KR20220058086A - Stabilized composition comprising an antifungal agent - Google Patents

Abstract

The present invention relates to a stabilized composition containing an antifungal agent, and particularly, to an external solution containing efinaconazole. The external solution containing efinaconazole according to the present invention has stable properties even under long-term or harsh storage conditions, and has a very low production rate of related substances. Therefore, the external solution can be usefully used to treat onychomycosis without a change in the appearance or quality of a drug or preparation.

Description

Stabilized composition comprising an antifungal agent

The present invention relates to a stabilized composition comprising an antifungal agent, in particular an external solution comprising efinaconazole.

Onychomycosis is a collective term for onychomycosis caused by several fungi, including dermatophytes. Onychomycosis is largely divided into Distal and Lateral Subungual Onychomycosis (DLSO), Proximal Subungual Onychomycosis (PSO), Superficial White Onychomycosis, SW It can be classified into five types: Total Dystrophic Onychomycosis (TDO) and Endonyx.

For the treatment of onychomycosis, oral antifungal agents containing itraconazole, terbinafine, fluconazole, and the like, or topical agents for topical application are used. Among these, topical application is attracting attention in the market due to its advantages of avoiding systemic side effects such as hepatotoxicity of oral antifungal drugs and having less drug interaction.

Efinaconazole was developed as an external application for topical application for the treatment of onychomycosis caused by dermatophytes, and is currently sold under the trade name Jublia External Solution.

Efinaconazole is an azole antifungal agent and has a mechanism of action to inhibit fungal lanosterol 14 α-demethylase, which is related to the biosynthesis of egosterol, a component of the fungal cell membrane.

The topical solution containing efinaconazole has a problem of stability, that is, discoloration within a short storage period, resulting in a color of the composition ranging from yellow to deep red or brown. In order to solve this stability problem, International Patent Publication No. WO2015/051183 (Patent Document 1) discloses a specific chelating agent, an antioxidant, and an acid, that is, ethylenediamine tetraacetic acid (EDTA) or a salt thereof, butylated hydroxytoluene ( A liquid or semi-solid composition comprising butylated hydroxytoluene (BHT), and citric acid has been disclosed.

International Patent Publication No. WO2015/051183

Poor storage stability of an external solution containing efinaconazole can affect patients' trust in drug safety, as well as reduce the quality of the drug due to the generation of related substances.

Accordingly, the present invention is to provide an efinaconazole external solution composition with high stability.

In International Patent Publication No. WO2015/051183, efinaconazole, ethanol, cyclomethicone, ethylenediaminetetraacetic acid (EDTA) disodium salt, C12-15 alkyl lactate, diisopropyl adipate, citric acid and butylated hydroxytoluene Disclosed is an external preparation containing (BHT).

WO2015/051183 teaches that the combination of BHT, EDTA and citric acid is the only useful stabilizer for efinaconazole formulations.

However, according to the research results of the present inventors, butylated hydroxyanisole (BHA) rather than butylated hydroxytoluene (BHT) showed superior results in the content test and related substances test under both long-term test conditions and accelerated test conditions. However, when the combination of BHT, EDTA and citric acid was changed to a combination of BHA, EDTA and citric acid, the viewpoint of poor property stability was observed. This is as previously confirmed through Example 1 of International Patent Publication No. WO2015/051183.

Accordingly, the present inventors studied to prepare a stabilized efinaconazole external solution having excellent stability in terms of content, related substances, and properties, and as a result, they arrived at an external solution composition according to the present invention.

The present invention provides an external solution comprising efinaconazole, ethanol, cyclomethicone, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, a nonvolatile solvent, an acid, and butylated hydroxyanisole (BHA) and vitamin E as antioxidants A composition is provided.

The combination of using butylated hydroxyanisole (BHA) and vitamin E as antioxidants solves the stability problem of the existing efinaconazole external solution. In particular, control of related substances along with their properties is important in terms of patient reliability and quality control of pharmaceutical preparations for external use.

Efinaconazole may exhibit yellow or reddish-brown properties due to poor storage stability, which does not give the patient confidence in the drug, and may be easily stained on clothes or bedding due to the nature of the formulation of the external solution composition. causes discomfort in

The topical composition according to the present invention using butylated hydroxyanisole (BHA) and vitamin E as antioxidants is colorless when initially formulated. The composition for topical application according to the present invention exhibits colorless to pale yellow properties after storage for 4 weeks at a temperature of 40° C. and an accelerated condition of RH 75% during the stability test. Preferably, the external solution composition according to the present invention exhibits colorless to pale yellow properties after storage for 6 weeks, 8 weeks, 10 weeks, or 12 weeks at a temperature of 40°C and an accelerated condition of RH 75%. The measurement of color may be performed by a test method determined by a regulatory authority, but is not limited thereto, and may be performed with the naked eye or absorbance measurement according to a known technique.

