A pharmaceutical containing efinaiconazole

Abstract

The purpose of the present invention is to provide, substantially without using an ethylenediaminetetraacetate salt, a stable efinaconazole formulation that during storage does not develop a discoloration that is nonconforming with a pharmaceutical formulation standard (Clenafin (registered trademark) 10% topical nail solution). The formulation is a therapeutic agent for onychomycosis and contains efinaconazole; at least one nonvolatile ester selected from the mono-, di- and triesters of a C1-3 monoalcohol or polyhydric alcohol with a C8-18 aliphatic monocarboxylic acid or aliphatic dicarboxylic acid; a pH regulator; and an antioxidant.

Description

Technical Field

[0001] The present invention relates to a formulation containing efinaconazole.

Background Art

[0002] Efinaconazole is a triazole compound represented by formula (I) having antifungal activity:

Chemical Formula

[0003] Generally, since the retention of a topical agent varies depending on the affected area and the disease condition, several dosage forms are often used appropriately. Also, taking into account the patient's feeling of use and the spreadability of the formulation, etc., there may be multiple dosage forms on the market for the same active ingredient. For example, ketoconazole, which is a therapeutic agent for dermatomycosis, is provided as a cream and a lotion (see, for example, the interview form of Nizoral (registered trademark) cream 2% and lotion 2%). Also, for example, luliconazole, which is a therapeutic agent for dermatomycosis and onychomycosis, is provided as a cream, a liquid, and an ointment as a therapeutic agent for dermatomycosis, and a liquid is provided as a therapeutic agent for onychomycosis (see the interview form of Luricon (registered trademark) cream 1%, liquid 1%, ointment 1%, and Lukonak (registered trademark) topical solution 5%).

[0004] As described above, it is preferable that pharmaceuticals for external application be provided in various dosage forms. However, in the case of a therapeutic agent for onychomycosis, the problem of the permeability of the active ingredient to the affected area of the nail bed must be overcome, and also, a triazole-based active ingredient containing efinaconazole has a problem of discoloration during the storage period, and it is extremely difficult to design a formulation recipe excellent in the stability of the active ingredient over time while overcoming these problems.

[0005] So far, regarding topical onychomycosis therapeutic agents containing efinaconazole, as shown in Patent Documents 1 to 3, many formulation prescriptions have been devised.

[0006] Patent Document 1 discloses a composition for treating nail diseases containing efinaconazole. For example, a formulation containing efinaconazole, a non-volatile solvent (diisopropyl adipate), and an antioxidant (butylated hydroxytoluene) is disclosed.

[0007] Patent Document 2 discloses that by combining butylated hydroxytoluene and a salt of ethylenediaminetetraacetic acid, the stability of an efinaconazole formulation over time is achieved, and it is disclosed that it is colorless or light yellow after being stored at a temperature of at least about 40°C for at least 3 weeks.

[0008] Patent Document 3 discloses a formulation with high nail permeability, which contains efinaconazole, a non-volatile solvent (medium-chain fatty acid triglyceride), and a permeation enhancer (ethyl lactate). It is necessary to provide efinaconazole formulations in various dosage forms including anhydrous formulations by using a stability technology over time that is not available in the prior art as described above.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0010] An object of the present invention is to provide a stable efinaconazole preparation that does not substantially use a salt of ethylenediaminetetraacetic acid and does not cause discoloration that is incompatible with the pharmaceutical formulation specifications (10% Klenafine (registered trademark) topical solution for nails) during the storage period. Thereby, it becomes possible to provide efinaconazole preparations in various dosage forms including anhydrous preparations.

Means for Solving the Problems

[0011] The present inventors have intensively studied to develop an efinaconazole preparation that achieves the above problems. Generally, when the results of long-term storage tests (25°C / 3 years) and accelerated tests (40°C / 6 months) are equivalent, the activation energy of the decomposition of the active ingredient is calculated to be 22.1 kcal / mol (Sumie Yoshioka, Stability of Pharmaceuticals, p. 142, 1995, Nankodo). The storage at 60°C / 4 weeks at that time (thermal stress test) is equivalent to a period of 4 years or more in terms of 25°C storage. Regarding 10% Klenafine (registered trademark) topical solution for nails, an increase in related substances over time was observed in the thermal stress test (60°C / 4 weeks), but it was within the specification range and was stable during the storage period of 25°C / 3 years (see the interview form of 10% Klenafine (registered trademark) topical solution for nails). From this, it can also be determined whether the storage period of 25°C / 3 years is ensured in various efinaconazole preparations by evaluating the preparation stored at 60°C / 4 weeks. Therefore, first, the present inventors prepared various efinaconazole preparations and conducted preliminary studies (storage at 60°C / 8 days). As a result, surprisingly, when isopropyl myristate and medium-chain fatty acid triglyceride were used as the base, it was found that the combination of citric acid and dibutylhydroxytoluene could prevent the discoloration of the efinaconazole preparation over time.

[0012] Next, the inventors prepared various efina-conazole formulations and stored them at 60 °C for 4 weeks (thermal stress test). As a result, when a specific non-volatile ester was used, it was found that the combination of a pH adjuster and an antioxidant could prevent the discoloration of the efina-conazole formulation over time, and no discoloration over time that deviated from the formulation specifications occurred, thus completing the present invention.

