WO2021054535A2 - Stabilized efinaconazole-containing pharmaceutical composition comprising combination of chelating agent, antioxidant, and acid - Google Patents

Abstract

The present invention provides a pharmaceutical composition for topical administration, in the form of an efinaconazole-containing solution, comprising a specific combination of a chelating agent, an antioxidant and an acid. The pharmaceutical composition of the present invention has excellent physicochemical stability.

Description

Stabilized efinaconazole-containing pharmaceutical composition comprising a combination of a chelating agent, an antioxidant, and an acid

The present invention relates to a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole. More particularly, it relates to an efinaconazole-containing pharmaceutical composition for topical administration in the form of a solution comprising a specific combination of a chelating agent, an antioxidant, and an acid.

Epinaconazole is a triazole-based antifungal agent having the structure of the following formula (1), and its chemical name is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine- 1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol[(2R,3R)-2-(2,4-difluorophenyl)-3-(4- methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol].

<Formula 1>

Epinaconazole has the activity of inhibiting lanosterol 14α-demethylase in the ergosterol biosynthetic pathway, and a 10% topical solution formulation for the treatment of onychomycosis (trade names: JUBLIA ^TM , Kaken Pharmaceutical Co., Ltd.). The topical solution formulation, together with efinaconazole, may contain ethanol as a volatile solvent; Cyclomethicone as a wetting agent; And diisopropyl adipate and C ₁₂ -C ₁₅ alkyl lactate as non-volatile solvents (US Pat. Nos. 7,214,506, 8,039,494, 8,486,978, 9,302,009, 9,566,272, 9,861,698, and 9,877,955, etc.).

Solution formulations containing efinaconazole have a problem of stability, that is, discoloration within a short storage period resulting in a composition color ranging from yellow to dark red or brown. In order to solve this stability problem, U.S. Patent No. US 9,662,394 and International Patent Publication No. WO 2015/051183 disclose specific combinations of chelating agents, antioxidants, and acids, namely ethylenediaminetetraacetic acid (EDTA) or a salt thereof, butyl. A liquid or semi-solid composition comprising butylated hydroxytoluene (BHT), and citric acid has been disclosed.

The present inventors have conducted various studies to develop a formulation for topical administration in the form of a solution containing efinaconazole. In particular, the present inventors have studied combinations of various chelating agents, antioxidants, and acids in order to develop a formulation capable of improving physicochemical stability by reducing the generation of related substances. As a result, certain chelating agents; Antioxidants; It has been found that when formulation is performed using a combination of an acid and an acid, more excellent physicochemical stability can be secured compared to a known formulation.

Thus, the present invention provides specific chelating agents; Antioxidants; It is an object of the present invention to provide a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole, including a combination of an acid and an acid.

According to one aspect of the invention, efinaconazole; ethanol; Cyclomethicone; _{Diisopropyl adipate, C 12} -C ₁₅ alkyl lactate, or mixtures thereof as non-volatile solvents; Chelating agents; Antioxidants; And a pharmaceutical composition for topical administration in the form of a solution containing an acid, comprising: the chelating agent; Antioxidants; And the acid is (i) benzotriazole; Palmitic acid; And citric acid, (ii) DL-methionine; Monothioglycerol; And citric acid, (iii) tetrahydroxypropyl ethylenediamine; Butylated hydroxytoluene; And citric acid, or (iv) ethylenediaminetetraacetic acid or sodium salt thereof; Chlorogenic acid; And there is provided a pharmaceutical composition for topical administration in the form of a solution, characterized in that sorbic acid.

In the pharmaceutical composition of the present invention, the chelating agent may be present in an amount of 0.0001 to 1.5% by weight, preferably 0.0001 to 0.05% by weight, more preferably 0.00025 to 0.05% by weight, based on the total weight of the composition.

In the pharmaceutical composition of the present invention, the antioxidant may be present in an amount of 0.01 to 2% by weight, preferably 0.1 to 1% by weight, more preferably about 0.1% by weight, based on the total weight of the composition.

In the pharmaceutical composition of the present invention, the acid may be present in an amount of 0.05 to 0.25% by weight, preferably about 0.1% by weight, based on the total weight of the composition.