In addition, the external solution composition according to the present invention exhibits colorless to pale yellow properties after storage for 4 weeks under severe conditions of a temperature of 60° C. during stability testing. Preferably, the external solution composition according to the present invention exhibits colorless to pale yellow properties after storage for 6 weeks, 8 weeks, 10 weeks, or 12 weeks under severe conditions at a temperature of 60°C.

The present invention also provides an efinaconazole external solution composition in which the related substances are controlled. The combination using butylated hydroxyanisole (BHA) and vitamin E as antioxidants has a lower rate of production of related substances than the conventional efinaconazole external solution using butylated hydroxytoluene (BHT).

In the external solution composition according to the present invention, the total amount of related materials is less than 0.5% after storage for 4 weeks at a temperature of 40°C and an accelerated condition of RH of 75% during the stability test. Preferably, the external solution composition according to the present invention contains less than 0.45%, less than 0.4%, less than 0.35%, 0.3% of the total 　 related materials after storage for 4 weeks at a temperature of 40°C and an accelerated condition of RH 75% during the stability test less than, less than 0.25%, less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05%.

In addition, the external solution composition according to the present invention has less than 0.5% of total 　 related materials after storage for 4 weeks under severe conditions of a temperature of 60°C during the stability test. Preferably, the external solution composition according to the present invention contains less than 0.45%, less than 0.4%, less than 0.35%, less than 0.3%, less than 0.25% of the total 　 related substances after storage for 4 weeks under severe conditions of a temperature of 60°C during the stability test less than, less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05%.

In the efinaconazole external solution composition according to the present invention, the content of efinaconazole may be 1 wt% to 15 wt% based on the total weight of the external solution composition. For example, the content of efinaconazole may be 5 wt% to 15 wt%, 8 wt% to 12 wt%, for example, about 10 wt%, based on the total weight of the external solution composition, but is not limited thereto.

The content of the antioxidant in the efinaconazole external solution composition according to the present invention may be 0.01wt% to 0.4wt%, for example, 0.01wt% to 0.3wt%, based on the total weight of the external solution composition.

The content of butylated hydroxyanisole (BHA) used as one of the antioxidants may be 0.01wt% to 0.3wt% based on the total weight of the external solution composition. For example, the content of butylated hydroxyanisole (BHA) may be 0.02wt% to 0.2wt%, 0.05wt% to 0.15wt%, 0.08wt% to 0.12wt% based on the total weight of the external solution composition. However, the present invention is not limited thereto.

In the present invention, the content of vitamin E as an antioxidant used in combination with butylated hydroxyanisole (BHA) may be 0.0005 wt% to 0.1 wt% based on the total weight of the external solution composition. For example, the content of vitamin E may be 0.001wt% to 0.05wt%, 0.001wt% to 0.01wt%, 0.001wt% to 0.005wt%, based on the total weight of the external solution composition, but is not limited thereto .

The vitamin E may be at least one selected from the group consisting of alpha tocopherol, beta tocopherol, gamma tocopherol, alpha tocotrienol, and tocopersolan. As can be seen in the examples below, the combination of butylated hydroxyanisole (BHA) and vitamin E improves the stability of the properties of BHA without being limited to specific types of vitamin E.

Although not limited thereto, a preferred embodiment of vitamin E in the external solution composition according to the present invention is alpha-tocopherol acetate. The combination of butylated hydroxyanisole (BHA) and alpha-tocopherol acetate showed superior effects compared to the embodiment of butylated hydroxyanisole (BHA) and other vitamin E in terms of reducing related substances.

The topical solution composition according to the present invention contains ethanol as a volatile solvent. The content of ethanol in the composition for external application according to the present invention includes 40 wt% to 65 wt%, for example, 45 wt% to 60 wt%, based on the total weight of the composition for external application.

In the external solution composition according to the present invention, ethanol is not limited thereto, but preferably has a moisture content of less than 10 v/v%. For example, the ethanol is less than 10 v/v%, less than 9 v/v%, less than 8 v/v%, less than 7 v/v%, less than 6 v/v%, less than 5 v/v% of water. , It is preferable to include less than 4 v/v%, less than 3 v/v%, less than 2 v/v%, and less than 1 v/v%. According to the following examples, the lower the water content in ethanol, the lower the rate of formation of unknown related substances, so that the stability of the external solution can be further improved. Preferably, the ethanol in the external solution composition according to the present invention may be absolute ethanol, that is, the water content may be less than 1 v/v%.