[0013] That is, the present invention includes the following inventions.

[0014]

[01] A therapeutic agent for onychomycosis, comprising: a) efina-conazole; b) one or more non-volatile esters selected from mono, di, and triesters of a monohydric alcohol or polyhydric alcohol having 1 to 3 carbon atoms and an aliphatic monocarboxylic acid or aliphatic dicarboxylic acid having 8 to 18 carbon atoms; c) a pH adjuster; d) an antioxidant; and being an external preparation substantially free of ethylenediaminetetraacetic acid or its salts.

[0015]

[02] The external preparation according to

[01] , wherein the content of efina-conazole is 8 w / w% to 12 w / w% based on the total amount of the preparation.

[03] The external preparation according to

[01] , wherein the content of efina-conazole is 10 w / w% based on the total amount of the preparation.

[0016]

[04] The external preparation according to any one of

[01] to

[03] , wherein the non-volatile ester is selected from the group consisting of glycerin fatty acid esters such as medium-chain fatty acid triglycerides, medium-chain fatty acid diglycerides, medium-chain fatty acid monoglycerides, and glycerin monostearate; isopropyl palmitate, isopropyl myristate, diisopropyl sebacate, diethyl sebacate, propylene glycol monostearate, polyethylene glycol monolaurate, propylene glycol monocaprylate, and propylene glycol dicaprylate.

[0017]

[05] The external preparation according to any one of

[01] to

[03] , wherein the non-volatile ester is selected from the group consisting of medium-chain fatty acid triglycerides, isopropyl myristate, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate.

[06] The external preparation according to any one of

[01] to

[03] , wherein the non-volatile ester is selected from the group consisting of medium-chain fatty acid triglycerides, isopropyl myristate, and propylene glycol dicaprylate.

[0018]

[07] The external preparation according to any one of

[01] to

[06] , wherein the content of the non-volatile ester is 1 w / w% to 80 w / w% based on the total amount of the preparation.

[0019]

[08] The external preparation according to any one of

[01] to

[06] , wherein the content of the non-volatile ester is 10 w / w% to 50 w / w% based on the total amount of the preparation.

[0020]

[09] The external preparation according to any one of

[01] to

[06] , wherein the content of the non-volatile ester is 15 w / w% to 45 w / w% based on the total amount of the preparation.

[0021]

[10] The external preparation according to any one of

[01] to

[09] , wherein the pH adjuster is an organic acid selected from the group consisting of citric acid, malic acid, lactic acid, acetic acid, oxalic acid, tartaric acid, adipic acid, maleic acid, gluconic acid, and succinic acid, an inorganic acid selected from the group consisting of carbonic acid, boric acid, hydrochloric acid, sulfuric acid, and phosphoric acid, or a pharmaceutically acceptable salt thereof.

[0022]

[11] The external preparation according to any one of

[01] to

[09] , wherein the pH adjuster is an organic acid selected from the group consisting of citric acid, malic acid, lactic acid, and tartaric acid, or a pharmaceutically acceptable salt thereof.

[12] The topical preparation according to any one of

[01] to

[09] above, wherein the pH adjuster is an organic acid selected from the group consisting of citric acid and tartaric acid, or a pharmaceutically acceptable salt thereof.

[13] The topical preparation according to any one of

[01] to

[09] above, wherein the pH adjuster is anhydrous citric acid.

[0023]

[14] The topical preparation according to any one of

[01] to

[13] above, wherein the content of the pH adjuster is 0.001 w / w% to 1.0 w / w% based on the total amount of the preparation.

[15] The topical preparation according to any one of

[01] to

[13] above, wherein the content of the pH adjuster is 0.05 w / w% to 0.25 w / w% based on the total amount of the preparation.

[0024]

[16] The topical preparation according to any one of

[01] to

[15] above, wherein the antioxidant is an oil-soluble antioxidant selected from the group consisting of dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, propyl gallate, ascorbyl palmitate, soy lecithin, thio glycolic acid ester, benzotriazole, and 2-mercaptobenzimidazole.

[17] The topical preparation according to any one of

[01] to

[15] above, wherein the antioxidant is selected from the group consisting of dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, and propyl gallate.

[18] The topical preparation according to any one of

[01] to

[15] above, wherein the antioxidant is dibutylhydroxytoluene.

[0025]

[19] The topical preparation according to any one of

[01] to

[18] above, wherein the antioxidant is 0.001 w / w% to 1.0 w / w% based on the total amount of the preparation.

[20] The topical preparation according to any one of

[01] to

[18] above, wherein the antioxidant is 0.05 w / w% to 0.25 w / w% based on the total amount of the preparation.

[0026]

[21] Further, a topical preparation according to any one of

[01] to

[20] above, containing ethanol.

[22] Further, a topical preparation according to any one of

[01] to

[21] above, wherein the water content is 3 w / w% or less based on the total preparation amount.

[23] A topical preparation according to any one of

[01] to

[22] above, which is a anhydrous preparation.