Certain chelating agents; Antioxidants; It has been found by the present invention that when the formulation is carried out using a combination of an acid and an acid, an efinaconazole-containing pharmaceutical composition having excellent physicochemical stability is obtained. Therefore, the pharmaceutical composition of the present invention can be usefully used as a formulation for topical administration having excellent stability.

The present invention is efinaconazole; ethanol; Cyclomethicone; _{Diisopropyl adipate, C 12} -C ₁₅ alkyl lactate, or mixtures thereof as non-volatile solvents; Chelating agents; Antioxidants; And a pharmaceutical composition for topical administration in the form of a solution containing an acid, comprising: the chelating agent; Antioxidants; And the acid is (i) benzotriazole; Palmitic acid; And citric acid, (ii) DL-methionine; Monothioglycerol; And citric acid, (iii) tetrahydroxypropyl ethylenediamine; Butylated hydroxytoluene; And citric acid, or (iv) ethylenediaminetetraacetic acid or sodium salt thereof; Chlorogenic acid; And it provides a pharmaceutical composition for topical administration in the form of a solution, characterized in that sorbic acid.

The pharmaceutical composition of the present invention contains efinaconazole as an active ingredient. Epinaconazole may be contained in therapeutically effective amounts, for example, in the range of 8 to 12% by weight, preferably in an amount of about 10% by weight based on the total weight of the composition. , But is not limited thereto.

The pharmaceutical composition of the present invention comprises a specific chelating agent; Antioxidants; And combinations of acids, ie (i) benzotriazole; Palmitic acid; And a combination of citric acid, (ii) DL-methionine; Monothioglycerol; And a combination of citric acid, (iii) tetrahydroxypropyl ethylenediamine; Butylated hydroxytoluene; And a combination of citric acid, or (iv) ethylenediaminetetraacetic acid or sodium salt thereof; Chlorogenic acid; And a combination of sorbic acid.

In the pharmaceutical composition of the present invention, the chelating agent (i.e., benzotriazole, DL-methionine, tetrahydroxypropyl ethylenediamine, ethylenediaminetetraacetic acid (EDTA) or sodium salt thereof) is a composition It may be present in an amount of 0.0001 to 1.5% by weight, preferably 0.0001 to 0.05% by weight, more preferably 0.00025 to 0.05% by weight, based on the total weight.

In the pharmaceutical composition of the present invention, the antioxidant (i.e., palmitic acid, monothioglycerol, butylated hydroxytoluene, or chlorogenic acid) is 0.01 to 2% by weight based on the total weight of the composition. , Preferably 0.1 to 1% by weight, more preferably about 0.1% by weight.

In the pharmaceutical composition of the present invention, the acid (citric acid or sorbic acid) may be present in an amount of 0.05 to 0.25% by weight, preferably about 0.1% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention comprises ethanol as a volatile solvent; Cyclomethicone as a wetting agent; Non-volatile solvents include diisopropyl adipate, C ₁₂ -C ₁₅ alkyl lactate, or mixtures thereof. The volatile solvent, wetting agent, and non-volatile solvent may be used in an amount used in a conventional efinaconazole-containing solution formulation (eg, US Patent No. US 9,662,394, etc.). For example, ethanol may be present in an amount of 50 to 65% by weight, preferably about 53.79975% by weight, based on the total weight of the composition. For example, the cyclomethicone may be present in an amount of 10 to 15% by weight, preferably about 13% by weight based on the total weight of the composition. For example, diisopropyl adipate may be present in an amount of 8 to 15% by weight, preferably about 12% by weight, based on the total weight of the composition. For example, the C ₁₂ -C ₁₅ alkyl lactate may be present in an amount of 8 to 15% by weight, preferably about 10% by weight, based on the total weight of the composition. In addition, if necessary, the pharmaceutical composition of the present invention may further contain a small amount of water (for example, 5% by weight or less, preferably about 1% by weight).

In one embodiment, 8-12% by weight of efinaconazole; Ethanol 50-65% by weight; 10 to 15% by weight of cyclomethicone; 8-15% by weight of diisopropyl adipate; 8-15% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.0001 to 1.5% by weight of benzotriazole; 0.01 to 2% by weight of palmitic acid; From 0.05 to 0.25% by weight of citric acid; And there is provided a pharmaceutical composition comprising 0 to 5% by weight of water. In a particularly preferred embodiment, 10% by weight of efinaconazole; 53.79975% ethanol by weight; 13% by weight cyclomethicone; 12% by weight of diisopropyl adipate; 10% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.00025% by weight of benzotriazole; 0.1% by weight palmitic acid; 0.1% citric acid; And there is provided a pharmaceutical composition consisting of 1% by weight of water.

