Nail treatment topical medication

Abstract

To provide a nail topical agent that allows efinaconazole or a pharmaceutically acceptable salt thereof to effectively penetrate nails.SOLUTION: A nail topical agent comprises efinaconazole or a pharmaceutically acceptable salt thereof, and a C2-10 alkanediol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external preparation for nails, a method for improving the nail permeability of efinaconazole or a pharmaceutically acceptable salt thereof, and a method for improving the stability of efinaconazole or a pharmaceutically acceptable salt thereof.

Background Art

[0002] Onychomycosis (nail athlete's foot, nail mycosis) is a refractory disease caused by, for example, dermatophytes existing inside the nail plate or on the nail bed entering the nail tissue, characterized by symptoms such as the nail becoming cloudy white or yellow, thickening of the tip of the nail, and deformation of the nail. Oral antifungal drugs are widely used for the treatment of onychomycosis, but in many cases, it is difficult to administer oral antifungal drugs due to side effects and drug-drug interactions. Therefore, there is increasing expectation for external preparations used for the treatment of onychomycosis in terms of having fewer side effects and drug-drug interactions.

[0003] So far, as external preparations used for the treatment of onychomycosis, external preparations containing efinaconazole with high nail permeability as an active ingredient are known (Patent Documents 1 to 4).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0005] Designing the formulation is crucial for efficiently delivering sufficient active ingredients into the nail. The nail permeability of active ingredients varies greatly depending not only on the properties of the active ingredient itself, but also on the properties of each formulation component and their respective proportions. Therefore, an inappropriate formulation design can result in a loss of nail permeability for the active ingredients.

[0006] The present invention has been made in view of the above circumstances, and its object is to provide a topical nail preparation that exhibits excellent nail permeability for efinaconazole or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0007] As a result of various studies, the inventors have found that the above objective can be achieved by the present invention as described below. That is, a topical preparation for nails according to one aspect of the present invention comprises efinaconazole or a pharmaceutically acceptable salt thereof and an alkanediol having 2 to 10 carbon atoms.

[0008] Furthermore, it is preferable that the above-mentioned topical preparation for nails contains the alkanediol in a proportion of 4% by mass or more and 25% by mass or less of the total amount of the topical preparation for nails.

[0009] Furthermore, it is preferable that the nail preparation contains other non-volatile solvents in addition to the alkanediol.

[0010] Furthermore, if the nail preparation contains the other non-volatile solvents, it is preferable that the mass ratio of the alkanediol to the other non-volatile solvents is 10:90 to 90:10.

[0011] Furthermore, it is preferable that the nail preparation contains at least one of butylhydroxyanisole (BHA) and dibutylhydroxytoluene (BHT).

[0012] Furthermore, a method for improving the nail permeability of efinaconazole or a pharmaceutically acceptable salt thereof according to a further aspect of the present invention involves using a topical nail preparation containing efinaconazole or a pharmaceutically acceptable salt thereof and an alkanediol having 2 to 10 carbon atoms.

[0013] Furthermore, a method for improving the stability of efinaconazole or a pharmaceutically acceptable salt thereof according to a further aspect of the present invention involves using a topical nail preparation comprising efinaconazole or a pharmaceutically acceptable salt thereof, an alkanediol having 2 to 10 carbon atoms, and at least one of butylhydroxyanisole (BHA) and dibutylhydroxytoluene (BHT). [Effects of the Invention]

[0014] According to the present invention, it is possible to provide a topical nail preparation that exhibits excellent nail permeability for efinaconazole or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0015] The embodiments of the present invention will be described below, but the present invention is not limited thereto.

[0016] The nail topical preparation of this embodiment comprises efinaconazole or a pharmaceutically acceptable salt thereof and an alkanediol having 2 to 10 carbon atoms. The inventors have found that this configuration makes it possible to provide a nail topical preparation with excellent nail permeability.

[0017] [Topical nail treatment] (Active ingredients) Efinaconazole, the active ingredient in the nail topical preparation of this embodiment, is also known as (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol.

[0018] The efinaiconazole that can be used in this embodiment may be free efinaiconazole or a pharmaceutically acceptable salt of efinaiconazole. The pharmaceutically acceptable salt is not particularly limited and may be an inorganic salt or an organic salt. Examples of the inorganic salt of efinaiconazole include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., and examples of the organic salt include formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, methanesulfonate, toluenesulfonate, etc. From the perspective of ease of obtaining, it is preferable to use free efinaiconazole.

