KR20150131593A - Antifungal pharmaceutical composition - Google Patents

Abstract

Provided in the present invention is an antifungal medicine for external use, characterized by containing a compound represented by chemical formula 1, 50-95 wt% of alcohol such as ethanol, 0.1-35 wt% water and the like, and 0.01-5 wt% of a cellulose-based thickener.

Description

[0001] ANTIFUNGAL PHARMACEUTICAL COMPOSITION [0002]

The present invention relates to an external preparation for skin, specifically, an external preparation for an antifungal agent.

Diseases caused by fungi such as athlete's foot, candidiasis, etc. are infectious diseases and it is difficult to completely heal by repeated improvement and recurrence. Recently, female patients tend to increase with the advancement of women's society, and antifungal agents that can be treated easily are socially demanded.

As a promising antifungal agent, it has been found that a compound represented by the formula (1), which is a novel imidazole compound having an antifungal activity, has an effect of shortening the treatment period of a disease caused by fungi. Especially, the optically active luliconazole, Can be exemplified. Such compounds are also useful for nail fungus infection, and preparations for nail fungus infection are already known (see, for example, WO 03/105841).

That is, the compound represented by the formula (1) can be said to be a useful active ingredient widely used for mycosis (having an antifungal activity).

Among the mycosis, there are fungus ringworm, body part ringworm, psoriasis, coralline ringworm, bronchopulmonary wilt, epiglottis and seborrheic dermatitis, which are proliferated and manifested by fungal growth on the skin, In diseases, it is preferable to be used directly as a external preparation for a disease site.

In addition, many antifungal agents have adverse side effects such as hepatic insufficiency and renal failure due to oral administration.

In the case of oral administration, since the drug is metabolized in the liver or the like due to the first-pass effect and the like, a large amount of drug is administered in order to reach an effective concentration at the disease site, and burden on organs such as liver associated with metabolism is given. For this reason, the use of external preparations for antifungal agents that can avoid the first passage in the liver is less burdensome to the elderly who have lowered their physical strength in the age of becoming an aging society, and can be easily administered. .

On the other hand, in the compound having an asymmetric carbon, since the stereostructure in a solution is unstable, maintenance of the stereostructure in addition to solubility is an important problem in a compound having an asymmetric carbon among the drugs of the antifungal drug, and various investigations have been made. This is because in some cases, a steric hindrance is likely to occur in a dissolved state. In response to this, for example, saccharides are added. In addition, it is known that imidazole derivatives are easily dissolved by polyethylene glycol, and that the stability is good (see JP 05-070351 A). However, there is no certain rule for the retention of such a three-dimensional structure, and it can be said that the case where the three-dimensional structure can be maintained is rare. In addition, such a combination is also found inadvertently. In the preparation containing the compound represented by the formula (1), it is not known at all whether the retention of the stereostructure of the compound is a problem, and it has not been known how to maintain such stereostructure. Under such background, a means for securing a suitable stability for the compound represented by the general formula (1) has been required in the pharmacopoeia. It is known that alcohols such as ethanol and water are commonly used medium for formulation and these components are sometimes known to cause hydrolysis and the like in stability of the active ingredient. It was not known at all to contribute.

In addition, although seborrhoeic dermatitis is one of the fungal diseases suitable for use as an external preparation for skin, a preparation used for seborrheic dermatitis has a scalp around the hair, and the amount of use thereof is higher than that of the fungus of the body part, A solvent called methyl ethyl ketone is in a state of limited use due to problems such as the possibility of irritation and flammability, and there is a need for a preparation which can be easily administered without side effects such as irritation and the like. In order to secure the effect, it is preferable that the drug is sufficiently dissolved in the preparation and is in the form of a single phase solution in which the drug is easily transferred to the skin. Since the solubility of the compound represented by the formula (1) is limited in water, one of the problems is how to formulate a solution in the form of a single phase without impairing its solubility.

When developing a topical skin preparation for medical use, the most important technique is to sufficiently absorb the active ingredient into the skin. Since the skin has a function of defending against physical and chemical stimuli from the outside, the amount of absorption from the skin is generally very small. Therefore, a method of improving transdermal absorption by various methods has been studied, and a method using a transdermal absorption promoter has been studied (see Japanese Patent Application Laid-Open No. 08-3070).