In another embodiment, 8-12% by weight efinaconazole; Ethanol 50-65% by weight; 10 to 15% by weight of cyclomethicone; 8-15% by weight of diisopropyl adipate; 8-15% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.0001 to 1.5% by weight of DL-methionine; 0.01 to 2% by weight of monothioglycerol; From 0.05 to 0.25% by weight of citric acid; And there is provided a pharmaceutical composition comprising 0 to 5% by weight of water. In a particularly preferred embodiment, 10% by weight of efinaconazole; 53.79975% ethanol by weight; 13% by weight cyclomethicone; 12% by weight of diisopropyl adipate; 10% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.00025% by weight of DL-methionine; 0.1% by weight of monothioglycerol; 0.1% citric acid; And there is provided a pharmaceutical composition consisting of 1% by weight of water.

In another embodiment, 8-12% by weight of efinaconazole; Ethanol 50-65% by weight; 10 to 15% by weight of cyclomethicone; 8-15% by weight of diisopropyl adipate; 8-15% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.0001 to 1.5% by weight of tetrahydroxypropyl ethylenediamine; 0.01 to 2% by weight of butylated hydroxytoluene; From 0.05 to 0.25% by weight of citric acid; And there is provided a pharmaceutical composition comprising 0 to 5% by weight of water. In a particularly preferred embodiment, 10% by weight of efinaconazole; 53.75% ethanol by weight; 13% by weight cyclomethicone; 12% by weight of diisopropyl adipate; 10% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.05% by weight of tetrahydroxypropyl ethylenediamine; 0.1% by weight of butylated hydroxytoluene; 0.1% citric acid; And there is provided a pharmaceutical composition consisting of 1% by weight of water.

In another embodiment, 8-12% by weight of efinaconazole; Ethanol 50-65% by weight; 10 to 15% by weight of cyclomethicone; 8-15% by weight of diisopropyl adipate; 8-15% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.0001 to 1.5% by weight of ethylenediaminetetraacetic acid or its sodium salt; 0.01 to 2% by weight of chlorogenic acid; 0.05 to 0.25% by weight of sorbic acid; And there is provided a pharmaceutical composition comprising 0 to 5% by weight of water. In a particularly preferred embodiment, 10% by weight of efinaconazole; 53.79975% ethanol by weight; 13% by weight cyclomethicone; 12% by weight of diisopropyl adipate; 10% by weight of C ₁₂ -C _{15 alkyl lactate;} 0.00025% by weight of ethylenediaminetetraacetic acid or sodium salt thereof; 0.1% by weight of chlorogenic acid; 0.1% by weight of sorbic acid; And there is provided a pharmaceutical composition consisting of 1% by weight of water.

The pharmaceutical composition of the present invention can be prepared by mixing according to a conventional method using the above ingredients. If necessary, a stock solution containing a chelating agent and a stock solution containing efinaconazole are prepared, respectively, and then appropriately mixed with other ingredients to form a solution, thereby preparing the pharmaceutical composition of the present invention.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples illustrate the present invention, and the present invention is not limited thereto.

Example 1. Preparation of solution and analysis of related substances

(1) Preparation of solution

According to the components and contents in Table 1 below, a solution containing efinaconazole was prepared. The content of each component in Table 1 represents the weight percent of the solution. Stock solutions were prepared by dissolving benzotriazole, DL-methionine, tetrahydroxypropyl ethylenediamine (THPE), and ethylenediaminetetraacetic acid disodium salt (EDTA disodium) in purified water at a concentration of 0.025 mg/mL, respectively. In addition, efinaconazole (0.2 g) was dissolved in ethanol (0.076 g) to prepare an efinaconazole-containing stock solution. Cyclomethicone, diisopropyl adipate, C ₁₂ -C ₁₅ alkyl lactate (Ashland), antioxidant (palmitic acid, monothioglycerol, butylated hydroxytoluene (BHT) in efinaconazole-containing ethanol solution) , Or chlorogenic acid), an acid (citric acid or sorbic acid), and a chelating agent (added in the form of a stock solution prepared above) were sequentially added and mixed to prepare a solution containing efinaconazole.