[0019] Such efinaiconazole or its pharmaceutically acceptable salt may be prepared by a known method or a commercially available product may be used.

[0020] Also, hereinafter, unless otherwise specified in this specification, efinaiconazole or its pharmaceutically acceptable salt is collectively referred to simply as "efinaiconazole".

[0021] The content of efinaiconazole is not particularly limited, but from the perspective of obtaining sufficient drug efficacy, it is preferably 1% by mass or more based on the total amount of the external preparation for nails. More preferably, it is 5% by mass or more, and still more preferably, it is 8% by mass or more. On the other hand, the upper limit is preferably 50% by mass or less. More preferably, it is 30% by mass or less, and still more preferably, it is 12% by mass or less. Also, from the perspective of obtaining sufficient drug efficacy, it is preferable that 1 g of the external preparation for nails contains 10 mg or more of efinaiconazole, more preferably 50 mg or more, still more preferably 80 mg or more, and most preferably 100 mg or more. On the other hand, the content of efinaiconazole in 1 g of the external preparation for nails is preferably 500 mg or less, more preferably 300 mg or less, and still more preferably 120 mg or less.

[0022] (Non-volatile solvent) The nail preparation in this embodiment contains an alkanediol having 2 to 10 carbon atoms. The alkanediol having 2 to 10 carbon atoms that can be used in this embodiment is a non-volatile solvent that remains on the affected area and maintains the dissolved state of the active ingredient, efinaconazole. Therefore, efinaconazole can penetrate into the nail while maintaining its dissolved state.

[0023] The C2-C10 alkanediols that can be used in this embodiment are not particularly limited, but specifically, as C2 alkanediols, they include ethylene glycol; as C3 alkanediols, they include 1,3-propanediol and 1,2-propanediol; as C4 alkanediols, they include 1,2-butanediol, 1,3-butanediol and 1,4-butanediol; as C5 alkanediols, they include isopentyldiol, 1,2-pentanediol and 1,3-pentanediol; and as C6 alkanediols, they include 1,2-hexanediol and 1,3-hexanediol. Examples of C7 alkanediols include 1,2-heptanediol, 2,4-heptanediol, and 3,4-heptanediol, while C8 alkanediols include 1,2-octanediol and 2-ethyl-1,3-hexanediol. C9 alkanediols include 1,2-nonanediol, 1,3-nonanediol, 1,9-nonanediol, and 2-butyl-2-ethyl-1,3-propanediol. C10 alkanediols include 1,2-decanediol, 1,3-decanediol, and 1,10-decanediol. Among these, it is preferable to use a C8 alkanediol (octanediol) from the viewpoint of improving nail permeability. Furthermore, it is even more preferable to use 2-ethyl-1,3-hexanediol. Alkanediols with 2 to 10 carbon atoms can be used individually or in combination of two or more.

[0024] The C2-C10 alkanediols that can be used in this embodiment may be those produced by known methods or commercially available products.

[0025] Furthermore, while there are no particular limitations on the content of alkanediols having 2 to 10 carbon atoms, it is preferable that it be 2% by mass or more relative to the total amount of the topical nail preparation. A content of 2% by mass or more ensures that a topical nail preparation with excellent nail permeability can be obtained more reliably. More preferably, it is 4% by mass or more, and even more preferably 8% by mass or more. On the other hand, an upper limit of 25% by mass or less is preferable. A content of 25% by mass or less has the advantage of suppressing an increase in the viscosity of the topical nail preparation, even with highly viscous octanediol, making it easier to dispense the topical nail preparation from the container. More preferably, it is 16% by mass or less, and even more preferably 12% by mass or less.

[0026] Furthermore, in this embodiment, the topical nail preparation preferably further contains other non-volatile solvents other than C2-C10 alkanediols. This allows for more reliable improvement of nail permeability. The other non-volatile solvents are not particularly limited, but are compounds that remain on the affected area and maintain the soluble state of the active ingredient, efinaconazole. Examples include lauromacrogol, benzyl alcohol, N-methyl-2-pyrrolidone, propylene carbonate, diisopropyl adipate, isopropyl myristate, diethyl sebacate, triacetin, medium-chain triglyceride, oleyl alcohol, and alkyl lactate. The other non-volatile solvents may be used alone or in combination of two or more. In this embodiment, the inclusion of lauromacrogol as the other non-volatile solvent is preferred from the viewpoint of improving nail permeability.