The chelating agent used in the present invention is ethylenediaminetetraacetic acid (EDTA) or a salt thereof. Although the salt of EDTA is not specifically limited, EDTA sodium salt, for example, EDTA disodium salt, EDTA tetrasodium salt, etc. can be used. In the external solution composition according to the present invention, the content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof may be 0.0001 wt% to 0.001 wt% based on the total weight of the external solution composition. For example, the content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof may be 0.0001 wt% to 0.0005 wt%, 0.0002 wt% to 0.0005 wt%, based on the total weight of the external solution composition.

The composition for topical application according to the present invention also contains an acid for stability of properties. The acid known to be preferred for use in the efinaconazole external composition is citric acid or sorbic acid, but is not limited thereto. The content of the acid in the composition for external application according to the present invention may be 0.01 wt% to 1 wt% based on the total weight of the composition for external application. For example, the content of the acid may be 0.05wt% to 0.5wt%, 0.05wt% to 0.2wt% based on the total weight of the external solution composition, but is not limited thereto.

The present invention also includes cyclomethicone as a wetting agent. The content of cyclomethicone in the composition for external application according to the present invention may be 5 wt% to 20 wt% based on the total weight of the composition for external application. For example, the content of the cyclomethicone may be 8wt% to 18wt%, 10wt% to 15wt%, based on the total weight of the external solution composition, but is not limited thereto.

The present invention also includes non-volatile solvents. The nonvolatile solvent may include, for example, one or more C12-15 alkyl lactate, diisopropyl adipate, myristyl lactate, isopropyl myristate, capric/capryl triglyceride, and the like. In one embodiment according to the present invention, a mixture of C12-15 alkyl lactate and diisopropyl adipate was used. The content of the nonvolatile solvent in the composition for topical application according to the present invention may be 10 wt% to 35 wt% based on the total weight of the composition for topical application. For example, the content of the nonvolatile solvent may be 15 wt% to 30 wt% based on the total weight of the external solution composition.

The external solution composition according to the present invention may further include water. Water is used in a small amount for dissolving EDTA or its salt, acid, and vitamin E when preparing efinaconazole external preparation. Preferably, the water content is 3 wt% or less, 2% wt or less, based on the total weight of the external solution composition , for example, 0.01wt% to 2wt%, may be 0.1wt% to 1wt%.

In one embodiment, the topical composition according to the present invention contains 5 wt% to 15 wt% of efinaconazole, 0.01 wt% to 0.3 wt% of butylated hydroxyanisole (BHA), 0.001 based on the total weight of the composition for topical application wt% to 0.1wt% vitamin E, 40wt% to 65wt% ethanol, 0.0001wt% to 0.001wt% ethylenediaminetetraacetic acid (EDTA) or a salt thereof, 0.01wt% to 1wt% acid, 5wt% to 20wt % cyclomethicone, 15 wt% to 30 wt% non-volatile solvent, 0.01 wt% to 2 wt% water.

The topical solution composition according to the present invention is better than the known efinaconazole external solution containing a combination of BHT, EDTA and citric acid, that is, in terms of lowering properties and production rate of related substances that may appear during storage compared to the brand name Jublia. stable

An external solution composition containing efinaconazole may be used for the treatment of onychomycosis caused by dermatophytes.

The present invention provides an external solution comprising efinaconazole, ethanol, cyclomethicone, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, a nonvolatile solvent, an acid, and butylated hydroxyanisole (BHA) and vitamin E as antioxidants Provided is a method of treating onychomycosis caused by dermatophytes comprising administering the composition to a subject.

In the present invention, 'subject' means a warm-blooded animal such as a mammal suffering from a specific disease, disorder or disease, for example, humans, orangutans, chimpanzees, mice, rats, dogs, cattle, chickens, pigs, goats , amounts, and the like, but are not limited to these examples.

In the present invention, 'treatment' includes, but is not limited to, alleviating symptoms, temporarily or permanently removing the cause of symptoms, or preventing or slowing the appearance of symptoms and the progression of diseases, disorders or diseases.

The effective amount of the active ingredient of the external preparation of the present invention means an amount required to achieve the treatment of a disease. Therefore, the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of formulation and the age, weight, general health status, sex and diet of the patient, administration time, administration route and composition It can be adjusted according to various factors including secretion rate, duration of treatment, and concomitant drugs. For example, the pharmaceutical composition of the present invention may apply an external preparation containing 100 mg/g of efinaconazole to the infected nail once a day, but is not limited thereto.