[0027]

[24] A topical preparation according to any one of

[01] to

[23] above, wherein the topical preparation is a topical solution for applying to nails.

[25] Further, a topical preparation according to any one of

[01] to

[24] above, substantially not containing a film-forming agent. [Effect of the Invention]

[0028] In the topical preparation of efinaconazole, discoloration over time does not occur during the storage period, and a preparation stable as a pharmaceutical can be provided. [Modes for Carrying Out the Invention]

[0029] Hereinafter, the present invention will be described in detail.

[0030] The topical preparation of efinaconazole according to the present invention is effective against any disease type of onychomycosis. The topical preparation of efinaconazole according to the present invention is preferably a topical administration preparation for applying to nails.

[0031] The topical preparation of the present invention contains efinaconazole as an active ingredient, and its content is preferably 8 w / w% to 12 w / w%, particularly preferably 10 w / w%, based on the total preparation amount. In the present specification, when the range is described as "A to B", "A - B" or "A~B", etc., the numerical values at the ends are also included unless otherwise noted. The topical preparation of the present invention includes a solution, a lotion, an ointment, a cream, and a gel, but is preferably a solution or a gel, more preferably a solution. In this specification, the "liquid preparation" preferably has a state in which the prescription components are dissolved in a solvent and / or a state in which they are dissolved and mixed without separation.

[0032] The topical preparation of efinaconazole according to the present invention does not undergo discoloration over time during the storage period and is a preparation that is storage-stable as a pharmaceutical product. Here, "storage-stable" means that even due to temperature rise or the like caused by changes in the environment, temperature, etc. during the storage period, discoloration that makes the preparation non-compliant with the pharmaceutical product specifications (Klenafine (registered trademark) nail topical solution 10%) does not occur. In the following experimental examples, the storage stability of the topical preparation of efinaconazole is evaluated by storage at 60°C for 4 weeks (thermal stress test).

[0033] In this specification, the "non-volatile ester" is selected from mono-, di-, and triesters of a monohydric alcohol or polyhydric alcohol having 1 to 3 carbon atoms and an aliphatic monocarboxylic acid or aliphatic dicarboxylic acid having 8 to 18 carbon atoms. Preferably, the non-volatile ester is selected from mono-, di-, and triesters of a monohydric alcohol or polyhydric alcohol having 1 to 3 carbon atoms and an aliphatic monocarboxylic acid or aliphatic dicarboxylic acid having 8 to 14 carbon atoms. More preferably, the non-volatile ester is selected from mono-, di-, and triesters of a monohydric alcohol or polyhydric alcohol having 1 to 3 carbon atoms and a saturated aliphatic monocarboxylic acid or saturated aliphatic dicarboxylic acid having 8 to 14 carbon atoms.

[0034] In the case of a therapeutic agent for onychomycosis to be topically applied, the non-volatile ester is added for the purpose of promoting the nail permeability of efinaconazole and / or for the purpose of dissolving and mixing the active ingredient and additives in the solvent. The selection of the non-volatile ester is extremely important. By appropriately selecting the non-volatile ester of the present invention, precipitation at the application site of the active ingredient and additives can be prevented, and good nail permeability of the active ingredient can be expected without impairing the usability and aesthetic appearance after application.

[0035] In the non-volatile esters of the present invention, "monoester" refers to an ester having one ester group in one molecule, "diester" refers to an ester having two ester groups in one molecule, and "triester" refers to an ester having three ester groups in one molecule.

[0036] "Monoalcohol or polyhydric alcohol having 1 to 3 carbon atoms" refers to mono-, di-, and tri-alcohols having 1 to 3 carbon atoms. "Monoalcohol" is an organic compound having one hydroxyl group (-OH) in the molecule. Specific examples include methyl alcohol, ethyl alcohol, normal propyl alcohol, isopropyl alcohol, etc. "Dialcohol" is an organic compound having two hydroxyl groups (-OH) in the molecule. Specific examples include ethylene glycol, propylene glycol, 1,3-propanediol, etc. "Tri-alcohol" is an organic compound having three hydroxyl groups (-OH) in the molecule. Specific examples include glycerin, etc.

[0037] In one embodiment of the present invention, "monoester" can be derived from a combination of a monoalcohol having 1 to 3 carbon atoms and an aliphatic monocarboxylic acid having 8 to 18 carbon atoms, or a combination of one OH group of a polyhydric alcohol having 1 to 3 carbon atoms and an aliphatic monocarboxylic acid having 8 to 18 carbon atoms, etc.

[0038] In one embodiment of the present invention, "diester" can be derived from a combination of two monoalcohols having 1 to 3 carbon atoms and an aliphatic dicarboxylic acid having 8 to 18 carbon atoms, or a combination of two OH groups of a polyhydric alcohol having 1 to 3 carbon atoms and two aliphatic monocarboxylic acids having 8 to 18 carbon atoms, etc.

[0039] In one embodiment of the present invention, "triester" can be derived from a combination of glycerin (glycerol) and three aliphatic monocarboxylic acids having 8 to 18 carbon atoms, etc.