[0027] In this embodiment, when an alkanediol having 2 to 10 carbon atoms is used in combination with the other non-volatile solvents mentioned above as a non-volatile solvent, the total content of the non-volatile solvents in the nail topical preparation is not particularly limited, but is preferably 35% by mass or less of the total content of the nail topical preparation. On the other hand, the lower limit is not particularly limited, but is preferably 10% by mass or more. Having the non-volatile solvent within the above content range has the advantage of making application to the affected area easier. Furthermore, a content of 10% by mass or more is preferable from the viewpoint of being able to sufficiently dissolve the active ingredient, efinaconazole.

[0028] Furthermore, in this embodiment, when an alkanediol having 2 to 10 carbon atoms is used in combination with the other non-volatile solvent, it is preferable that the mass ratio of the alkanediol having 2 to 10 carbon atoms to the other non-volatile solvent is 10:90 to 90:10. This makes it possible to more reliably obtain a topical nail preparation with excellent nail permeability. The mass ratio of the alkanediol having 2 to 10 carbon atoms to the other non-volatile solvent is more preferably 15:85 to 85:15, even more preferably 30:70 to 70:30, and most preferably 40:60 to 50:50.

[0029] Furthermore, the nail preparation in this embodiment may contain pharmaceutically acceptable additives. Specifically, it may contain any component such as antioxidants, stabilizers, volatile solvents, buffers, solubilizers, preservatives, and thickeners. In addition, the nail preparation may optionally contain one or more pharmaceutically acceptable solvents.

[0030] (Antioxidant) The inclusion of an antioxidant in the nail topical preparation of this embodiment has the advantage of suppressing the increase of efinaconazole-derived related substances and improving the storage stability of the nail topical preparation. The antioxidant is not particularly limited, but examples include butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), propyl gallate, and α-tocopherol. Among these, it is preferable that the nail topical preparation contains at least one of BHA and BHT, and this configuration has the advantage of suppressing the increase of efinaconazole-derived related substances and more reliably improving the storage stability of the nail topical preparation. The antioxidant may be used alone or in combination of two or more types.

[0031] In this embodiment, when the topical nail preparation contains an antioxidant, the antioxidant content is not particularly limited, but is preferably 0.01% by mass or more relative to the total amount of the topical nail preparation. More preferably 0.05% by mass or more, and even more preferably 0.1% by mass or more. On the other hand, it is preferable that the upper limit be 5% by mass or less. More preferably 1% by mass or less, and even more preferably 0.5% by mass or less. By having an antioxidant content of 0.01% by mass or more and 5% by mass or less relative to the total amount of the topical nail preparation, it is possible to suppress the increase of efinaconazole-derived related substances and more reliably improve the stability of the topical nail preparation.

[0032] (Stabilizer) The stabilizers that can be used in this embodiment are not particularly limited, but examples include sodium edetate hydrate, dipotassium edetate, ethylenediamine succinic acid, diethylenetriaminepentaacetic acid, trisodium ethylenediamine hydroxyethyl triacetate, hydroxyethanediphosphonic acid, and phytic acid. Among these, sodium edetate hydrate is preferred. These may be used individually or in combination of two or more. In this embodiment, if the nail preparation contains a stabilizer, the amount of stabilizer can be appropriately set depending on the type of stabilizer, the type and amount of other ingredients, etc.

[0033] (Volatile solvent) The volatile solvents that can be used in this embodiment are not particularly limited, but are compounds that evaporate from the surface of the nail at room temperature when the nail topical agent is applied, and for example, volatile silicones can be used. Examples of volatile silicones include cyclic volatile silicones and linear polysiloxanes. Examples of cyclic volatile silicones include polydimethylcyclosiloxane, cyclopentasiloxane, cyclotetrasiloxane, and decamethylcyclopentasiloxane, which are commonly known as cyclomethicone. Examples of linear polysiloxanes include hexamethyldisiloxane and octamethyltrisiloxane. In addition to volatile silicones, other examples of volatile solvents include acetone, 2-amino-2-methyl-1-propanol, 2-butanol, ethanol, ethyl acetate, n-heptane, isobutanol, 1-propanol, and 2-propanol. The above volatile solvents may be used individually or in combination of two or more.