The external solution containing efinaconazole according to the present invention has stable properties even under long-term or severe storage conditions and has a very low production rate of related substances. Therefore, it can be usefully used to treat onychomycosis without change in appearance or quality of the drug or formulation.

Advantages and features of the present invention, and methods for achieving them, will become apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in a variety of different forms, and only these embodiments allow the disclosure of the present invention to be complete, and common knowledge in the technical field to which the present invention belongs It is provided to fully inform the possessor of the scope of the invention, and the present invention is only defined by the scope of the claims.

[Example]

Experimental method

1. Content test

For the sample solution, take 100 mg of efinaconazole and use it as 100 mL of the mobile phase. Take 5 mL of this solution, add the mobile phase to make 50 mL, and use it as the sample solution. For the standard solution, take the equivalent of 25 mg of the efinaconazole standard, make 50 mL of the mobile phase, and use it as the standard solution. In the following examples, high performance liquid chromatography (HPLC) analysis was performed under the following conditions.

HPLC conditions

Mobile phase A: pH 3.0 buffer solution (KH2PO4)

Mobile phase B: acetonitrile

Detector: UV 210 nm

Column: Inertsil ODS-4V, 4.6 mm x 250 mm; 5 μm or equivalent column

Flow rate: 1.0 mL/min

Sample injection volume: 10 μL

Column temperature: 40 °C

Analysis time: 18 minutes

Test Method: Gradient

Gradient Program:

2. Related substance test

For the sample solution, take 100 mg of efinaconazole and use it as 100 mL of the mobile phase as the sample solution. For the standard solution, take the equivalent of 25 mg of the efinaconazole standard and use it as 50 mL of the mobile phase. Take 5 mL of this solution, make 25 mL of the mobile phase, and use it as the standard solution. In the following examples, high performance liquid chromatography (HPLC) analysis was performed under the following conditions.

HPLC conditions

Mobile phase A: pH 3.0 buffer solution (KH2PO4)

Mobile phase B: acetonitrile

Detector: UV 210 nm

Column: Inertsil ODS-4V, 4.6 mm x 250 mm; 5 μm or equivalent column

Flow rate: 1.0 mL/min

Sample injection volume: 10 μL

Column temperature: 40°C

Analysis time: 50 minutes

Test Method: Gradient

Gradient Program:

3. Volatility test

After putting the external solution prepared in Preparation Example below in a screw vial and storing it for 4 weeks under severe test conditions (60° C.), the loss ratio relative to the initial weight was calculated.

Experimental Example 1: Evaluation of suitability using BHA and BHT

In order to select an antioxidant suitable for use in efinaconazole, the reactivity was evaluated by mixing efinaconazole with butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT).

After mixing efinaconazole and each antioxidant (BHT, BHA) in a 1:1 weight ratio, the long-term test conditions (25℃/60% RH) or accelerated test conditions (40℃/75% RH) for 4 weeks After storage, the properties, content, and related substances were evaluated. The test results are shown in Tables 1 to 3.

property test division drug antioxidant Exam conditions appearance Early 2 weeks 4 weeks One efinaconazole BHT 25℃/60% RH colorless or pale yellow colorless or pale yellow colorless or pale yellow 2 efinaconazole BHT 40℃/75% RH colorless or pale yellow colorless or pale yellow colorless or pale yellow 3 efinaconazole BHA 25℃/60% RH colorless or pale yellow colorless or pale yellow colorless or pale yellow 4 efinaconazole BHA 40℃/75% RH colorless or pale yellow colorless or pale yellow buff

content test division drug antioxidant Exam conditions Content test (90~110.0 %) Early 2 weeks 4 weeks One efinaconazole BHT 25℃/60% RH 98.64 97.90 98.62 2 efinaconazole BHT 40℃/75% RH 98.64 99.96 98.25 3 efinaconazole BHA 25℃/60% RH 99.75 99.58 100.71 4 efinaconazole BHA 40℃/75% RH 99.75 98.96 98.80

Related substance test division drug antioxidant Exam conditions Related substances test (less than 0.50 %) Early 2 weeks 4 weeks One efinaconazole BHT 25℃/60% RH 0.10% 0.21% 1.62% 2 efinaconazole BHT 40℃/75% RH 0.10% 3.04% 4.63% 3 efinaconazole BHA 25℃/60% RH 0.23% 0.17% 0.47% 4 efinaconazole BHA 40℃/75% RH 0.23% 0.63% 1.36%

As can be seen in Tables 2 and 3, in the test group using BHA versus BHT, the content test and related substance test results were excellent in both long-term test conditions and accelerated test conditions. However, in terms of properties, the test group using BHA exhibited pale yellow properties under accelerated test conditions, and thus, a disadvantage was observed compared to BHT.