As a method for improving the percutaneous absorption property of the external preparation for skin for antifungal use, it has been known that the skin external preparation for antifungal use can be effectively absorbed by containing a certain amount of ethyl cellulose, water and plasticizer (JP-A-07-223971 ). However, no effective method for improving the percutaneous absorbability has been known at all to develop the compound represented by the formula (1) as an external preparation for antifungal use. In particular, a method of stably maintaining the stereostructure of the compound and improving the percutaneous absorption Not reviewed.

The present invention has been made under these circumstances, and it is an object of the present invention to provide a preparation in which the stereostructure of the compound represented by the formula (1) is kept in a stable state and the transdermal absorption property is improved.

The present inventors have made intensive research efforts to find a method capable of improving the transdermal absorption of external preparations containing a compound represented by the formula (1) and maintaining the stereostructure of the compound. As a result, it has been found that the preparation of a compound represented by the formula It has been found that the stability related to the three-dimensional structure is improved by dissolving the compound represented by the formula (1) in an alcohol such as ethanol and adding a certain proportion of water, and by containing a cellulose-based thickener at a certain ratio, The transdermal absorbability is improved. The mass ratio of the alcohol, water and cellulose thickener, such as ethanol, to the total amount of the preparation is preferably from 0.1 to 35 mass%, from 0.01 to 5 mass% of the cellulose based thickener, from 50 to 95 mass% to be. In addition, the system of such a preparation can be employed without particular limitation as long as it is a formulation usually used as an external medicine for skin, but it is preferable to take a single-phase solution form.

By these discoveries, the present inventors have come to complete the invention. That is, the present invention is as follows.

(1) A compound represented by the formula (1). (2) 50 to 95 mass% of alcohol, (3) 0.1 to 35 mass% of water and / or an anionic surfactant, and 4) 0.01 to 5 mass% of cellulose thickener.

(2) The external preparation for an antifungal agent according to (1), wherein the compound represented by the formula (1) is luliconazole.

(3) The external preparation for antifungal use according to (1) or (2), wherein the flammable solvent excluding alcohol is contained in an amount of 1% by mass or less based on the total amount of the external preparation for antifungal use.

(4) The external preparation for antifungal use according to any one of (1) to (3), which is in the form of a single phase solution.

(5) The method according to any one of (1) to (4), wherein the disease to which the disease is applied is tinea line, body tinea or tinea tinea, psoriasis, candidiasis (bronchioles or interstitial erosion) (6) The external preparation for an antifungal agent according to (5), wherein the disease to be treated is seborrheic dermatitis.

According to the present invention, it is possible to provide a formulation containing the compound represented by the general formula (1), which is stable and highly transdermal. These preparations can be applied to mycoses such as tinea ringworm, tinea ringworm, or psoriasis, psoriasis, candidiasis (bronchial astringent or interstitial erosion), wind tunnel or seborrheic dermatitis, and particularly useful for seborrheic dermatitis.

In the external preparation for antifungal drugs of the present invention, a part or all of the compound represented by the formula (1), 50 to 95 alcohol such as ethanol and the like may be substituted with an anionic surfactant.

When X of the compound represented by the general formula (1) is halogen, examples of the halogen include chlorine, bromine, iodine and fluorine. Among them, chlorine is preferable.

The content of the compound represented by the formula (1) is preferably 0.01 to 20% by mass, more preferably 0.1 to 10% by mass with respect to the total amount of the composition.

The alcohol represented by ethanol is preferably contained in an amount of 50 to 95 mass%, more preferably 70 to 90 mass%, based on the total amount of the external preparation for antifungal use, in order to dissolve the compound.

