, aerosols, gels, creams, powders and ointments. It can be used as an agent or a patch.

In these preparations, the content ratio of the mixture consisting of the imidazole antifungal substance or its salt and tolnaphthalate is not particularly limited, but is preferably 0.01 to 50% by weight, particularly preferably 0.01 to 10% by weight. .

The dose of the active ingredient in the composition of the present invention may be appropriately increased or decreased depending on the dosage form, the content ratio of both active ingredients, the type of causative bacterium to be treated, the symptoms, etc.
It is administered in the range of 1 to 500 mg / kg / day, preferably 1 to 50 mg / kg / day.

Further, in addition to the imidazole antifungal substance and tolnaphthalate which are active ingredients, the composition of the present invention includes, for example, diphenhydramine, diphenylpyraline hydrochloride,
Lidocaine, crotamiton, tesit, ethyl aminobenzoate, dibucaine, methyl salicylate, menthol,
Antipruritic, antiphlogistic, analgesic or local anesthetic such as camphor, lauromacrogol, glycyrrhetinic acid, glycyrrhizinic acid, azulene or a salt thereof; benzalkonium chloride, chlorhexidine, decalinium chloride, resorcin, phenol, tego 51, chlorobutanol, iodo, Fungicide such as boric acid, triacetylammonium pentachlorophenate or its salt; Keratin softening penetrant such as salicylic acid, diethyl sebacate, urea, sulfur; Astringent or repairing agent such as zinc chloride, allantoin, dihydroxyaluminum or its salt You may mix | blend an agent etc. suitably.

The composition of the present invention can be formulated into various dosage forms as described above by mixing various bases and carriers by a conventional method. For example, examples of the liquid carrier include water, lower alcohol, ethylene glycol, glycerin, and other various solvents.

As the carrier of the aerosol, for example, a carrier of the liquid agent as described above and Freon gas, liquefied propane gas or the like can be mixed and used.

As the gel base, for example, a combination of the above-mentioned liquid carrier and a gel forming agent can be used. As the gel forming agent, for example, carboxyvinyl polymer and organic amine or sodium hydroxide aqueous solution can be used. And the like, a cellulose ether such as hydroxypropyl cellulose, sodium alginate, propylene glycol alginate, and the like.

As the cream base, an emulsifier such as a nonionic surfactant and a gel base, an ointment base and / or an aqueous base can be used in combination.

Examples of powder bases include inert diluents such as calcium carbonate, calcium phosphate, lactose, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium stearate, aluminum stearate, talc, and silicone.
Granulating agents, dispersants, binders and the like can be used alone or in combination.

As the ointment base, peanut oil, olive oil, sesame oil, coconut oil, paraffin oil, lanolin, petrolatum, zinc oxide, beeswax, macrogol, stearyl alcohol, cetanol, propylene glycol,
Fatty acids, fatty acid esters and the like can be used alone or in combination.

As the base of the patch, a silicone-based, acrylic-based, rubber-based or other pressure-sensitive adhesive may be used alone or in combination with a suitable plasticizer, dispersant, solvent or the like.

Further, the antifungal external composition of the present invention comprises
In addition to the above-mentioned bases and additives, conventional dissolution aids,
It is also possible to combine stabilizers, moisturizers, preservatives and the like in combination. These various formulations can be prepared by a conventional method, for example, can be produced in the same manner as the method described in the 12th revised Japanese Pharmacopoeia.

The antifungal external composition of the present invention is, for example,
It shows an excellent effect for the treatment of so-called athlete's foot such as ringworm of the hands and feet, ringworm (tinea corporis), ringworm tinea (tinea cruris), ringworm tinea (tinea capitis).

[0023]

EXAMPLES The present invention will be described in more detail with reference to the following examples, which are merely examples and do not limit the present invention.