[0034] In this embodiment, when the topical nail preparation contains a volatile solvent, the content of the volatile solvent is not particularly limited, but is preferably 50% by mass or more of the total amount of the topical nail preparation. More preferably 60% by mass or more, and even more preferably 65% ​​by mass or more. On the other hand, an upper limit of 80% by mass or less is preferred. More preferably 75% by mass or less, and even more preferably 70% by mass or less. A volatile solvent content of 50% by mass or more and 80% by mass or less of the total amount of the topical nail preparation has the advantage of being able to sufficiently dissolve the active ingredient efinaconazole and other additives.

[0035] (buffering agent) The buffering agents that can be used in this embodiment are not particularly limited, but examples include anhydrous citric acid, tartaric acid, lactic acid, phosphoric acid, acetic acid, malic acid, and their salts. These may be used individually or in combination of two or more. In this embodiment, when the nail topical preparation contains a buffering agent, the amount of buffering agent can be appropriately set depending on the type of buffering agent, the type and amount of other ingredients, etc. Furthermore, the pH of the nail topical preparation can be adjusted by adjusting the amount of buffering agent.

[0036] (solvent) Other solvents that may be used in this embodiment are not particularly limited, but include, for example, water. One solvent may be used alone, or two or more may be used in combination. In this embodiment, if the nail preparation contains the solvent, the solvent content can be appropriately set depending on the type of solvent, the type and content of other ingredients, etc.

[0037] (pH of topical nail treatment) In this embodiment, the pH of the topical nail preparation is not particularly limited, but is preferably 5.0 to 6.0. Having the pH within this range has the advantage of suppressing the increase of efinaconazole-derived related substances and more reliably ensuring the stability of the topical nail preparation. More preferably, it is 5.1 to 5.7, and even more preferably 5.3 to 5.5. The pH of the topical nail preparation can be adjusted by adjusting the content of the buffering agent, etc.

[0038] (Surface tension of topical nail preparations) In this specification, the surface tension of the nail topical agent is measured at 20°C using a contact angle meter. In this embodiment, the surface tension of the nail topical agent is not particularly limited, but is preferably 25 dyn / cm or less. Having a surface tension within this range allows the nail topical agent to be easily dispensed from the container and to spread sufficiently over the entire nail and into the gap between the nail and the finger. On the other hand, the lower limit of the surface tension is not particularly limited, but is usually around 10 dyn / cm or more.

[0039] (Kinematic viscosity of topical nail preparations) In this specification, the kinematic viscosity of the nail topical agent is measured at 20°C using a cone-plate viscometer. In this embodiment, the nail topical agent has a kinematic viscosity of 1 mm, from the viewpoint of ease of application to the affected area. 2 / s or more 5mm 2 It is preferable that the value be less than or equal to / s.

[0040] (Method of manufacturing topical preparation for nails) The nail preparation in this embodiment can be prepared by mixing and stirring efinaconazole or a pharmaceutically acceptable salt thereof, an alkanediol having 2 to 10 carbon atoms, and, if necessary, further mixing and stirring other non-volatile solvents, volatile solvents, antioxidants, stabilizers, buffers, and solvents. The order of mixing is not particularly limited; for example, they may be added sequentially, or the stabilizer and solvent may be dissolved in advance, stirred and mixed, and then efinaconazole, non-volatile solvents, volatile solvents, antioxidants, etc., may be added.

[0041] Furthermore, in the manufacturing method of topical preparations for nails, the explanations of each component, such as "efinaconazole or its pharmaceutically acceptable salts," "alkanediols having 2 to 10 carbon atoms," "other non-volatile solvents," and "volatile solvents," are as described above.

[0042] (form) The form of the nail preparation in this embodiment is not particularly limited, and examples include liquid preparations, semi-solid preparations, etc. Examples of liquid preparations include topical liquid preparations, and examples of semi-solid preparations include ointments, creams, gels, etc., but among these, topical liquid preparations are preferred.

[0043] (Application) The nail topical preparation in this embodiment contains efinaconazole and can therefore be used as a treatment for onychomycosis. It is preferable to apply the nail topical preparation in this embodiment to the treatment site of a patient with onychomycosis at a rate of approximately 0.2 mL once a day for at least two weeks.

[0044] (container) The container that can be filled with the topical nail preparation in this embodiment is not particularly limited and can be any commonly used container. Furthermore, from the viewpoint of storage stability of the topical nail preparation, a light-shielded, airtight container is preferable.

