KR20210032868A - Stabilized efinaconazole-containing pharmaceutical compositions comprising sorbic acid as an acid - Google Patents

Abstract

The present invention provides a pharmaceutical composition for topical administration in a form of an efinaconazole-containing solution, which comprises sorbic acid as an acid. The pharmaceutical composition of the present invention has excellent physicochemical stability. Therefore, the pharmaceutical composition of the present invention can be usefully used as a formulation for topical administration having excellent stability.

Description

Stabilized efinaconazole-containing pharmaceutical compositions comprising sorbic acid as an acid

The present invention relates to a pharmaceutical composition for topical administration in the form of a solution containing efinaconazole. More specifically, it relates to a pharmaceutical composition for topical administration containing efinaconazole in the form of a solution containing sorbic acid as 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. 9,662,394 and International Patent Publication No. WO2015/051183 disclose a specific combination of a chelating agent, an antioxidant, and an acid, that is, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, butylated. A liquid or semi-solid composition comprising 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 a combination of various chelating agents, antioxidants, and acids in order to develop a formulation that can effectively improve problems such as discoloration and improve physicochemical stability by reducing the production of related substances. . As a result, it was found that when the formulation was carried out by combining sorbic acid as an acid with diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof, more excellent physicochemical stability can be secured compared to known formulations.

Accordingly, the present invention relates to a solution form containing efinaconazole, comprising a combination of a specific acid (i.e. sorbic acid) and a specific chelating agent (i.e. diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof). It is an object of the present invention to provide a pharmaceutical composition for topical administration of.

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; Butylated hydroxytoluene; Chelating agents; And a pharmaceutical composition for topical administration in the form of a solution containing an acid, wherein the chelating agent is diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or a sodium salt thereof; There is provided a pharmaceutical composition for topical administration in the form of a solution, wherein the acid is 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 0.0025% by weight, more preferably about 0.00025% 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.

It was found by the present invention that when the formulation is carried out by combining sorbic acid as an acid with diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or its sodium salt, an efinaconazole-containing pharmaceutical composition having excellent physicochemical stability is obtained. lost. 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; Butylated hydroxytoluene; Chelating agents; And a pharmaceutical composition for topical administration in the form of a solution containing an acid, wherein the chelating agent is diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or a sodium salt thereof; It provides a pharmaceutical composition for topical administration in the form of a solution, characterized in that the acid is 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 includes diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid (EDTA) or a sodium salt thereof as a chelating agent. The chelating agent may be present in an amount of 0.0001 to 1.5% by weight, preferably 0.0001 to 0.0025% by weight, more preferably about 0.00025% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention also comprises sorbic acid as an acid. The acid (ie, 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 contains butylated hydroxytoluene as an antioxidant. 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.

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;} 0.01 to 2% by weight of butylated hydroxytoluene; 0.0001 to 1.5% by weight of diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof; 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 another embodiment, 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;} 0.1% by weight of butylated hydroxytoluene; 0.00025% by weight of diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof; 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 evaluation of stability

(1) Preparation of solution

According to the components and contents of Tables 1 and 2 below, a solution containing efinaconazole was prepared. The content of each component in Tables 1 and 2 represents the weight% in the solution. Stock solutions were prepared by dissolving diethylenetriaminepentaacetic acid (DTPA) 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), antioxidants (palmitic acid, linoleic acid, butylated hydroxytoluene (BHT), or Butylated hydroxyanisole (BHA)), 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 53.79975 53.79975 Cyclomethicone 13 13 13 13 Diisopropyl adipate 12 12 12 12 C ₁₂ -C ₁₅ alkyl lactate 10 10 10 10 EDTA disodium 0.00025 0.00025 0.00025 0.00025 Palmitic acid 0.1 Linoleic acid 0.1 BHT 0.1 BHA 0.1 Purified water One One One One Sorbic acid 0.1 0.1 0.1 0.1 Sum(%) 100 100 100 100

