Liquid agent container and applicator

Abstract

The present invention provides a liquid agent container to be filled with a liquid agent of efinaconazole, the liquid agent container having two contradictory characteristics such that the content amount of the liquid agent can be visually recognized from the outside while maintaining light stability.　Provided is a liquid agent container which can be filled with a liquid agent that contains 10% of efinaconazole, wherein: the liquid agent container is formed of a synthetic resin that contains titanium oxide (IV); the liquid agent container has a light transmittance of 0.20% or less at a wavelength of 200 nm to 360 nm, and a light transmittance of 0.25% or more at a wavelength of 700 nm; and the content amount of the liquid agent filled in the liquid agent container can be visually recognized from the outside.

Description

Liquid container and applicator

[0001] The present invention relates to a liquid container for filling with a liquid containing efinaconazole. The present invention also relates to an applicator having the liquid container.

[0002] Efinaconazole is a compound of the following formula (I) which has antifungal activity: Efinaconazole is a triazole compound represented by the formula: Efinaconazole is known as an active ingredient in topical onychomycosis treatments. A liquid formulation containing efinaconazole is sold under the pharmaceutical names Clenafin (registered trademark) Nail Topical Solution 10% in Japan and JUBLIA (registered trademark) Topical Solution, 10% in the United States (Non-Patent Document 1).

[0003] In liquid formulations containing efinaconazole, an increase in efinaconazole-related substances has been observed in light stress tests. Therefore, using a container (e.g., a colorless, transparent glass container) that allows the remaining amount of liquid to be easily visible from the outside will accelerate the decomposition of efinaconazole. Therefore, it is extremely important to ensure the stability of the formulation against light exposure. Therefore, conventional efinaconazole formulations are filled in white, opaque, light-blocking containers. However, detailed information regarding the photostability of efinaconazole has not been known to date.

[0004] Treatment for onychomycosis is long-term, and when a liquid formulation containing efinaconazole is used, the administration period can last for several months or more. It is preferable for patients to visit the hospital before they finish using the liquid. Therefore, being able to visually check the remaining amount of liquid from the outside is important from the perspective of improving patient adherence (i.e., compliance with medication). However, because conventional efinaconazole formulation containers are white, opaque, and light-blocking, the amount of liquid inside cannot usually be seen from the outside.

[0005] Efinaconazole is used as a liquid formulation to be applied topically to nails. Therefore, an applicator that integrates a liquid container for filling the drug with the drug and a brush member for applying the drug to nails is preferred. As an example of such an applicator container with a brush, Patent Document 1 discloses an applicator for applying an onychomycosis drug to an affected area. As an example of a liquid container (i.e., a bottle portion) constituting the applicator, a liquid container formed from an organic material and capable of holding a liquid drug is disclosed. Examples of organic materials include polyolefins such as polyethylene and polypropylene, and aromatic polyesters such as polyethylene terephthalate and polybutylene terephthalate. However, this document does not mention efinaconazole at all, much less a liquid container that can be filled with efinaconazole and stably hold it.

[0006] Various medical containers have been proposed that allow the content volume of a liquid formulation to be visually confirmed from the outside and prevent degradation of the active ingredient due to light. Patent Document 2 discloses an ultraviolet-blocking medical container made of plastic, in which 0.01 to 1.00 wt % of titanium oxide having an average particle size of 10 to 40 mμ is added to a thermoplastic resin. Patent Document 3 discloses a transparently packaged pharmaceutical formulation containing tranilast or a salt thereof, in which the transparent package is provided with a light-blocking means for blocking light with a wavelength of 350 to 450 nm. Patent Document 4 discloses a container made of a colored transparent resin containing a coloring material, which has a transmittance of 10% or less for light with a wavelength of 200 to 500 nm and a transmittance of 80% or more for light with a wavelength of 540 to 800 nm.

[0007] However, the containers described in Patent Documents 2 to 4 are not applicators for applying liquid to nails. Furthermore, even in the container described in Patent Document 2, deterioration of the contents is likely to occur based on the description therein. The containers described in Patent Documents 3 and 4 are also not capable of completely blocking light in the ultraviolet region.

[0008] International Publication No. 2013 / 005434 Japanese Patent Application Laid-Open No. 8-98870 Japanese Patent Application Laid-Open No. 2014-015467 Japanese Patent Application Laid-Open No. 2007-061192

[0009] Clenafin (registered trademark) Nail Topical Solution 10% Pharmaceutical Interview Form Revised July 2022 (8th edition)

[0010] One of the problems to be solved by the present invention is to provide a liquid container for filling a liquid formulation of efinaconazole, which has two contradictory characteristics of maintaining photostability while allowing the amount of the liquid formulation to be visually confirmed from the outside.

[0011] Another problem to be solved by the present invention is to provide an applicator container with a brush (in other words, an applicator) for filling and applying a liquid formulation of efinaconazole, which maintains photostability while allowing the amount of liquid contained therein to be visually confirmed from the outside and enabling an appropriate amount of liquid to be applied.

[0012] In order to solve the above-mentioned problems, the present inventors conducted detailed studies on the photostability of efinaconazole. As a result, it was found that efinaconazole is extremely sensitive to ultraviolet light, and yellowing and / or an increase in related substances over time was observed. Furthermore, it was revealed that even a container with a transmittance of ultraviolet light of, for example, about 1% accelerates the decomposition of efinaconazole. As described above, various containers have been proposed as containers for liquid formulations that suppress the transmission of ultraviolet light and enable confirmation of the remaining amount of content. However, none of these containers are liquid formulation containers or applicators for applying liquid formulations to nails. Furthermore, because efinaconazole is extremely sensitive to ultraviolet light, it was impossible to use previously proposed containers as containers for efinaconazole formulations.

[0013] As a result of studies by the present inventors, it was found that by precisely controlling the light transmittance of the container for both ultraviolet and visible light, it is possible to realize a container that has two contradictory properties: maintaining the photostability of efinaconazole while allowing the liquid formulation to be visually confirmed from the outside. Specifically, the present inventors found that the photostability of efinaconazole is maintained by using a container in which the light transmittance for ultraviolet light is controlled to a range of 0% to 0.20%. Furthermore, the present inventors found that in order to make the remaining amount of liquid formulation visible, the light transmittance for light of a specific wavelength included in the visible range must be 0.25% or more.