The effects of the antifungal external composition of the present invention will be described with reference to test examples. (Test Example 1) As a test bacterium, the antibacterial activity of trnaphthalate (T) alone, econazole nitrate (E) alone, and a mixture of torunafate (T) and econazole nitrate (E) having the following composition against tinea bacilli was examined. The results are shown in Table 1. Furthermore,
The effect of combined use of tolnaphthalate and econazole nitrate on Trichophyton mentaglophytes MTU-19005 was investigated using the checkerboard method. The results are shown in Table 2.

Trichophyton Mentaglofites
MTU-19005 Trico Phyton Rublum IFO-5467 Trico Phyton Mentaglophytes IFO-7522

(1) Preparation of Test Drug Composition A: T (100 mg) was dissolved in 50 ml of dimethyl sulfoxide, and 1 ml of the solution was taken and mixed with 9 ml of dimethyl sulfoxide to prepare a liquid A. Composition B: E (100 mg) was dissolved in 50 ml of dimethylsulfoxide, 1 ml of the solution was taken and mixed with 9 ml of sterilized water to prepare a liquid B. Composition C: Liquids A and B obtained above were mixed at a volume ratio of 1: 4 to prepare Liquid C. Composition D: Liquids A and B obtained above were mixed in a volume ratio of 1: 2 to prepare a liquid D. Composition E: Liquid E was prepared by mixing the liquids A and B obtained above in a volume ratio of 1: 1. Composition F: Liquid F was produced by mixing the liquids A and B obtained above in a volume ratio of 2: 1. Composition G: Liquid G was prepared by mixing liquids A and B obtained above in a volume ratio of 8: 1.

(2) Test Method Each of the above liquids A to G was diluted and mixed with Sabouraud agar medium to prepare agar plates with various concentrations. The test strains were inoculated on the agar plates of various concentrations and cultured at 25 ° for 1 week, and then the minimum inhibitory concentration (MIC: μg / ml) at which the growth of each test strain was inhibited was determined. The results are shown in Table 1. Further, the FIC index value which is generally used as an index showing the synergistic action of the antifungal external composition of the present invention was determined by the following formula. The results are shown in Table 1.

[0028]

[Equation 1]

(Where a is MIC of composition A, b is M of composition B)
IC, c is the MIC of the mixed composition of composition A and composition B, d is the ratio of composition A to the total capacity of both of the mixed compositions of composition A and composition B, and e is the mixed composition of composition A and composition B The ratios of the composition B to the total capacity of both of them are shown. )

[0030]

[Table 1]

[0031]

[Table 2]

Generally, if the FIC index is 1.0 or less, it is recognized that there is a synergistic action. However, as shown in Table 1, the FIC index of the antifungal composition containing tolnaphthalate and econazole nitrate is in any test example. Is 1.0 or less, and it is clear that the composition of torunaphthalate and the imidazole antifungal substance according to the present invention has a synergistic action against Trichophyton. Also,
From Table 2 as well, a remarkable synergistic effect by the combined use is recognized between tolnaphthalate and econazole nitrate.

(Test Example 2) As test bacteria, with respect to the following fungi other than Trichophyton, tolnaphthalate (T) alone, econazole nitrate (E) alone, tolnaphthalate (T) and econazole nitrate were used.
The antibacterial activity of the 1: 2 mixture of (E) was investigated. The results are shown in Table 3.

Candid Sud tropicalis (Candid
a pseudotropicalis) Y06-01 Candida krusei IFO-0011 Cryptococcus neoformance
eoformans) KF-33

(1) Preparation of test drug Composition A: T (20 mg) was dissolved in 20 ml of dimethylsulfoxide, 0.5 ml of the solution was taken and mixed with 4.5 ml of dimethylsulfoxide to prepare a liquid A. Composition B: E (20 mg) was dissolved in 20 ml of dimethylsulfoxide, 0.5 ml of the solution was taken and mixed with 4.5 ml of sterilized water to prepare a liquid B. Composition C: Liquids A and B obtained above were mixed in a volume ratio of 1: 2 to prepare a liquid C.