Accordingly, the present inventors decided to use BHA, which has excellent results in the content test and related substance test, as an antioxidant, and conducted the following experiments to see if the properties of the formulation using BHA could be improved.

Experimental Example 2: Characteristics, content, and related substances tests according to antioxidants and chelating agents

According to the components and contents of Table 4 below, solutions containing efinaconazole of Preparation Examples 1 and 2 were prepared. The content of each component in Table 4 represents weight% in the solution. Each preparation was prepared using 10% by weight of efinaconazole, antioxidant and chelating agent in a water/alkyl lactate/diisopropyl adipate/cyclomethicone/ethanol solvent system.

ingredient Preparation Example 1
Preparation 2
(control group) efinaconazole 10 10 cyclomethicone 13 13 Diisopropyl Adipate (Ceraphyl 230) 12 12 C12-15 Alkyllactate (Ceraphyl 41) 10 10 Butylated Hydroxyanisole (BHA) 0.1 - Butylated Hydroxytoluene (BHT) - 0.1 citric anhydride 0.31 0.31 EDTA disodium - 0.001 Hydroxyethylethylene diaminetriacetic acid (HEDTA) 0.01 - Purified water One One Ethanol (95 v/v%) 100% filling 100% filling

*HEDTA: Hydroxyethylethylenediaminetriacetic acid Preparation Examples 1 and 2 were stored for 12 weeks at 40 ° C./75 % RH. The formulation of Preparation Example 2 (control), a known formulation containing BHT, EDTA, and citric acid, and the formulation of Preparation Example 1 containing BHA, HEDTA and citric acid were stored at 40°C/75% RH after 4 weeks. It was confirmed that there was no change in the test.

property test division ingredient time to change 4 weeks 8 weeks 12 weeks Preparation Example 1 BHA,HEDTA,Citric acid - no change no change no change Preparation 2
(control group) BHT, EDTA, Citric acid - no change no change no change

The results of the related substances test for Preparation Examples 1 and 2 are shown in Table 6 below. As can be seen in Table 6, it was confirmed that the formulation of Preparation Example 2 had good related substance test results, whereas the formulation of Preparation Example 1 had a significant increase in the related substance content after 12 weeks.

As a result, the formulation of Preparation Example 1 using HEDTA and citric acid along with BHA was improved in terms of properties, but on the contrary, poor results were obtained in terms of related substances.

Amount of related substances produced when stored under 40℃/75% RH conditions division ingredient Early 4 weeks 12 weeks Preparation Example 1 BHA, HEDTA, Citric acid 0.35% 0.26% 1.08% Preparation 2 BHT, EDTA, Citric acid 0.01% 0.07% 0.33%

Accordingly, the present inventors determined that the use of HEDTA as a chelating agent can prevent a change in properties, but increase related substances. Accordingly, EDTA was selected as a chelating agent, and additional stabilizing agents were screened as follows.

Experimental Example 3: t -Test on properties, content, and related substances according to the use of butylhydroquinone (TBHQ)

According to the components and contents of Table 7 below, solutions containing efinaconazole of Preparation Examples 3 to 6 further including TBHQ as an antioxidant were prepared.

ingredient Preparation 3 Preparation 4 Preparation 5 Preparation 6 efinaconazole 10 10 10 10 cyclomethicone 13 13 13 13 Diisopropyl Adipate (Ceraphyl 230) 12 12 12 12 C12-15 Alkyllactate (Cerophyl 41) 10 10 10 10 Butylated Hydroxyanisole (BHA) 0.1 0.1 0.1 0.1 t -Butylhydroquinone (TBHQ) 0.02 0.02 0.02 0.02 citric anhydride 0.31 0.31 0.4 0.4 EDTA disodium 0.001 - 0.001 - Purified water One One One One Ethanol (95 v/v%) 100% filling 100% filling 100% filling 100% filling

As a result of performing a property test for Preparation Examples 3 to 6, as can be seen in Table 8, it was confirmed that all of these Preparation Examples were not suitable due to a change in properties within 4 to 8 weeks.

property test ingredient time of change in appearance 4 weeks 8 weeks 12 weeks Preparation 3 BHA, TBHQ, EDTA, Citric acid 4 weeks buff yellow yellow Preparation 4 BHA, TBHQ, Citric acid 4 weeks bright
buff yellow yellow Preparation 5 BHA, TBHQ, EDTA, Citric acid 4 weeks light pale yellow buff buff Preparation 6 BHA, TBHQ, Citric acid 4 weeks yellow yellow yellow

Accordingly, the present inventors decided to introduce other ingredients to improve the properties of the efinaconazole-containing solution.