[0014] Based on the above findings, the present inventors conducted further detailed studies to find a container suitable for filling a liquid preparation containing efinaconazole.

[0015] As mentioned above, an applicator suitable for use with an onychomycosis treatment agent has been proposed, which includes a generally cylindrical container with an opening, and a columnar brush member formed by bundling synthetic fibers into a columnar shape attached to the opening (Patent Document 1). The brush member functions as an applicator, and the user can apply the solution to the nails by inverting the container to allow the solution to penetrate the brush member. However, when the container is inverted for use, depending on the usage environment and the container design, an excessive amount of solution may be discharged or the amount of solution discharged may be small. This may hinder smooth application of the solution. Therefore, to achieve a favorable usability for a brush-equipped applicator container for nail application, the container's material, hardness, and / or thickness must be appropriately designed so that an appropriate amount of solution is quickly dispensed from the container under actual use conditions. On the other hand, because the thickness of the container also affects light transmittance, it is difficult to design a container that balances various issues, including light stability and visibility.

[0016] In light of the above, the inventors conducted further research and discovered that an excellent container could be obtained that comprehensively resolved various issues, such as light stability, visibility, and usability as an application container with a brush.

[0017] As a result of the above-mentioned investigations, according to one embodiment of the present invention, a liquid agent container suitable for use in an applicator for applying a liquid agent to nails can be provided. Furthermore, according to one embodiment of the present invention, an applicator can be provided in which a columnar brush member formed by bundling synthetic fibers into a columnar shape is installed at the opening of the above-mentioned liquid agent container. The above-mentioned applicator equipped with a liquid agent container according to one embodiment of the present invention can quickly dispense an appropriate amount of liquid agent when inverted under actual use conditions, providing an excellent usability.

[0018] Furthermore, an applicator according to one embodiment of the present invention is characterized in that when 4 mL of a 10% efinaconazole ethanol solution is filled into the applicator and the applicator is placed inverted in an environment at 32°C, it takes 7 to 10 drops of the solution to stop dripping within one minute.

[0019] As described above, the present inventors have investigated a liquid container suitable for filling a liquid formulation of efinaconazole. As a result, the present inventors have found a container that ensures the photostability of the active ingredient of the liquid formulation, allows the remaining amount of the liquid formulation to be visually confirmed, and is extremely comfortable to use, and have completed the present invention.

[0020] That is, the present invention is as follows. [1] A liquid container capable of being filled with a liquid containing 10% efinaconazole, the liquid container being formed from a synthetic resin containing titanium(IV) oxide, and having a light transmittance of 0.20% or less for wavelengths of 200 to 360 nm and a light transmittance of 0.25% or more for wavelengths of 700 nm, allowing the amount of liquid filled in the container to be visually confirmed from the outside. [2] The liquid container according to [1], wherein the liquid container is a substantially cylindrical polyethylene container having an opening at the top, the container is made of a single layer in which at least titanium(IV) oxide is homogeneously dispersed in the polyethylene, and the container is non-flexible and hard. [3] The liquid container according to [1] or [2], wherein the liquid container has an internal volume of 8 to 12 mL and a sidewall thickness of 0.8 to 1.0 mm. [4] The liquid container according to any one of [1] to [3], characterized in that it contains 0.09 to 0.33 parts by weight of titanium (IV) oxide per 100 parts by weight of synthetic resin. [5] The liquid container according to any one of [1] to [4], characterized in that it contains 0.10 to 0.30 parts by weight of titanium (IV) oxide per 100 parts by weight of synthetic resin. [6] The liquid container according to any one of [1] to [5], characterized in that it contains 0.18 to 0.22 parts by weight of titanium (IV) oxide per 100 parts by weight of synthetic resin. [7] The liquid container according to any one of [1] to [6], characterized in that it contains no coloring component other than titanium (IV) oxide. [8] The liquid container according to any one of [1] to [6], wherein the liquid container has a light transmittance of 0.25% or more for wavelengths of 700 to 780 nm. [9] The liquid container according to any one of [1] to [8], wherein the liquid container has a light transmittance of 0.40% or more for all wavelengths of 700 to 780 nm.

[10] The liquid container according to any one of [1] to [9], wherein the liquid container has a light transmittance of 0.10% or less for all wavelengths of 200 to 360 nm.

[11] The liquid container according to any one of [1] to

[10] , which is not packaged with an ultraviolet absorbing film.

[12] An applicator having a liquid agent container described in any one of [1] to

[11] , a columnar brush member formed by bundling synthetic fibers into a columnar shape, and a bottomed tubular holder having a tubular body and a bottom between the liquid agent container and the columnar brush member, wherein the bottomed tubular holder is liquid-tightly fitted to the opening of the liquid agent container, the bottom of the bottomed tubular holder has at least one pore, the columnar brush member is inserted inside the tubular body of the bottomed tubular holder, and the liquid agent can pass from the liquid agent container to the columnar brush member through the pore, so that when the liquid agent container is inverted during use, the liquid agent permeates the columnar brush member, making it possible to apply the liquid agent to the user's nails.

[13] The applicator according to

[12] , wherein the columnar brush member is formed by bundling synthetic fibers having a fiber diameter in the range of 7 to 50 μm at a density in the range of 0.25 to 0.50, and the bottomed tubular holder has one circular pore having a diameter of 0.9 to 1.3 mm.

[14] The applicator according to

[12] or

[13] , wherein, when the applicator filled with 4 mL of the solution is inverted in an environment of 32°C, the number of drops required for the dripping to stop in one minute is 7 to 10 drops.

[15] A method for photostabilizing efinaconazole, comprising the step of filling the solution container according to any one of [1] to

[11] or the applicator according to any one of

[12] to

[14] with a solution containing 10% efinaconazole.

[0021] Use of a liquid container according to one embodiment of the present invention inhibits photodecomposition of efinaconazole, allowing for stable storage of efinaconazole liquid over long periods of time. Furthermore, the user can visually check the remaining amount of liquid filled in the liquid container from the outside. Furthermore, an applicator can be constructed by attaching a columnar brush member, formed by bundling synthetic fibers into a columnar shape, to the opening of a liquid container having the above characteristics. The applicator can quickly dispense the liquid when inverted under actual use, and the amount of liquid dispensed is appropriate, providing a pleasant feel when used.