[0040] "Aliphatic monocarboxylic acids with 8 to 14 carbon atoms" refer to fatty acids having 8 to 14 carbon atoms. Specific examples include caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, etc. "Aliphatic monocarboxylic acids with 8 to 18 carbon atoms" refer to fatty acids having 8 to 18 carbon atoms. Specific examples include, in addition to the above-mentioned aliphatic monocarboxylic acids with 8 to 14 carbon atoms, palmitic acid, stearic acid, etc.

[0041] "Aliphatic dicarboxylic acids with 8 to 14 carbon atoms" refer to organic compounds having 8 to 14 carbon atoms and two carboxyl groups (-COOH) in the molecule. Specific examples include aliphatic dicarboxylic acids such as suberic acid, azelaic acid, sebacic acid, etc. "Aliphatic dicarboxylic acids with 8 to 18 carbon atoms" refer to organic compounds having 8 to 18 carbon atoms and two carboxyl groups (-COOH) in the molecule.

[0042] In one embodiment of the present invention, preferred monoesters include, for example, glycerin fatty acid esters such as medium-chain fatty acid monoglycerides, glycerin monostearate, etc., isopropyl palmitate, isopropyl myristate, ethyl myristate, ethyl decanoate, polyethylene glycol monolaurate, and propylene glycol monocaprylate.

[0043] More preferred monoesters of the present invention include isopropyl myristate and propylene glycol monocaprylate. Even more preferred monoesters of the present invention are isopropyl myristate.

[0044] In one embodiment of the present invention, preferred diesters of the present invention include medium-chain fatty acid diglycerides, propylene glycol dicaprylate, diisopropyl sebacate, and diethyl sebacate, etc.

[0045] More preferred diesters of the present invention include medium-chain fatty acid diglycerides, diethyl sebacate, and propylene glycol dicaprylate. Even more preferred diesters of the present invention include diethyl sebacate, and propylene glycol dicaprylate. Even more preferred diester of the present invention is propylene glycol dicaprylate.

[0046] In one embodiment of the present invention, preferred triesters of the present invention include glyceryl trioctanoate, medium-chain fatty acid triglycerides, and the like. A preferred triester of the present invention is a medium-chain fatty acid triglyceride.

[0047] As used herein, medium-chain fatty acid triglyceride refers to a non-volatile triester in which three molecules of fatty acid are ester-bonded to one molecule of glycerin, and the fatty acids in the ester bond are saturated fatty acids having 8 to 14 carbon atoms. The preferred number of carbon atoms of the fatty acid is 8 to 12. For example, caprylic acid, capric acid, lauric acid, etc. are selected. Preferred medium-chain fatty acid triglycerides include triglyceride caprylate, triglyceride capric acid, a triglyceride mixture of caprylic acid and capric acid, a triglyceride mixture of caprylic acid, capric acid, and lauric acid, tri(caprylic acid / capric acid) glyceride, and the like. For example, Miglyol (registered trademark) 810 and 812 can be used. Particularly preferred "medium-chain fatty acid triglyceride" of the present invention is tri(caprylic acid / capric acid) glyceride.

[0048] As used herein, medium-chain fatty acid diglyceride refers to a non-volatile diester in which two molecules of fatty acid are ester-bonded to one molecule of glycerin, and medium-chain fatty acid monoglyceride refers to a non-volatile monoester in which one molecule of fatty acid is ester-bonded to one molecule of glycerin.

[0049] In one embodiment of the present invention, the formulation of the present invention may contain two or more non-volatile esters. When the preparation of the present invention contains two or more non-volatile esters, a preparation containing two or more non-volatile esters selected from the above-mentioned preferred non-volatile esters is preferred. For example, the preparation of the present invention may contain two monoesters, a monoester and a diester, a monoester and a triester, two diesters, a diester and a triester, or two triesters.

[0050] In one embodiment of the present invention, a preferred preparation of the present invention contains a monoester and a triester. In one embodiment of the present invention, a preferred preparation of the present invention contains isopropyl myristate and medium-chain fatty acid triglyceride.

[0051] The preferred content of the non-volatile ester in the present invention is 1 w / w% to 80 w / w% based on the total amount of the preparation, more preferably 5 w / w% to 70 w / w% based on the total amount of the preparation, still more preferably 10 w / w% to 50 w / w% based on the total amount of the preparation, even more preferably 15 w / w% to 40 w / w% based on the total amount of the preparation, and particularly preferably 30 w / w% based on the total amount of the preparation.

[0052] In one embodiment of the present invention, preferred non-volatile esters include isopropyl myristate, medium-chain fatty acid triglyceride, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate, and two or more of these can be used.

[0053] In the present specification, the "pH adjuster" refers to a pharmaceutically acceptable pH adjuster, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or a salt thereof, or an organic acid such as citric acid or tartaric acid or a salt thereof. In one embodiment of the present invention, a preferred pH adjuster is an organic acid.

[0054] An organic acid refers to the acid of an organic compound. Preferred organic acids used as the pH adjuster in the present invention are acids of organic compounds having one or more carboxyl groups (-COOH).