This is because when the alcohol content is low, the compound may not be sufficiently dissolved, and there is a possibility that the compound precipitates over time. The alcohol used in the present invention is preferably ethanol, but other alcohols used as external preparations for skin may be used instead of ethanol. As such alcohols other than ethanol, those which can be mixed with water in an arbitrary ratio are preferred, and specific examples include polyhydric alcohols such as propylene glycol, 1,3-butanediol, glycerin and polypropylene glycol. When an alcohol other than ethanol is used, a form in which a part of ethanol is substituted with one or more kinds selected from alcohols other than ethanol is particularly preferable. At this time, it is preferable that ethanol does not lower than 50 mass% of the total alcohol. This content is particularly preferred in order to exhibit a single phase solution form. Conversely, a large amount of alcohol may impair the degree of prescription freedom. Further, the addition of water makes it possible to change the compound in the preparation with time, such as the SE form represented by the formula (2) and the Z form represented by the formula (3) It is preferable that the ratio of water to the total weight in the preparation is 0.1 to 35 mass%, more preferably 1 to 30 mass%, and an aqueous thickener other than cellulose is used , It is preferably 5 to 35% by mass, and more preferably 10 to 30% by mass. In addition to water, there are anionic surfactants such as sodium dodecyl sulfate and sodium polyoxyethylene (4) lauryl phosphate in addition to water, and it is also possible to use such components in place of water However, in a portion other than a nail, such a component may induce a stimulation. Therefore, in the present invention, it is preferable to use only water without using such a component. In addition, in the external preparation for skin of the present invention, an emulsifying agent may be employed, but in order to make the skin permeability excellent due to the use of alcohol such as ethanol as a solvent, the external preparation for antifungal use of the present invention is a single- . The term "single phase solution" as used herein means that no clouding is observed in a commonly used liquid material, and neither liquid crystal nor microcrystals are observed under polarized light.

The ratio of the content of water to the content of alcohol such as ethanol in the antifungal external preparation of the present invention is preferably from 1:99 to 4: 6 by mass ratio, more preferably from 5:95 to 3: 7, : 4 is particularly preferable. When the anionic surfactant is contained in the external preparation for antifungal according to the present invention, the preferable ratio of the content of the anionic surfactant to the content of the alcohol is 1:99 to 4: 6. When water and an anionic surfactant are contained in the external preparation for antifungal drugs of the present invention, water and an anionic surfactant are preferably contained so that the ratio of water to anionic surfactant is 20: 1 to 1: 1.

Further, as a secondary effect, it is possible to formulate without using flammable hazardous materials (first petroleum), for example, methyl ethyl ketone or the like. By taking this form, versatility is enhanced, so that a form that does not contain flammable dangerous substances is more preferable. Further, by adding the cellulose-based thickening agent, the percutaneous absorption property can be improved while maintaining the stereostructure in a stable state. As the cellulose-based thickener for obtaining such an effect, hydroxypropylmethylcellulose and hydroxypropylcellulose can be preferably exemplified. The content of the cellulose thickener is preferably 0.01 to 5% by mass with respect to the total amount of the external preparation for antifungal use, more preferably 0.1 to 2.5% by mass to ensure a solution form of a single phase. If the content of the cellulose thickener is less than 0.01 mass%, the effect of improving the transdermal absorbability can not be expected. If the content is more than 5 mass%, the viscosity becomes too high and the preparation becomes not suitable for a wide range of applications.

≪ Formula 1 >

(2)

(3)