[0022] FIG. 1 is a schematic front view showing an example of an applicator equipped with a liquid container according to one embodiment of the present invention. FIG. 2 is a schematic cross-sectional view of the applicator shown in FIG. 1 equipped with a cap covering the columnar brush member. A schematic cross-sectional view for explaining the liquid container shown in FIG. 1. A schematic oblique view for explaining the columnar brush member shown in FIG. 1. A schematic cross-sectional view for explaining the bottomed cylindrical holder shown in FIG. 1. FIG. 3 shows the light transmission spectrum for wavelengths of 200 nm to 800 nm for the container of Comparative Example 1. FIG. 4 is an enlarged view of the vertical axis of FIG. 3. FIG. 5 shows the light transmission spectrum for wavelengths of 200 nm to 800 nm for the container of Comparative Example 2. FIG. 6 shows the light transmission spectrum for wavelengths of 200 nm to 800 nm for the container of Comparative Example 3. FIG. 7 shows the light transmission spectrum for wavelengths of 200 nm to 800 nm for the container of Comparative Example 4. FIG. 8 shows the light transmission spectrum for wavelengths of 200 nm to 800 nm for the container of Example 1. FIG. 9 is an enlarged view of the vertical axis of FIG. 8. Figure 10 shows the light transmittance spectrum for wavelengths of 200 nm to 800 nm for the container of Example 2. Figure 11 shows an enlargement of the vertical axis of Figure 10. Figure 12 shows the light transmittance spectrum for wavelengths of 200 nm to 800 nm for the container of Example 3. Figure 13 shows the light transmittance spectrum for wavelengths of 200 nm to 800 nm for the container of Example 4. Figure 14 shows the light transmittance spectrum for wavelengths of 200 nm to 800 nm for the container of Example 5.

[0023] The terms used in this specification will be explained below. In this specification, when a numerical range is indicated using "to", the range includes both ends of the range.

[0024] In this specification, the term "ultraviolet region" refers to light with a wavelength of 200 nm to 360 nm, and the term "visible region" refers to light with a wavelength of 400 nm to 780 nm.

[0025] <1> Container In this specification, a liquid agent container may be simply referred to as a "container." Furthermore, a liquid agent container to which a columnar brush element is attached may be collectively referred to as a "brush-equipped applicator container" or an "applicator." One embodiment of the present invention is shown in FIGS. 1 and 2. FIG. 1 is a schematic front view showing an example of an applicator equipped with a liquid agent container according to one embodiment of the present invention, and FIG. 2 is a schematic cross-sectional view of the applicator shown in FIG. 1 , equipped with a cap covering the columnar brush element. As shown in FIG. 1 , an applicator 100 according to one embodiment of the present invention may be an applicator equipped with a substantially cylindrical liquid agent container 1 capable of being filled with a liquid agent, a bottomed cylindrical holder 2, and a columnar brush element 3. Furthermore, as shown in FIG. 2 , the applicator 100 may be equipped with a detachable cap 4 that covers the brush element 3. FIG. 2A is a schematic cross-sectional view showing the liquid agent container 1 alone. The liquid agent container 1 includes a liquid agent container body 11 and a liquid agent container neck 12. In the illustrated example, the container body 11 is generally cylindrical, with its upper portion formed continuously with the container neck 12 by a curved surface. The container neck 12 has an opening 14 through which the columnar brush element 3 is installed via a bottomed cylindrical holder 2 (see FIG. 2 ). The outer surface of the container neck 12 is provided with a screw thread 15 that can be threaded with the cap 4. The container body 11 includes a side wall 11a and a bottom wall 11b extending circumferentially around the generally cylindrical container body 11. The side wall 11a and the bottom wall 11b define a filling space S that can be filled with the liquid. When the applicator is not in use or is stored, the outer surface of the bottom wall 11b is placed in contact with a flat surface such as a desk. The side wall 11a is gripped by the user when the applicator 100 is in use. FIG. 2B is a schematic perspective view illustrating the columnar brush element 3. The columnar brush member 3 is a member formed by bundling synthetic fibers into a columnar shape. The columnar brush member 3 comprises a columnar brush member body 31, a columnar brush member neck portion 32, and a columnar brush member tip portion 33. The outer surfaces of the columnar brush member body 31 and the columnar brush member neck portion 32 are solidified with adhesive, and the synthetic fibers made of fine polyester contained inside the columnar brush member 3 are integrated. The columnar brush member tip portion 33 is formed in a brush shape by loosening the synthetic fiber bundle fixed with adhesive at the tip portion of the columnar brush member neck portion 32.Because there are gaps between the synthetic fibers within the columnar brush member body 31 and the columnar brush member neck 32 that allow liquid chemicals to pass through, when the end face of the columnar brush member body 31 is immersed in liquid chemicals, the liquid chemicals seep out from the other end of the synthetic fibers due to capillary action. Figure 2C is a schematic cross-sectional view illustrating the bottomed tubular holder 2. The bottomed tubular holder 2 includes a bottomed tubular holder body 21 and an annular flange 22. The bottomed tubular holder body 21 has a cylindrical shape. The cylindrical shape can be appropriately modified to match the outer peripheral shape of the columnar brush member 3 so that the columnar brush member 3 can be inserted. As shown in Figure 2C, the bottomed tubular holder 2 has a bottom 23, and the bottom 23 and the cylindrical bottomed tubular holder body 21 are joined together without any gaps. A fine hole 24 is provided in the center of the bottom 23. The structure is such that the liquid agent placed inside the liquid agent container 1 can move through the pores 24 into the bottomed tubular holder 2. In Figure 2C, 35 is a support member formed on the inner surface of the bottomed tubular holder main body 21 that supports the columnar brush member 3. However, the specific shapes of the components of the applicator 100 according to one embodiment of the present invention are not limited to those shown in the figure.

[0026] An applicator according to one embodiment of the present invention is inverted during use. At this time, the brush member receives liquid from the liquid container at one end, and the liquid permeates through the brush member due to capillary action. The other end of the brush member functions as an applicator member for applying the liquid to the nail. In this way, the liquid is supplied to the nail via the brush member installed at the opening of the liquid container. By inverting an applicator according to one embodiment of the present invention (and therefore the liquid container), the user can quickly permeate the liquid from the opening of the liquid container into the brush member, smoothly applying an appropriate amount of liquid to the nail. Therefore, the applicator and liquid container according to one embodiment of the present invention have a pleasant feel when used.