[0045] [Methods to improve nail permeability] One embodiment of the present invention provides a method for improving the nail permeability of efinaconazole or a pharmaceutically acceptable salt thereof, using a topical nail preparation comprising efinaconazole or a pharmaceutically acceptable salt thereof and an alkanediol having 2 to 10 carbon atoms.

[0046] The method for improving the nail permeability of efinaconazole or its pharmaceutically acceptable salt according to this embodiment can improve the nail permeability of efinaconazole, which is the active ingredient in topical nail preparations. Therefore, the method for improving the nail permeability of efinaconazole or its pharmaceutically acceptable salt according to this embodiment is useful in designing topical nail preparations with excellent nail permeability.

[0047] In this specification, the nail permeability of efinaconazole is measured by the method shown in the examples below. In this embodiment, the nail permeability rate of the topical nail preparation is 0.20 μg / cm². 2 It is preferable that the concentration be 0.25 μg / cm³ or more. 2 It is more preferable that the concentration be 0.28 μg / cm³ or higher, and more preferably 0.28 μg / cm³. 2 It is even more preferable if it is 1 / day or more.

[0048] [Methods to improve stability] One embodiment of the present invention provides a method for improving the stability of efinaconazole or a pharmaceutically acceptable salt thereof, using a topical nail preparation comprising efinaconazole or a pharmaceutically acceptable salt thereof, and an alkanediol having 2 to 10 carbon atoms, and at least one of butylhydroxyanisole (BHA) and dibutylhydroxytoluene (BHT).

[0049] The method for improving the stability of efinaconazole or its pharmaceutically acceptable salt according to this embodiment can suppress the increase of efinaconazole-derived related substances, which are the active ingredients of topical nail preparations, and improve the storage stability of topical nail preparations.

[0050] In this specification, the stability of efinaconazole or a pharmaceutically acceptable salt thereof can be evaluated by calculating the amount of an unknown related substance detected at a relative retention time of approximately 0.18 relative to efinaconazole when the nail preparation is stored at 70°C for 4 days and then measured by the method shown in the examples described below. In this embodiment, it is preferable from the viewpoint of stability that the amount of the unknown related substance after storage at 70°C for 4 days is 0.2% or less. More preferably it is 0.15% or less, and even more preferably 0.10% or less.

[0051] In the above-mentioned method for improving nail permeability and the above-mentioned method for improving stability, the descriptions of each component, such as "efinaconazole or a pharmaceutically acceptable salt thereof," "alkanediol having 2 to 10 carbon atoms," "other non-volatile solvents," and "volatile solvents," are as described above.

[0052] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited thereto. [Examples]

[0053] (Examples 1-4, Comparative Example 1) First, the components of the nail topical preparation used in this embodiment are shown below.

[0054] (Active ingredients) • Efinaconazole (Non-volatile solvent) Lauromacrogol ·2-ethyl-1,3-hexanediol Benzyl alcohol N-methyl-2-pyrrolidone • Propylene carbonate (Volatile solvent) Decamethylcyclopentasiloxane Anhydrous ethanol (Antioxidant) Butylhydroxyanisole (BHA) (buffering agent) Anhydrous citric acid (Stabilizer) • Sodium edetate hydrate (solvent) ·Purified water Each component was blended in the proportions shown in Table 1 below to produce the nail topical preparations of Examples 1-4 and Comparative Example 1. All numerical values ​​regarding the composition of the nail topical preparations shown in Table 1 are in mass percent.

[0055] [Table 1]

[0056] (pH measurement) When the pH of the nail preparation in Example 1 was measured using a pH meter, the pH was found to be 5.4.

[0057] (Kinematic viscosity measurement) The kinematic viscosity of the nail topical agent from Example 1 was measured at 20°C using a cone-plate viscometer, and the kinematic viscosity was 3.7 mm³. 2 It was / s.

[0058] (Surface tension measurement) When the surface tension of the nail topical agent of Example 1 was measured at 20°C using a contact angle meter, the surface tension was found to be 20 dyn / cm.

[0059] (Nail permeability) The nail permeability of efinaconazole was evaluated for the nail topical preparations obtained in Examples 1-4 and Comparative Example 1. Specifically, human nails that had been frozen were thawed at room temperature and then soaked in water to be used as nail samples. A phosphate buffer solution with macrogol added was used as the receptor solution. A Franz-type diffusion cell and a nail adapter were prepared, the prepared nail samples were placed in the nail adapter, and the receptor solution was filled into the Franz-type diffusion cell. The nail adapter was placed in the Franz-type diffusion cell and incubated overnight at 32°C with stirring.