	Formulation Example (% by weight)
	1-1	1-2	1-3	1-4
Epinaconazole	10	10	10	10
ethanol	53.79975	53.79975	53.75	53.79975
Cyclomethicone	13	13	13	13
Diisopropyl adipate	12	12	12	12
C 12 -C 15 alkyl lactate	10	10	10	10
Benzotriazole	0.00025
DL-methionine		0.00025
THPE			0.05
EDTA disodium				0.00025
Palmitic acid	0.1
Monothioglycerol		0.1
BHT			0.1
Chlorogenic acid				0.1
Purified water	One	One	One	One
Citric acid	0.1	0.1	0.1
Sorbic acid				0.1
Sum(%)	100	100	100	100

(2) Analysis of related substances

After the solutions prepared in Formulation Examples 1-1 to 1-4 were stored at 80° C. for 3 weeks, the total amount of related substances was measured using high-speed liquid chromatography (HPLC). In addition, after storing the solutions prepared in Formulation Examples 1-2 and 1-3 at 65° C. for 4 weeks, the total amount of related substances was measured using HPLC. As a control formulation, JUBLIA ^™ (containing 10% efinaconazole-topical solution formulation, EDTA disodium, butylated hydroxytoluene (BHT), and citric acid, Kaken Pharmaceutical Co., Ltd.) was used.

High-speed liquid chromatography (HPLC) analysis conditions are as follows.

<HPLC conditions>

-Column: Kinetex5uEVOC18 100 Å 4.6 X 250 mm (Phenomenex)

-Mobile phase A: 10 mM octane-1-sulfonic acid sodium salt, 10 mM KH ₂ PO ₄ buffer (pH 2.5)

-Mobile phase B: acetonitrile:methanol (5:5, v/v)

-Flow rate: 1.0 mL/min

-Injection volume: 20 μL

-Detection: Ultraviolet absorption photometer (measurement wavelength: 210 nm)

The results of measuring the total amount of related substances as described above are shown in Table 2 below.

Formulation example	Total amount of related substances (%)
	Stored at 80℃ for 3 weeks	Stored at 65℃ for 4 weeks
1-1	1.82	-
1-2	1.88	0.47
1-3	1.30	0.32
1-4	1.85	-
Control formulation	2.05	0.58

From the results of Table 2, it can be seen that the solution obtained according to the present invention has excellent stability by showing a significantly lower total amount of related substances compared to the control formulation.

Example 2. Preparation of solution and analysis of related substances

(1) Preparation of solution

According to the components and contents of Tables 3 to 5 below, a solution containing efinaconazole was prepared in the same manner as in Example 1 (1). The content of each component in Tables 3 to 5 represents a weight percent of the solution.

	Formulation Example (% by weight)
	2-1	2-2	2-3	2-4	2-5	2-6	2-7	2-8	2-9
Epinaconazole	10	10	10	10	10	10	10	10	10
ethanol	62.75	56.75	50.75	62.79975	50.79975	62.79975	50.79975	56.79975	62.79975
Cyclomethicone	10	12	14	10	14	10	14	10	14
Diisopropyl adipate	8	11	13	8	13	8	13	8	13
C 12 -C 15 alkyl lactate	8	9	11	8	11	8	11	8	11
THPE	0.05	0.05	0.05
Benzotriazole				0.00025	0.00025
DL-methionine						0.00025	0.00025
EDTA disodium								0.00025	0.00025
BHT	0.1	0.1	0.1
Palmitic acid				0.1	0.1
Monothioglycerol						0.1	0.1
Chlorogenic acid								0.1	0.1
Purified water	One	One	One	One	One	One	One	One	One
Citric acid	0.1	0.1	0.1	0.1	0.1	0.1	0.1
Sorbic acid								0.1	0.1
Sum(%)	100	100	100	100	100	100	100	100	100