[0027] In one embodiment of the present invention, the liquid container may have any shape as long as it is a container that can be filled with the liquid without leakage. For example, a substantially cylindrical container having an opening at the top as shown in FIG. 2A is preferred.

[0028] The main material of the liquid container according to one embodiment of the present invention is not particularly limited as long as it is a synthetic resin suitable for filling the interior with a drug. However, polyethylene terephthalate, polybutylene terephthalate, polyethylene, polystyrene, polypropylene, or vinyl chloride is preferred as the base resin, with polyethylene being particularly preferred. In one embodiment of the present invention, the liquid container is a hard synthetic resin container that is not elastically deformable under normal use conditions, i.e., is inelastic or inflexible. A hard synthetic resin container does not require the user to adjust the amount of liquid dispensed by the user's gripping force. The liquid diffuses passively through the brush member due to capillary action. Therefore, the amount of dispensed is less likely to vary between users, making it a preferred container from that perspective.

[0029] In one embodiment of the present invention, the internal volume of the liquid container is not particularly limited, but is preferably 8 to 12 mL. In one embodiment of the present invention, the thickness of the side wall of the liquid container is not particularly limited, but is preferably 0.8 mm to 1.0 mm in order to comprehensively solve the problems of the present invention.

[0030] In this specification, "blocking light" refers to preventing light from passing through by using a substance that scatters or absorbs light. In the present invention, the specific means for blocking light in the ultraviolet region is not particularly limited, but the following means can be used, for example, by using a substance that can block ultraviolet light in a predetermined wavelength range, as described below: a) A method in which a substance that blocks light in the ultraviolet region is contained in a synthetic resin used for the container (for example, a method in which a substance that blocks ultraviolet light, such as titanium oxide, is added to a base resin and then molded into the shape of a container). b) A method in which a member (for example, a film, etc.) containing a substance that blocks ultraviolet light is separately attached to the surface of the container (for example, a method in which a shrink film containing an ultraviolet scattering agent is attached to the container). c) A method in which a substance that blocks ultraviolet light is applied to the surface of the container.

[0031] Of the above-mentioned methods, b) and c) are not economical because they require many manufacturing steps and materials. On the other hand, a) is preferable because the manufacturing process is simple, but it is not easy to block only UV rays while ensuring visibility. Furthermore, if the container material is not selected appropriately, there is a possibility that components of the container material will leach into the liquid contained therein.

[0032] In one embodiment of the present invention, a preferred liquid container is formed to block ultraviolet rays by incorporating an ultraviolet-blocking substance into the synthetic resin used for the container. Therefore, in one embodiment of the present invention, a preferred liquid container is a container consisting of a single layer in which the ultraviolet-blocking substance is homogeneously dispersed in the main component of the container material. Here, "ultraviolet-blocking substance" refers to a substance that blocks ultraviolet rays, preferably titanium(IV) oxide. That is, "a container consisting of a single layer in which the ultraviolet-blocking substance is homogeneously dispersed in the main component of the container material" refers to a container molded with a coloring component such as titanium(IV) oxide homogeneously dispersed in the base resin. In one embodiment of the present invention, a preferred liquid container is formed of a single thermoplastic synthetic resin layer, not multiple layers. Furthermore, the container does not have a portion of the container side that is free of the ultraviolet-blocking substance (or a portion with a lower concentration of the ultraviolet-blocking substance than other portions). While such a portion can function as a window or gauge for visually checking the content, a preferred container in one embodiment of the present invention does not have such a window or gauge. In one embodiment of the present invention, the liquid container can be molded in a single molding step because the material components used in the liquid container are homogeneously dispersed in each other. Therefore, the liquid container according to one embodiment of the present invention can be manufactured by a simple and low-cost manufacturing method.

[0033] In one embodiment of the present invention, a preferred liquid container is a synthetic resin container that is not wrapped with an ultraviolet-absorbing film. Examples of ultraviolet absorbers used in the film include salicylates, benzophenones, triazines, benzotriazoles, and cyanoacrylates. The ultraviolet-absorbing film can contain, for example, a shrinkable PET resin as a base material. By shrinking such an ultraviolet-absorbing film to cover the surface of a liquid container, it is possible to achieve the same effect as a synthetic resin container containing an ultraviolet blocking agent. However, when using an ultraviolet-absorbing film, partial or complete damage to the ultraviolet-absorbing film may occur due to user error or intentional misconduct, unintentionally affecting the photostability of the contents. Furthermore, the use of an ultraviolet-absorbing film may increase manufacturing costs. Therefore, particularly for pharmaceutical containers, it is preferable to incorporate an ultraviolet-blocking substance into the material of the liquid container and form a single layer in which the ultraviolet-blocking substance is homogeneously dispersed in the container material, rather than using an ultraviolet-absorbing film.

[0034] The liquid container of the present invention is a white (including translucent) synthetic resin container characterized by containing titanium(IV) oxide as a coloring component. Titanium(IV) oxide functions as an ultraviolet blocking substance. In one embodiment of the present invention, a preferred liquid container is a white synthetic resin container characterized by containing titanium(IV) oxide and not containing any other coloring component other than titanium(IV) oxide. Such a liquid container according to one embodiment of the present invention is preferred because components in the material of the container do not leach into the liquid contained therein.

[0035] When manufacturing the liquid container of the present invention, the method of adding titanium(IV) oxide is not particularly limited. For example, a predetermined amount of titanium(IV) oxide may be directly blended with a base resin and then molded. A masterbatch method is also preferred. In the masterbatch method, for example, titanium(IV) oxide is melted and / or kneaded in advance with a small amount of resin to prepare a masterbatch (MB) containing titanium(IV) oxide at a high concentration. By blending this masterbatch with a base resin, the titanium(IV) oxide can be diluted to a predetermined concentration. In this case, the masterbatch that can be used is not particularly limited, but examples thereof include Polycool Master: EPH-W3380 (manufactured by Polycool Corporation).