(2) Test method Each of the liquids A to C obtained as described above was diluted,
The test was conducted under the same conditions as in Test Example 1.

[0037]

[Table 3]

From the results in Table 3, it is recognized that the compounded composition retains the broad antibacterial spectrum of econazole nitrate.

Next, the preferred embodiments of the compounding agent of the present invention will be described, but the present invention is not limited to this, and various application in pharmaceutical technology, such as addition of the third component,
Improvements in the manufacturing process can also be applied.

Example 1

[0041]

[Table 4]

4.0 g tolnaphthalate and econazole nitrate 8.
An ointment was produced by heating 0 g of white petrolatum 788.0 g, squalane 120.0 g, and cholesterol 80.0 g by heating and dissolving them to homogenize by stirring.

Example 2

[0044]

[Table 5]

5.0 g tolnaphthalate and econazole nitrate 5.
0 g to white vaseline 200.0 g, cetostearyl alcohol 4
Heat and dissolve in a mixture of 0.0 g, sorbitan sesquioleate 50.0 g, polysorbate 6060.0 g, and glyceryl monostearate 20.0 g, and mix evenly. On the other hand, 100.0 g of propylene glycol is heated and dissolved in 520.0 g of purified water,
After mixing uniformly, the above main drug solution was added and emulsified, and uniformly dissolved to prepare a cream.

Example 3

[0047]

[Table 6]

8.0 g tolnaphthalate and econazole nitrate 4.
0 g for Macrogol 400 100.0 g, propylene glycol
60.0 g, diisopropyl adipate 20.0 g, ethanol
A solution prepared by dissolving in 400.0 g of carboxyvinyl polymer 20.0 g and diisopropanolamine 2.0 g in purified water 386.0 g was added and stirred uniformly to prepare a gel preparation.

Example 4

[0050]

[Table 7]

Tolnaphthalate 4.0 is added to 700 ml of ethanol.
g, miconazole 8.0 g, macrogol 400 100.0 g, crotamiton 50.0 g, and methacrylic acid copolymer 3.0 g were dissolved, purified water was added to 1000 ml, and the mixture was uniformly stirred to produce a liquid preparation for external use.

Embodiment 5

[0053]

[Table 8]

A dusting agent for spraying was produced by uniformly mixing the above-mentioned respective components in the form of powder.

Example 6

[0056]

[Table 9]

Tolnaphthalate 2.0 g and Isoconazole 2.
After dissolving 0 g in 350.0 g of ethanol, 10.0 g of methacrylic acid / butyl acrylate copolymer and 10.0 g of isopropyl palmitate were added and uniformly dissolved and mixed to obtain liquefied petroleum gas.
By adding 30.0 g and filling the aerosol container,
An aerosol formulation was produced.

[0058]

The combined use of imidazole antifungal substance and tolnaphthalate shows a remarkable synergistic effect.
It has excellent antifungal activity at low doses, such as tinea pedis,
It is useful as a therapeutic agent for so-called athlete's foot such as tinea tinea (tinea corporis), tinea tinea (tinea cruris), and tinea tinea (tinea capitis).

Claims (5)

[Claims] 1. An antifungal composition for external use, which comprises an imidazole antifungal substance or a salt thereof and torunaphthalate as active ingredients. 2. The content ratio of the imidazole antifungal substance or its salt and torunaphthalate is 1:20 to 10: by weight.
The antifungal external composition according to claim 1, which is 1. 3. The blending ratio of the imidazole antifungal substance or its salt and torunafate is 1:10 to 4: 1 by weight.
The antifungal external composition according to claim 1, which is 4. The antifungal external composition according to claim 1, wherein the compounding ratio of the imidazole antifungal substance or its salt and torunaphthalate is 1: 2 to 2: 1 by weight. 5. The imidazole antifungal substance or a salt thereof is econazole or a salt thereof.
The antifungal topical composition according to the item.