JP2022176219A - External preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a preparation which is presented in a crooked-neck container filled with an external agent containing menthol, an alcohol having 1 to 4 carbon atoms, and water, and in which precipitation of menthol on the underside of the neck is suppressed.

SOLUTION: Provided is an external preparation, comprising (a) an external agent and (b) a container containing the external agent (a). The external agent (a) contains loxoprofen and/or a pharmaceutically acceptable salt thereof, menthol, an alcohol having 1 to 4 carbon atoms, and water. The container (b) comprises a body portion and a neck portion with a mouth, the neck portion being inclined with respect to the longitudinal central axis of the body portion.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention relates to topical preparations.

BACKGROUND ART Conventionally, external preparations containing menthol as a cooling component have been used as external preparations applied to stiff shoulders and the like (Patent Document 1).

JP 2011-074032 A

The inventor of the present invention has proposed a container consisting of a body and a neck having a mouth, the neck being inclined with respect to the longitudinal center axis of the body, wherein the body contains an external preparation during storage, and when used. A container (in the present specification, may be referred to as a "neck bent container") that can be tilted to discharge the external preparation from the mouth and apply it to the affected area, is blended with menthol as an active ingredient, and these are mixed with a lower alcohol. I came up with the idea of filling and using an external preparation mixed with a solvent containing water and water.

However, the present inventors have found a problem that menthol precipitates on the underside of the neck when the external preparation thus obtained is stored after being used as described above. The present invention provides a preparation in which an external preparation containing menthol, an alcohol having 1 to 4 carbon atoms, and water is packed in a bent-neck container, and in which precipitation of menthol on the underside of the neck is suppressed. The task is to

In order to solve the above problems, the inventors conducted intensive studies and found that menthol, carbon number 1
In a composition containing an alcohol of ~4 and water, by filling an external preparation obtained by containing loxoprofen in a container with a bent neck, even if it is stored after use, precipitation of menthol on the lower side of the neck was found to be suppressed. The present invention was completed by further studies based on such findings, and includes the following aspects.

Section 1.
(a) a topical preparation, and (b) a topical preparation comprising a container containing the topical preparation (a),
The topical agent (a) is:
at least one selected from the group consisting of loxoprofen and/or a pharmaceutically acceptable salt thereof;
menthol;
an alcohol having 1 to 4 carbon atoms; and an external preparation containing water,
A preparation for external use, wherein the container (b) comprises a body and a neck provided with a mouth, wherein the neck is tilted with respect to the longitudinal central axis of the body.
Section 2.
Item 2. The external preparation according to Item 1, wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
Item 3.
Item 3. The topical preparation according to Item 1 or 2, wherein the topical preparation further contains a polyhydric alcohol.
Section 4.
Item 4. The external preparation according to any one of Items 1 to 3, wherein the container is made of polyethylene or polypropylene.
Item 5.
Item 5. The topical preparation according to any one of Items 1 to 4, wherein the length of the underside of the neck is 0.5 to 10 cm.

According to the present invention, an external preparation containing menthol, an alcohol having 1 to 4 carbon atoms, and water is an external preparation filled in a container with a curved neck, and precipitation of menthol on the lower side of the neck is suppressed. A topical formulation can be provided.

It is a schematic diagram of the neck bending container used by this invention. 1 is a schematic diagram of the external preparation of the present invention during storage. FIG. 1 is a schematic diagram of the external preparation of the present invention in use. FIG. 4 is a photograph showing evaluation results of Comparative Example 1 and Examples 1 and 2. FIG. 4 is a photograph showing evaluation results of Comparative Example 2 and Example 3. FIG.

1. External preparation and its preparation method
The topical agent used in the present invention is:
at least one selected from the group consisting of loxoprofen and/or a pharmaceutically acceptable salt thereof;
menthol;
It contains an alcohol with 1 to 4 carbon atoms; and water.

1.1. Loxoprofen and its pharmaceutically acceptable salts (loxoprofens)
By containing loxoprofens, the external preparation used in the present invention is one in which precipitation of menthol at the neck of the curved container is suppressed.

Loxoprofen (2-[4-(2-oxocyclopentylmethyl)phenyl]propionic acid) is a propionic acid-based non-steroidal antipyretic analgesic anti-inflammatory drug (NSAID) having antipyretic, analgesic and antiphlogistic effects.

In the present invention, in addition to loxoprofen itself, a pharmaceutically acceptable salt thereof can also be used. Such salts also include solvates of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol, or the like. These are known compounds and can be produced by known methods, and commercially available ones can also be used.