	Formulation Example (% by weight)
	2-10	2-11	2-12	2-13	2-14	2-15	2-16	2-17	2-18
Epinaconazole	10	10	10	10	10	10	10	10	10
ethanol	53.7999	53.79	53.7	53.7999	53.7975	53.7999	53.7975	53.7999	53.7975
Cyclomethicone	13	13	13	13	13	13	13	13	13
Diisopropyl adipate	12	12	12	12	12	12	12	12	12
C 12 -C 15 alkyl lactate	10	10	10	10	10	10	10	10	10
THPE	0.0001	0.01	0.1
Benzotriazole				0.0001	0.0025
DL-methionine						0.0001	0.0025
EDTA disodium								0.0001	0.0025
BHT	0.1	0.1	0.1
Palmitic acid				0.1	0.1
Monothioglycerol						0.1	0.1
Chlorogenic acid								0.1	0.1
Purified water	One	One	One	One	One	One	One	One	One
Citric acid	0.1	0.1	0.1	0.1	0.1	0.1	0.1
Sorbic acid								0.1	0.1
Sum(%)	100	100	100	100	100	100	100	100	100

	Formulation Example (% by weight)
	2-19	2-20	2-21	2-22	2-23	2-24	2-25	2-26	2-27
Epinaconazole	10	10	10	10	10	10	10	10	10
ethanol	53.84	53.35	52.85	53.88975	52.89975	53.88975	52.89975	53.88975	52.89975
Cyclomethicone	13	13	13	13	13	13	13	13	13
Diisopropyl adipate	12	12	12	12	12	12	12	12	12
C 12 -C 15 alkyl lactate	10	10	10	10	10	10	10	10	10
THPE	0.05	0.05	0.05
Benzotriazole				0.00025	0.00025
DL-methionine						0.00025	0.00025
EDTA disodium								0.00025	0.00025
BHT	0.01	0.5	One
Palmitic acid				0.01	One
Monothioglycerol						0.01	One
Chlorogenic acid								0.01	One
Purified water	One	One	One	One	One	One	One	One	One
Citric acid	0.1	0.1	0.1	0.1	0.1	0.1	0.1
Sorbic acid								0.1	0.1
Sum(%)	100	100	100	100	100	100	100	100	100

(2) Analysis of related substances

After each of the solutions prepared in Formulation Examples 2-1 to 2-27 were stored at 80° C. for 3 weeks, analysis of related substances was performed in the same manner as in Example 1 (2). The results are shown in Table 6 below.

Formulation example	Total amount of related substances (%)
2-1	1.30
2-2	1.31
2-3	1.29
2-4	1.83
2-5	1.81
2-6	1.88
2-7	1.87
2-8	1.84
2-9	1.85
2-10	1.40
2-11	1.32
2-12	1.25
2-13	1.86
2-14	1.78
2-15	1.89
2-16	1.85
2-17	1.86
2-18	1.80
2-19	1.36
2-20	1.28
2-21	1.19
2-22	1.88
2-23	1.70
2-24	1.91
2-25	1.78
2-26	1.88
2-27	1.79
Control formulation	2.05

From the results of Table 6, it can be seen that the solution obtained according to the present invention has excellent stability by showing a significantly lower total amount of related substances compared to the control formulation.

Claims (17)

1. Efinaconazole; ethanol; Cyclomethicone; _{Diisopropyl adipate, C 12} -C ₁₅ alkyl lactate, or mixtures thereof as non-volatile solvents; Chelating agents; Antioxidants; And in the pharmaceutical composition for topical administration in the form of a solution containing an acid,

   The chelating agent; Antioxidants; And acid

   (i) benzotriazole; Palmitic acid; And citric acid,

   (ii) DL-methionine; Monothioglycerol; And citric acid,

   (iii) tetrahydroxypropyl ethylenediamine; Butylated hydroxytoluene; And citric acid, or

   (iv) ethylenediaminetetraacetic acid or its sodium salt; Chlorogenic acid; And sorbic acid, a pharmaceutical composition for topical administration in the form of a solution.
2. The pharmaceutical composition according to claim 1, wherein the chelating agent is present in an amount of 0.0001 to 1.5% by weight based on the total weight of the composition.
3. The pharmaceutical composition according to claim 1, wherein the chelating agent is present in an amount of 0.0001 to 0.05% by weight based on the total weight of the composition.
4. The pharmaceutical composition according to claim 1, wherein the chelating agent is present in an amount of 0.00025 to 0.05% by weight based on the total weight of the composition.
5. The pharmaceutical composition according to claim 1, wherein the antioxidant is present in an amount of 0.01 to 2% by weight based on the total weight of the composition.
6. The pharmaceutical composition according to claim 1, wherein the antioxidant is present in an amount of 0.1 to 1% by weight based on the total weight of the composition.
7. The pharmaceutical composition according to claim 1, wherein the antioxidant is present in an amount of 0.1% by weight based on the total weight of the composition.
8. The pharmaceutical composition according to claim 1, wherein the acid is present in an amount of 0.05 to 0.25% by weight based on the total weight of the composition.
9. The pharmaceutical composition according to claim 1, wherein the acid is present in an amount of 0.1% by weight based on the total weight of the composition.
10. The method of claim 1,