[0055] In one embodiment of the present invention, a preferred pH adjuster is a hydroxy acid or its salt. A hydroxy acid refers to an organic acid having a hydroxyl group and a carboxyl group, and specifically includes aliphatic hydroxy acids such as lactic acid, malic acid, tartaric acid, citric acid, and aromatic hydroxy acids such as salicylic acid. In one embodiment of the present invention, a preferred pH adjuster is an aliphatic hydroxy acid or its salt, and more preferably a C2-C6 aliphatic hydroxy acid or its salt.

[0056] C2-C6 aliphatic hydroxy acid refers to a non-aromatic hydroxy acid having 2 to 6 carbon atoms, and examples include glycolic acid, lactic acid, tartronic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitric acid, mevalonic acid, pantothenic acid, etc. In one embodiment of the present invention, more preferred pH adjusters are citric acid, malic acid, lactic acid, and tartaric acid, or pharmaceutically acceptable salts thereof, and even more preferred pH adjusters are citric acid and tartaric acid, or pharmaceutically acceptable salts thereof, and even more preferred pH adjuster is citric acid.

[0057] In this specification, when simply described as "citric acid", it includes anhydrous citric acid, citric acid monohydrate, etc. In one embodiment of the present invention, a particularly preferred pH adjuster is anhydrous citric acid. In one embodiment of the present invention, the formulation of the present invention may contain two or more pH adjusters. In this case, a formulation containing two or more pH adjusters selected from the above preferred pH adjusters is preferred.

[0058] The preferred content of the pH adjuster in the present invention is from 0.001 w / w% to 1.0 w / w% based on the total formulation amount. The more preferred content of the pH adjuster is from 0.005 w / w% to 0.75 w / w% based on the total formulation amount, more preferably from 0.01 w / w% to 0.5 w / w% based on the total formulation amount, even more preferably from 0.05 w / w% to 0.25 w / w% based on the total formulation amount, and particularly preferably 0.1 w / w% based on the total formulation amount. Here, the "pH adjuster" is preferably citric acid, malic acid, lactic acid, tartaric acid, or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment of the present invention, the preferred pH adjuster is anhydrous citric acid at 0.001 w / w% to 1.0 w / w% based on the total formulation amount, the more preferred pH adjuster is anhydrous citric acid at 0.01 w / w% to 0.5 w / w% based on the total formulation amount, and the even more preferred pH adjuster is anhydrous citric acid at 0.1 w / w% based on the total formulation amount.

[0060] In this specification, the "antioxidant" refers to a pharmaceutically acceptable antioxidant, which is an additive for preventing the oxidation / deterioration of the active ingredient and other components contained in the formulation. The antioxidant of the present invention acts as a free radical scavenger and refers to a substance that captures and inactivates reactive oxygen species (such as oxygen free radicals, superoxide anions, hydroxyl radicals, hydrogen peroxide, etc.). However, the definition of the term "antioxidant" in this specification excludes chelating agents (such as EDTA, etc.).

[0061] The antioxidant in the present invention includes water-soluble antioxidants and oil-soluble antioxidants. Examples of water-soluble antioxidants include ascorbic acid, sodium pyrosulfite, alpha thioglycerol, erythorbic acid, potassium dichloroisocyanurate, L-cysteine hydrochloride hydrate, sodium thiomalate, sodium pyrosulfite, and the like.

[0062] Examples of oil-soluble antioxidants include alpha thioglycerol, erythorbic acid, dibutylhydroxytoluene (BHT), tocopherol, propyl gallate, ascorbyl palmitate, soy lecithin, or butylhydroxyanisole (BHA), etc. In one embodiment of the present invention, a preferred antioxidant is an oil-soluble antioxidant.

[0063] In one embodiment of the present invention, more preferred antioxidants include BHT, tocopherol, propyl gallate, or BHA, and even more preferred antioxidants include BHT or BHA. In one embodiment of the present invention, the formulation of the present invention may contain two or more antioxidants. In this case, a formulation containing two or more antioxidants selected from the above preferred antioxidants is preferred.

[0064] In one embodiment of the present invention, the preferred content of the antioxidant is from 0.001 w / w% to 1.0 w / w% based on the total formulation amount. More preferably, it is from 0.005 w / w% to 0.75 w / w% based on the total formulation amount, even more preferably from 0.01 w / w% to 0.5 w / w% based on the total formulation amount, still more preferably from 0.05 w / w% to 0.25 w / w% based on the total formulation amount, and particularly preferably 0.1 w / w% based on the total formulation amount. Here, the "antioxidant" is preferably BHT, ascorbic acid, tocopherol, propyl gallate, or BHA.

[0065] In one embodiment of the present invention, the preferred antioxidant is BHT or BHA at 0.001 w / w% to 1.0 w / w% based on the total formulation amount. A more preferred antioxidant is BHT or BHA at 0.01 w / w% to 0.5 w / w% based on the total formulation amount, and an even more preferred antioxidant is 0.1 w / w% of BHT or BHA.