[0036] From the viewpoint of suppressing decomposition of efinaconazole, the light transmittance in the ultraviolet region of the liquid container of the present invention is preferably 0.20% or less, and more preferably 0.10% or less, for all light wavelengths from 200 nm to 360 nm.

[0037] The lower limit of the amount of titanium(IV) oxide contained in the container of the present invention can be set so as to achieve the above-mentioned high light-blocking effect in the ultraviolet region. In one embodiment of the present invention, the lower limit of the content of titanium(IV) oxide contained in a polyethylene solution container having a thickness of 0.8 mm to 1.0 mm is preferably 0.09 parts by weight, more preferably 0.10 parts by weight, even more preferably 0.11 parts by weight, and even more preferably 0.18 parts by weight, per 100 parts by weight of synthetic resin. In this specification, 100 parts by weight of synthetic resin refers to the total weight of the materials forming the container of the present invention, such as the base resin and titanium(IV) oxide or masterbatch.

[0038] On the other hand, with regard to the light transmittance in the visible region of the liquid container according to one embodiment of the present invention, from the viewpoint of visibility of the remaining amount of liquid inside the container, the light transmittance at a wavelength of 700 nm is preferably 0.25% or more, more preferably 0.40% or more. In another embodiment of the present invention, with regard to the light transmittance in the visible region of the liquid container, the light transmittance at wavelengths of 700 nm to 780 nm is preferably 0.25% or more, more preferably 0.40% or more.

[0039] The upper limit of the amount of titanium(IV) oxide contained in the container of the present invention can be set so as to ensure the above-mentioned light transmittance in the visible region. In one embodiment of the present invention, the upper limit of the content of titanium(IV) oxide in a polyethylene solution container having a thickness of 0.8 mm to 1.0 mm is preferably 0.33 parts by weight, more preferably 0.30 parts by weight, even more preferably 0.27 parts by weight, and still more preferably 0.22 parts by weight, relative to 100 parts by weight of synthetic resin.

[0040] Therefore, one preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.20% or less for all wavelengths from 200 to 360 nm and a light transmittance of 0.25% or more for all wavelengths from 700 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.20% or less for all wavelengths from 200 to 360 nm and a light transmittance of 0.25% or more for all wavelengths from 700 to 780 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.10% or less for all wavelengths from 200 to 360 nm and a light transmittance of 0.25% or more for all wavelengths from 700 to 780 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.10% or less for all wavelengths from 200 to 360 nm and a light transmittance of 0.25% or more for all wavelengths from 700 to 780 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.20% or less for all wavelengths of 200 to 360 nm and a light transmittance of 0.40% or more for all wavelengths of 700 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.20% or less for all wavelengths of 200 to 360 nm and a light transmittance of 0.40% or more for all wavelengths of 700 to 780 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.10% or less for all wavelengths of 200 to 360 nm and a light transmittance of 0.40% or more for all wavelengths of 700 nm. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container having a light transmittance of 0.10% or less for all wavelengths of 200 to 360 nm and a light transmittance of 0.40% or more for all wavelengths of 700 to 780 nm.

[0041] One preferred embodiment of the liquid container of the present invention is a synthetic resin container containing 0.09 to 0.33 parts by weight of titanium(IV) oxide per 100 parts by weight of the synthetic resin. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container containing 0.10 to 0.30 parts by weight of titanium(IV) oxide per 100 parts by weight of the synthetic resin. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container containing 0.11 to 0.27 parts by weight of titanium(IV) oxide per 100 parts by weight of the synthetic resin. Another preferred embodiment of the liquid container of the present invention is a synthetic resin container containing 0.18 to 0.22 parts by weight of titanium(IV) oxide per 100 parts by weight of the synthetic resin.

[0042] The liquid container according to one embodiment of the present invention as described above is a container that solves two contradictory problems. That is, one embodiment of the present invention provides a liquid container that can suppress decomposition of efinaconazole due to ultraviolet light and that allows easy visual confirmation of the remaining amount of the content by precisely controlling the light transmittance for both ultraviolet and visible light.

[0043] In this specification, "light transmittance at a wavelength of X to Y nm" means light transmittance at any one wavelength selected from the entire range of wavelengths of X to Y nm. The light transmittance can be measured using, for example, a commercially available spectrophotometer (U-3310, manufactured by Hitachi, Ltd.). The "transmittance spectrum" is a continuous spectrum representing the light transmittance at any measured wavelength range.

[0044] The configuration of the brush member provided in the applicator of the present invention is not particularly limited as long as the effects of the present invention can be obtained, but a brush member having the configuration described with reference to Figure 2B is preferred.

[0045] Specifically, in one embodiment of the present invention, a preferred brush member is a columnar brush member made by bundling a plurality of synthetic fibers made of polyester. In another embodiment of the present invention, a preferred brush member is a columnar brush member made by bundling a plurality of synthetic fibers made of polyethylene or nylon. The synthetic fibers used in the present invention preferably have a fiber diameter in the range of 7 to 50 μm, and more preferably in the range of 10 to 30 μm.

[0046] The synthetic fibers used in the present invention may also be bonded with an adhesive. The density of the adhesive used to bond the synthetic fibers is preferably in the range of 0.15 to 0.65 (porosity 85% to 35%), more preferably 0.25 to 0.50 (porosity 75% to 50%). In this specification, density refers to the proportion of synthetic fibers and the adhesive bonding them per unit cross-sectional area, based on a cross-section of the brush member cut perpendicular to the fiber direction. If the density of the synthetic fibers is less than 0.15, the number of chemical flow paths (voids) is large, resulting in excessive liquid being discharged when the container is inverted to dispense the liquid. Furthermore, since the structural portion is small, it becomes difficult to maintain the strength of the columnar brush member body, making the brush member more susceptible to breakage. On the other hand, if the density of the synthetic fibers is greater than 0.65, the number of chemical flow paths (voids) is small, making it difficult for the chemical to penetrate and hindering smooth chemical application.

[0047] The preferred volume of the brush element depends on the volume of the liquid that penetrates and is held in the columnar brush element by capillary action, the viscosity of the liquid, etc. If the viscosity of the liquid used in the present invention is low, it is preferable to increase the volume of the columnar brush element. In one embodiment of the present invention, the preferred volume of the brush element is 400 to 600 mm ３ The range is.

