JPH0242812B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to imidazole-based antifungal topical gel preparations, and more specifically to 1-[1-
The present invention relates to a gel preparation containing o-(m-chlorobenzyloxy)phenylvinyl]-1H-imidazole or a pharmaceutically acceptable salt thereof as an active ingredient. As imidazole-based antifungal external preparations, clotrimazole, miconazole, and econazole are currently commercially available in the form of cream or liquid formulations, but cream formulations have disadvantages in terms of feel, such as stickiness, and liquid formulations cause skin irritation. There is no problem with this, but there are some problems with its effectiveness. The present inventors have discovered that imidazole antifungal drug 1
In creating a topical preparation containing -[1-o-(m-chlorobenzyloxy)phenylvinyl]-1H-imidazole or a pharmaceutically acceptable salt thereof as an active ingredient, we solved the above-mentioned drawbacks of existing antifungal topical preparations. Attempts were made to formulate the product into a non-sticky dosage form, and it was discovered that the intended purpose could be achieved by using a gel base having the composition shown below. Furthermore, it was discovered that a more preferable effect could be obtained by limiting the composition ratio of the gale base as described below, and the present invention was completed. The composition and preferred composition ratio of the gel preparation of the present invention are as follows. (1) 1-[1-o-(m-chlorobenzyloxy)
phenylvinyl]-1H-imidazole or its pharmaceutically acceptable salt approximately 0.2 to 2% by weight (2) Carboxyvinyl polymer approximately 0.5 to 3% by weight (3) Monohydric alcohol with C ₃ or less approximately 5 to 30% by weight (4 ) C ₂ - C ₆ dihydric alcohol Approximately 5 - 50% by weight (5) Polyethylene glycol with an average molecular weight of approximately 200 - 1500 Approximately 5 - 20% by weight (6) Organic amine Appropriate amount (7) Water Required amount (100% in total) do). In addition to the above-mentioned composition, the gel preparation of the present invention may contain additives commonly used in preparations, such as stabilizers, if necessary. 1-[1-o-(m-chlorobenzyloxy)phenylvinyl]-1H-imidazole, which is the main drug of the present invention, is disclosed in JP-A-55-164677 and J.Med.
Chem, Vol. 26, p. 768 (1983), and has the following structural formula. In the present invention, the above compound or a pharmaceutically acceptable salt thereof, such as hydrochloride, oxalate, succinate, etc., is used, and approximately
0.2-2% by weight is contained as an active ingredient. The carboxyvinyl polymer as a gelling agent is preferably about 0.5 to 3% by weight based on the total amount of the gel preparation.
More preferably, it is used in a proportion of about 0.5 to 2% by weight. Examples of carboxyvinyl polymers include commercially available Carbopol 934 (manufactured by Gutsudoritsuchi Chemical Co., Ltd.), Carbopol 940, Carbopol 941, HIVISWAKO 103 (manufactured by Wako Pure Chemical Industries, Ltd.),
Examples include 104 and 105. Specifically, the _C3 or lower monohydric alcohol used in this gel preparation includes methanol, ethanol, propanol, isopropanol, etc., and is preferably about 5 to 30% by weight, more preferably about 5% by weight based on the total amount of the gel preparation. It is used in a proportion of ~20% by weight. C ₂ - C ₆ dihydric alcohol is a linear or branched dihydric alcohol having 2 to 6 carbon atoms,
Dihydric alcohols with relatively high boiling points and low melting points such as ethylene glycol, propylene glycol, trimethylene glycol, 1,3-butanediol, 1,4-butanediol, 1,5-pentadiol, and 1,6-hexanediol is a suitable example. These dihydric alcohols preferably account for about 5 to 50% by weight, more preferably about 10% by weight based on the total amount of the preparation.
It is used in a proportion of ~30% by weight. Polyethylene glycol has an average molecular weight of about 200~
For example, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol
1500 etc. are used. Polyethylene glycols are preferably used in an amount of about 5 to 20% by weight, more preferably about 5 to 15% by weight, based on the total amount of the preparation. Organic amines are used to adjust the pH value of formulations, and specifically include diethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, and triisopropanolamine (also known as Examples include tris(2-hydroxypropyl)amine), tributylamine, and trioctylamine.
The gel preparation of the present invention is adjusted to have a pH of usually 4 to 7, preferably 5 to 7, by adding these organic amines. Stabilizers added as necessary include antioxidants, preservatives, chelating agents, etc. that are usually used in external preparations. Examples of antioxidants include:
Gallic acid alkyl esters, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, soodipropionic acid, nordihydroguaiaretic acid, etc.; examples of preservatives include parahydroxybenzoic acid esters, dehydroacetic acid, Orthophenylphenol, sorbic acid, etc. are used, and as a chelating agent, ethylenediaminetetraacetic acid disodium salt, etc. are used, and the amount of addition thereof follows a usual example. A preferred example of the gel preparation of the present invention includes a gel preparation containing the main drug (hydrochloride), carboxyvinyl polymer, isopropanol, propylene glycol, polyethylene glycol 400, triisopropanolamine, and water. The gel preparation of the present invention is adjusted depending on the solubility of the main drug. If the active ingredient is water-soluble, add monohydric alcohol, dihydric alcohol, and polyethylene glycol to the aqueous suspension of carboxyvinyl polymer, stir, etc. to make it homogeneous, then add the aqueous solution of active ingredient and mix uniformly to remove the remaining Add water, if present, and then neutralize with organic amine. When the main drug is insoluble in water, the main drug is dissolved in a mixture of one or both of alcohols and polyethylene glycol to be added to the aqueous suspension of carboxyvinyl polymer, and added together with the aqueous suspension of carboxyvinyl polymer. Any remaining water is then added and neutralized with an organic amine. When adding a stabilizer, it is preferable to dissolve it in an appropriate component of the composition and add it during the formulation process, depending on the desired solubility of the stabilizer. The gel preparation of the present invention having the above-mentioned components, particularly preferably the above-mentioned composition ratios, causes less skin irritation,
Excellent spreadability and non-stickiness. Another important point is that in this gel preparation, the active ingredient is appropriately dissolved in the base, so the active ingredient is released well into the skin, and the rate of absorption of the active ingredient into the skin is extremely high, resulting in excellent therapeutic effects. That's true. This excellent therapeutic effect is further enhanced by the phenomenon that the active ingredient does not dissipate due to the formation of a film on the application surface, which is unique to gel formulations. Next, the results of a safety and efficacy test of the gel preparation of the present invention using a commercially available imidazole antifungal external preparation as a control drug are shown below. The formulation of the test preparation is shown in the correspondingly numbered Examples. (1) Safety test (skin irritation test) a Test method Commercially available punch (Finn chamber)
Apply the test preparation to the chamber (manufactured by Taisho Pharmaceutical),
This will be applied to the back of the subject and removed after 48 hours. According to Sugai's method (Tetsuro Sugai, Dermatology Vol. 19, p. 210 (1977)), the degree of erythema (degree of irritation to the skin) of the patch was determined 48 and 72 hours after the patch was removed, and the skin irritation index was determined. was calculated. b Test results are shown in Table 1. Note that the safety index is calculated by setting the index of the preparation according to the present invention as 100 and the index of the control drug, and the higher the value, the stronger the irritation and the lower the safety. (2) Efficacy test (anti-ringworm test) a Test method The hair was removed from four places on the back of a guinea pig, and the spore solution of Trichophyton asteroides was inoculated.
From 2 days after infection with the fungus, apply the test preparation to 3 areas once a day8.
Apply continuously for several days, and use one area as an infection control. The day after the final treatment, the guinea pigs were sacrificed, the skin surface of the treated area was excised, cut into small pieces, and treated with cyclohexamide.
After culturing on a Sabouraud glucose agar medium containing 500 μg/ml and penicillin G 100 μg/ml at 28° C. for 7 days, the presence or absence of bacterial growth was determined, and the bacterial negative rate was calculated. b Test results are shown in Table 2. Note that the efficacy index is calculated by setting the index of the preparation according to the present invention as 100 and the index of the control drug, and the larger the value, the higher the efficacy.