Experimental Example 4: Test of properties and related substances according to the use of vitamin E-based compounds

According to the components and contents of Table 9 below, a solution containing efinaconazole containing a vitamin E-based compound was prepared. The content of each component in Table 9 represents weight % in the solution. Ethylenediaminetetraacetic acid disodium salt (EDTA disodium), citric anhydride, and vitamin E (alpha tocopherol acetate/natural alpha tocopherol/beta tocopherol/gamma tocopherol/alpha tocotrienol/tocopersolan) were dissolved in 1.0 g of purified water to prepare it. In addition, efinaconazole (10 g) was dissolved in ethanol (53.8 g) to prepare an efinaconazole-containing stock solution. Purified water ( added in the form of a stock solution) were sequentially added and mixed to prepare a solution containing efinaconazole. In addition, Preparation Example 13 (Comparative Example), an efinaconazole solution containing alpha tocopherol acetate but not including butylated hydroxyanisole (BHA), was prepared and compared with the efinaconazole solutions of Preparation Examples 7 to 12. .

Efinaconazole solution containing vitamin E-based compounds ingredient Preparation 7 Preparation 8 Preparation 9 Preparation 10 Preparation 11 Preparation 12 Preparation 13
(Comparative example) efinaconazole 10 10 10 10 10 10 10 cyclomethicone 13 13 13 13 13 13 13 Diisopropyl Adipate (Cerophyl 230) 12 12 12 12 12 12 12 C12-15 Alkyl Lactate (Ceraphyl 41) 10 10 10 10 10 10 10 Butylated Hydroxyanisole (BHA) 0.1 0.1 0.1 0.1 0.1 0.1 - Alpha Tocopherol Acetate 0.002 0.002 natural alpha tocopherol 0.002 beta tocopherol 0.002 Gamma Tocopherol 0.002 Alpha Tocotrienols 0.002 tocopersolane 0.002 citric anhydride 0.1 0.1 0.1 0.1 0.1 0.1 0.31 EDTA disodium 0.00025 0.00025 0.00025 0.00025 0.00025 0.00025 0.00025 Purified water One One One One One One One Ethanol (95 v/v%) 100% filling 100% filling 100% filling 100% filling 100% filling 100% filling 100% charge

After storing each solution of Preparation Examples 7 to 12 at accelerated (40°C/75% RH) and harsh (60°C) for 4 weeks, the properties and related substances of the preparations of Preparation Examples 7 to 12 through the above analysis method was analyzed. The results are shown in Tables 10 to 12.

Experimental conditions: 40℃/75% RH Preparation 7 Preparation 8 Preparation 9 Preparation 10 Preparation 11 Preparation 12 appearance Early to 4 weeks no change no change no change no change no change no change related substances Early 0.01 0.01 0.02 0.01 0.01 0.01 2 weeks 0.02 0.08 0.08 0.09 0.07 0.05 4 weeks 0.03 0.05 0.07 0.06 0.05 0.04

Experimental conditions: 60℃ Preparation 7 Preparation 8 Preparation 9 Preparation 10 Preparation 11 Preparation 12 appearance Early to 4 weeks no change no change no change no change no change no change related substances Early 0.01 0.01 0.02 0.01 0.01 0.01 2 weeks 0.19 0.31 0.22 0.3 0.32 0.31 4 weeks 0.26 0.72 0.67 0.5 0.58 0.68

Severe test 4 weeks: Relative retention time 0.85 (Relative retention time, RRT 0.85) increase trend of unknown related substances Experimental conditions: 60℃ Preparation 7 Preparation 8 Preparation 9 Preparation 10 Preparation 11 Preparation 12 appearance Early to 4 weeks no change no change no change no change no change no change unknown related substances
(RRT 0.85) Early ND ND ND ND ND ND 4 weeks 0.16 0.30 0.27 0.20 0.24 0.27

As can be seen in Tables 10 and 11, the properties of the efinaconazole solution containing BHA were improved in all of Preparation Examples 7 to 12 including the vitamin E-based compound. In addition, it was confirmed that the use of vitamin E-based compounds significantly reduced the content of related substances in the related substance test under accelerated and severe conditions. Even compared to Preparation Example 2, which is a known formulation containing BHT, as described above, the content of related substances confirmed when stored for 4 weeks under accelerated (40°C/75% RH) conditions was 0.33% in the formulation of Preparation Example 2, whereas , It was confirmed that the content of related substances in the formulations of Preparation Examples 7 to 12 was only 0.03% to 0.07%, so that the vitamin E-based compound provides an advantageous effect in terms of reducing related substances.

