Pharmaceutical composition for preventing or treating nail and skin tinea

Abstract

A pharmaceutical composition for preventing or treating nail and skin tinea is disclosed. It may contain an antifungal agent, a crystal growth inhibitor, and a keratin affinity inhibitor. One embodiment of the composition is an external preparation containing an antifungal agent. It inhibits crystal growth during storage, preventing crystal precipitation after application, and inhibits keratin affinity, improving skin and nail permeability and antibacterial activity. The composition may contain an antifungal agent as an active ingredient and auxiliary ingredients such as a crystal growth inhibitor, a keratin affinity inhibitor, a chelating agent, and additives (e.g., a vehicle, antioxidant, pH adjuster).

Description

[Technical Field]

[0001] The present disclosure relates to pharmaceutical compositions for the prevention or treatment of nail and skin tinea. [Background technology]

[0002] Tinea is a general term for superficial mycoses caused by dermatophytes. Dermatophytes are keratinophilic fungi that contain keratinase, which can dissolve keratin, and parasitize the keratin in the stratum corneum of the epidermis, hair, nails, and toenails.

[0003] Tinea is generally classified into tinea captis (tinea captis), tinea corporis (tinea coporis), tinea cruris (tinea cruris), tinea barbae (tinea barbae), tinea faciei (tinea faciel), tinea manus (tinea manus), tinea pedis (tinea pedis), and tinea unguium (tinea unguium) depending on the site of occurrence [Non-Patent Document 1: Byung Ho Oh, Kyu Joong Ahan. "Drug Therapy of Dermatophytosis" J Korean Med. Assoc. 2009, 52(11):1109-1114].

[0004] The causative bacteria of ringworm vary depending on the site of onset and the patient's age, but common causative bacteria include Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyt floccosum, Microsporum canis, the yeast Candida albicans, and the mold Aspergillus niger.

[0005] Among the several causative fungi of tinea, Trichophyton rubrum accounts for 60% and Trichophyton mentagrophytes accounts for 20%. Tinea unguium is particularly common in people aged 40 and over, with Trichophyton rubrum accounting for 91.0% and Trichophyton mentagrophytes accounting for 7.7% of the causative fungi of tinea unguium [Non-Patent Document 2: Uwe Wollina, Holger Haenssle, Dtsch Arztebl Int. 2016; 113(29-30): 509-518].

[0006] Depending on the route and location of fungal invasion into the nail, onychomycosis can be classified into (1) distal and lateral subungual onychomycosis (DLSO), (2) proximal subungl onychomycosis (PSO), (3) white superficial subungual onychomycosis (WSO), (4) endonyx onychomycosis (EO), and (5) total dystrophic onychomycosis (TDO).

[0007] Antifungal agents are broadly classified into polyenes, azoles, allylamines, benzylamines, morpholinos, hydroxypyridones, oxaboroles, etc. Among these, luliconazole (1% cream / 5% liquid), efinaconazole (10% liquid), terbinafine (1% cream / spray), amorolfine (5% nail lacquer), ciclopirox (8% nail lacquer), tavaborole (5% liquid), etc. are widely available commercially as onychomycosis treatments.

[0008] However, most antifungal agents have low solubility, which can lead to crystallization due to temperature changes during storage or when the drug is applied to the affected area and dried. This crystallization can be explained by the Ostwald ripening theory, in which small particles with a high equilibrium concentration in solution are dissolved into larger particles with a low equilibrium concentration, forming larger particles.

[0009] Furthermore, conventional antifungal agents have a high affinity with keratin in the skin and nails, which significantly reduces the drug permeability, resulting in a technical limitation in which the effectiveness of preventing and treating tinea is reduced.

[0010] Meanwhile, currently widely available antifungal products include Jubulia (Efinaconazole 10%), which contains cyclomethicone and ethylenediamine tetraacetic acid salt, Luconac (Luliconazole 5%), which contains N-methylpyrrolidone, and Kerydin (Tavabole 5%), which contains ethylenediamine tetraacetic acid salt.

[0011] However, cyclomethicone is harmful to the environment and its use is restricted in many countries, and methylpyrrolidone is classified as a carcinogen, mutagen, or reproductive toxicant and its use is strictly restricted. Also, ethylenediaminetetraacetate, which has long been used as a chelating agent, has poor biodegradability and may deposit heavy metals in soil and water, leading to the inflow of heavy metals through the food chain, making its use undesirable from an environmental standpoint.

[0012] Therefore, there is a need to develop a new technology that can not only resolve the problems caused by harmful ingredients contained in currently available products, but also inhibit the crystal growth of antifungal agents, improve their solubility, and reduce their affinity for keratin, thereby significantly improving their skin and nail penetration ability and antibacterial effect. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] 1. Byung Ho Oh, Kyu Joong Ahan. “Drug Therapy of Dermatophytosis” J Korean Med.Assoc.2009, 52(11):1109-1114. [Non-patent document 2] 2. Uwe Wollina, Holger Haenssle, Dtsch Arztebl Int.2016;113(29-30):509-518. Summary of the Invention [Problem to be solved by the invention]

[0014] The technical idea of ​​the present disclosure is intended to solve the above-mentioned problems, and its purpose is to provide a technology that can prevent antifungal agents from precipitating as crystals, improve storage stability, and enhance the therapeutic effect of the drug. Another object of the technical concept of the present disclosure is to provide a technology that reduces the keratin affinity of antifungal agents to increase their ability to penetrate skin and nails.

[0015] At the same time, another object of the technical idea of ​​the present disclosure is to provide a technology that can fundamentally solve the problems caused by the use of cyclomethicone, methylpyrrolidone, and ethylenediaminetetraacetate.

[0016] The problems to be solved by the present invention are not limited to the above-mentioned problems, and other technical problems not mentioned above will be clearly understood by those having ordinary skill in the art to which the present invention pertains from the contents to be described below. [Means for solving the problem]

[0017] To achieve this object, in one embodiment of the present invention, a pharmaceutical composition for preventing or treating nail and skin tinea comprises an antifungal agent; a crystal growth inhibitor; a keratin affinity inhibitor; and an additive; wherein the antifungal agent comprises efinaconazole, the content of the antifungal agent being 10 wt% based on the total weight of the composition; the crystal growth inhibitor comprises 1,2-pentanediol and acetyl tributyl citrate in a weight ratio of 1:2, the content of the crystal growth inhibitor being 0.1 to 30 wt% based on the total weight of the composition; the keratin affinity inhibitor comprises cystamine dihydrochloride or octenidine dihydrochloride, the content of the keratin affinity inhibitor being 0.01 to 10 wt% based on the total weight of the composition; and the causative fungus of tinea comprises at least one selected from Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans.

[0018] On the other hand, the pharmaceutical composition for preventing or treating ringworm may further comprise a chelating agent. The content of the chelating agent may be 0.0001 to 5% by weight based on the total weight of the composition. At the same time, the chelating agent can include ethylenediamine trisodium disuccinate. The additive may include at least one selected from the group consisting of a vehicle, an antioxidant, and a pH adjuster.

[0019] The pharmaceutical composition for preventing or treating tinea may be prepared in at least one dosage form selected from the group consisting of a liquid, an aerosol, a stick, and a semi-solid. At the same time, the semi-solid agent may include at least one of a gel, a lotion, a cream, and an ointment. The pharmaceutical composition for preventing or treating tinea may be applied at a pH of 2 to 10. The density of the pharmaceutical composition for preventing or treating ringworm is 0.5 to 2 g / cm 3 It can be applied in At the same time, the pharmaceutical composition for preventing or treating ringworm may be applied with a water content of 0.1 to 90% by weight as measured by the Karl Fischer method. The surface tension of the pharmaceutical composition for the prevention or treatment of tinea may be 1 to 76 dyn / cm.