Formulation Example (% by weight) 1-5 1-6 1-7 1-8 Epinaconazole 10 10 10 10 ethanol 53.79975 53.79975 53.79975 53.79975 Cyclomethicone 13 13 13 13 Diisopropyl adipate 12 12 12 12 C ₁₂ -C ₁₅ alkyl lactate 10 10 10 10 DTPA 0.00025 0.00025 0.00025 0.00025 Palmitic acid 0.1 Linoleic acid 0.1 BHT 0.1 BHA 0.1 Purified water One One One One Sorbic acid 0.1 0.1 0.1 0.1 Sum(%) 100 100 100 100

(2) Stability evaluation

After the solutions prepared in Formulation Examples 1-1 to 1-8 were stored at 65° C. for 4 weeks, respectively, absorbance at 500 nm and 600 nm of the solution was measured. 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. The results are shown in Table 3 below.

Formulation example EDTA disodium or DTPA / antioxidant / sorbic acid Absorbance 500 nm 600 nm 1-1 Palmitic acid 0.071 0.012 1-2 Linoleic acid 0.106 0.044 1-3 Butylated Hydroxytoluene (BHT) 0.018 0.014 1-4 Butylated Hydroxyanisole (BHA) 0.154 0.037 1-5 Palmitic acid 0.094 0.025 1-6 Linoleic acid 0.093 0.024 1-7 Butylated Hydroxytoluene (BHT) 0.018 0.007 1-8 Butylated Hydroxyanisole (BHA) 0.041 0.009 Control agent Butylated hydroxytoluene 0.022 0.017

From the results of Table 3, it can be seen that solutions obtained using sorbic acid as an acid and butylated hydroxytoluene as an antioxidant (Formulation Examples 1-3 and 1-7) exhibit superior stability compared to the control formulation.

Example 2. Preparation of solution and evaluation of stability

(1) Preparation of solution

According to the components and contents of Tables 4 to 7 below, a solution containing efinaconazole was prepared in the same manner as in Example 1 (1). The content of each component in Tables 4 to 7 represents weight% in the solution.

Formulation Example (% by weight) 2-1 2-2 2-3 2-4 2-5 2-6 Epinaconazole 10 10 10 10 10 10 ethanol 62.79975 56.79975 50.79975 62.79975 56.79975 50.79975 Cyclomethicone 10 12 14 10 12 14 Diisopropyl adipate 8 11 13 8 11 13 C ₁₂ -C ₁₅ alkyl lactate 8 9 11 8 9 11 EDTA disodium 0.00025 0.00025 0.00025 DTPA 0.00025 0.00025 0.00025 BHT 0.1 0.1 0.1 0.1 0.1 0.1 Purified water One One One One One One Sorbic acid 0.1 0.1 0.1 0.1 0.1 0.1 Sum(%) 100 100 100 100 100 100

Formulation Example (% by weight) 2-7 2-8 2-9 2-10 2-11 2-12 Epinaconazole 10 10 10 10 10 10 ethanol 62.79975 56.79975 50.79975 62.79975 56.79975 50.79975 Cyclomethicone 13 13 13 13 13 13 Diisopropyl adipate 12 12 12 12 12 12 C ₁₂ -C ₁₅ alkyl lactate 10 10 10 10 10 10 EDTA disodium 0.0001 0.001 0.0025 DTPA 0.0001 0.001 0.0025 BHT 0.1 0.1 0.1 0.1 0.1 0.1 Purified water One One One One One One Sorbic acid 0.1 0.1 0.1 0.1 0.1 0.1 Sum(%) 100 100 100 100 100 100

Formulation Example (% by weight) 2-13 2-14 2-15 2-16 2-17 2-18 Epinaconazole 10 10 10 10 10 10 ethanol 62.79975 56.79975 50.79975 62.79975 56.79975 50.79975 Cyclomethicone 13 13 13 13 13 13 Diisopropyl adipate 12 12 12 12 12 12 C ₁₂ -C ₁₅ alkyl lactate 10 10 10 10 10 10 EDTA disodium 0.00025 0.00025 0.00025 DTPA 0.00025 0.00025 0.00025 BHT 0.01 0.5 One 0.01 0.5 One Purified water One One One One One One Sorbic acid 0.1 0.1 0.1 0.1 0.1 0.1 Sum(%) 100 100 100 100 100 100