In the present invention, loxoprofen sodium hydrate is preferred as loxoprofens.

The topical agent used in the present invention may contain one type of loxoprofen alone, or may contain a combination of a plurality of types.

The content of loxoprofens is not particularly limited, and can be appropriately set in consideration of the effects of the present invention and antipyretic, analgesic and anti-inflammatory actions. The total content of loxoprofens can be, for example, 0.1 to 20% by mass in terms of loxoprofen sodium anhydride based on the total amount of the external preparation used in the present invention. When the total content of loxoprofens is 0.1% by mass or more in terms of loxoprofen sodium anhydride relative to the total amount of the external preparation, sufficient antipyretic, analgesic and anti-inflammatory effects can be obtained. From this point of view, the total content of loxoprofens relative to the entire external preparation is 0.2 in terms of loxoprofen sodium anhydride.
It is preferably at least 0.5% by mass, more preferably at least 0.5% by mass, and even more preferably at least 1% by mass. In addition, from the viewpoint of the minimum amount that provides sufficient antipyretic, analgesic, and antiphlogistic effects, the total content of loxoprofens in the external preparation used in the present invention is preferably 15 mass in terms of loxoprofen sodium anhydride. % or less, more preferably 10 mass % or less, and even more preferably 5 mass % or less.

1.2. menthol
The topical preparation used in the present invention has a refreshing feeling due to the menthol contained therein.

The menthol contained in the topical preparation used in the present invention is not particularly limited, and may be any of l-menthol, d-menthol and dl-menthol, or one or more of these.

The content of menthol is not particularly limited and can be appropriately set in consideration of the effect of the present invention that precipitation at the neck is suppressed and the efficacy as a cooling agent. The total content of menthol can be, for example, 0.1 to 20% by mass with respect to the total external preparation used in the present invention. From the viewpoint of the effect of suppressing cloudiness, the total content of menthol is preferably 1% by mass or more, more preferably 2% by mass or more, based on the total amount of the external preparation. In addition, from the viewpoint of the minimum amount that provides a sufficient cooling effect, the total content of menthol is preferably 10% by mass or less, more preferably 6% by mass or less, and still more preferably 3% by mass, based on the total amount of the external preparation. % or less.

1.3. Alcohols with 1 to 4 carbon atoms (lower alcohols)
The topical preparation used in the present invention contains a lower alcohol. There are no particular restrictions on the lower alcohol, and a wide range of lower alcohols can be used as long as they function as effective bases for the above components.

Specific examples of lower alcohols include methanol, ethanol, propyl alcohol and isopropyl alcohol, with ethanol being preferred.

The topical preparation preferably contains 40 to 90% by mass of lower alcohol relative to the total topical preparation. Specifically, when the external preparation contains ethanol as a lower alcohol, the ethanol content is preferably 50% by mass or more, more preferably 50 to 90% by mass, and still more preferably 6% by mass.
0 to 90% by weight, more preferably 65 to 80% by weight. In addition, when the external preparation contains isopropanol as a lower alcohol, the isopropanol content is preferably 40% by mass or more, more preferably 40 to 90% by mass, even more preferably 50 to 90% by mass, and still more preferably 50 to 80% by mass. %include.

1.4. Polyhydric alcohol
The topical preparation used in the present invention may further contain a polyhydric alcohol.

Glycols and the like can be used as the polyhydric alcohol. Glycols are not particularly limited and include, for example, glycerin, propylene glycol, 1,3-butylene glycol, octanediol, ethylene glycol, polyethylene glycol, D-sorbitol and the like. Glycerin, propylene glycol and 1,3-butylene glycol are preferred.

A polyhydric alcohol may be used individually by 1 type, and may be used in combination of multiple types.

The external preparation contains a polyhydric alcohol in a total amount of the total external preparation, preferably 1 to 30% by mass.
, more preferably 2 to 20% by mass, more preferably 3 to 15% by mass.

1.5. Other ingredients
In addition to the above ingredients, blood circulation-promoting ingredients can also be added to external preparations as long as they do not interfere with the effects of the present invention.

Examples of blood circulation-promoting components include capsaicinoids and the like.

As a capsaicinoid, N-acylvanillylamide can be used.

The acyl group in the N-acylvanillylamide may be linear or branched. The number of carbon atoms in the acyl group in the N-acylvanillylamide is not particularly limited, and can be, for example, 5-15, preferably 6-11.

Specific examples of N-acylvanillylamides include nonanoic acid vanillylamide and capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin.