[0020] The above-described solutions to the problems are merely exemplary and are not to be construed as limiting the present invention. In addition to the exemplary embodiments described above, there may be additional embodiments described in the drawings and detailed description of the invention. [Effects of the Invention]

[0021] As described above, various embodiments of the present invention inhibit the crystal growth of the poorly soluble antibacterial agents luliconazole, efinaconazole, and tavaborole as active ingredients, thereby improving the solubility of the drug, thereby preventing the precipitation of crystals even when the temperature changes during long-term storage. Furthermore, when the drug is applied to the affected area of ​​the skin or nail, the generation of fine precipitates at the affected area after the volatile solvent evaporates is prevented, and the permeability of the drug is significantly improved. Furthermore, according to various embodiments of the present invention, crystal growth of the drug is inhibited, so no precipitates are formed, and the antibacterial activity is excellent.

[0022] In addition, according to various embodiments of the present invention, when a drug is applied to the affected areas of the skin and nails, the keratin affinity of the antibacterial agent, which is the active ingredient, is inhibited, thereby further increasing the drug permeability, which has the advantage of being very effective in preventing and treating tinea pedis and tinea unguium.

[0023] At the same time, various embodiments of the present invention have an excellent effect of preventing crystal precipitation after application of the drug, which results in high compliance with the drug and excellent drug permeability and antibacterial activity in the skin and nails.

[0024] In addition, since it does not contain cyclomethicone and N-methylpyrrolidone, which are restricted substances contained in currently available products, or ethylenediaminetetraacetate, which is poorly biodegradable, it is less harmful and more environmentally friendly than products containing these substances, and can be widely used as a pharmaceutical composition for external preparations for the prevention or treatment of tinea pedis and tinea unguium.

[0025] The effects of the various embodiments of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description of the claims. [Brief explanation of the drawings]

[0026] [Figure 1] 1 is a graph showing the results of the cumulative permeation concentration of luliconazole over 10 days in Control Example 1, Comparative Example 1, and Production Examples 1 to 5. [Figure 2] 1 is a graph showing the cumulative permeation concentration of efinaconazole over 10 days in Control Example 2, Comparative Example 2, and Production Examples 6 to 10. [Figure 3] 1 is a graph showing the cumulative transmittance concentration results for 10 days of tababorole in Control Example 3, Comparative Example 3, and Production Examples 11 to 15. DETAILED DESCRIPTION OF THE INVENTION

[0027] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will now be described in more detail with reference to the accompanying drawings, but well-known technical details will be omitted or simplified for the sake of brevity. References herein to "one" or "an" embodiment of the present invention are not necessarily to the same embodiment, but rather to at least one. In the following examples, the singular expression includes the plural expression unless the context clearly indicates otherwise. In the following examples, the terms "comprise" or "have" mean that the features or components described in the specification are present, but do not preclude the possibility that one or more other features or components may be added.

[0028] As used herein, the term "prevention" refers to any action that inhibits or delays the onset, spread or recurrence of a disease by administering a pharmaceutical composition according to various embodiments of the present invention. As used herein, the term "treatment" refers to any action that improves or favorably alters the symptoms of a disease by administering a pharmaceutical composition according to various embodiments of the present invention. As used herein, the term "administering" means providing an active ingredient to a subject by any suitable means. As used herein, the term "subject" includes, but is not limited to, mammals, including humans, guinea pigs, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, or rabbits, and preferably is a human. As used herein, the term "external preparation" refers to a pharmaceutical agent that is administered by applying, spraying, or adhering to the skin. As used herein, the term "pharmaceutically acceptable" means that a substance is physiologically acceptable and does not normally cause gastrointestinal disorders, allergic reactions such as dizziness, or similar reactions when administered to humans.

[0029] As used herein, the term "salt" refers to an acid addition salt formed with a pharmaceutically acceptable free acid. Therefore, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as inorganic ion salts prepared with calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc.; acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, Examples include organic acid salts prepared from ascorbic acid, carboxylic acids, or vanillic acid; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid; amino acid salts prepared from glycine, arginine, or lysine; or amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, or picoline; but the types of salts referred to in this specification are not limited to these salts.

[0030] TIFF2026508197000002.tif26166

[0031] As used herein, the term "water content" refers to the water content in a pharmaceutical composition expressed as a percentage. The water content described herein is measured by Karl Fischer titration, and may be measured using a Metrohm 901 KF Titrando water meter.

[0032] TIFF2026508197000003.tif39166

[0033] According to one embodiment, the pharmaceutical composition for preventing or treating tinea may include an antifungal agent as an active ingredient, and may further include auxiliary ingredients (e.g., crystal growth inhibitors, keratin affinity inhibitors, chelating agents, additives, etc.). In one embodiment, the pharmaceutical composition for preventing or treating tinea cutaneous and tinea unguium may be embodied as a pharmaceutical composition for external application containing an antifungal agent.

[0034] According to one embodiment, the pharmaceutical composition for preventing or treating tinea may include an antifungal agent, a crystal growth inhibitor, and a keratin affinity inhibitor. In one embodiment, the content of the antifungal agent may be 0.1 to 20 wt % based on the total weight of the composition.

[0035] As a specific example, the content of the antifungal agent is 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, and The antifungal agent may be provided in an amount of 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20% by weight. The content of the antifungal agent may range from one or more of the above values ​​to one or less of the above values.

[0036] For example, the content range of the antifungal agent can be provided in the range of 0.1% to 18% by weight, 0.5% to 17% by weight, 1% to 16% by weight, 2% to 15% by weight, 3% to 14% by weight, 4% to 13% by weight, 5% to 20% by weight, 8% to 20% by weight, 10% to 16% by weight, 1% to 10% by weight, 5% to 15% by weight, or 0.1% to 20% by weight.

[0037] At the same time, the content of the antifungal agent may be one or more of the above values, or one or less of the above values, for example, the content of the antifungal agent may be 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, or 8 wt% or less, or 20 wt% or less, 19 wt% or less, 18 wt% or less, 17 wt% or less, 16 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or 10 wt% or less.

[0038] In one embodiment, the content of the antifungal agent may be applied in an amount effective for preventing or treating tinea skin and tinea unguium. The level of an amount effective for preventing or treating tinea skin and tinea unguium may be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route, excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field. Taking all of the above factors into consideration, it is important to administer an amount that achieves maximum effect with the minimum amount without side effects, which can be easily determined by one skilled in the art.

[0039] In one embodiment, the antifungal agent is a chemical substance that exhibits bactericidal activity against Trichophyton rubrum, Trichophyton Mentagrophytes, Candida albicans, etc., and the type of antifungal agent is not limited to a specific type as long as it exhibits antibacterial activity against the aforementioned fungi.

[0040] In one embodiment, the antifungal agent may include at least one selected from luliconazole, luliconazole salts, efinaconazole, efinaconazole salts, tavaborole, and tavaborole salts as an azole and oxaborole antibacterial agent. In one embodiment, the structural formula of luliconazole can be represented by the following Chemical Formula 1:

[0041] [C1] TIFF2026508197000004.tif32166

[0042] In addition, in one embodiment, the luliconazole salt is a pharmaceutically acceptable salt of luliconazole, and may be applied in the form of at least one selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts, and amine salts. In one embodiment, the structural formula of efinaconazole can be represented by the following Chemical Formula 2:

[0043] [Case 2] TIFF2026508197000005.tif39166

[0044] In one embodiment, the efinaconazole salt is a pharmaceutically acceptable salt of efinaconazole, and may be applied in the form of at least one selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts, and amine salts.

[0045] In one specific example, the structural formula of tababorole can be represented by the following chemical formula 3.

[0046] [C3] TIFF2026508197000006.tif39166

[0047] In one embodiment, the tavaborole salt is a pharmaceutically acceptable salt of tavaborole, and may be at least one selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts, and amine salts.