Formulation Example (% by weight) 2-19 2-20 2-21 2-22 2-23 2-24 Epinaconazole 10 10 10 10 10 10 ethanol 62.79975 56.79975 50.79975 62.79975 56.79975 50.79975 Cyclomethicone 13 13 13 13 13 13 Diisopropyl adipate 12 12 12 12 12 12 C ₁₂ -C ₁₅ alkyl lactate 10 10 10 10 10 10 EDTA disodium 0.00025 0.00025 0.00025 DTPA 0.00025 0.00025 0.00025 BHT 0.1 0.1 0.1 0.1 0.1 0.1 Purified water One One One One One One Sorbic acid 0.05 0.15 0.2 0.05 0.15 0.2 Sum(%) 100 100 100 100 100 100

(2) Stability evaluation

After storing the solutions prepared in Formulation Examples 2-1 to 2-24 at 65° C. for 4 weeks, respectively, the absorbance was measured in the same manner as in Example 1 (2). The results are shown in Table 8 below.

Formulation example Absorbance 500 nm 600 nm 2-1 0.020 0.015 2-2 0.018 0.014 2-3 0.018 0.014 2-4 0.020 0.007 2-5 0.018 0.007 2-6 0.018 0.007 2-7 0.019 0.013 2-8 0.018 0.013 2-9 0.018 0.013 2-10 0.018 0.007 2-11 0.017 0.007 2-12 0.017 0.006 2-13 0.019 0.013 2-14 0.009 0.008 2-15 0.006 0.006 2-16 0.018 0.009 2-17 0.012 0.008 2-18 0.008 0.008 2-19 0.018 0.014 2-20 0.018 0.013 2-21 0.015 0.009 2-22 0.018 0.007 2-23 0.017 0.007 2-24 0.015 0.006 Control formulation 0.022 0.017

From the results of Table 8, it can be seen that a solution obtained using sorbic acid as an acid and butylated hydroxytoluene as an antioxidant has excellent stability.

Example 3. Related substances analysis

After storing the solution prepared in Formulation Example 1-3 at 80° C. for 3 weeks, the total amount of related substances was measured using high performance liquid chromatography (HPLC). In addition, after storing the solution prepared in Formulation Example 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 9 below.

Formulation example Total amount of related substances (%) Stored at 80℃ for 3 weeks Stored at 65℃ for 4 weeks 1-3 1.77 0.48 Control formulation 2.05 0.58

From the results of Table 9, 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 (8)

Efinaconazole; ethanol; Cyclomethicone; _{Diisopropyl adipate, C 12} -C ₁₅ alkyl lactate, or mixtures thereof as non-volatile solvents; Butylated hydroxytoluene; Chelating agents; And in the pharmaceutical composition for topical administration in the form of a solution containing an acid,
The chelating agent is diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or a sodium salt thereof;
Pharmaceutical composition for topical administration in the form of a solution, characterized in that the acid is sorbic acid. 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. The pharmaceutical composition according to claim 1, wherein the chelating agent is present in an amount of 0.0001 to 0.0025% by weight based on the total weight of the composition. The pharmaceutical composition of claim 1, wherein the chelating agent is present in an amount of 0.00025% by weight based on the total weight of the composition. 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. 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. 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;}
0.01 to 2% by weight of butylated hydroxytoluene;
0.0001 to 1.5% by weight of diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof;
0.05 to 0.25% by weight of sorbic acid; And
0 to 5% by weight of water
Pharmaceutical composition comprising a. 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;}
0.1% by weight of butylated hydroxytoluene;
0.00025% by weight of diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid or sodium salt thereof;
0.1% by weight of sorbic acid; And
1% by weight of water
A pharmaceutical composition consisting of.