JP2022122562A - Efinaconazole-containing topical pharmaceutical composition - Google Patents

Abstract

To provide a topical pharmaceutical composition in which uniformity of a pharmaceutical composition applied to an affected part is improved.SOLUTION: A topical pharmaceutical composition contains (1) efinaconazole, (2) N-methyl-2-pyrolidone, and/or diethylene glycol monoethyl ether,(3) oil content or fat, and (4) volatile solvent.SELECTED DRAWING: None

Description

The present invention relates to topical pharmaceutical compositions containing efinaconazole.

Efinaconazole is marketed, for example, as a topical solution for treating onychomycosis. International Publication WO2001/007643 (Patent Document 1) describes an external therapeutic agent for onychomycosis containing efinaconazole as an active ingredient. Japanese Patent Application Laid-Open No. 2015-38101 (Patent Document 2) describes a composition containing efinaconazole for treating nail diseases, and in order to increase the penetration of this composition into the nail, , describes that volatile silicon (cyclomethicone) is blended. International Publication WO2015/051183 (Patent Document 3) also describes an efinaconazole composition containing cyclomethicone.

The commercially available efinaconazole solution for external use and the composition of Example 1 of Patent Document 3 contain cyclomethicone, ethanol, purified water, and fats and oils (such as alkyl lactate) as ingredients. When these compositions are applied to the affected nail, ethanol evaporates, leaving a composition in which efinaconazole, cyclomethicone, and oil are mixed with purified water on the nail, and efinaconazole is applied to the nail. Penetrating.

International publication WO2001/007643 Japanese Unexamined Patent Application Publication No. 2015-38101 International publication WO2015/051183

The present inventors applied a composition containing efinaconazole to the affected nail as described above, and when the ethanol volatilized from the applied composition, the composition remaining on the nail, cyclomethicone and oil, Purified water has poor compatibility, and it was found that the composition separated on the nail and became non-uniform. Such separation of the composition on the affected area may result in non-uniform distribution of the active ingredient and variable efficacy.

It is therefore an object of this invention to provide a topical pharmaceutical composition containing efinaconazole with improved uniformity of the pharmaceutical composition applied to the affected area.

The topical pharmaceutical composition according to the present invention comprises (1) efinaconazole, (2) N-methyl-2-pyrrolidone and/or diethylene glycol monoethyl ether, (3) an oil or fat, ( 4) contains a volatile solvent;

As a result of intensive studies, the present inventors found that among the ingredients of the formulation of Example 1 of Patent Document 3, by changing cyclomethicone to N-methyl-2-pyrrolidone or diethylene glycol monoethyl ether, it can be applied to the affected area. It has been found that the compatibility of non-volatile components in the pharmaceutical composition is improved and the uniformity of the composition after volatilization is improved. Improved uniformity of the composition applied to the affected area results in even distribution of the active ingredient over the affected area and consistent efficacy.

As described above, according to the present invention, it is possible to provide an efinaconazole-containing topical pharmaceutical composition with improved uniformity of the pharmaceutical composition applied to the affected area.

The topical pharmaceutical composition according to the present invention comprises (1) efinaconazole, (2) N-methyl-2-pyrrolidone and/or diethylene glycol monoethyl ether, (3) an oil or fat, ( 4) contains a volatile solvent;

Topical pharmaceutical compositions according to the invention are formulated, for example, in the form of liquid compositions or semi-solid compositions. The liquid composition may be, for example, in the form of an aqueous solution, emulsion (emulsion) or suspension. Semi-solid compositions may be in the form of, for example, ointments, lotions, gels, creams, pastes. Preferably, the topical pharmaceutical composition is formulated as a solution.

A topical pharmaceutical composition according to the present invention can be, for example, an external preparation. The topical pharmaceutical composition according to the present invention is used for topical administration to the affected area to treat skin or nail conditions. Skin or nail conditions for which the topical pharmaceutical compositions of the present invention are applied include tinea pedis, tinea capitis, tinea unguium, tinea cruris, tinea corporis, and yeast infections. The topical pharmaceutical composition of the present invention is preferably an external solution for treating tinea unguium, more preferably for treating tinea unguium. When the topical pharmaceutical composition of the present invention is used as an external solution for treating tinea unguium, it is preferably applied to the entire affected nail once a day.

As used herein, (1) efinaconazole is (2R,3R)-2-(2,4-fluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H -1,2,4-triazol-1-yl)butan-2-ol and its pharmaceutically acceptable salts. In the topical pharmaceutical composition according to the present invention, (1) the efinaconazole content varies depending on the application, but is preferably 5% by mass or more and 15% by mass or less, more preferably 8% by mass or more and 12% by mass or less. , particularly preferably 100 mg in 1 g of topical pharmaceutical composition.