[0048] In one embodiment, the crystal growth inhibitor can inhibit the crystallization of a specific component contained in the pharmaceutical composition, for example, the crystal growth inhibitor can prevent the antifungal agent contained in the composition from precipitating as crystals.

[0049] In one embodiment, the content of the crystal growth inhibitor may be 0.1 to 70 wt% based on the total weight of the composition. Specific examples of the content of the crystal growth inhibitor include 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%, 10.5 wt%, and 1 wt%. It may be prepared in an amount of 1 wt%, 11.5 wt%, 12 wt%, 12.5 wt%, 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17 wt%, 17.5 wt%, 18 wt%, 18.5 wt%, 19 wt%, 19.5 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, or 70 wt%. The content of the crystal growth inhibitor may be in a range of one or more of the above values ​​and one or less of the above values.

[0050] For example, the content range of the crystal growth inhibitor may be 0.1 wt% to 18 wt%, 0.5 wt% to 17 wt%, 1 wt% to 16 wt%, 2 wt% to 15 wt%, 3 wt% to 14 wt%, 4 wt% to 13 wt%, 5 wt% to 20 wt%, 8 wt% to 20 wt%, 10 wt% to 16 wt%, 1 wt% to 10 wt%, 5 wt% to 15 wt%, 0.1 wt% to 20 wt%, 10 wt% to 15 wt%, 10 wt% to 30 wt%, 10 wt% to 40 wt%, 20 wt% to 50 wt%, 30 wt% to 60 wt%, 40 wt% to 70 wt%, or 0.1 wt% to 70 wt%.

[0051] The content of the crystal growth inhibitor may be one or more of the above values, or one or less of the above values, for example, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, 10 wt% or more, or 15 wt% or more, or 70 wt% or less, 60 wt% or less, 50 wt% or less, 40 wt% or less, 30 wt% or less, 20 wt% or less, or 10 wt% or less.

[0052] According to one embodiment, the crystal growth inhibitor may include 1,2-pentanediol and an ester compound, and the ester compound may be at least one selected from the group consisting of acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, and diethyl carbonate.

[0053] In one embodiment, the weight ratio of 1,2-pentanediol to the ester compound may be 1: 2. If the weight ratio of 1,2-pentanediol to the ester compound is outside of 1: 2, crystals may be deposited or precipitates may form during storage of the composition, which may negatively affect the penetration and antibacterial activity of the composition.

[0054] In one embodiment, the keratin affinity inhibitor can inhibit the antifungal agent from being adsorbed onto keratin in the skin or nails. In one embodiment, the content of the keratin affinity inhibitor may be 0.01 to 30 wt % based on the total weight of the composition.

[0055] Specific examples of the content of the keratin affinity inhibitor include 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% by weight, 5% by weight, 5.5% by weight, 6% by weight, 6.5% by weight, 7% by weight, 7.5% by weight, 8% by weight, 8.5% by weight, 9% by weight, 9.5% by weight, and 10% by weight. , 10.5wt%, 11wt%, 11.5wt%, 12wt%, 12.5wt%, 13wt%, 13.5wt%, 14wt%, 14.5wt%, 15wt%, 15.5wt%, 16wt%, 16.5wt%, 17wt%, 17.5wt%, 18wt%, 18.5wt%, 19wt%, 19.5wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt%, or 30wt%. In addition, the content of the keratin affinity inhibitor may be in a range of one or more of the above values ​​and one or less of the above values.

[0056] For example, the content range of the keratin affinity inhibitor may be 0.1% to 18% by weight, 0.5% to 17% by weight, 1% to 16% by weight, 2% to 15% by weight, 3% to 14% by weight, 4% to 13% by weight, 5% to 20% by weight, 8% to 20% by weight, 10% to 16% by weight, 1% to 10% by weight, 5% to 15% by weight, 0.1% to 20% by weight, 10% to 15% by weight, 10% to 30% by weight, 20% to 30% by weight, or 0.01% to 30% by weight.

[0057] The content of the keratin affinity inhibitor may be one or more of the above values, or one or less of the above values. For example, the content of the keratin affinity inhibitor may be 0.01 wt% or more, 0.05 wt% or more, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, 10 wt% or more, or 30 wt% or less, 25 wt% or less, 20 wt% or less, 19 wt% or less, 18 wt% or less, 17 wt% or less, 16 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, or 10 wt% or less.

[0058] In one embodiment, the keratin affinity inhibitor may include cystamine dihydrochloride. In another embodiment, the keratin affinity inhibitor may further include at least one selected from lauryl choline, tricaprylin, and octenidine dihydrochloride. Depending on the implementation, the keratin affinity inhibitor may be a single component of the above-mentioned keratin affinity inhibitor, or a combination of two or more components.

[0059] Meanwhile, the pharmaceutical composition for preventing or treating ringworm according to one embodiment may further comprise a chelating agent, in one embodiment, the content of the chelating agent may be 0.0001 to 5 wt % based on the total weight of the composition.

[0060] Specifically, the content of the chelating agent may be 0.0001 wt%, 0.001 wt%, 0.01 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, or 5 wt%, and the content of the chelating agent may be in a range of one or more of the above values ​​and one or less of the above values.

[0061] For example, the content range of the chelating agent can be provided in the range of 0.0001 wt % to 5 wt %, 0.0001 wt % to 4 wt %, 0.0001 wt % to 3 wt %, 0.0001 wt % to 2 wt %, 0.0001 wt % to 1 wt %, 0.0001 wt % to 0.5 wt %, 0.01 wt % to 5 wt %, 0.01 wt % to 1 wt %, 0.01 wt % to 0.1 wt %, or 0.1 wt % to 5 wt %.

[0062] At the same time, the content of the chelating agent may be one or more of the above values, or one or less of the above values. For example, the content of the chelating agent may be 0.0001 wt% or more, 0.001 wt% or more, 0.01 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, or 4.5 wt% or more, or 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less, 0.5 wt% or less, 0.1 wt% or less, 0.01 wt% or less, 0.001 wt% or less, 0.005 wt% or less, or 0.007 wt% or less. In one embodiment, the chelating agent can include ethylenediamine trisodium disuccinate.

[0063] In one embodiment, the pharmaceutical composition for preventing or treating ringworm may further include an additive, which may include at least one selected from the group consisting of a vehicle, an antioxidant, and a pH adjuster.

[0064] In one embodiment, the vehicle is an additive that can maintain the shape of the composition. The vehicle according to one embodiment may be at least one selected from the group consisting of purified water, glycerin, mineral oil, lanolin oil, sorbitol, ethanol, isopropyl alcohol, acetone, ethyl acetate, and mixtures thereof. Preferably, purified water, ethanol, isopropyl alcohol, glycerin, etc. may be used as the vehicle. In one embodiment, the content of the vehicle may be in the range of 0.1 to 90 wt% based on the total weight of the composition.

[0065] As specific examples, the vehicle content is 0.1 weight%, 0.2 weight%, 0.3 weight%, 0.4 weight%, 0.5 weight%, 0.6 weight%, 0.7 weight%, 0.8 weight%, 0.9 weight%, 1 weight%, 1.5 weight%, 2 weight%, 2.5 weight%, 3 weight%, 3.5 weight%, 4 weight%, 4.5 weight%, 5 weight%, 5.5 weight%, 6 weight%, 6.5 weight%, 7 weight%, 7.5 weight%, 8 weight%, 8.5 weight%, 9 weight%, 9.5 weight%, 10 weight%, 10.5 weight%, 11 weight%, 11.5 weight%, It can be provided in 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight.

[0066] In one embodiment, the antioxidant may be at least one selected from the group consisting of butylhydroxytoluene, butylhydroxyanisole, ferulic acid, ascorbic acid, and tocopherol. Preferably, butylhydroxytoluene is used as the antioxidant. In one embodiment, the content of the antioxidant may be in the range of 0.0001 to 1 wt% based on the total weight of the composition.