The external preparation for an antifungal agent of the present invention may contain, in addition to these components, an optional ingredient usually used as a skin external preparation. Examples of such optional components include macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, horseradish, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid lanolin, hardened palm oil, Castor oil, beeswax, candelilla wax, carnauba wax, pewter, lanolin, reduced lanolin, hard lanolin, jojoba wax. Gadolcean. Erucic acid, butyric acid. Caproic acid. Caprylic acid. Mount Margarita. Bihhenic acid. Lignoceric acid. Nerubansan. Mt. Team nodon., Brass Mountain. ., Eicosanoic acid, nerbansan, parnaric acid, timodone, brassic acid. Higher fatty acids such as cyclopadonic acid, and the like; Higher alcohols such as oleyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol and cetostearyl alcohol; Diisopropyl sebacate, diisopropyl sebacate, di-2-ethylhexyl sebacate, cetyl lactate, diisostearyl malate, diisostearyl sebacate, diisostearate, Ethylhexanoic acid ethylene glycol, dicaprylic acid neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, triisostearic acid trimethylol Synthetic ester oils such as propane and tetra-2-ethylhexanoic acid pentane erythritate; Emulsions such as silicone oil not classified by the above silicone such as modified polysiloxanes such as amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane and fluorine-modified polysiloxane; Anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate and the like), potassium lauryl sulfate, triethanolamine alkyl ether sulfate and sodium polyoxyethylene lauryl phosphate; Cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride and laurylamine oxide; (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt and the like), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, Amphoteric surfactants, etc.) and acylmethyltaurine; Sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan monolaurate, sorbitan sesquioleate), glycerin fatty acids (such as glycerin monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate) , Hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, monostearic acid polyoxyethylene sorbitan, monolauric polyoxyethylene sorbitan, etc.), POE sorbit fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate etc.), POE alkyl ethers (POE lauryl ether, POE oleyl ether, POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE POE · POP alkyl ethers (POE · POP2-decyltetradecyl ether and the like), Tetronic acids, POE castor oil-hardened castor oil derivatives (POE castor oil, POE nonylphenyl ether and POE nonylphenyl ether) , POE hardened castor oil, etc.), sucrose fatty acid esters and alkyl glucosides; Moisturizing classifications such as sodium pyrrolidonecarboxylate, lactic acid, and sodium lactate; PH adjusting agents such as phosphoric acid and citric acid; Mica, talc, kaolin, synthetic mica and barium sulfate which may be surface-treated; Inorganic pigments such as red iron oxide, sulfur iron oxide, black iron oxide, cobalt oxide, ultramarine, ultrafiltration, titanium oxide and zinc oxide which may be surface-treated; Pearl formulations, such as mica titanium, noble metal, and bismuth oxychloride, which may be surface treated; Red No. 202, Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204; Polyethylene powder, polymethyl methacrylate, nylon powder, and organopolysiloxane elastomer; Para-aminobenzoic acid-based ultraviolet absorbers; Anthranilic acid-based ultraviolet absorber; A salicylic acid-based ultraviolet absorber; Shin Nam acid ultraviolet absorber; Benzophenone-based ultraviolet absorbers; Ultraviolet absorber; Ultraviolet absorbers such as 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane; Lower alcohols such as ethanol and isopropanol; Vitamin B such as vitamin A or a derivative thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or a derivative thereof, vitamin B12, vitamin B15 or a derivative thereof; vitamin E such as? -tocopherol,? -tocopherol,? -tocopherol and vitamin E acetate, vitamins such as vitamin D, vitamin H, pantothenic acid, pantethine and pyrroloquinoline quinone; Benzyl alcohol, triacetin, crotamiton, carbonic acid diesters such as propranol carbonate, and solvents such as ethylene glycol salicylate, and the like. In the case of application to seborrheic dermatitis, it is preferable that it has a proper viscosity so that the medicine does not dissipate in addition to the application site due to liquid dripping. For this purpose, a cellulose thickener which is an essential ingredient is contained, Methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and ethyl cellulose. Depending on the purpose, methyl vinyl ether maleic anhydride copolymer, acrylic resin alkanolamine solution, polyvinyl pyrrolidone, alkyl-modified It is preferable to contain a gelling agent such as a carboxyvinyl polymer.

When other gelling agents are added in addition to the cellulose type thickening agent, it is preferable that the cellulose type thickening agent and other gelling agents are contained in a total amount of 0.05 to 4 mass% with respect to the total amount of the external preparation for antifungal use, By mass to 4% by mass. In this embodiment, the content of the cellulose-based thickening agent is preferably 0.01 to 5% by mass, more preferably 0.1 to 2.5% by mass based on the total amount of the external preparation for antifungal therapy. If the amount is too small, the effect of preventing liquid spillage may not be exhibited. If the amount is too small, the solution form of the single phase, which is a preferable form of the present invention, may be impaired or the gel strength may be too high to reach the target tissues such as pores This is because there is a case where it is not.

In the external preparation for the antifungal drug of the present invention, a flammable solvent other than the alcohol represented by ethanol such as methyl ethyl ketone or N-methyl-2-pyrrolidone may be contained in the solvent, By mass or less, more preferably 1% by mass or less, and more preferably substantially not. This is because, even if such a solvent is not present, the composition of the single phase solution can be realized in the composition of the external preparation for antifungal according to the present invention, and the negative factors such as the possibility of stimulation and flammability which the solvent has can be excluded. The flammable solvent referred to in the present invention refers to the special phosphates and the first petroleum products defined by the Fire Service Act.

The anti-fungal external preparations of the present invention can be prepared by treating the essential components, preferable components, optional components, and the like in accordance with a conventional method. For example, it is preferable to prepare the external preparations by the procedure shown in the following Examples.

The external preparation for antifungal use of the present invention thus produced is applied to cosmetics containing quasi-drugs, skin pharmaceutical preparations, dermatological products, and the like, but it is particularly preferred to be applied as a dermatological drug for antifungal agents. As the external preparation for the antifungal use, it is preferable to apply it to the external skin medicine for seborrheic dermatitis, which is applied to a site which has a wide range of application sites and is likely to feel irritation, because its characteristics can be further improved. However, The present invention can also be effectively applied to foot fungus infections such as tinea pedis and tinea pedis such as tinea tinea. Therefore, the application to such fungal infections also falls within the technical scope of the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to these examples.

