JPH03206033A - Antitrichophytic agent - Google Patents

Abstract

PURPOSE:To provide an antitrichophytic agent containing an alkyldimethylamine tetraborate as an active component, exhibiting antifungal activity against tricophytons, usable without generating resistant trichophyton and suitable for the clinical remedy for athlete's foot. CONSTITUTION:The compound of formula (R is 10-14C alkyl) or its hydrate is used as an active component of the objective agent. It can be used in the form of an ointment by using liquid paraffin, petrolatum, etc., as a base or a liquid agent by using a mixture of ethanol and water as a base. The ratio of the active compound of formula in the preparation is 0.1-100wt.% preferably 0.5-10wt.%. The compound of formula can be synthesized e.g. by reacting octyldimethylamine with metaboric acid at 140-170 deg.C, preferably 140-150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a therapeutic agent for athlete's foot (sweating fungus) containing an alkyldimethylamine tetraborate as an effective ingredient.

(Conventional technology) Athlete's foot is caused by P. albicans in areas with a thick stratum corneum and relatively high moisture content.
For example, it is a skin disease that grows and causes lesions on the soles of the feet and palms of the hands. Conventionally, many types of external medicines for athlete's foot have been commercially available. However, even though all of these drugs have the effect of inhibiting the growth of white mold in test subjects, it is difficult to completely cure athlete's foot even if they are used. Even if the athlete's foot appears to have been cured, the bacteria often remain deep in the stratum corneum of the epidermis, and may grow again in the summer, or for a while after the medication has been stopped. It often happens that athlete's foot recurs due to the growth of the athlete's foot. The reason why athlete's foot is difficult to cure is that the bacteria are parasitic in the stratum corneum, which is difficult for drugs to penetrate, and that there are relatively many types of bacteria that are resistant to drugs due to the frequent use of drugs. It is said that this is due to From this perspective, external medicines for athlete's foot still need to be developed. The present invention has been made in consideration of the above circumstances, and its objective is to provide an anti-white mold agent that exhibits extremely good clinical therapeutic effects in a short period of time and can suppress recurrence.

(Means and effects for solving the problem) As a result of various studies, the present inventors have found that a composition containing an alkyldimethylamine tetraborate represented by the following structural formula or a hydrate thereof as an effective ingredient has been found. We have found a solution to the above problems.

Structural formula; 1 CH3 (in the formula, R is an alkyl group of C10=C14) The antibacterial properties of alkyldimethylamine tetraborate have already been clarified (Public Patent Publication, Hei 1-211506)
It was not yet known that the alkyldimethylamine tetraborate having the above structure has antibacterial properties against white mold.

The alkyldimethylamine constituting this compound specifically includes octyldimethylamine, decyldimethylamine, lauryldimethylamine, dodecyldimethylamine, and the like.

The compound of this invention can be obtained by reacting the above-mentioned amine with metaboric acid, orthoboric acid, tetraboric acid, or a mixture thereof.

Usually, metaboric acid or orthoboric acid is used, and it is particularly preferable to use metaboric acid.

The reaction is carried out at about 140'C to 170°C, preferably about 1
It is preferable to carry out heating in the range of 40°C to 150'C.

Considering the reaction products, it is believed that orthoboric acid and metaboric acid react with a tetraboric acid structure.

Metaboric acid, orthoboric acid, or tetraboric acid is usually used in an equimolar amount in terms of tetraboric acid with respect to the amine. However, the amine may also serve as a solvent and may be used in excess. Particularly when tetraboric acid is used, it is preferred to use an excess amount of the amine.

The reaction time depends on the reaction temperature. metaboric acid,
When orthoboric acid is used, it is preferable to carry out the reaction while removing by-product water from the system. After the reaction is completed, when the reaction product is cooled, the reaction product precipitates out, and the target product can be easily obtained by filtering it.

As shown in Table 1 Solvent Solubility, the reaction product obtained in this way emulsifies when added in a small amount (5% or less) to water, and completely dissolves when added in a large amount (10% or more). .

In addition, this reaction product was tested for mutagenicity (Ames test).
was negative and acute toxicity (orl-mus) was 1.99.
It is a substance with low toxicity at 5mg/Kg.

○: Soluble △: Partially dissolved ×: Insoluble The alkyldimethylamine tetraborate thus obtained showed extremely significant anti-white mold activity. Preferred dosage forms of the anti-white mold agent according to the present invention include ointments, emulsions, powders, solutions, tinctures, aerosols, etc., and various dosage forms similar to those of known anti-white mold agents may be used. As the base for this purpose, any known base can be used. For example, oil bases for ointments include liquid paraffin, solid paraffin,
Examples include lanolin and petrolatum. Examples of emulsion bases for ointments include water-absorbing ointments and Oyaki Vaseline. Examples of emulsifiers include sorbitan. Examples of the base for liquid agents include a mixture of ethanol and water.