[0067] Specifically, for example, the content of the antioxidant may be 0.0001 wt%, 0.001 wt%, 0.01 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, or 1 wt%.

[0068] In one embodiment, the pH adjuster may be at least one selected from the group consisting of citric acid, pentetic acid, tartaric acid, and succinic acid, and preferably, citric acid may be used as the pH adjuster. In one embodiment, the content of the pH adjuster may be prepared in the range of 0.0001 to 5 wt% based on the total weight of the composition.

[0069] As a specific example, the content of the pH adjuster may be provided at 0.0001 wt%, 0.001 wt%, 0.01 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, or 5 wt%.

[0070] According to one embodiment, the pharmaceutical composition for preventing or treating tinea may be prepared in at least one dosage form selected from the group consisting of a liquid, an aerosol, a stick, and a semi-solid formulation. In one embodiment, the semi-solid formulation may include at least one of a gel, a lotion, a cream, and an ointment.

[0071] The pH of the pharmaceutical composition for preventing or treating tinea according to one embodiment may be 2 to 10. As a specific example, the pH of the pharmaceutical composition for preventing or treating tinea may be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. The pH of the pharmaceutical composition for preventing or treating tinea according to one embodiment may be in a range of one or more of the above values ​​and one or less of the above values. For example, the pH range of the pharmaceutical composition may be 2 to 10, 4 to 10, 5 to 9.5, 6 to 8, or 7 to 8.

[0072] The density of the pharmaceutical composition for preventing or treating tinea according to one embodiment is 0.5 to 2 g / cm 3 As a specific example, the density of the pharmaceutical composition for preventing or treating ringworm can be 0.5 g / cm 3 , 0.6g / cm 3 , 0.7g / cm 3 , 0.8g / cm 3 , 0.9g / cm 3 , 1g / cm 3 , 1.1g / cm 3 , 1.2g / cm 3 , 1.3g / cm 3 , 1.4g / cm 3 , 1.5g / cm 3 , 1.6g / cm 3 , 1.7g / cm 3 , 1.8g / cm 3 , 1.9g / cm 3 or 2g / cm 3 It can be applied in

[0073] In one embodiment, the density of the pharmaceutical composition for topical application containing an antifungal agent as an active ingredient may be in the range of one or more of the above values ​​and one or less of the above values. For example, the density of the pharmaceutical composition may range from 0.5 to 2 g / cm. 3 , 0.8 to 2 g / cm 3 , 1.2 to 1.8 g / cm 3 , 1.5 to 1.7 g / cm 3or 1.5 to 2 g / cm 3 can be prepared in a range of

[0074] In one embodiment, the water content of the pharmaceutical composition for the prevention or treatment of tinea may be measured by the Karl Fischer method, and the water content of the composition measured by the Karl Fischer method may be 0.1 to 90 wt%. As a specific example, the water content of the pharmaceutical composition for preventing or treating ringworm may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111 It can be applied at 9%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%.

[0075] Furthermore, the water content of the pharmaceutical composition for topical application containing an antifungal agent as an active ingredient may range from one or more to one or less than the above values. For example, the water content of the pharmaceutical composition may range from 0.1 to 90%, 0.5 to 80%, 1 to 70%, 2 to 5%, 3 to 5%, 5 to 85%, 7 to 60%, 8 to 55%, 9 to 50%, 10 to 45%, 10 to 20%, 10 to 15%, 10 to 13%, 15 to 40%, or 20 to 35%.

[0076] In one embodiment, the surface tension of the pharmaceutical composition for the prevention or treatment of tinea may be 1 to 76 dyn / cm. Specific examples of the surface tension of the pharmaceutical composition for the prevention or treatment of tinea at 25°C include 1 dyn / cm, 2 dyn / cm, 3 dyn / cm, 4 dyn / cm, 5 dyn / cm, 6 dyn / cm, 7 dyn / cm, 8 dyn / cm, 9 dyn / cm, 10 dyn / cm, 11 dyn / cm, 12 dyn / cm, 13 dyn / cm, 14 dyn / cm, 15 dyn / cm, 16 dyn / cm, 17 dyn / cm, 18 dyn / cm, 19 dyn / cm, 20 dyn / cm, 21 dyn / cm, 22 dyn / cm, 23 dyn / cm, 24 dyn / cm, 25 dyn / cm, 26 dyn / cm, 27 dyn / cm, 28 dyn / cm, 29 dyn / cm, 30 dyn / cm, 31 dyn / cm, 32 dyn / cm, 33 dyn / cm, 34 dyn / cm, 35 dyn / cm, 36 dyn / cm, 37 dyn / cm, 38 dyn / cm, 39 dyn / cm, 40 dyn / cm, 41 dyn / cm, 42 dyn / cm, 43 dyn / cm, 44 dyn / cm, 45 dyn / cm, 46 dyn / cm, 47 dyn / cm, 48 dyn / cm, 49 dyn / cm, 50 dyn / cm, 51 dyn / cm, dyn / cm, 19dyn / cm, 20dyn / cm, 21dyn / cm, 22dyn / cm, 23dyn / cm, 24dyn / cm, 25dyn / cm, 26dyn / cm, 27dyn / cm, 28 dyn / cm, 29dyn / cm, 30dyn / cm, 31dyn / cm, 32dyn / cm, 33dyn / cm, 34dyn / cm, 35dyn / cm, 36dyn / cm, 37dyn / cm, 38d yn / cm, 39dyn / cm, 40dyn / cm, 41dyn / cm, 42dyn / cm, 43dyn / cm, 44dyn / cm, 45dyn / cm, 46dyn / cm, 47dyn / cm, 48d yn / cm, 49dyn / cm, 50dyn / cm, 51dyn / cm, 52dyn / cm, 53dyn / cm, 54dyn / cm, 55dyn / cm, 56dyn / cm, 57dyn / cm, 58dy n / cm, 59 dyn / cm, 60 dyn / cm, 61 dyn / cm, 62 dyn / cm, 63 dyn / cm, 64 dyn / cm, 65 dyn / cm, 66 dyn / cm, 67 dyn / cm, 68 dyn / cm, 69 dyn / cm, 70 dyn / cm, 71 dyn / cm, 72 dyn / cm, 73 dyn / cm, 74 dyn / cm, 75 dyn / cm or 76 dyn / cm.

[0077] Furthermore, the surface tension of the pharmaceutical composition for topical application containing an antifungal agent as an active ingredient may be in a range of one or more of the above values ​​and one or less of the above values. For example, the surface tension ranges of the pharmaceutical composition include 1 dyn / cm to 76 dyn / cm, 5 dyn / cm to 60 dyn / cm, 10 dyn / cm to 50 dyn / cm, 15 dyn / cm to 65 dyn / cm, 20 dyn / cm to 60 dyn / cm, 10 dyn / cm to 40 dyn / cm, 15 dyn / cm to 30 dyn / cm, 25 dyn / cm to 55 dyn / cm, and 30 dyn / cm to 50 dyn / cm. , 41 dyn / cm to 50 dyn / cm, 42 dyn / cm to 50 dyn / cm, 43 dyn / cm to 50 dyn / cm, 44 dyn / cm to 50 dyn / cm, 45 dyn / cm to 50 dyn / cm, 41 dyn / cm to 45 dyn / cm, 41 dyn / cm to 44 dyn / cm, 41 dyn / cm to 43 dyn / cm or 50 dyn / cm to 76 dyn / cm.