<Prescription>

An appropriate amount of ethanol was added to ruliconazole to dissolve it. Hydroxypropyl cellulose (&quot; HPC-H &quot;, manufactured by Nippon Soda Co., Ltd.) was gradually added thereto and water was further added thereto to make it uniform (Table 1). This was referred to as external preparation for skin A, and the amount of hydroxypropyl cellulose in external preparation for skin A was reduced to 1.5% by mass and the weight loss was replaced by ethanol. As a control, a solution in which 1.2% by mass of ruliconazole was added with ethanol alone was prepared and designated as skin external preparation C.

Manufactured by Daicel Chemical Industries, Ltd.) was gradually added, and further water was added thereto to make it uniform (Table 1). This was referred to as external preparation for skin A, and the amount of hydroxypropyl cellulose in external preparation for skin A was reduced to 1.5% by mass and the weight loss was replaced by ethanol. As a control, a solution in which 1.2% by mass of ruliconazole was added with ethanol alone was prepared and designated as skin external preparation C.

Form of preparation: Visually confirm that it is uniformly dissolved in a single day

The irritation of this preparation was not confirmed.

Percutaneous absorption test

The above external preparation for skin was applied to the foot of the excised Mormot's hind leg at room temperature and allowed to stand at room temperature for 2 hours. Then, the external preparation for skin was wiped from the application site and the applied area was tape-stripped 5 times with cellophane tape.

After doing so, the plantar part was cut out, the stratum corneum was peeled off, and the shape of the plant was cut to a predetermined size, followed by drying under reduced pressure for 24 hours. Methanol was added to the obtained dry matter, and ruliconazole was measured in an ultrasonic crusher. After filtration through a filter, the concentration of ruliconazole in the stratum corneum was measured under the following analysis conditions.

Concentrations in the stratum corneum were as follows, and it was confirmed that the addition of hydroxypropylcellulose increased the concentration of ruricinazol in the stratum corneum and improved percutaneous absorption. It was also confirmed that the amount of percutaneous absorption was increased by increasing the hydroxypropyl cellulose content from 1.5% by mass to 1.8% by mass.

<Prescription>

An appropriate amount of ethanol was added to ruliconazole to dissolve it. Hydroxypropylmethylcellulose ("Metro Oz 60SH-4000"; manufactured by Shin-Etsu Chemical Co., Ltd.) was gradually added to the solution, and water was added thereto to make it uniform (Table 4). This was referred to as external preparation for skin D, and as a control, 1.2% by mass of ruliconazole was added with ethanol alone to prepare external skin preparation E.

Form of preparation: Visually confirm that it is uniformly dissolved in a single day

The irritation of this preparation was not confirmed.

The concentration in the stratum corneum was as follows, and it was confirmed that the addition of hydroxypropylmethylcellulose 2910 increased the concentration of ruricinazole in the stratum corneum and improved percutaneous absorption

By combining the compound represented by the formula (1) with an alcohol such as ethanol having a certain range content, water, etc., and a cellulose-based thickening agent, the stability of the stereostructure of the compound can be maintained and the absorbability to the skin can be improved.

Claims (6)

Characterized in that it contains a compound represented by the general formula (1), 50 to 95% by mass of an alcohol, 0.1 to 35% by mass of water and / or an anionic surfactant, and 0.01 to 5% by mass of a cellulose- The external preparation for an antifungal agent according to claim 1, wherein the compound represented by the formula (1) is luliconazole. The external preparation for an antifungal agent according to claim 1 or 2, wherein the flammable solvent excluding alcohol is contained in an amount of 1% by mass or less based on the total amount of the external preparation for antifungal use. The external preparation for an antifungal agent according to any one of claims 1 to 3, which is in the form of a single phase solution. The method according to any one of claims 1 to 4, characterized in that the disease to which it is applied is tingling (tine tinea, body tinea or tinea tinea), candida, psoriasis (biliary or interstitial erosion) Wherein the composition is an external preparation for an antifungal agent. The external preparation for an antifungal agent according to claim 5, wherein the disease to be treated is seborrheic dermatitis.