The content ratio of effective precepts in these preparations is o. i
-ioo weight %, preferably 0.5 to 10 weight %. If the content is too low, no medicinal efficacy can be obtained, and if the content is too high, it may be difficult to apply the drug.

In addition to the alkyl dimethylamine salts which are effective ingredients, the antiwhite mold agent of this invention includes, for example, crotamiton, diphenhydramine, diphenylbilarin hydrochloride, lidocaine,
De-jealousy, ethyl aminobenzoate, dibucaine, methyl salicylate, menthol, camphor, lauromacrogol, glycyrrhetinic acid, anti-inflammatory, analgesic or local anesthetics such as azulene or its salts, resorcinol, phenol, Tego 51, chloro Bactericidal agents such as butanol, iodine, boric acid, trimethylcetylammonium, pentachlorophenate or its salts, keratin softening penetrants such as salicylic acid, diethyl sebacate, urea, sulfur, etc., zinc chloride, allantoin, hydroxyaluminum or its salts, etc. An astringent or restorative agent may be added as appropriate.

In addition to the above-mentioned examples, external bases, preservatives, and other additives known in the art may be appropriately selected and used. Adjustment conditions for external drugs are also selected and utilized as appropriate. The application method also employs a known method.

(Example) Next, the present invention will be explained with reference to production examples, test examples, and examples.

Production Example 1 0.2 mol of lauryl dimethylamine and 0.2 mol of orthoboric acid were placed in a three-wall flask equipped with a distillation device and a stirrer, and stirred at 140'C to 150'C for 1 hour. About 20 minutes after the start of the reaction, the reaction solution became an almost transparent viscous liquid. Water produced as a by-product during the reaction was removed from the thread using a distillation device. After the reaction is complete, cool to room temperature. The precipitate was washed with 200 ml of hexane to remove unreacted amine. Insoluble substances are filtered out and ground into powder in a mortar. Add 200 ml of hexane again, stir at about 50'C for 1 hour, and then filter. After repeating this process twice, the insoluble material was dried for one day to obtain lauryl dimethylamine tetraborate.

．． Test Example 1 Lauryldimethylamine borate was selected from among the alkyldimethylamine borates and antibacterial properties were evaluated.

[Test Strain J White Bacterium; Trichophyton mentagrophytes IFO
6202 [Preparation of bacterial solution for inoculation] The bacterial strain to be used was diluted with potato dextrose agar medium (Eiken).
After culturing at 5°C for 14 days, conidia were suspended in sterilized water containing 0.005% dioctyl sodium sulfosuccinate so that the number of bacteria was approximately 106 cells/ml.

[Test summary and results] Dispense 0.5 ml of lauryl dimethylamine borate aqueous solution and 9.5 ml of sterilized agar medium into a sterilized petri dish, mix uniformly, and solidify to obtain a lauryl dimethyl amine borate concentration of 10,000 pg/ml to 2. Test plates were prepared in a series of double dilutions up to 39 pg/ml. A loopful of the test bacterial solution for inoculation was placed on a test plate, and after culturing at 30'C for 48 hours, the presence or absence of bacterial growth was observed. the result,
Lauryl dimethylamine borate concentration 39 pg/ml
However, no bacterial growth was observed.

[Example j 1) Lauryldimethylamine borate 1.0 parts by weight 2
) Cabric acid monoglyceride 5.0 parts by weight 3)
Methyl ethyl ketone 25.0 parts by weight 4)
Triacetone 25.0 parts by weight 5
) Isopropyl alcohol 44. ONiR1
) to 5) were weighed into a brown glass bottle, stirred at room temperature until 1) was completely dissolved, and then filled into a container to prepare an external medicine for athlete's foot.

For comparison, a comparative topical drug was prepared excluding only 1).

Patients aged 19 to 35 with athlete's foot fungus at the time of initial diagnosis.
Twelve patients with almost the same skin rashes were asked to simply apply the topical drug for athlete's foot of the present invention, the comparative topical drug, and the commercially available imidazole topical drug for athlete's foot, twice a day in the morning and evening. The degree of improvement in the skin eruption was observed two weeks after the start of the test, and determined by the following method.

Evaluation method for effectiveness: Effective: The eruption disappears or significant improvement is observed. Moderately effective: The eruption improves. Ineffective: The eruption remains unchanged and no improvement is observed. Exacerbation: The eruption worsens. The number of people for each judgment item is shown in the table below.

(Effects of the Invention) As a result of the above, it was found that the antibacterial agent according to the present invention has excellent laboratory drug effects and clinical drug effects. Furthermore, since the alkyldimethylamine tetraborate of the present invention is a new chemical substance that is chemically different from commonly used antibiotics, it is not resistant to white fungi.
It can be said that it is an antifungal agent suitable for clinical treatment.

Claims (1)

[Claims] The following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is an alkyl group of C_1_0 to C_1_4) Containing a compound or its hydrate as an active ingredient An antifungal agent characterized by.