[0078] According to one embodiment, when the pharmaceutical composition for preventing or treating ringworm is applied topically, the daily application amount may be 0.01 to 60 g / day. For example, when the pharmaceutical composition is applied as an external preparation, the daily application amount may be 0.01 g / day, 0.02 g / day, 0.03 g / day, 0.04 g / day, 0.05 g / day, 0.06 g / day, 0.07 g / day, 0.08 g / day, 0.09 g / day, 0.1 g / day, 0.2 g / day, 0.3 g / day, 0.4 g / day, 0.5 g / day, 0.6 g / day, day, 0.7g / day, 0.8g / day, 0.9g / day, 1g / day, 2g / day, 3g / day, 4g / day, 5g / day, 6g / day, 7g / day, 8g / day , 9g / day, 10g / day, 11g / day, 12g / day, 13g / day, 14g / day, 15g / day, 16g / day, 17g / day, 18g / day, 19g / da y, 20g / day, 21g / day, 22g / day, 23g / day, 24g / day, 25g / day, 26g / day, 27g / day, 28g / day, 29g / day, 30g / day, 31g / day, 32g / day, 33g / day, 34g / day, 35g / day, 36g / day, 37g / day, 38g / day, 39g / day, 40g / day, 41 g / day, 42g / day, 43g / day, 44g / day, 45g / day, 46g / day, 47g / day, 48g / day, 49g / day, 50g / day, 51g / day, 52g / day, 53g / day, 54g / day, 55g / day, 56g / day, 57g / day, 58g / day, 59g / day or 60g / day.

[0079] Furthermore, when a pharmaceutical composition for topical application containing an antifungal agent as an active ingredient is topically applied, the daily application amount may be in the range of one or more of the above values ​​and one or less of the above values. For example, when a pharmaceutical composition is topically applied, the daily application amount may be in the range of 0.01 to 60 g / day, 0.1 to 60 g / day, 0.01 to 1 g / day, 0.01 to 0.5 g / day, 0.05 to 0.1 g / day, 1 to 60 g / day, 5 to 50 g / day, 10 to 40 g / day, 15 to 35 g / day, or 20 to 30 g / day.

[0080] In one embodiment, when the pharmaceutical composition is prepared as an external preparation and applied topically, a method of applying, spraying, or attaching an appropriate amount of the composition to the treatment area (e.g., nail, skin, etc.) of the patient can be used.

[0081] Meanwhile, the pharmaceutical composition for preventing or treating tinea according to one embodiment may be free of cyclomethicone, methylpyrrolidone, and ethylenediaminetetraacetate. That is, according to one embodiment, the pharmaceutical composition for preventing or treating tinea does not contain cyclomethicone, methylpyrrolidone, and ethylenediaminetetraacetate, thereby fundamentally eliminating the harmful effects of the corresponding ingredients.

[0082] According to one embodiment, the color of the pharmaceutical composition for external use containing an antifungal agent as an active ingredient may be colorless or pale yellow. In addition, the pharmaceutical composition according to one embodiment does not precipitate crystals even after being stored at -10°C for at least two weeks, and does not precipitate crystals even after being applied to the skin or nails and left at room temperature (25°C) for 24 hours.

[0083] The present invention will be described in more detail below through specific preparation examples. The following preparation examples are merely illustrative examples to aid in understanding the present invention, and are not intended to limit or restrict the scope of the present invention.

[0084] Control Examples 1 to 3, Comparative Examples 1 to 3, and Control Examples 1 to 15: Preparation of topical formulation solutions

[0085] External preparation solutions containing antifungal agents (luliconazole, efinaconazole, tavaborole) as active ingredients were prepared according to the following procedure, and the ingredients and composition of each external preparation solution are as shown in Tables 1, 2, and 3 below.

[0086] 1. Preparation of Solution A: Antifungal agents (luliconazole, efinaconazole, tavaborole) were dissolved in ethanol, and then 1,2-pentanediol, acetyl tributyl citrate, cystamine dihydrochloride, butylhydroxytoluene, and glycerin were added in that order at room temperature (25°C) and dissolved to prepare Solution A. 2. Preparation of Solution B: Citric acid and ethylenediamine trisodium disuccinate were added sequentially to purified water and dissolved to prepare Solution B. 3. Solution B was added to solution A, mixed and dissolved, and then filtered through a 0.45 μm filter to prepare a transparent solution for external use.

[0087] 4. The pH of the prepared topical formulation solution was measured and found to be within the range of 4.5 to 7.5, and the surface tension of the prepared topical formulation solution was measured and found to be within the range of 25 to 50 dyn / cm at 25°C.

[0088] [Table 1]

[0089] [Table 2]

[0090] [Table 3]

[0091] Test Example 1: Evaluation test of crystal precipitation inhibitor ability at low temperatures

[0092] 10 ml of each sample from Control Examples 1 to 3, Comparative Examples 1 to 3, and Production Examples 1 to 15 was placed in a 20 ml vial and stored at −10°C in a low-temperature freezer for 2 weeks. After that, the state of crystal and precipitate formation was observed with the naked eye at room temperature (25°C). The results are shown in Table 4.

[0093] [Table 4]

[0094] Referring to the results in Table 4, in Comparative Examples 1, 2, and 3 and Preparation Examples 3, 8, and 13, in which the weight ratio of 1,2-pentanediol and acetyl tributyl citrate as the crystal growth inhibitor was 1:2 and the content of the crystal growth inhibitor was 30 wt% relative to the total weight of the external preparation solution, it was confirmed that no crystal precipitation occurred even after storage at -10°C for 2 weeks.

[0095] Test Example 2: Evaluation of the ability of topical preparations to inhibit crystal precipitation when they dry after application

[0096] Each sample from Control Examples 1 to 3, Comparative Examples 1 to 3, and Production Examples 1 to 15 was dropped at 0.5 ml onto a slide glass measuring 26 mm wide x 76 mm long, and then applied with a cotton swab. After leaving the slide at room temperature (25°C) for 24 hours, the results of visual observation were shown in Table 5.

[0097] [Table 5]

[0098] Referring to the results in Table 5, in Comparative Examples 1, 2, and 3 and Preparation Examples 3, 8, and 13, in which the weight ratio of 1,2-pentanediol and acetyl tributyl citrate as the crystal growth inhibitor was 1:2 and the content of the crystal growth inhibitor was 30 wt% relative to the total weight of the topical preparation solution, it was confirmed that no crystal precipitation occurred even after the topical preparation was applied to a slide glass and left at room temperature for 24 hours.

[0099] Test Example 3. Susceptibility testing for evaluating antibacterial activity

[0100] Generally, clinical treatment results can be predicted through susceptibility testing of antifungal agents. The test strains used in the susceptibility testing to evaluate antibacterial activity are Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans, which are typical pathogens that induce superficial fungal infections. To evaluate antibacterial activity against the three microorganisms mentioned above, this experiment was carried out using the tube dilution technique. Antibacterial activity was evaluated using the minimum growth inhibitor concentration (MIC) for each microorganism. 90 The results of comparing Control Examples 1, 2, and 3 with Comparative Examples 1, 2, and 3 and Production Examples 3, 8, and 13 as Minimum Inhibitor Concentrations (MCI) are shown in Table 6 below. The minimum growth inhibitor concentration test was conducted in accordance with the classification standards of the Clinical and Laboratory Standards Institute (CLSI), with the fungi Trichophyton rubrum and Trichophyton mentagrophytes tested according to the CLSI M38-A2:2008 test method, and the yeast Candida albicans tested according to the CLSI M27-A3:2008 test method, as follows.

[0101] 1) Pre-culture of test bacteria (1) Trichophyton rubrum and Trichophyton mentagrophytes: The strains were smeared on OA (6% oatmeal, 1.25% agar, pH 6.0) medium and cultured at 30±2°C for 4 to 5 days.

[0102] (2) Candida albicans: It was inoculated into SDA (Sabouraud Dextrose Agar) medium and cultured at 35±2°C for 20 to 24 hours.

[0103] 2) Preparation of test bacterial solution and spore suspension

[0104] (1) Trichophyton rubrum and Trichophyton mentagrophytes: RPMI 1640 medium (Gibco) was buffered with 0.165 mol / L 3-N-morpholinolinopropane sulfonic acid (MOPS), and then (2–3) × 10 3 A spore suspension of CFU / ml was prepared and used as the test bacterial solution.