[0066] In one embodiment of the present invention, the topical preparation of efinaiconazole of the present invention is prepared by dissolving efinaiconazole, a monoalcohol or polyhydric alcohol having 1 to 3 carbon atoms, and one or more non-volatile esters selected from mono, di, and triesters of an aliphatic monocarboxylic acid or aliphatic dicarboxylic acid having 8 to 18 carbon atoms, a pH adjuster, and an antioxidant in a solvent. Here, the solvent that can be used is not particularly limited as long as it can dissolve efinaiconazole and can mix other components such as non-volatile esters in any proportion without dissolution and / or separation. Typical examples include lower alcohols such as ethanol, isopropanol, and butanol. In this specification, "ethanol" includes various grades of ethanol as long as the intended purpose is achieved. For example, it includes absolute ethanol and 95% ethanol. In one embodiment of the present invention, the preferred ethanol is 95% ethanol. In another embodiment of the present invention, the preferred ethanol is absolute ethanol. In one embodiment of the present invention, the preferred content of ethanol is 20 w / w% to 90 w / w% based on the total preparation amount, more preferably 30 w / w% to 80 w / w%, still more preferably 40 w / w% to 75 w / w%, and even more preferably 50 w / w% to 70 w / w%. In another embodiment of the present invention, the preferred content of ethanol is 50 w / w% to 90 w / w% based on the total preparation amount, more preferably 50 w / w% to 85 w / w%, still more preferably 50 w / w% to 80 w / w%, and even more preferably 50 w / w% to 75 w / w%.

[0067] In this specification, the "water-free preparation" refers to a preparation to which no water and / or an aqueous solution in which other additives are dissolved is added in the manufacturing process of the preparation. In this specification, the "water-added preparation" refers to a preparation to which water or an aqueous solution in which other additives are dissolved is added in the manufacturing process of the preparation.

[0068] In one embodiment of the present invention, the preparation of the present invention is a preparation in which the water content is 0 w / w% to 20 w / w% based on the total preparation amount, preferably 0 w / w% to 10 w / w%, more preferably 0 w / w% to 5 w / w%, and even more preferably 0 w / w% to 3 w / w%. In another embodiment of the present invention, the preparation of the present invention substantially does not contain water.

[0069] In another embodiment of the present invention, the preparation of the present invention is an anhydrous preparation or a preparation without added water. In another embodiment of the present invention, the preparation of the present invention is an anhydrous preparation or a preparation in which the water content is 3 w / w% or less based on the total preparation amount.

[0070] Usually, when adding a chelating agent such as EDTA to a formulation prescription, in order to dissolve the chelating agent, it is added to the formulation as an aqueous solution of the chelating agent. Therefore, when manufacturing an anhydrous preparation, it is difficult to use a chelating agent such as EDTA. In this regard, since the preparation of the present invention substantially does not contain a chelating agent such as EDTA, it can also be manufactured as an anhydrous preparation.

[0071] In one embodiment of the present invention, the external preparation of the present invention substantially does not contain EDTA. In another embodiment of the present invention, the external preparation of the present invention substantially does not contain a chelating agent. In another embodiment of the present invention, in the manufacturing process of the preparation of the present invention, an aqueous solution in which a chelating agent is dissolved is not added. In another embodiment of the present invention, in the manufacturing process of the preparation of the present invention, an aqueous solution in which EDTA is dissolved is not added. In another embodiment of the present invention, in the manufacturing process of the preparation of the present invention, EDTA is not added. In another embodiment of the present invention, the preparation of the present invention substantially does not contain a surfactant. In another embodiment of the present invention, in the manufacturing process of the preparation of the present invention, no surfactant is added.

[0072] As used herein, "substantially free of" means that the target formulation component is either not contained at all or is present at a low concentration such that its normal required function cannot be exerted. Thus, for example, "substantially free of EDTA" means that EDTA is either not contained at all or is present at a low concentration such that the chelating effect of EDTA is not sufficiently exerted. As used herein, "substantially free of" means, for example, less than 0.00025 w / w% based on the total amount of the preparation, preferably 0.0001 w / w% or less, more preferably 0.00001 w / w% or less, still more preferably 0.000001 w / w% or less, and even more preferably below the detection limit.

[0073] In one embodiment of the present invention, the topical preparation of the present invention is a non-film-forming preparation that is substantially free of a film-forming agent. In this case, the topical preparation of the present invention either does not contain a film-forming agent at all or, even if it is contained in the preparation, is present at a low concentration such that a film is not substantially formed on the surface of the nail after application.

[0074] As used herein, a "film-forming agent" is an additive for forming an aqueous or water-insoluble film having good stability after being applied to the nail. Examples of film-forming agents include water-soluble polymers such as copovidone, povidone, or polyvinyl alcohol; water-insoluble polymers such as copolymers of acrylic acid esters and methacrylic acid esters, pyroxylin, methyl methacrylate·butyl methacrylate, dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, nitrocellulose, or hydroxypropyl chitosan.

[0075] In one embodiment of the present invention, the topical preparation of the present invention is substantially free of cyclomethicone. In another embodiment of the present invention, the topical preparation of the present invention is substantially free of volatile silicone.