[0048] The brush member described in the examples of the present invention below was obtained by molding polyethylene fibers with a fiber diameter of 18 μm and a fineness of 3.3 dtex into a columnar shape with a density of 0.42 (porosity of 58%). The volume of the columnar brush member used in this example was 490 mm ３ is.

[0049] In another embodiment of the present invention, the brush member may be a brush-shaped brush member formed by welding one end of a bundle of synthetic fibers.

[0050] In one embodiment of the present invention, the applicator may further include a bottomed tubular holder. The configuration of the bottomed tubular holder included in the applicator according to one embodiment of the present invention is not particularly limited as long as the effects of the present invention can be obtained, but a bottomed tubular holder having the configuration described with reference to Figure 2C is preferred.

[0051] The bottomed tubular holder is used to hold the brush member and securely connect it to the liquid container. The bottomed tubular holder is cylindrical and the brush member is inserted inside. In this case, the inner surface of the bottomed tubular holder and the outer surface of the brush member are in close contact with each other, with no gaps. Furthermore, the outer surface of the bottomed tubular holder fits tightly with the opening of the liquid container, with no gaps. This prevents liquid leakage.

[0052] The bottom of the bottomed tubular holder has a pore at its bottom, which functions as a flow path for the liquid from the liquid container to the brush member. In one embodiment of the present invention, when the applicator is held with the brush member side facing downwards, the liquid filled inside the liquid container penetrates into the bottomed tubular holder through the pore and reaches one end face of the brush member (the side held by the bottomed tubular holder). The liquid that reaches the end face of the brush member reaches the other end face of the brush member (the side that is applied to the nail) due to capillary action. This makes it possible to apply the liquid to the nail.

[0053] The amount of liquid medicine discharged can also be increased or decreased by the shape and size of the pores provided in the bottom of the bottomed tubular holder. The position, number, shape, and size of the pores can be appropriately set depending on the properties of the liquid medicine used, such as the viscosity. For example, in addition to a circle, shapes such as an ellipse, a polygon, or a parallelogram can be selected depending on the purpose and application. Furthermore, the size of the pores, based on a plane parallel to the bottom of the bottomed tubular holder, preferably has a maximum diameter in the range of 0.5 to 5 mm, more preferably 0.9 to 1.3 mm.

[0054] The applicator described in the Examples of this specification below includes a bottomed cylindrical holder having the above-described characteristics, and the hole is circular (1.1 mm in diameter) and located at the center of the bottom. Regarding the applicator of the present invention, "good usability" means that when a user ejects the liquid from the applicator, the liquid can be smoothly applied to the entire affected nail without excess or deficiency. For example, an applicator has a good usability if a single dose can be appropriately applied without being affected by the usage environment (e.g., temperature) and / or the user's grip strength.

[0055] <2> Liquid Preparation In the present invention, a "liquid preparation" refers to a preparation in which an active ingredient and additives are dissolved, emulsified, or suspended in a solvent. The liquid preparation container and applicator of the present invention are applicable to a liquid preparation containing efinaconazole as the active ingredient. The liquid preparation container and applicator of the present invention are used to treat onychomycosis by applying the efinaconazole solution to the entire affected nail once daily. One embodiment of a "liquid preparation containing efinaconazole" is a liquid preparation in which efinaconazole, and optionally one or more pharmaceutically acceptable additives, are added and dissolved in water, an organic solvent, or a mixed solvent of water and an organic solvent. In the present invention, the content of efinaconazole is 10% by weight of the total liquid preparation.

[0056] The liquid preparation filled in the container of the present invention may contain, if necessary, a pharmaceutically acceptable additive, which may be an antioxidant, preferably dibutylhydroxytoluene (BHT) and ethylenediaminetetraacetic acid (EDTA).

[0057] The solvent used in the liquid formulation filled in the container of the present invention can be water, an organic solvent, or a mixed solvent of water and an organic solvent. Usable organic solvents include ethanol, propylene glycol, glycerin, triacetin, isopropanol, isopropyl adipate, alkyl lactate, cyclomethicone, and mixed solvents comprising two or more of these organic solvents. The preferred solvent in the present invention is ethanol. Therefore, the preferred liquid formulation filled in the container of the present invention is an ethanol solution formulation in which the content of efinaconazole is 10% based on the total weight of the liquid.

[0058] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to the following examples.

[0059] <Manufacturing Example> Each liquid container was manufactured according to Table 1. Specifically, a predetermined amount of MB (masterbatch: Polycool Master, EPH-W-3380) was added to a base resin (Novatec (registered trademark) HD, HB332R), and after melt-kneading, each container was manufactured by blow molding. Each liquid container was rigid and inflexible. The thickness of the side wall of the container was measured as the container thickness. Each container was filled with a 10% solution of efinaconazole, and a bottomed cylindrical holder with a brush member inserted was attached, and the cap was tightened to manufacture each applicator. The 10% efinaconazole solution used was a solution consisting of 0.00025% by weight of disodium EDTA, 1.00% by weight of purified water, 0.10% by weight of anhydrous citric acid, 0.10% by weight of BHT, 10.00% by weight of C12-15 alkyl lactate, 12.00% by weight of diisopropyl adipate, 13.00% by weight of cyclomethicone, 10.00% by weight of efinaconazole, and an appropriate amount of 95% ethanol (amounts that totaled 100.00% by weight).

[0060] *1 MB (master batch): Polycool Master, EPH-W-3380 (manufactured by Polycol Corporation) *2 The light transmittance of the containers in the table from 200 nm to 360 nm is the maximum value at 360 nm.