[0105] (2) Candida albicans: RPMI 1640 medium (Gibco) was buffered with 0.165 mol / L 3-ene-morpholinopropanesulfonic acid, and 5.0 × 10 2 ~2.5×10 3 A spore suspension of CFU / ml was prepared and used as the test bacterial solution.

[0106] 3) Inoculation of test bacteria solution (1) Trichophyton rubrum, Trichophyton mentagrophytes: 1 ml of test bacterial solution was inoculated into wells containing test solutions of various concentrations. Wells containing 0.2 ml of solution (Control Examples 1, 2, 3, Comparative Examples 1, 2, 3, and Preparation Examples 3, 8, and 13) in RPMI 1640 (buffered with MOPS 0.165 mol / L) medium were used as negative controls, while wells containing 0.1 ml of solution (Control Examples 1, 2, 3, Comparative Examples 1, 2, 3, and Preparation Examples 3, 8, and 13) and 0.1 ml of test bacterial solution in RPMI 1640 (buffered with MOPS 0.165 mol / L) medium were used as positive controls. The tubes containing the test bacterial solution were then cultured at 35±2°C for 46 to 50 hours.

[0107] (2) Candida albicans: 0.9 ml of test bacteria solution was inoculated into wells containing test solutions of various concentrations. Wells containing 1.0 ml of solution (Control Examples 1, 2, 3, Comparative Examples 1, 2, 3, and Preparation Examples 3, 8, and 13) in RPMI 1640 (buffered with MOPS 0.165 mol / L) were used as negative controls, while wells containing 0.1 ml of solution (Control Examples 1, 2, 3, Comparative Examples 1, 2, 3, and Preparation Examples 3, 8, and 13) and 0.9 ml of test bacteria solution in RPMI 1640 (buffered with MOPS 0.165 mol / L) medium were used as positive controls. The tubes containing the test bacteria solution were then cultured at 35±2°C for 24 to 48 hours. 4) Result judgment

[0108] After incubation, the growth of bacteria in each tube was visually observed. The minimum concentration at which bacteria did not grow was determined as the minimum growth inhibitor concentration (MIC). 90 After incubation, no growth should be observed in the negative control group, and bacterial growth should be observed in the positive control group. The results obtained using the above antibacterial activity test method are shown in Table 6.

[0109] [Table 6]

[0110] As can be seen from the results in Table 6, against Trichophyton rubrum, Preparations 3, 8, and 13 were 2.6 to 3.2 times more effective than Controls 1, 2, and 3, and 1.6 to 2.3 times more effective than Comparative Examples 1, 2, and 3. Against Trichophyton mentagrophytes, Preparations 3, 8, and 13 were 2.1 to 4.4 times more effective than Controls 1, 2, and 3, and 1.7 to 2.3 times more effective than Comparative Examples 1, 2, and 3. Against Candida albicans, Preparations 3, 8, and 13 were 2.1 to 2.5 times more effective than Controls 1, 2, and 3, and 1.8 to 2.3 times more effective than Comparative Examples 1, 2, and 3. Therefore, since the pharmaceutical compositions according to the Preparations showed good susceptibility test results against causative bacteria that cause ringworm, it can be predicted that they will not only be able to simultaneously treat the aforementioned causative bacteria, but will also show excellent clinical treatment results.

[0111] <Antifungal agent content analysis method> In the following Test Examples 4, 5, and 6, the content of luliconazole was analyzed using a UV-Visible Spectrophotometer under the following conditions. *Luliconazole content analysis - Equipment: Mega-800 (Scinco, Korea), Double beam method - Measurement cell: 10mm Quartz cuvettes - Solvent: Methanol

[0112] - Preparation of standard solution preparation solution: Dissolve 50 mg of luliconazole standard in 30 ml of methanol, sonicate for 10 minutes, fill up to 50 ml with methanol, and then dilute 1 ml of this solution with 100 ml of methanol.

[0113] - Sample treatment solution preparation: Accurately weigh approximately 1 gram of the solution to be used as a sample and dissolve it in 70 ml of methanol, sonicate for 10 minutes, fill up to 100 ml with methanol, filter through Whatman filter paper, and dilute 5 ml of the filtrate with 50 ml of methanol. - Measurement procedure: Measure the absorbance of the standard preparation solution and sample treatment solution at 296 nm using a UV-visible spectrophotometer with a blank cell as a reference.

[0114] TIFF2026508197000013.tif26166

[0115] *Efinaconazole content analysis - Apparatus: Agilent 1100 (DAD); Time-dependent concentration gradient - Column: Inertsil ODS3V (250 x 4.6 mm, 5.0 μm) -Column temperature: 40°C - Mobile phase: a buffer solution b acetonitrile:methanol (50:50% by volume) -Flow rate: 1.0ml / min -Detector: UV detector -Detection wavelength: 210nm -Sample injection volume: 10.0 μl - Sample concentration: 0.3mg / ml * Preparation of buffer solution: Dissolve 1.36g of KH2PO4 and 2.16g of 1-octanesulfonic acid sodium in 1,000ml of purified water, adjust the pH to 2.5, then filter and deaerate through a 0.45μ membrane filter before preparation.

[0116] TIFF2026508197000014.tif13166

[0117] In the following Test Examples 4, 5, and 6, the content of tavaborole was analyzed using a UV-Visible Spectrophotometer under the following conditions. *Tavaborole content analysis (wt%) - Equipment: Mega-800 (Scinco, Korea), Double beam method - Measurement cell: 10mm Quartz cuvettes - Solvent: Methanol

[0118] - Preparation of standard solution preparation solution: Dissolve 50 mg of tavaborole standard in 30 ml of methanol, sonicate for 10 minutes, fill up to 50 ml with methanol, and then dilute 1 ml of this solution with 100 ml of methanol.

[0119] - Preparation of sample treatment solution: Accurately weigh approximately 1 gram of the solution to be used as a sample and dissolve it in 70 ml of methanol, sonicate for 10 minutes, fill up to 100 ml with methanol, filter through Whatman filter paper, and dilute 5 ml of the filtrate with 50 ml of methanol. - Measurement procedure: Measure the absorbance of the standard preparation solution and the sample treatment solution at 272 nm using a UV-visible spectrophotometer with a blank cell as a reference.

[0120] TIFF2026508197000015.tif13166

[0121] Test Example 4. Evaluation of keratin affinity inhibitor performance

[0122] Bovine hooves were frozen in liquid nitrogen, crushed into powder with a particle size of 5 mm or less, sterilized with ethylene oxide gas, washed and degreased sequentially with saline, distilled water, ethanol / ether (1 / 1, v / v%), and acetone, and then dried to produce keratin powder. Keratin powder and solutions from Controls 1-3, Comparative Examples 1-3, and Preparations 3, 8, and 13 were mixed in a 30 ml glass vial at a fixed ratio (0.5 ml of solution per 1 g of keratin powder), shaken in a water bath at 37°C for 2 hours, and then centrifuged at 1,500 rpm for 5 minutes. The resulting supernatant was analyzed for the concentration of unadsorbed drug on keratin. The adsorption rate and the keratin affinity inhibitor rate relative to the control were calculated as follows, and the results are shown in Table 7. **Keratin adsorption rate (%) = {(added drug concentration - drug concentration in supernatant) / added drug concentration} x 100

[0123] [Table 7]

[0124] As shown in Table 7, the keratin affinity reduction rate (%) was 3.4% for Comparative Example 1 and 13.6% for Preparation Example 3 compared to Control Example 1, 3.8% for Comparative Example 2 and 14.3% for Preparation Example 8 compared to Control Example 2, and 3.4% for Comparative Example 3 and 15.8% for Preparation Example 13 compared to Control Example 3. This indicates that cystamine dihydrochloride contained in the composition exhibits excellent effects as a keratin affinity inhibitor and plays an important role in increasing drug permeability.