[0060] For each example, 2 μL of the topical nail preparation was added to the nail sample. From the following day until 14 days later, 500 μL samples were taken once daily, and the receptor solution was replenished after each sample. The sampled solutions were analyzed by tandem mass spectrometry (ESI, positive mode) to measure the amount of efinaconazole permeated. The nail permeation rate was calculated from the cumulative permeation amount at three time points, 12 to 14 days after the start of the test. The measured nail permeation rates are shown in Table 2.

[0061] [Table 2]

[0062] The results in Table 2 clearly show that the topical nail preparations of Examples 1-4, which contain alkanediols with 2-10 carbon atoms, exhibit excellent nail permeability. On the other hand, the topical nail preparation of Comparative Example 1, which does not contain alkanediols with 2-10 carbon atoms, was found not to provide sufficient nail permeability.

[0063] (Examples 5-9) In Examples 5-6, the content of BHA as an antioxidant was changed, and in Examples 7-9, dibutylhydroxytoluene (BHT), propyl gallate, or α-tocopherol was used instead of BHA as an antioxidant. The nail topical preparations of Examples 5-9 were prepared in the same manner as in Example 1.

[0064] Table 3 shows the compositions of the topical nail preparations for Examples 5-9, and the composition of the topical nail preparation for Example 1 is also listed. All numerical values ​​for the composition of the topical nail preparations shown in Table 3 are in mass percent.

[0065] [Table 3]

[0066] (Measurement of related substance amounts) The nail preparations obtained in Examples 1, 5-9 were stored at 70°C for 4 days, and then unknown related substances derived from efinaconazole were measured by liquid chromatography.

[0067] The measurement conditions for the liquid chromatography used in this measurement are as follows: • Detector: UV absorbance spectrophotometer (measurement wavelength 260 nm) • Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm was packed with 5 μm octadecylsilylated silica gel for liquid chromatography. • Column temperature: A constant temperature of around 40°C Mobile phase A: 1.9 g of ammonium formate was dissolved in 1000 mL of water, and formic acid was added to adjust the pH to 4.0. Mobile phase B: Acetonitrile • Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B according to the time elapsed after sample injection, as shown in Table 4.

[0068] [Table 4]

[0069] • Flow rate: 1.5 mL per minute Then, for the amount of the unknown related substance detected at a relative retention time of approximately 0.18 relative to efinaconazole, the percentage of the unknown related substance was calculated by setting the total peak area derived from efinaconazole obtained on the chromatogram to 100. The results are shown in Table 5.

[0070] [Table 5]

[0071] The results in Table 5 show that in Examples 1, 5-7, which contained BHA or BHT as an antioxidant, the increase in efinaconazole-derived analogs was suppressed compared to Examples 8-9, indicating superior storage stability.

Claims

1. Efinaconazole or a pharmaceutically acceptable salt thereof, A topical preparation for nails containing 2-ethyl-1,3-hexanediol.

2. The topical nail preparation according to claim 1, comprising 2-ethyl-1,3-hexanediol in a proportion of 4% by mass or more and 25% by mass or less of the total topical nail preparation.

3. Furthermore, the nail topical preparation according to claim 1 comprises at least one non-volatile solvent selected from the group consisting of lauromacrogol, benzyl alcohol, N-methyl-2-pyrrolidone, propylene carbonate, diisopropyl adipate, isopropyl myristate, diethyl sebacate, triacetin, medium-chain triglyceride, oleyl alcohol, and alkyl lactate.

4. The topical nail preparation according to claim 3, wherein the mass ratio of 2-ethyl-1,3-hexanediol to the non-volatile solvent is 10:90 to 90:

10.

5. Furthermore, the nail preparation according to any one of claims 1 to 4, comprising at least one of butylhydroxyanisole (BHA) and dibutylhydroxytoluene (BHT).

6. A method for improving the nail permeability of efinaconazole or a pharmaceutically acceptable salt thereof, using a topical nail preparation comprising efinaconazole or a pharmaceutically acceptable salt thereof and 2-ethyl-1,3-hexanediol.

7. A method for improving the stability of efinaconazole or a pharmaceutically acceptable salt thereof, using a nail preparation comprising efinaconazole or a pharmaceutically acceptable salt thereof, 2-ethyl-1,3-hexanediol, and at least one of butylhydroxyanisole (BHA) and dibutylhydroxytoluene (BHT).

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