JP7206043B2 - external composition - Google Patents

Description

The present invention relates to topical compositions.

Loxoprofen and its pharmaceutically acceptable salts (hereinafter collectively referred to as "loxoprofens"), which are propionate non-steroidal antipyretic analgesic anti-inflammatory drugs (NSAIDs), are other Similar to NSAIDs, it has antipyretic, analgesic and anti-inflammatory effects based on the inhibitory action of prostaglandin biosynthesis.

Various external preparations containing loxoprofens as active ingredients for antipyretic, analgesic and/or anti-inflammatory actions have been developed. It has also been proposed to add tocopherols (for example, tocopherol acetate) and the like to these external preparations (Patent Document 1).

JP 2015-98469 A

The present inventors have found a problem that white turbidity occurs when loxoprofens and tocopherols are blended as active ingredients in an external composition and then mixed with a solvent containing a lower alcohol and water. An object of the present invention is to provide a composition for external use containing loxoprofens, tocopherols, an alcohol having 1 to 4 carbon atoms, and water, wherein white turbidity is suppressed.

In order to solve the above-mentioned problems, the present inventors conducted extensive studies and found that the addition of menthol to a composition containing loxoprofens, tocopherols, alcohols having 1 to 4 carbon atoms, and water causes white turbidity. found to be suppressed. The present invention was completed by further studies based on such findings, and includes the following aspects.

(I) External composition
(I-1)
menthol,
loxoprofen and/or a pharmaceutically acceptable salt thereof;
tocopherols,
A composition for external use comprising an alcohol having 1 to 4 carbon atoms and water.
(I-2)
The external composition according to (I-1), wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
(I-3)
The composition for external use according to (I-1) or (I-2), wherein the tocopherol is tocopherol acetate.
(I-4)
The composition for external use according to any one of (I-1) to (I-3), which is used for pain relief.
(I-5)
The composition for external use according to any one of (I-1) to (I-4), which is a liquid formulation.

(II) Method for Suppressing White Turbidity in Compositions Containing Loxoprofens, Tocopherols, C1-C4 Alcohols and Water
(II-1)
A method for suppressing white turbidity in a composition containing loxoprofens, tocopherols, an alcohol having 1 to 4 carbon atoms and water, comprising:
A method comprising the step of including menthol in said composition.
(II-2)
The method according to (II-1), wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
(II-3)
The method according to (II-1) or (II-2), wherein the tocopherol is tocopherol acetate.
(II-4)
The method according to any one of (II-1) to (II-3), wherein the composition is a liquid formulation.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an external composition containing loxoprofens, tocopherols, an alcohol having 1 to 4 carbon atoms, and water, in which white turbidity is suppressed.

1. External composition and preparation method thereof
The composition for external use of the present invention is
menthol,
loxoprofen and/or its pharmaceutically acceptable salts (loxoprofens),
tocopherols,
It contains alcohol with 1 to 4 carbon atoms and water.

1.1. menthol
By containing menthol, the composition for external use of the present invention is suppressed in white turbidity. In addition, menthol can impart a cooling sensation to the composition for external use.

The menthol contained in the topical composition of 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 of suppressing cloudiness 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 entire topical composition of 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, relative to the entire topical composition of the present invention. 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 8% by mass or less, and more preferably 8% by mass or less, based on the total amount of the external composition of the present invention. Preferably, it is 5% by mass or less.

In addition, the ratio of menthol can also be set in consideration of the ratio to the total of loxoprofens and tocopherols contained in the composition for external use. Specifically, the ratio of menthol is usually set to be in the range of 0.01 to 15 parts by mass, preferably 0, per 1 part by mass of loxoprofens and tocopherols in total contained in the composition for external use. .1 to 10 parts by weight, more preferably 0.5 to 8 parts by weight, and even more preferably 1 to 5 parts by weight.

1.2. Loxoprofen and its pharmaceutically acceptable salts (loxoprofens)
The external composition of the present invention contains loxoprofen and/or a pharmaceutically acceptable salt thereof.

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 composition for external use of 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 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 composition for external use of the present invention. Sufficient antipyretic, analgesic and anti-inflammatory actions can be obtained when the total content of loxoprofens in the entire composition is 0.1% by mass or more in terms of loxoprofen sodium anhydride. From this point of view, the total content of loxoprofens in the entire composition is preferably 0.2% by mass or more, more preferably 0.5% by mass or more, in terms of loxoprofen sodium anhydride. , more preferably 1% by mass or more. In addition, from the viewpoint of the minimum amount that provides sufficient antipyretic, analgesic and anti-inflammatory effects, the total content of loxoprofens in the external composition of 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.

1.3. Tocopherols
The composition for external use of the present invention contains a tocopherol as a blood circulation-promoting ingredient.

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 composition for external use of the present invention may contain one type of tocopherols alone, or may contain a combination of two or more types of tocopherols.

The content of tocopherols in the present invention is not particularly limited, and can be appropriately set in consideration of the effect of the present invention and the effect of promoting blood circulation. The total content of tocopherols can be, for example, 0.01 to 1.0% by mass with respect to the entire topical composition of the present invention. When the total amount of tocopherols contained in the composition is 0.01% by mass or more, a sufficient effect of promoting blood circulation can be obtained. From this point of view, the total amount of tocopherols contained in the composition is preferably 0.05% by mass or more. Further, when the total content of tocopherols is 0.8% by mass or less with respect to the entire composition, white turbidity is remarkably suppressed. From this point of view, the total amount of tocopherols contained in the composition is preferably 0.5% by mass or less.