[0125] Test Example 5. Evaluation of skin permeability using human skin

[0126] The skin permeability of antifungal agents was evaluated using human skin in a Franz diffusion cell using solutions from Control Examples 1 to 3, Comparative Examples 1 to 3, and Preparation Examples 1 to 15. HuSKin (Hans Biomed Co.) was used for human skin hydration for 2 hours, and the hydrated skin was then mounted on a Franz diffusion cell. 200 μl of each test sample was applied to the donor compartment, and 5 ml of phosphate-buffered saline (PBS) containing 1.0% (w / v) Tween 80 and 0.002% (w / v) kanamycin sulfate was filled in the acceptor compartment. The diffusion area was 1.13 cm. 2 The sample volume was 200 μl for each measurement, and the solution in the receiving chamber was replenished with the same volume. The stirring speed was 600 rpm, the temperature was 37±0.5°C, and the test was repeated three times. Samples were collected every 24 and 48 hours. Each sample was analyzed using the antifungal agent content analysis method described above, and the results are shown in Tables 8, 9, and 10.

[0127] [Table 8]

[0128] As shown in Table 8, Preparation Example 3 exhibited the highest 24-hour penetration concentration, 2.5 times and 1.3 times higher than Control Example 1 and Comparative Example 1, and the highest 48-hour cumulative penetration concentration, 3.3 times and 1.6 times higher than Control Example 1 and Comparative Example 1. Therefore, when the crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate weight ratio of 1:2) is contained in an amount of 30 wt % based on the total weight of the composition and the keratin affinity inhibitor (cystamine dihydrochloride) is contained in an amount of 10 wt % based on the total weight of the composition, the therapeutic efficacy of tinea can be more significantly improved.

[0129] [Table 9]

[0130] As shown in Table 9, Preparation Example 8 exhibited the highest 24-hour penetration concentration, 2.6 times and 1.5 times higher than Control Example 2 and Comparative Example 2, and the highest 48-hour cumulative penetration concentration, 3.8 times and 1.6 times higher. Therefore, when the crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate weight ratio of 1:2) is contained in an amount of 30 wt % based on the total weight of the composition and the keratin affinity inhibitor (cystamine dihydrochloride) is contained in an amount of 10 wt % based on the total weight of the composition, the therapeutic efficacy of tinea can be more significantly improved.

[0131] [Table 10]

[0132] As shown in Table 10, Preparation Example 13 exhibited the highest 24-hour penetration concentration, 3.2 times and 1.5 times higher than Control Example 3 and Comparative Example 3, and the highest 48-hour cumulative penetration concentration, 3.7 times and 1.8 times higher than Control Example 3 and Comparative Example 3. Therefore, when the crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate weight ratio of 1:2) is contained in an amount of 30 wt % based on the total weight of the composition and the keratin affinity inhibitor (cystamine dihydrochloride) is contained in an amount of 10 wt % based on the total weight of the composition, the therapeutic efficacy of tinea can be more significantly improved.

[0133] Test Example 6: Evaluation of human nail transmittance

[0134] Nails excised from healthy adult humans were washed with saline solution and then hydrated with saline for 2 hours. The hydrated nails were mounted in Franz diffusion cells, and 100 μL of each sample (Control Examples 1-3, Comparative Examples 1-3, and Preparation Examples 1-15) was applied to the donor compartment once daily for 10 days, and 200 μL of sample was collected from the acceptor compartment. The acceptor compartment was filled with 5 mL of phosphate buffered saline containing 1.0% (w / v) Tween 80 and 0.002% (w / v) kanamycin sulfate, with a diffusion area of ​​1.13 cm. 2The amount of sample taken was 200 μl for each measurement, and the solution in the receptor chamber was replenished with the same amount. The stirring speed was 600 rpm, the temperature was 32±0.5°C, and the number of repetitions per test was three. Samples were taken at 1, 3, 7, 13, 21, and 24 hours on Day 1, and every 48 hours from Day 2 to Day 10. Each sample was analyzed according to the antifungal agent content analysis method described above, and the results were confirmed as the cumulative permeation concentration (μg / ml) and the mean value with standard deviation. The results are shown in Figures 1, 2, and 3.

[0135] Figure 1 is a graph showing the results of the 10-day cumulative penetration concentration of luliconazole in Control Example 1, Comparative Example 1, and Preparation Examples 1 to 5. Referring to Figure 1, Preparation Example 3 showed the highest penetration concentrations, being 6.5-fold and 1.4-fold higher on Day 1, 5.3-fold and 1.4-fold higher on Day 2, 4.7-fold and 1.7-fold higher on Day 6, and 3.9-fold and 1.8-fold higher on Day 10 (the final day), than Control Example 1 and Comparative Example 1. Therefore, it can be seen that Preparation Example 3, which contains 30 wt% of the crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate in a 1:2 weight ratio) and 10 wt% of the keratin affinity inhibitor (cystamine dihydrochloride) relative to the total weight of the composition, can more effectively treat onychomycosis and tinea cruris than Control Example 1, which does not contain a crystal growth inhibitor or a keratin affinity inhibitor, and Comparative Example 1, which does not contain a keratin affinity inhibitor.

[0136] Figure 2 is a graph showing the cumulative penetration concentration of efinaconazole over 10 days in Control Example 2, Comparative Example 2, and Preparation Examples 6 to 10. Referring to Figure 2, Preparation Example 8 exhibited the highest penetration concentrations, being 6.1-fold and 1.3-fold higher on Day 1, 4-fold and 1.2-fold higher on Day 2, 3.5-fold and 1.3-fold higher on Day 6, and 4.5-fold and 1.5-fold higher on Day 10 (the final day) than Control Example 2 and Comparative Example 2. Therefore, compared to Control Example 2, which does not contain a crystal growth inhibitor or a keratin affinity inhibitor, and Comparative Example 2, which does not contain a keratin affinity inhibitor, Preparation Example 8, which contains a crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate in a weight ratio of 1:2) at 30 wt% of the total composition and a keratin affinity inhibitor (cystamine dihydrochloride) at 10 wt% of the total composition, can more effectively treat onychomycosis and tinea cruris.

[0137] Figure 3 is a graph showing the cumulative permeation concentration of tavaborole over 10 days for Control Example 3, Comparative Example 3, and Preparation Examples 11 to 15. Referring to Figure 3, Preparation Example 13 exhibited the highest permeation concentrations, being 6.3 times and 1.2 times higher than Control Example 3 and Comparative Example 3 in terms of permeation concentration on Day 1, 5.4 times and 1.2 times higher in terms of cumulative permeation concentration on Day 2, 4.4 times and 1.5 times higher in terms of cumulative permeation concentration on Day 6, and 5.0 times and 1.7 times higher on Day 10 (the final day). Therefore, compared to Control Example 3, which does not contain a crystal growth inhibitor or a keratin affinity inhibitor, and Comparative Example 3, which does not contain a keratin affinity inhibitor, Preparation Example 13, which contains a crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate in a weight ratio of 1:2) at 30 wt% of the total composition and a keratin affinity inhibitor (cystamine dihydrochloride) at 10 wt% of the total composition, can more effectively treat onychomycosis and tinea cruris.

[0138] Test Example 7. Storage stability evaluation

[0139] 10 ml of each of Control Examples 1 to 3, Comparative Examples 1 to 3, and Preparation Examples 3, 8, and 13 was placed in a 20 ml transparent vial, hermetically sealed, and stored at 50°C for 4 weeks. The UV-visible absorption spectra of the samples were measured initially and after 4 weeks at 50°C. Measurements were performed at 400 nm and 600 nm using a Mega-800 (Scinco, Korea) spectrophotometer, and the evaluation results are shown in Tables 11 and 12 below.