[0076] In one embodiment of the present invention, a topical preparation of efinaconazole containing the above-mentioned preferred pH adjuster and preferred antioxidant together is preferred. For example, the preparation of the present invention preferably contains a hydroxy acid and an oil-soluble antioxidant, and more preferably contains a C2-C6 aliphatic hydroxy acid and an oil-soluble antioxidant. In one embodiment of the present invention, a topical preparation of efinaconazole containing the above-mentioned preferred non-volatile ester, preferred pH adjuster, and preferred antioxidant together is preferred.

[0077] Next, a preferred combination of each formulation component in the preparation of the present invention will be described.

[0078] In one embodiment of the present invention, a preferred combination of ethanol and a non-volatile ester is a combination of 10 w / w% to 50 w / w% of the non-volatile ester and 80 w / w% to 40 w / w% of ethanol, and a more preferred combination is a combination of 15 w / w% to 45 w / w% of the non-volatile ester and 75 w / w% to 45 w / w% of ethanol. Here, the "non-volatile ester" preferably includes isopropyl myristate, medium-chain fatty acid triglyceride, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate, and two or more of these can be used.

[0079] In one embodiment of the present invention, a preferred combination of a pH adjuster and an antioxidant is a combination of 0.001 w / w% to 1.0 w / w% of the pH adjuster and 0.001 w / w% to 1.0 w / w% of the antioxidant with respect to the total formulation amount, more preferably a combination of 0.005 w / w% to 0.75 w / w% of the pH adjuster and 0.005 w / w% to 0.75 w / w% of the antioxidant, even more preferably a combination of 0.01 w / w% to 0.5 w / w% of the pH adjuster and 0.01 w / w% to 0.5 w / w% of the antioxidant, still more preferably a combination of 0.05 w / w% to 0.25 w / w% of the pH adjuster and 0.05 w / w% to 0.25 w / w% of the antioxidant, and particularly preferably a combination of 0.1 w / w% of the pH adjuster and 0.1 w / w% of the antioxidant. Here, the "pH adjuster" is preferably BHT, ascorbic acid, tocopherol, propyl gallate, or BHA, and the "antioxidant" is preferably citric acid, malic acid, lactic acid, and tartaric acid, or pharmaceutically acceptable salts thereof.

Example

[0080] Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples. However, the following Examples and Test Examples are merely examples of the present invention and do not limit the scope of the rights of the present invention.

[0081] <Test Example 1> Anti-coloring effect of various stabilizers in a 10 w / w% topical formulation of efinaconazole (1)

[0082] Regarding Example 1, after mixing and dissolving each additive except the active ingredient, efinaconazole was added and dissolved to produce a formulation. Examples 2 and Comparative Examples 1 to 3 were also produced in the same manner. The formulation details are shown in the following table.

[0083]

Table 1

[0084] Evaluation of presence or absence of coloring (stored at 60°C in the dark) The preparations of Examples 1 and 2 and Comparative Examples 1, 2, and 3 were stored at 60°C (measured value: 57.7 to 61.3°C) under light-shielded conditions, and the properties (color tone and clarity) were visually observed once a day. The test was completed on the 8th day of storage. The number of days until coloring that did not meet the specifications occurred, and the color tone and color name of the object color on the 8th day from the start of the test were evaluated. The expression of color in terms of properties was evaluated according to JIS Z 8721 "Method of color display - display by three attributes", which is a citation standard of JIS Z 8102 2001 "Color names of object colors", and the color name (hue, lightness / chroma) of the object color was specified. The results are shown in the table below.

[0085]

Table 2

[0086] All formulations were colorless and clear at the start of the test. Comparative Examples 1 to 3 that did not contain an antioxidant changed to slightly yellow and clear on the 4th day after the start of the test. In Comparative Examples 1 and 2, discoloration that did not meet the specifications was observed within 8 days after the start of the test. Comparative Example 3 was slightly yellow and clear even on the 8th day after the start of the test, and at this point, it met the specifications, but the degree of coloring became stronger over time. On the other hand, in Examples 1 and 2 containing both a pH adjuster and an antioxidant, surprisingly, no change was observed in the color tone and object color at the start of the test even on the 8th day after the start of the test. That is, as a result of this test, it was found that in an efinaconazole formulation using medium-chain fatty acid triglyceride and isopropyl myristate as non-volatile esters, adding citric acid and dibutylhydroxytoluene can effectively prevent discoloration over time.

[0087] <Test Example 2> Anti-coloring effect of various stabilizers in a 10 w / w% topical formulation of efinaconazole (2) (thermal stress test (60°C / 4 weeks))

[0088] Following the same procedure as in Test Example 1, Examples 3 to 13, Comparative Example 4, and Comparative Example 5 were also manufactured in the same manner. The formulation details of each example and each comparative example are shown in the table below.

[0089]

Table 3

[0090]

Table 4

[0091] Evaluation of presence or absence of coloring (storage at 60°C, protected from light) The efinaconazole formulations of Examples 3 to 13, Comparative Example 4, and Comparative Example 5 were stored at 60°C (measured values: 60.2 to 60.3°C) under light-protected conditions, and the properties (color tone) on the 8th day after the start of the test and the properties (color tone and clarity) on the 4th week were observed. For formulations that did not show discoloration not meeting the specifications at the 4th week, observations were made at approximately weekly intervals until 8 weeks after the start of the test, and data on the number of weeks until discoloration not meeting the specifications was observed was obtained. The results are shown in the table below.