1.4. Alcohols with 1 to 4 carbon atoms (lower alcohols)
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 composition for external use of the present invention preferably contains 40 to 90% by mass of lower alcohol relative to the total composition. Specifically, when the composition for external use of the present invention contains ethanol as a lower alcohol, ethanol is preferably 50% by mass or more, more preferably 50 to 90% by mass, still more preferably 60 to 90% by mass, and More preferably 65 to 80% by mass. In addition, when the composition for external use of the present invention 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 even more preferably Contains 50 to 80% by mass.

1.5. Other ingredients
In addition to the above ingredients, the composition for external use of the present invention may contain other blood circulation-promoting ingredients as long as they do not interfere with the effects of the present invention.

Another blood circulation-promoting ingredient includes, for example, capsaicinoid.

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 nicotinic acid ester derivatives, nicotinic acid benzyl ester is preferred.

In addition to the above components, the composition for external use of the present invention 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 agents contained in the topical composition of the present invention are preferably d-borneol, dl-borneol, menthane, peppermint oil and cool mint.

In addition to the above components, the external composition of the present invention may also contain a pharmacological 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 components, the composition for external use of the present invention contains active ingredients, pH adjusters, antiseptics, preservatives, antioxidants, stabilizers, and other additives commonly used in external compositions. Agents can be blended as appropriate.

1.6. Form and manufacturing method
Although the form of the composition for external use of the present invention is not particularly limited, it is preferably a liquid formulation (including lotions, spray formulations, aerosol formulations, and emulsion formulations).

The composition for external use of the present invention can be prepared according to a conventional method according to such formulation form. For example, loxoprofens and tocopherols, and optionally other ingredients, are mixed with a general-purpose base used for topical preparations as described below, containing a lower alcohol and water, and then dissolved or dispersed as desired. can be exemplified.

The pH is not limited as long as it does not adversely affect the skin, and is usually adjusted to pH 3.5 to 8.5, preferably pH 4 to 8, more preferably pH 4 to 7.5.

For example, when the composition for external use of the present invention is prepared as a liquid formulation, loxoprofens, tocopherols, and optionally other ingredients are mixed with a base containing a lower alcohol and water as main ingredients. can be prepared by The base may contain at least one selected from glycols, water and emulsifiers.

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. Glycols may be used singly or in combination.

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 composition for external use of the present invention is preferably prepared as an external preparation in the form of a coating, and can be topically administered.

The dosage of the composition for external use of the present invention depends on the severity of the symptoms to be treated, but the total applied dosage of loxoprofens and tocopherols as active ingredients contained therein is 100 mg or less per day. It is desirable that the amount is

The topical composition of the present invention is preferably a pharmaceutical composition. The topical composition, which is the pharmaceutical composition of the present invention, can be used as an external anti-inflammatory analgesic for shoulder pain associated with stiff shoulders, joint pain, lumbago, muscle pain, tenosynovitis (hand/wrist pain), elbow pain (tennis elbow, etc.). ), bruise pain, sprain pain, bone fracture pain, neuralgia, etc., for the purpose of analgesic use.

2. Method for suppressing cloudiness in composition containing loxoprofens, tocopherols, alcohol having 1 to 4 carbon atoms and water
The method of the present invention is a method for suppressing white turbidity in a composition containing loxoprofens, tocopherols, alcohols having 1 to 4 carbon atoms and water,
A method comprising the step of including menthol in the composition.

Menthol, loxoprofens, tocopherols and other components to be blended in such compositions are described in 1. above. of the composition for external use of the present invention.

The step of including menthol in the composition is not particularly limited. can be performed by mixing each component as described in the topical composition of the present invention. The order of mixing the components is not particularly limited.

In the step of including menthol in the composition, the starting composition preferably contains less than 0.5% by mass, preferably less than 0.3% by mass, more preferably less than 0.1% by mass of menthol, More preferably less than 0.05 wt%, even more preferably less than 0.01 wt%, most preferably less than 0.001 wt%.

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 the mass (g) per 100 g of the composition (that is mass %).

As described in Table 1 (unit: % by mass), liquid compositions were prepared by weighing each component and dissolving them by stirring (Reference Example 1, Comparative Example 1 and Examples 1 to 4). .

Each of the obtained compositions was placed in a glass bottle (M-225, manufactured by Kashiwa Glass Co., Ltd.), and the presence or absence of cloudiness was observed. The white turbidity was evaluated in two stages of "yes" and "no".

As shown in Table 1, when tocopherol acetate was dissolved in a mixed solvent of ethanol and water, it did not become cloudy, but when loxoprofen sodium hydrate was dissolved therein, it was found to be cloudy (Comparative Example 1). However, it was found that dissolving 1-menthol in addition to loxoprofen sodium hydrate and tocopherol acetate eliminated the cloudiness (Examples 1 to 4).

Claims (5)

menthol,
loxoprofen and/or a pharmaceutically acceptable salt thereof;
at least one tocopherol selected from the group consisting of tocopherol, an ester of carboxylic acid and tocopherol, and a diester of phosphoric acid and tocopherol ;
A composition for external use containing ethanol and water,
A composition for external use containing 60 to 90% by mass of the ethanol with respect to the entire composition for external use. 2. The topical composition according to claim 1, wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate. 3. The composition for external use according to claim 1 or 2, wherein the tocopherol is tocopherol acetate. The composition for external use according to any one of claims 1 to 3, which is used for pain relief. The composition for external use according to any one of claims 1 to 4, which is a liquid formulation.