A topical pharmaceutical composition according to the present invention comprises (2) N-methyl-2-pyrrolidone and/or diethylene glycol monoethyl ether and preferably does not contain cyclomethicone. Commercially available products can be used as N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether. In the topical pharmaceutical composition according to the present invention, the content of N-methyl-2-pyrrolidone is preferably 1% to 11% by weight, more preferably 1% to 5% by weight, and diethylene glycol mono The content of ethyl ether is preferably 1% to 11% by mass, more preferably 4% to 8% by mass. When both N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether are included, the preferred total content is 2% by mass or more and 11% by mass or less.

The topical pharmaceutical composition according to the present invention preferably contains diethyl sebacate as (3) the oil or fat. (3) The content of oil or fat is preferably 4% by mass or more and 14% by mass or less, more preferably 7% by mass or more and 11% by mass or less. The oil or fat may be, for example, diisopropyl adipate or alkyl lactate, and the oil or fat may further include diisopropyl adipate or alkyl lactate in addition to diethyl sebacate.

The topical pharmaceutical composition according to the present invention contains (4) as a volatile solvent, without limitation, acetone, 2-amino-2-methyl-1-propanol, 1,2-butanediol, 1,4-butane Diols, 2-butanol, ethanol, ethyl acetate, n-heptane, isobutanol, isopropyl alcohol, 1-propanol, 2-propanol, and water can be included. Preferably, (4) the volatile solvent is ethanol. (4) The content of the volatile solvent is preferably 57% by mass or more and 70% by mass or less, more preferably 60% by mass or more and 67% by mass or less.

The topical pharmaceutical composition according to the present invention can contain pharmaceutically acceptable ingredients such as excipients in addition to the above ingredients (1) to (4). Examples of such pharmaceutically acceptable ingredients include sugars such as lactose hydrate, corn starch, and meglumine.

The topical pharmaceutical composition according to the present invention can further contain additives as desired. For example, when the topical pharmaceutical composition is an external preparation, specific additives include buffering agents, tonicity agents, solubilizers, viscous bases, chelating agents, cooling agents, pH adjusters, preservatives, antioxidants, stabilizers and the like.

Examples of buffers include phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, Tris buffers, amino acids and the like.

Examples of isotonizing agents include sugars such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid and the like.

Examples of solubilizing agents include glycerin and macrogol.

Examples of the viscous base include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol and carboxyvinyl polymer; celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose.

Chelating agents include, for example, sodium edetate (EDTA), citric acid and the like.

Cooling agents include, for example, l-menthol, borneol, camphor, eucalyptus oil and the like.

Examples of pH adjusters include alkalis such as sodium hydroxide and potassium hydroxide; acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid and tartaric acid.

Preservatives include, for example, sorbic acid, potassium sorbate, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorohexidine gluconate, boric acid, dehydroacetic acid, dehydro Sodium acetate, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, sodium chlorite and the like.

Examples of antioxidants include tetrasodium etidronate, disodium edetate, tetrasodium edetate, vitamin C, vitamin E, dibutylhydroxytoluene (BHT), butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite. , potassium sulfite, potassium pyrosulfite, sulfur dioxide, chlorogenic acid, catechin and the like.

Stabilizers include, for example, polyvinylpyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, sodium edetate, taurine, tocopherol and the like.

Active ingredients in quasi-drugs can be further added to the topical pharmaceutical composition of the present invention. Examples of active ingredients in quasi-drugs include bactericides, anti-inflammatory agents, enzymes, and vitamins.

The topical pharmaceutical compositions of the present invention can be prepared using known techniques. For example, (1) efinaconazole, (2) N-methyl-2-pyrrolidone and/or diethylene glycol monoethyl ether, (3) oils or fats, (4) volatile solvents, and other additives. agents to obtain a topical pharmaceutical composition. Each component of the topical pharmaceutical composition of the present invention can be added in any order.

Examples of the present invention will be described below. The content (%) of each component is % by mass unless otherwise specified.

[Compatibility evaluation]
The components in column A and the components in column B of Table 1 were mixed at a mass ratio of 1:1 at room temperature using a magnetic stirrer for 5 minutes or more, and the uniformity of the resulting liquid was visually evaluated. In Table 1, "O" indicates that the liquid was homogeneous, "X" that it was non-uniform, and "-" that it was not tested. "Cyclomethicone + fat" in column A is a mixture of cyclomethicone and fat at a mass ratio of 1:1 using alkyl lactate (C12-15) as fat, and "cyclomethicone + fat + 95% ethanol" is , Alkyl lactate (C12-15) was used as fat, and cyclomethicone, fat and 95% ethanol were mixed at a mass ratio of 1:1:1.

As shown in Table 1, cyclomethicone is immiscible with purified water and 95% ethanol, and the mixture of cyclomethicone and fats and oils is miscible with 95% ethanol, but not with purified water. . On the other hand, a mixture of cyclomethicone, fat and 95% ethanol was mixed with purified water. Cyclomethicone is used in the formulation of Example 1 of Patent Document 3, and the results show that the composition of Example 1 of Patent Document 3 lacks ethanol or fat, resulting in a non-uniform liquid. rice field. On the other hand, N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether were mixed with purified water, 95% ethanol, and fats and oils to obtain homogeneous liquids. From the above results, by using N-methyl-2-pyrrolidone and/or diethylene glycol monoethyl ether in place of cyclomethicone, the composition after volatilization of ethanol can be made uniform.