[0061] <Test Example 1> <Photostability Test> A photostability test was conducted on each of the containers shown in Table 1, which were used in Comparative Examples 1 and 2 and Examples 1 to 3. These containers were variations in container thickness and titanium (IV) oxide content. Each container was filled with 4 mL of a 10% solution of efinaconazole, fitted with a bottomed cylindrical holder into which a brush element was inserted, and then capped. The samples were then placed sideways in a photostability tester and stored under the following conditions: The photostability tester used was a "Stability Tester for Photostability Testing" (LTL-200A-14WCD, manufactured by Nagano Science Co., Ltd.). Light source: D65 fluorescent lamp; Illuminance: 2000 lux; Temperature: 25°C ± 2°C; Humidity: 60% RH ± 5% RH. Samples were taken at the start of the test (before exposure to the D65 fluorescent lamp) and after approximately 1.2 million lux-hr (25 days) for quality evaluation. Impurities were analyzed by high-performance liquid chromatography. For the chromatogram of the sample solution, the peak areas were measured using the automatic integration method, and their amounts were calculated using the area percentage method. For each of three containers in Comparative Examples 1-2 and Examples 1-3, the largest peak among the unknown impurity peaks newly generated in the sample was identified, and its average amount was calculated. In the photostability test herein, if the largest value of the unknown impurity peaks newly generated upon irradiation with 1.2 million lux-hr was 0.20% or less, photostability was determined to be guaranteed, and the photostability column was marked with an A (rating A). On the other hand, if the largest value exceeded 0.20%, photostability was determined to be unguaranteed, and the photostability column was marked with a B (rating B). The results are shown in Table 2.

[0062] * RRT (relative retention time): Relative retention time to the retention time of efinaconazole

[0063] In Comparative Example 1, the maximum value of the unknown impurity peak newly generated upon irradiation at 1.2 million lux-hr was 0.28%, and the container did not meet the evaluation criteria for photostability in this test (Rating B). Comparative Example 2 and Examples 1 to 3 met the evaluation criteria for photostability (Rating A). Furthermore, in Examples 1 to 3, the total impurity amount upon irradiation at 1.2 million lux-hr was 0.08 to 0.15%. These results demonstrated that the containers of Examples 1 to 3 are containers capable of stably storing efinaconazole solution.

[0064] As is clear from Table 2, the light transmittance at wavelengths of 200 nm to 360 nm decreased with increasing titanium (IV) oxide content. Furthermore, the light transmittance at wavelengths of 200 nm to 360 nm decreased with increasing container thickness. Comparative Example 2, Example 1, Example 2, and Example 3 enabled stable storage of efinaconazole solutions. On the other hand, it was confirmed that Comparative Example 1 was unable to suppress the increase in efinaconazole-derived impurities. This demonstrates that the photostability of the efinaconazole solutions filled in each container depends on the light transmittance at wavelengths of 200 nm to 360 nm, and that efinaconazole solutions can be stably stored when the light transmittance at wavelengths of 200 nm to 360 nm is 0.20% or less.

[0065] These results confirm that light transmittance in the wavelength range of 200 nm to 360 nm is important for preventing the increase of impurities in efinaconazole liquid formulations due to light exposure, and that blocking light in this wavelength range can suppress the decomposition of efinaconazole. Here, Examples 4 and 5, which are not shown in Table 2, transmit almost no ultraviolet light, similar to Example 3 (Table 1). Example 4 is a container with the same container thickness as Examples 2 and 3, which meet the evaluation criteria for the photostability test, but with a higher titanium (IV) oxide content than Examples 2 and 3. Example 5 is a container with the same titanium (IV) oxide content as Examples 1 and 3, which meet the evaluation criteria for the photostability test, but with a thicker sidewall than Examples 1 and 3. Therefore, the containers of Examples 4 and 5 are considered to be more stable to light and meet the evaluation criteria for the photostability test in this specification (Rating A).

[0066] <Test Example 2> <Light Transmittance Test> The sidewall of each container of Comparative Examples 1 to 4 and Examples 1 to 5 was cut into a rectangular shape of approximately 1 cm x 2 cm using scissors. Each cut bottle piece was placed on the light-emitting side of a cell holder of a spectrophotometer, and the transmittance spectrum was measured at wavelengths of 200 to 800 nm. The measurement results and the results of an evaluation of whether the remaining amount of efinaconazole solution could be visually confirmed from outside the container when it was filled into the container are shown in Table 3.

[0067]

[0068] The nine types of containers used in the light transmittance test were shown in Table 3, with variations in container thickness and titanium (IV) oxide content. Table 3 also shows the light transmittance at a wavelength of 700 nm, the light transmittance at wavelengths of 700 nm to 780 nm, and whether the amount of liquid filled in each container was visible from the outside of the container. In Comparative Examples 2 to 4, it was difficult to visually observe the liquid inside, while in Comparative Example 1 and Examples 1 to 5, the liquid inside was visible. For each container, the transmittance spectrum for wavelengths of 700 nm to 780 nm rose steadily, with the light transmittance at a wavelength of 700 nm being the lowest within this range. The transmittance spectra for each container of Comparative Examples 1 to 4 and Examples 1 to 5 are shown in Figures 3 to 14. In Figures 3 to 14, the horizontal axis represents wavelength (nm) and the vertical axis represents light transmittance (%).

[0069] As is clear from Table 3, the light transmittance at wavelengths of 700 nm to 780 nm decreased with an increase in the titanium (IV) oxide content in the container. Furthermore, the light transmittance at wavelengths of 700 nm to 780 nm decreased with an increase in the thickness of the container. The visibility of the efinaconazole solution filled in each container from outside the container is related to the light transmittance at wavelengths of 700 nm to 780 nm. The contents of Comparative Example 1 and Examples 1, 2, 3, 4, and 5, which had a light transmittance at a wavelength of 700 nm of 0.25% or more, were visible. On the other hand, the contents of Comparative Examples 2, 3, and 4, which had a light transmittance at a wavelength of 700 nm of less than 0.25%, were not visible.

[0070] From the above results, it was confirmed that a container that allows the efinaconazole liquid to be visually recognized must have a light transmittance of at least 0.25% at a wavelength of 700 nm.

[0071] <Test Example 3> <Application test> 4 mL of a 10% solution of efinaconazole was filled into the containers of Comparative Example 2 and Example 3 shown in Table 1, and a bottomed cylindrical holder into which a brush member was inserted was attached, and the cap was then tightened to prepare a specimen. ２The solution was applied to the entire surface of each of five stainless steel pieces. The above method was repeated twice, and the solution was applied to the equivalent of 10 stainless steel pieces. After the solution was applied, the mass of the bottle after application was measured. Note that this procedure was performed assuming an application amount equivalent to 10 toenails. The application amount was calculated by subtracting the mass of the bottle after application from the mass of the bottle before application. When applying, the container was held as if gripping the entire container, and the inclination (angle) of the container during application was set to three angles relative to the application surface: 90°, 45°, and 10-20°. The test was performed five times for each container and application angle, and the average application amount and standard deviation were calculated. The results of this test are shown in Table 4 below.