As shown in Table 12, the increase in related substances in the accelerated test 4 week data was found to be due to an increase in the unknown related substances with a relative retention time of 0.85. Among the vitamin E series, alpha-tocopherol acetate not only decreased the total related substances but also It was also found that the retention time of 0.85 was the most excellent in the reduction of unknown related substances.

On the other hand, for Preparation Example 13 (Comparative Example) prepared using only alpha-tocopherol acetate as an antioxidant, the properties test and related substance test were performed while storage at 40 ° C/75 % RH for 12 weeks, as shown in Table 13 below. As can be seen, in the case of Preparation Example 13, which did not contain BHA or BHT at all, it was confirmed that it was difficult to use as a formulation because it appeared orange in the property test after 4 weeks of storage at 40° C./75 % RH. In addition, as can be seen in Table 14, in the case of Preparation Example 13 which did not contain BHA or BHT at all, it was confirmed that a significant amount of related substances were also generated.

division ingredient time of change in appearance 4 weeks 8 weeks 12 weeks Preparation 13
(Comparative example) Alpha Tocopherol Acetate, EDTA, Citric acid 4 weeks orange color yellow yellow

Amount of related substances produced when stored under 40℃/75% RH conditions division ingredient Early 4 weeks 12 weeks Preparation 13
(Comparative example) Alpha Tocopherol Acetate, EDTA, Citric acid 0.08% 0.69% 3.17%

Experimental Example 5: Stability evaluation

Additional stability evaluation was performed on the formulation of Preparation Example 2 (control group) and the formulation of Preparation Example 7 (test drug). Each solution of Preparation Example 2 and Preparation Example 7 was stored at accelerated (40°C/75% RH) and harsh (60°C) for 8 weeks, and then the content/related substances/volatility was confirmed through the above analysis method. The results are shown in Tables 15 to 17 below.

40℃/75% RH acceleration condition division standard Preparation 2 (control) Preparation 7 (test drug) Initial 1 week 2 weeks 4 weeks 8 weeks Initial 1 week 2 weeks 4 weeks 8 weeks content 90.0~110.0% 102.1 99.91 103.8 101.3 102.8 99.33 101.6 99.0 103.2 100.8 related substances 0.50% or less 0.01 0.05 0.05 0.07 0.16 0.01 0.01 0.02 0.03 0.13

60℃ harsh conditions division standard Preparation 2 (control) Preparation 7 (test drug) Initial 1 week 2 weeks 4 weeks Initial 1 week 2 weeks 4 weeks content 90.0~110.0% 102.17 99.66 105.6 102.92 99.33 101.4 99.9 103.79 related substances 0.50% or less 0.01 0.15 0.24 0.46 0.08 0.07 0.14 0.28

Both the control group and the test drug showed good results in the content test and related substance test under accelerated and severe conditions. The test drug was found to have a lower rate of production of related substances compared to the control group, especially under severe conditions.

Volatility test division Preparation 2 (control) Preparation 7 (test drug) 1 week 2 weeks 4 weeks 1 week 2 weeks 4 weeks Volatility (Loss rate) 0.41 1.84 2.31 0.59 0.29 0.76

* Loss rate during severe test (60℃)

In addition, in the volatility test, in the case of the control group, the loss rate was 2.31% when evaluated at a temperature of 60°C for 4 weeks, but in the case of the test drug, the loss rate was 0.76% when evaluated at a temperature of 60°C for 4 weeks, indicating that the test drug was superior to the control group It was found that stability was ensured.

Experimental Example 6: Reduction of unknown related substances according to the use of absolute ethanol

The formulations of Preparation Examples 7 to 12 were found to contain less than the reference value in the related substance test under accelerated or harsh conditions, but it was attempted to see if there is a way to further reduce the level of the unknown related substance.