[Evaluation of thermodynamic activity behavior]
The topical pharmaceutical compositions of Example A, Example B, and Comparative Example 1 (Example 1 of Patent Document 3) were prepared according to the formulations shown in Table 2, and their thermodynamic activity behavior was evaluated. In Examples A and B, (2) N-methyl-2-pyrrolidone or diethylene glycol monoethyl ether and (3) diethyl sebacate as an oil or fat were blended in the amounts shown in Table 3.

Each test preparation was dispensed on a glass petri dish, allowed to stand in a 32° C. environment, and then weighed to evaluate the volatilization amount over time. In addition, the test formulation placed under the same conditions was sampled, and the efinaconazole solubility was measured over time using a high-performance liquid chromatograph. At each sampling time point, the thermodynamic activity was calculated from the volatility and efinaconazole solubility to obtain the thermodynamic activity behavior. Based on the bioequivalence test guidelines for generic drugs, the f2 value is calculated between the thermodynamic activity behavior of each example and the thermodynamic activity behavior of Comparative Example 1, and the equivalence between the two is evaluated. It was used as an index to For Examples A1 to A10 and Examples B1 to B9, Tables 4 and 5 show f2 values up to 24 hours after application, f2 values up to 1 hour after application, and whether f2≧50. In Tables 4 and 5, "O" in "Criteria" indicates that f2 ≥ 50 both up to 1 hour after application and up to 24 hours after application, and "x" indicates f2 < 50. indicates that

As shown in Tables 4 and 5, in Examples A1 to A6 and A8 and Examples B1 to B8, compared to Comparative Example 1 (Example 1 of Patent Document 3), the thermodynamic activity behavior is were equivalent. Therefore, when diethyl sebacate is used as the oil or fat in the topical pharmaceutical composition of the present invention, and N-methyl-2-pyrrolidone is used in place of cyclomethicone, 8 to 9% by mass of diethyl sebacate is used. When diethyl sebacate is 10% by mass, the content of N-methyl-2-pyrrolidone is preferably 3% by mass or less, and when diethyl sebacate is 11% by mass, N The content of -methyl-2-pyrrolidone is preferably 2% by mass or less. In addition, when diethylene glycol monoethyl ether is used instead of cyclomethicone, the content of diethyl sebacate is preferably 8 to 9% by mass, and when diethyl sebacate is 10% by mass, diethylene glycol monoethyl ether is contained. Preferably the amount is 6% or less.

[Evaluation of uniformity after volatilization of volatile solvent]
A topical pharmaceutical composition was prepared according to the formulations of Example A5, Example B5, and Comparative Example 1, and the uniformity of the composition after volatilization of the volatile solvent was evaluated.

[Absorbance]
The absorbance (measurement wavelength: 380 nm) was measured using an absorptiometer for each of the test formulations that were dispensed into glass bottles and allowed to stand open in a 32° C. environment for 24 hours and those that had not yet been left to stand. Table 6 shows the results.

[brightness]
The lightness of the test specimens described above was also measured using an absorptiometer. Table 6 shows the results.

As shown in Table 6, in both Example A5 and Example B5, both the absorbance and brightness after volatilization of the volatile solvent were improved as compared with Comparative Example 1, and a more nearly transparent uniform composition was obtained. rice field.

Next, Example C1 is obtained by replacing diethyl sebacate with alkyl lactate in the formulation of Example A5, and Example D1 is obtained by replacing diethyl sebacate with alkyl lactate in the formulation of Example B5. The uniformity after evaporation of the solvent was evaluated. Table 7 shows the results.

As shown in Table 7, even when alkyl lactate was used as the oil or fat, both Example C1 and Example D1 exhibited improved absorbance and brightness after volatilization of the volatile solvent compared to Comparative Example 1. , a more nearly transparent homogeneous composition was obtained.

It should be considered that the embodiments and examples disclosed above are illustrative in all respects and not restrictive. The scope of the present invention is defined not by the above-described embodiments and examples, but by the scope of claims, and includes all modifications and variations within the scope and meaning equivalent to the scope of claims.

Claims (5)

(1) efinaconazole and
(2) N-methyl-2-pyrrolidone and/or diethylene glycol monoethyl ether;
(3) an oil or fat,
(4) a topical pharmaceutical composition containing a volatile solvent; 2. The topical pharmaceutical composition according to claim 1, wherein the (3) oil or fat is diethyl sebacate. 3. The topical pharmaceutical composition of claim 1 or claim 2, wherein the (4) volatile solvent is ethanol. 4. A topical pharmaceutical composition according to any one of claims 1 to 3 for treating tinea unguium. 5. The topical pharmaceutical composition according to claim 4, which is a topical liquid.