    8-12% by weight of efinaconazole;

    Ethanol 50-65% by weight;

    10 to 15% by weight of cyclomethicone;

    8-15% by weight of diisopropyl adipate;

    8-15% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.0001 to 1.5% by weight of benzotriazole;

    0.01 to 2% by weight of palmitic acid;

    From 0.05 to 0.25% by weight of citric acid; And

    0 to 5% by weight of water

    Pharmaceutical composition comprising a.
11. The method of claim 1,

    8-12% by weight of efinaconazole;

    Ethanol 50-65% by weight;

    10 to 15% by weight of cyclomethicone;

    8-15% by weight of diisopropyl adipate;

    8-15% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.0001 to 1.5% by weight of DL-methionine;

    0.01 to 2% by weight of monothioglycerol;

    From 0.05 to 0.25% by weight of citric acid; And

    0 to 5% by weight of water

    Pharmaceutical composition comprising a.
12. The method of claim 1,

    8-12% by weight of efinaconazole;

    Ethanol 50-65% by weight;

    10 to 15% by weight of cyclomethicone;

    8-15% by weight of diisopropyl adipate;

    8-15% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.0001 to 1.5% by weight of tetrahydroxypropyl ethylenediamine;

    0.01 to 2% by weight of butylated hydroxytoluene;

    From 0.05 to 0.25% by weight of citric acid; And

    0 to 5% by weight of water

    Pharmaceutical composition comprising a.
13. The method of claim 1,

    8-12% by weight of efinaconazole;

    Ethanol 50-65% by weight;

    10 to 15% by weight of cyclomethicone;

    8-15% by weight of diisopropyl adipate;

    8-15% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.0001 to 1.5% by weight of ethylenediaminetetraacetic acid or its sodium salt;

    0.01 to 2% by weight of chlorogenic acid;

    0.05 to 0.25% by weight of sorbic acid; And

    0 to 5% by weight of water

    Pharmaceutical composition comprising a.
14. The method of claim 1,

    10% by weight efinaconazole;

    53.79975% ethanol by weight;

    13% by weight cyclomethicone;

    12% by weight of diisopropyl adipate;

    10% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.00025% by weight of benzotriazole;

    0.1% by weight palmitic acid;

    0.1% citric acid; And

    1% by weight of water

    A pharmaceutical composition consisting of.
15. The method of claim 1,

    10% by weight efinaconazole;

    53.79975% ethanol by weight;

    13% by weight cyclomethicone;

    12% by weight of diisopropyl adipate;

    10% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.00025% by weight of DL-methionine;

    0.1% by weight of monothioglycerol;

    0.1% citric acid; And

    1% by weight of water

    A pharmaceutical composition consisting of.
16. The method of claim 1,

    10% by weight efinaconazole;

    53.75% ethanol by weight;

    13% by weight cyclomethicone;

    12% by weight of diisopropyl adipate;

    10% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.05% by weight of tetrahydroxypropyl ethylenediamine;

    0.1% by weight of butylated hydroxytoluene;

    0.1% citric acid; And

    1% by weight of water

    A pharmaceutical composition consisting of.
17. The method of claim 1,

    10% by weight efinaconazole;

    53.79975% ethanol by weight;

    13% by weight cyclomethicone;

    12% by weight of diisopropyl adipate;

    10% by weight of C ₁₂ -C _{15 alkyl lactate;}

    0.00025% by weight of ethylenediaminetetraacetic acid or sodium salt thereof;

    0.1% by weight of chlorogenic acid;

    0.1% by weight of sorbic acid; And

    1% by weight of water

    A pharmaceutical composition consisting of.