[0072]

[0073] The amount of application was appropriate for all containers, and they functioned appropriately as applicators. Comparing the amounts of application in Comparative Example 2 and Example 3, Example 3 tended to have a smaller amount of application. Regarding the application angle, the amount of application tended to increase as the container became closer to vertical (90°≧45°≧10-20°).

[0074] Test Example 4 Discharge Test (Drop Time) and Usability Test Five containers were prepared for each of Comparative Example 2 and Example 3. Each container was filled with 4 mL of a 10% efinaconazole solution, and a bottomed cylindrical holder with a brush member inserted was attached to the container for testing. Each container was fixed in an inverted position using a silicone tube connected to a constant-temperature water bath, heated to 32°C, and the dripping of the solution was observed. The number of droplets was counted, and the time required for each drip was measured. In Comparative Example 2 and Example 3, the time required from the start of the test to the first drip was 22.4 seconds and 41.5 seconds, respectively. The time required from the first drip to the second drip was 2.6 seconds and 6.3 seconds, respectively. The number of droplets required for dripping to stop within one minute was 13 and 8, respectively. Thus, when comparing Comparative Example 2 (side wall thickness: 0.7 mm) with Example 3 (side wall thickness: 0.9 mm), the latter requires a longer time for dripping.

[0075] Next, a sensory evaluation of the feel in use was conducted by 80 panelists for Comparative Examples 2 and 4. As a result, it was evaluated that Comparative Example 4 did not dispense too much liquid and allowed for smoother application of the liquid. Here, the content of titanium (IV) oxide in the container material does not affect the feel in use, so Examples 2 to 4, which have the same sidewall thickness as Comparative Example 4, are considered to have a favorable feel in use equivalent to that of Comparative Example 4.

[0076] As described above, Examples 1 to 5 are preferable because they can stably fill a 10% solution of efinaconazole and the content amount can be visually confirmed. In particular, Examples 2 to 4 are considered more preferable from the viewpoint of usability.

[0077] The container of the present invention is useful as a container for filling a liquid preparation of efinaconazole, because it blocks light of a wavelength that promotes the photodecomposition of efinaconazole while maintaining a pleasant feel when used, and makes it possible to visually check the remaining amount of the liquid preparation filled inside the container from outside the container.

[0078] S Filling space 1 Liquid container 2 Bottomed cylindrical holder 3 Columnar brush member 4 Cap 11 Liquid container body 11a Side wall 11b Bottom wall 12 Liquid container neck 14 Opening 15 Thread 21 Bottomed cylindrical holder body 22 Annular flange 23 Bottom 24 Spherical hole 31 Columnar brush member body 32 Columnar brush member neck 33 Columnar brush member tip 35 Support member 100 Applicator

Claims

1. A liquid container capable of being filled with a liquid containing 10% efinaconazole, said liquid container being made of a synthetic resin containing titanium (IV) oxide, said liquid container having a light transmittance of 0.20% or less for all wavelengths between 200 and 360 nm and a light transmittance of 0.25% or more for a wavelength of 700 nm, and allowing the content of the liquid filled in said liquid container to be visually confirmed from the outside.

2. The liquid container according to claim 1, characterized in that the liquid container is a generally cylindrical polyethylene container having an opening at the top, the container is a single-layer container in which at least titanium (IV) oxide is homogeneously dispersed in polyethylene, and the container is a non-flexible, hard container.

3. The liquid container according to claim 1 or 2, wherein the liquid container has an internal volume of 8 to 12 mL and a side wall of the liquid container has a thickness of 0.8 to 1.0 mm.

4. A liquid container according to any one of claims 1 to 3, characterized in that it contains 0.09 to 0.33 parts by weight of titanium (IV) oxide per 100 parts by weight of the synthetic resin.

5. A container according to any one of claims 1 to 4, which contains 0.10 to 0.30 parts by weight of titanium (IV) oxide per 100 parts by weight of the synthetic resin.

6. A liquid container according to any one of claims 1 to 5, characterized in that it contains 0.18 to 0.22 parts by weight of titanium (IV) oxide per 100 parts by weight of the synthetic resin.

7. A liquid container as described in any one of claims 1 to 6, characterized in that it does not contain any coloring component other than titanium (IV) oxide.

8. A liquid container according to any one of claims 1 to 7, wherein the liquid container has a light transmittance of 0.25% or more for all wavelengths of 700 to 780 nm.

9. A liquid container according to any one of claims 1 to 8, wherein the liquid container has a light transmittance of 0.40% or more for all wavelengths of 700 to 780 nm.

10. A liquid container according to any one of claims 1 to 9, wherein the liquid container has a light transmittance of 0.10% or less for all wavelengths of 200 to 360 nm.

11. The liquid container according to any one of claims 1 to 10, which is not wrapped in an ultraviolet absorbing film.

12. An applicator comprising: a liquid container as described in any one of claims 1 to 11; a columnar brush member formed by bundling synthetic fibers into a columnar shape; and a bottomed tubular holder having a tubular body and a bottom between the liquid container and the columnar brush member, wherein the bottomed tubular holder is liquid-tightly fitted to an opening of the liquid container, the bottom of the bottomed tubular holder has at least one pore, the columnar brush member is inserted inside the tubular body of the bottomed tubular holder, and the liquid can pass from the liquid container to the columnar brush member through the pore, so that when the container is inverted during use, the liquid permeates into the columnar brush member, allowing the liquid to be applied to a user's nails.

13. The applicator according to claim 12, wherein the columnar brush member is formed by bundling synthetic fibers having a fiber diameter in the range of 7 to 50 μm at a density in the range of 0.25 to 0.50, and the bottomed tubular holder has one circular pore having a diameter of 0.9 to 1.3 mm.

14. The applicator according to claim 12 or 13, characterized in that when the applicator filled with 4 mL of the liquid is inverted in an environment of 32°C, the number of drops required for the liquid to stop dripping in one minute is 7 to 10 drops.

15. A method for photostabilizing efinaconazole, comprising the step of filling a liquid containing 10% efinaconazole into a liquid container according to any one of claims 1 to 11 or an applicator according to any one of claims 12 to 14.

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