【table】

[Table] Liquid As is clear from the above test results, the gel preparation of the present invention is an excellent preparation with little skin irritation and high therapeutic effect on tinea. Next, embodiments of the present invention will be shown in Examples, but these Examples are not intended to limit the present invention in any way. Example 1-5 A gel preparation having the components and composition ratios shown in Table 3 is manufactured. To prepare the formulation, carboxyvinyl polymer is suspended in the required amount of water, monohydric alcohol, dihydric alcohol, and polyethylene glycol are added to the suspension, stirred uniformly, and then 1-
Add an aqueous solution of [1-o-(m-chlorobenzyloxy)phenylvinyl]-1H-imidazole hydrochloride (described as main drug in Table 3) and stir to make it homogeneous.
This was done by neutralizing with an organic amine. In addition,
The composition ratios in the table indicate weight percentages (weight to weight). Note that the reference examples are formulation examples that differ from the present invention in the components or composition ratios indicated by underlines. These were subjected to the above-mentioned safety or efficacy test at the same time as the formulations of the examples, and the safety or efficacy index for each reference example was calculated, taking the measured value of the formulation of the present invention as 100.

【table】

Claims (1)

[Claims] 1 1-[1-o-(m-chlorobenzyloxy)
about 0.2-2% by weight of [phenylvinyl]-1H-imidazole or its pharmaceutically acceptable salt, about 0.5-3% by weight of carboxyvinyl polymer, about 5-30% by weight of monohydric alcohol of _C3 or less, _C2 - _C6 An imidazole-based antifungal gel preparation for external use, which contains 5 to 50% by weight of dihydric alcohol, 5 to 20% by weight of polyethylene glycol having an average molecular weight of about 200 to 1,500, an appropriate amount of organic amine, and a required amount of water. 2. The formulation of claim 1, wherein the _C2 - _C6 dihydric alcohol is propylene glycol and the polyethylene glycol having an average molecular weight of about 200-1500 is polyethylene glycol 400. 3 1-[1-o-(m-chlorobenzyloxy)
phenylvinyl]-1H-imidazole hydrochloride,
carboxyvinyl polymer, isopropanol,
Propylene glycol, polyethylene glycol
400, triisopropanolamine and water.