In the present invention, the capsaicinoid may be a purified product, or a mixture containing other components in addition to the capsaicinoid may be used. Specific examples of mixtures containing such capsaicinoids include capsicums such as capsicum extracts, capsicum tinctures and capsicum powders.

The capsicum extract is not particularly limited and can be widely used. As the capsicum extract, a capsicum extract of a single type may be used, or a plurality of capsicum extracts may be used in combination. For example, a capsicum alcohol extract can be used as the capsicum extract. As the alcohol extract of capsicum, for example, an ethanol extract of capsicum can be used.

In the present invention, as the capsaicinoid, one type of capsaicinoid may be used alone, or two or more types may be used in combination.

Among the capsaicinoids, capsicum extract and/or nonanoic acid vanillylamide are preferable from the viewpoint that the effect of suppressing cloudiness in the composition is more likely to be obtained.

Still other blood circulation-promoting ingredients include, for example, ester derivatives of nicotinic acid.

The ester derivative of nicotinic acid is not particularly limited as long as it is pharmaceutically acceptable, and can be widely used. Examples include benzyl nicotinic acid, β-butoxyethyl nicotinic acid and methyl nicotinic acid. These nicotinic acid ester derivatives may be used singly or in combination of two or more. Among the ester derivatives of nicotinic acid,
Nicotinic acid benzyl ester is preferred.

Still other blood circulation-promoting ingredients include, for example, tocopherols and the like.

Tocopherols are not particularly limited and can be widely used including derivatives. The type of tocopherol itself may be α-tocopherol, β-tocopherol, γ-tocopherol or δ-tocopherol, but α-tocopherol is preferred.

Derivatives of tocopherol are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include esters with carboxylic acids such as acetic acid, nicotinic acid and succinic acid, and diesters with phosphoric acid. Among these tocopherol derivatives, esters with carboxylic acids are preferred, and tocopherol acetate (tocopherol acetate) is more preferred.

The external preparation may contain one type of tocopherol alone, or may contain a combination of multiple types.

In addition to the above ingredients, the external preparation may contain a cooling agent as long as it does not interfere with the effects of the present invention.

Such cooling agents include d-camphor, dl-camphor, d-borneol, dl-
borneol, menthane, menthyl lactate, geraniol, eucalyptus oil, terpene oil, bergamot oil, fennel oil, mint oil (peppermint), rose oil and cool mint. These cooling agents may be used singly or in any combination of two or more.

The cooling agent contained in the external preparation is preferably d-borneol, dl-borneol,
Menthane, peppermint oil (peppermint) and cool mint.

In addition to the above components, the external preparation may also contain a pharmacologically effective adjuvant as long as it does not interfere with the effects of the present invention.

Examples of such pharmacological adjuvants include anti-inflammatory agents and skin protective agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and its pharmaceutically acceptable salts; antihistamines such as lamin; crude drugs such as arnica tincture, Phellodendron bark extract, Japanese garden extract, Horse chestnut extract, Rohto extract, Belladonna extract, Angelica keiskei extract, Chikon extract, Sansho extract.

In addition to the above-mentioned ingredients, external preparations may contain additives such as active ingredients, pH adjusters, preservatives, preservatives, antioxidants, stabilizers, etc., which are commonly used in external preparations. be able to.

1.6. Form and manufacturing method
Although the form of the external preparation is not particularly limited, it is preferably a liquid preparation (including lotions and emulsions).

An external preparation can be prepared according to a conventional method according to such formulation form. For example, loxoprofens, menthol, and optionally other ingredients are dissolved or dispersed by mixing with a general-purpose base, such as those described below, containing lower alcohols and water, and adjusted to the desired pH.
can be mentioned.

The pH is not limited as long as it does not adversely affect the skin, and is usually pH 3.5 to 8.
. 5, preferably pH 4-8, more preferably pH 4-7.5.

For example, when preparing an external preparation as a liquid preparation, loxoprofens, menthol,
Furthermore, it can be prepared by mixing other components, if necessary, with a base containing a lower alcohol and water as main components. The base may contain at least one selected from polyhydric alcohols, water and emulsifiers. As the polyhydric alcohol, those mentioned above can be used.

The emulsifier is not particularly limited, and examples thereof include nonionic surfactants such as sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyl stearate, and lauromacrogol. Emulsifiers may be used alone or in combination of multiple types.

The external preparation is preferably prepared as an external preparation in the form of a coating, and can be topically administered topically.