[0092]

Table 5

[0093] As shown in Comparative Examples 4 and 5 in the table above, the efinaconazole formulations containing only one of the antioxidant and the pH adjuster showed discoloration over time in the heat stress test, and the properties at the 4th week did not meet the specifications. On the other hand, as revealed in Examples 3 to 7, in various efinaconazole formulations containing various non-volatile esters, formulations containing both a pH adjuster and an antioxidant had discoloration over time during the storage period suppressed, and in this test, Examples 3 to 7 met the specifications. Furthermore, as revealed in Examples 8 to 10, even when the pH adjuster was variously changed, discoloration of the efinaconazole formulation over time was suppressed, and in this test, Examples 8 to 10 met the standards. In addition, as revealed in Examples 11 to 13, even when the antioxidant was variously changed, discoloration of the efinaconazole formulation over time was suppressed, and in this test, Examples 11 to 13 met the standards.

Industrial Applicability

[0094] According to the present invention, it is possible to provide a stable efinaconazole formulation that does not substantially use a salt of ethylenediaminetetraacetic acid and does not cause discoloration that results in non-compliance with the formulation standards as a pharmaceutical product during the storage period, thereby enabling the provision of efinaconazole formulations in various dosage forms including anhydrous formulations.

Claims

Claim 1 A therapeutic agent for tinea unguium, comprising: a) Efinaconazole; and b) one or more non-volatile esters selected from the group consisting of medium-chain fatty acid triglycerides, isopropyl myristate, diethyl sebacate, propylene glycol monocaprylate, and propylene glycol dicaprylate; c) an organic acid selected from the group consisting of citric acid, malic acid, lactic acid, and tartaric acid, or a pharmaceutically acceptable salt thereof, as a pH adjuster; d) an antioxidant; and being a topical preparation substantially free of ethylenediaminetetraacetic acid or its salt and volatile silicone. Claim 2 The topical preparation according to claim 1, wherein the content of efinaconazole is 8 w / w% to 12 w / w% based on the total preparation amount. Claim 3 The topical preparation according to claim 1, wherein the content of efinaconazole is 10 w / w% based on the total preparation amount. Claim 4 The topical preparation according to any one of claims 1 to 3, wherein the non-volatile ester is selected from the group consisting of medium-chain fatty acid triglycerides, isopropyl myristate, and propylene glycol dicaprylate. Claim 5 The topical preparation according to any one of claims 1 to 4, wherein the content of the non-volatile ester is 1 w / w% to 80 w / w% based on the total preparation amount. Claim 6 The topical preparation according to any one of claims 1 to 4, wherein the content of the non-volatile ester is 10 w / w% to 50 w / w% based on the total preparation amount. Claim 7 The topical preparation according to any one of claims 1 to 4, wherein the content of the non-volatile ester is 15 w / w% to 45 w / w% based on the total preparation amount. Claim 8 The topical preparation according to any one of claims 1 to 7, wherein the pH adjuster is an organic acid selected from the group consisting of citric acid and tartaric acid, or a pharmaceutically acceptable salt thereof. Claim 9 The topical preparation according to any one of claims 1 to 7, wherein the pH adjuster is anhydrous citric acid. Claim 10 The topical preparation according to any one of claims 1 to 9, wherein the content of citric acid as the pH adjuster is 0.001 w / w% to 1.0 w / w% based on the total preparation amount. Claim 11 The topical preparation according to any one of claims 1 to 9, wherein the content of citric acid as the pH adjuster is 0.05 w / w% to 0.25 w / w% based on the total preparation amount. Claim 12 The external preparation according to any one of claims 1 to 11, wherein the antioxidant is an oil-soluble antioxidant selected from the group consisting of dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, propyl gallate, ascorbyl palmitate, soy lecithin, thiodiglycolic acid ester, benzotriazole, and 2-mercaptobenzimidazole.

13. The external preparation according to any one of claims 1 to 11, wherein the antioxidant is selected from the group consisting of dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, and propyl gallate.

14. The external preparation according to any one of claims 1 to 11, wherein the antioxidant is dibutylhydroxytoluene.

15. The external preparation according to any one of claims 1 to 14, wherein the antioxidant is 0.001 w / w% to 1.0 w / w% based on the total preparation amount.

16. The external preparation according to any one of claims 1 to 14, wherein the antioxidant is 0.05 w / w% to 0.25 w / w% based on the total preparation amount.

17. The external preparation according to any one of claims 1 to 16, further containing ethanol.

18. The external preparation according to any one of claims 1 to 17, wherein the water content is 3 w / w% or less based on the total preparation amount.

19. The external preparation according to any one of claims 1 to 18, which is a anhydrous preparation.

20. The external preparation according to any one of claims 1 to 19, wherein the external preparation is an external liquid preparation for application to nails.

21. The external preparation according to any one of claims 1 to 20, further substantially not containing a film-forming agent.

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