[0140] [Table 11]

[0141] [Table 12]

[0142] As shown in Tables 11 and 12, Preparation Examples 3, 8, and 13 exhibited significantly more stable results than Control Examples 1, 2, and 3 and Comparative Examples 1, 2, and 3. At 400 nm, Preparation Examples 3, 8, and 13 exhibited an increase in absorbance of 1.4 to 1.8%, while Control Examples 1, 2, and 3 exhibited an increase of 11.3 to 13.6%, and Comparative Examples 1, 2, and 3 exhibited an increase of 4.0 to 6.7%. At 600 nm, Preparation Examples 3, 8, and 13 exhibited an increase in absorbance of 1.4 to 2.3%, while Control Examples 1, 2, and 3 exhibited an increase of 11.1 to 14.6%, and Comparative Examples 1, 2, and 3 exhibited an increase of 5.3 to 7.1%. The stability results indicated that Control Examples 1, 2, and 3, which did not contain a crystal growth inhibitor or keratin affinity inhibitor, did not exhibit the best stability, and Comparative Examples 1, 2, and 3, which contained only a crystal growth inhibitor, also exhibited poor stability. In comparison, the stability of Preparation Examples 3, 8, and 13, which contained 30% by weight of the crystal growth inhibitor (1,2-pentanediol:acetyl tributyl citrate weight ratio of 1:2) relative to the total weight of the composition and 10% by weight of the keratin affinity inhibitor (cystamine dihydrochloride) relative to the total weight of the composition, was the best.

[0143] As described above, according to various embodiments of the present invention, the crystal growth of the poorly soluble antibacterial agents luliconazole, efinaconazole, and tavaborole as active ingredients is inhibited, thereby improving the solubility of the drug. This prevents the phenomenon of crystal precipitation even when stored for a long period of time or when the temperature changes. Furthermore, when the drug is applied to the affected area of ​​the skin or nail, the generation of fine precipitates at the affected area after the volatile solvent evaporates is prevented, thereby significantly improving the permeability of the drug.

[0144] In addition, various embodiments of the present invention have the advantage of inhibiting crystal growth that may occur during drug storage and after drug application, preventing crystal precipitation, and inhibiting affinity with keratin in skin and nails, thereby significantly improving drug penetration and antibacterial activity.

[0145] In addition, various embodiments of the present invention can inhibit crystal growth of a poorly soluble antibacterial agent, thereby improving the stability of the formulation; can prevent crystal precipitation after evaporation of a volatile solvent when applied to the skin and nails, thereby increasing antibacterial activity; and can inhibit the keratin affinity of the antibacterial agent to nails, thereby effectively increasing the drug permeability, thereby maximizing the effectiveness of treating and preventing tinea.

[0146] In addition, according to various embodiments of the present invention, when a drug is applied to the affected areas of the skin and nails, the keratin affinity of the active ingredient antibacterial agent is inhibited, thereby further increasing the drug permeability, which has the advantage of being very effective in preventing and treating ringworm.

[0147] At the same time, various embodiments of the present invention have an excellent effect of preventing crystal precipitation after application of the drug, which leads to high compliance with the drug and excellent drug permeability and antibacterial activity in the skin and nails.

[0148] In addition, since it does not contain cyclomethicone and N-methylpyrrolidone, which are restricted substances contained in currently available products, or ethylenediaminetetraacetate, which has low biodegradability, it is less harmful and more environmentally friendly than products that contain the restricted substances, and can be widely used as a pharmaceutical composition for external preparations for the prevention or treatment of ringworm.

[0149] In other words, the pharmaceutical compositions according to various embodiments of the present invention are environmentally friendly and harmless because they do not contain the environmentally hazardous substance cyclomethicone, the environmentally impacting substance ethylenediamine acetate, or the carcinogenic substance methylpyrrolidone. They eliminate harmful ingredients present in currently available products, and have the advantages of inhibiting crystal growth of antifungal agents, improving solubility, and reducing keratin affinity, thereby significantly improving the drug permeability through the skin and nails and antibacterial effect.

[0150] In various embodiments of the present invention, harmful substances such as cyclomethicone and N-methylpyrrolidone are not used as excipients, and ethylenediamine tetraacetic acid salt, which has low biodegradability, is not used as a chelating agent, so it has the advantage of being non-toxic and very environmentally friendly.

[0151] Thus, according to various embodiments of the present invention, the crystal growth inhibitor as an auxiliary ingredient of the pharmaceutical composition inhibits drug crystal growth, preventing precipitation during long-term storage and preventing crystallization after application to the affected area, thereby improving drug permeability. The keratin affinity inhibitor as an auxiliary ingredient significantly reduces the drug's affinity for keratin, further improving drug permeability. In other words, the pharmaceutical compositions according to various embodiments simultaneously perform the dual functions of crystal growth prevention and keratin affinity inhibitor, thereby significantly increasing drug permeability and significantly enhancing antibacterial activity. Such improved drug permeability and increased antibacterial activity can contribute to maximizing the preventive or therapeutic effects of skin and nail tinea.

[0152] In addition, the pharmaceutical compositions according to various embodiments do not contain cyclomethicone, an environmentally hazardous substance, ethylenediamine acetate, an environmentally influential substance, or methylpyrrolidone, a carcinogen, and are made of environmentally friendly and non-toxic compositions, so they are excellent in terms of safety for the human body and environmental friendliness.

[0153] As described above, the present invention has been specifically described using examples. However, the above examples are merely preferred examples of the present invention, and therefore the present invention should not be understood as being limited to the above examples. The scope of the present invention should be understood as the claims and their equivalents, which will be described later.

Claims

1. antifungal agents; a crystal growth inhibitor; and keratin affinity inhibitor; A pharmaceutical composition for preventing or treating nail and skin tinea, comprising:

2. The content of the antifungal agent is 0.1 to 20% by weight based on the total weight of the composition; The antifungal agent includes at least one selected from luliconazole, luliconazole salts, efinaconazole, efinaconazole salts, tavaborole, and tavaborole salts. The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

3. The content of the crystal growth inhibitor is 0.1 to 70 wt % based on the total weight of the composition; The crystal growth inhibitor comprises 1,2-pentanediol; and an ester compound; The weight ratio of the 1,2-pentanediol to the ester compound is 1:2, The ester compound is at least one selected from the group consisting of acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate, and diethyl carbonate. The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

4. The keratin affinity inhibitor includes cystamine dihydrochloride. The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

5. The keratin affinity inhibitor further comprises at least one selected from laurylcholine, tricaprylin, and octenidine dihydrochloride; The content of the keratin affinity inhibitor is 0.01 to 30% by weight based on the total weight of the composition. The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 4.

6. The pharmaceutical composition for preventing or treating nail and skin tinea further comprises a chelating agent; The content of the chelating agent is 0.0001 to 5% by weight based on the total weight of the composition; The chelating agent includes ethylenediamine trisodium disuccinate The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

7. The additive includes at least one selected from the group consisting of a vehicle, an antioxidant, and a pH adjuster. The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

8. The pharmaceutical composition for preventing or treating nail and skin tinea has at least one dosage form selected from a liquid, an aerosol, a stick, and a semi-solid, and the semi-solid includes at least one of a gel, a lotion, a cream, and an ointment; The pharmaceutical composition for preventing or treating nail and skin tinea has a pH of 2 to 10; The density of the pharmaceutical composition for preventing or treating nail and skin tinea is 0.01 to 2 g / cm ３ is The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

9. The pharmaceutical composition for preventing or treating nail and skin tinea does not contain cyclomethicone, methylpyrrolidone, and ethylenediaminetetraacetate, The pharmaceutical composition for preventing or treating nail and skin tinea has a water content of 0.1 to 90 wt % as measured by Karl Fischer's method, a surface tension of 1 to 76 dyn / cm, and a daily application amount of 0.001 to 60 g / day when the pharmaceutical composition for preventing or treating nail and skin tinea is topically applied. The pharmaceutical composition for preventing or treating nail and skin tinea according to claim 1.

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