The dosage of the topical preparation depends on the severity of the symptoms to be treated, but it should be such that the total applied dosage of loxoprofen, which is the active ingredient contained therein, is 100 mg or less per day. desirable.

The external preparation is preferably a pharmaceutical. The medicine for external use, which is the medicine of the present invention, is an external anti-inflammatory analgesic that can be used as an anti-inflammatory analgesic for external use. It can be suitably used for the purpose of analgesia for pain such as pain, sprain pain, bone fracture pain, and neuralgia.

2. bent-neck container
In the present invention, the external preparation (external preparation-applied product) can be obtained by filling the above-mentioned external preparation in a container with a curved neck. The bent-neck container used in the present invention is a container comprising a body and a neck provided with a mouth, wherein the neck is inclined with respect to the longitudinal central axis of the body. Specifically, the curved neck container used in the present invention accommodates the external preparation in the body during storage (Fig. 2), and tilts the container during use to discharge the external preparation from the mouth. It is a curved neck container used for application to the affected area (Fig. 3).

The inclination angle of the neck with respect to the longitudinal center axis of the trunk is preferably 30 to 90°, more preferably 40 to 90°, even more preferably 50 to 90°, even more preferably 55 to 90.
°. In general, as the angle approaches 90°, the external preparation remaining on the neck immediately after use becomes less likely to return to the body during subsequent storage, making menthol more likely to precipitate. The angle of inclination of the neck refers to the angle formed by the longitudinal center axis of the trunk and the longitudinal center axis of the neck (Fig. 1).

The material of the bendable container is not particularly limited and can be selected from a wide range. Polyethylene or polypropylene is preferable as the material of the bendable container.

If the length of the lower part of the neck is longer, the external preparation remaining in the neck immediately after use will not easily return to the body during subsequent storage, and menthol will precipitate more easily (Fig. 1). In the preparation for external use of the present invention, precipitation of menthol is suppressed by making the preparation for external use a specific composition. Even if there is, precipitation of menthol is suppressed. The length of the underside of the neck is typically 10 cm or less.

The mouth is not particularly limited, but for example, sponge (sponge head) or roll-on (
The external preparation can be applied to the affected area by a mechanism such as a roll-on head.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In the table, the unit represents % by mass.

<Test Example 1>
As shown in Table 1 (unit: % by mass), a liquid composition was prepared by weighing and dissolving each component by stirring.

Drop 10 μL of each liquid composition onto a polypropylene resin sheet with a pipetman,
A follow-up was performed. Two minutes after dropping, the case where white turbidity was observed was indicated by "x", and the case where no white turbidity was observed was indicated by "◯" in Table 1. The follow-up results for Comparative Examples 1 and 2 and Examples 1-3 are shown in FIGS.

In Comparative Example 1, white turbidity due to precipitation was immediately observed, and in Example, the white turbidity was suppressed.
Similar results were also obtained on a polyethylene resin sheet. In addition, when the wettability on the polypropylene resin sheet was visually observed, Comparative Examples 1 and 2 containing l-menthol and Examples 1 to 3 were all higher than the reference examples not containing l-menthol. rice field.

<Test Example 2>
The external preparations prepared in Examples 1 and 2 were placed in a container with the brand name "Ammerts Yokoyoko" (manufactured by Kobayashi Pharmaceutical Co., Ltd., 2017) in which the angle of inclination of the neck with respect to the longitudinal central axis of the body was about 60°. 25 as illustrated in FIG.
℃ for 5 days. No white turbidity was observed after standing.

1: Curved neck container 11: Body 12: Neck 13: Mouth 14: Vertical center axis of body 15: Vertical center axis of neck 16: Lower length of neck 2: External preparation

Claims (5)

(a) a topical preparation, and (b) a topical preparation comprising a container containing the topical preparation (a),
The topical agent (a) is:
at least one selected from the group consisting of loxoprofen and/or a pharmaceutically acceptable salt thereof;
menthol;
An external preparation containing at least one alcohol selected from the group consisting of methanol, ethanol, propyl alcohol and isopropyl alcohol; can be,
A preparation for external use, wherein the container (b) comprises a body and a neck provided with a mouth, wherein the neck is tilted with respect to the longitudinal central axis of the body. 2. The external preparation according to claim 1, wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate. The external preparation according to claim 1 or 2, wherein the external preparation further contains a polyhydric alcohol. The external preparation according to any one of claims 1 to 3, wherein the container is made of polyethylene or polypropylene. The external preparation according to any one of claims 1 to 4, wherein the length of the underside of the neck is 0.5 to 10 cm.

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