Accordingly, according to the components and contents of Table 18 below, a solution containing efinaconazole was prepared. The content of each component in Table 18 represents weight % in the solution. Prepared according to an efinaconazole and ethanol content of 10% by weight in a water/alkyl lactate/diisopropyl adipate/cyclomethicone/ethanol solvent system. The use of ethanol was prepared using ethanol (95v/v%, Preparation Example 7) and absolute ethanol (99v/v% or more, Preparation Example 14).

ingredient Preparation 7 Preparation 14 efinaconazole 10 10 cyclomethicone 13 13 diisopropyl adipate
(Ceraphyl 230) 12 12 C12-15 Alkyl Lactate
(Ceraphyl 41) 10 10 Butylated Hydroxyanisole
(BHA) 0.1 0.1 Alpha Tocopherol Acetate 0.002 0.02 citric anhydride 0.1 0.1 EDTA disodium 0.00025 0.00025 Purified water One One Ethanol (95 v/v%) 100% filling - Absolute Ethanol (99 v/v% or more) - 100% filling

After storing each solution prepared in Preparation Example 7 and Preparation Example 14 under accelerated conditions (40°C/75% RH) or harsh conditions (60°C) for 4 weeks, the properties and related substances were analyzed through the above analysis method. analyzed. The results are shown in Tables 19 and 20 below.

60℃ harsh conditions Preparation 7 Preparation 14 appearance Early to 4 weeks no change no change related substances Early 0.01 0.01 2 weeks 0.19 0.03 4 weeks 0.26 0.09

60℃ harsh conditions Preparation 7 Preparation 14 unknown related substances
(RRT 0.85) Early ND ND 4 weeks 0.16 0.01

As can be seen in Tables 19 to 20, it was confirmed that there was a difference in the increase of related substances depending on the amount of water in ethanol, and as a result, in particular, in the formulation of Preparation Example 14 using 99 v/v% or more of absolute ethanol It was confirmed that the amount of unknown related substances was significantly reduced.

Claims (19)

An external solution composition comprising efinaconazole, ethanol, cyclomethicone, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, a nonvolatile solvent, an acid, and butylated hydroxyanisole (BHA) and vitamin E as antioxidants. According to claim 1,
The composition for external solution exhibits colorless to pale yellow properties after storage for 4 weeks at a temperature of 40° C. and an accelerated condition of RH 75% during the stability test. According to claim 1,
The composition for external solution is a composition that exhibits colorless to pale yellow properties after storage for 4 weeks under severe conditions of a temperature of 60° C. during the stability test. According to claim 1,
The external solution composition is an external solution composition in which the sum of the total related substances is less than 0.5% after storage for 4 weeks at a temperature of 40°C and an accelerated condition of RH of 75% during the stability test. According to claim 1,
The external solution composition is an external solution composition in which the sum of the total related substances is less than 0.5% after storage for 4 weeks under severe conditions of a temperature of 60°C during the stability test. According to claim 1,
The content of efinaconazole is 1 wt% to 15 wt% based on the total weight of the composition for topical solution. According to claim 1,
The content of butylated hydroxyanisole (BHA) is 0.01wt% to 0.3wt% based on the total weight of the composition for topical solution. According to claim 1,
The content of vitamin E is 0.001 wt% to 0.1 wt% of the external solution composition based on the total weight of the external solution composition. According to claim 1,
Vitamin E is at least one selected from the group consisting of alpha tocopherol, beta tocopherol, gamma tocopherol, alpha tocotrienol and tocopersolan. The method of claim 1,
Vitamin E is alpha-tocopherol acetate. According to claim 1,
The content of ethanol is 40wt% to 65wt% external solution composition. According to claim 1,
The ethanol is absolute ethanol composition for external solution. According to claim 1,
The content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof is 0.0001wt% to 0.001wt% based on the total weight of the composition for topical solution. According to claim 1,
The content of the acid is 0.01wt% to 1wt% of the composition for external application based on the total weight of the composition for external application. According to claim 1,
An external solution composition wherein the acid is citric acid. According to claim 1,
The content of the cyclomethicone is 5 wt% to 20 wt% of the external solution composition based on the total weight of the external solution composition. According to claim 1,
The content of the non-volatile solvent is 15wt% to 30wt% of the external solution composition based on the total weight of the external solution composition. The method of claim 1,
Based on the total weight of the composition for topical solution, 5 wt% to 15 wt% of efinaconazole, 0.01 wt% to 0.3 wt% of butylated hydroxyanisole (BHA), 0.001 wt% to 0.1 wt% of vitamin E, 40 wt% to 65wt% ethanol, 0.0001wt% to 0.001wt% ethylenediaminetetraacetic acid (EDTA) or a salt thereof, 0.01wt% to 1wt% acid, 5wt% to 20wt% cyclomethicone, 15wt% to 30wt% ratio An external solution composition comprising a volatile solvent, 0.01 wt% to 2 wt% of water. The topical solution composition according to any one of claims 1 to 18, wherein the topical solution composition is for the treatment of onychomycosis caused by dermatophytes.