JP2018104369A - External composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition containing an ester derivative of nicotinic acid as an active ingredient, which suppresses redness after application to the skin. A composition containing an ester derivative of nicotinic acid and loxoprofen or a pharmaceutically acceptable salt thereof, wherein the ester derivative of nicotinic acid is 0.005 to 0 with respect to the entire composition. .External composition containing 1% by mass. [Selection diagram] None

Description

  The present invention relates to an external composition.

  Ester derivatives of nicotinic acid such as nicotinic acid benzyl ester have the effect of dilating peripheral blood vessels when applied to the skin, and as warming components in blood circulation promoters or external preparations for analgesia and / or anti-inflammatory, etc. (Patent Document 1).

JP 2011-74032 A

  The present inventor has found that an ester derivative of nicotinic acid has a problem that redness occurs in the skin when applied to the skin. This invention makes it a subject to provide the composition for external use which uses the ester derivative of nicotinic acid as an active ingredient in which the redness after application | coating of this skin was suppressed.

  The present inventor conducted intensive studies to solve the above problems, and the content ratio of the ester derivative of nicotinic acid was within a specific range of 0.005 to 0.1% by mass with respect to the entire composition. Loxoprofen and pharmaceutically acceptable salts thereof, which are adjusted and propionic acid-based nonsteroidal antipyretic analgesic / anti-inflammatory agents (NSAIDs) (in the present specification, these may be collectively referred to as “loxoprofen”). ) Was mixed with an ester derivative of nicotinic acid to find that redness after application to the skin was suppressed. The present invention has been completed by further studies based on such findings, and includes the following aspects.

Item 1. A composition comprising an ester derivative of nicotinic acid and loxoprofen or a pharmaceutically acceptable salt thereof, wherein the ester derivative of nicotinic acid is added in an amount of 0.005 to 0.1% by mass based on the entire composition. An external composition to contain.
Item 2. Item 2. The composition for external use according to Item 1, wherein the ester derivative of nicotinic acid is benzyl nicotinate.
Item 3. Furthermore, the external composition of claim | item 1 or 2 containing a C1-C4 alcohol.
Item 4. Item 4. The composition for external use according to any one of Items 1 to 3, which is used in analgesic applications.
Item 5. Item 5. The external composition according to any one of Items 1 to 4, which is a liquid agent.

  ADVANTAGE OF THE INVENTION According to this invention, it is an external composition containing the ester derivative of nicotinic acid as a warming component, Comprising: The composition with which the redness after skin application was suppressed can be provided.

It is a photograph which shows the browning observation result of Test Example 2.

  The composition for external use of the present invention is a composition comprising an ester derivative of nicotinic acid and loxoprofen or a pharmaceutically acceptable salt thereof (loxoprofen), wherein the ester derivative of nicotinic acid is added to the entire composition. 0.005 to 0.1% by mass with respect to the content.

1. Nicotinic Acid Ester Derivative The composition for external use of the present invention contains an nicotinic acid ester derivative as an active ingredient for warming action.

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

  The composition for external use of this invention contains 0.005-0.1 mass% of ester derivatives of nicotinic acid with respect to the whole composition. When the content of the ester derivative of nicotinic acid is 0.005% by mass or more based on the entire composition, a sufficient thermal effect can be obtained. When the content ratio of the ester derivative of nicotinic acid is 0.1% by mass or less with respect to the entire composition, redness after application to the skin is remarkably suppressed. In this respect, the content ratio of the ester derivative of nicotinic acid is preferably 0.05% by mass or less.

2. Loxoprofen and pharmaceutically acceptable salts thereof (loxoprofen)
The external composition of the present invention contains loxoprofen. The composition for external use of the present invention has an effect that redness produced in the skin due to the ester derivative of nicotinic acid after application to the skin is suppressed by combining loxoprofen with the ester derivative of nicotinic acid.

  Furthermore, the composition for external use of the present invention also has the effect that the browning of the entire composition caused by loxoprofen over time is suppressed by combining loxoprofen with an ester derivative of nicotinic acid. .

  Although it does not specifically limit, loxoprofen may be mix | blended as an active ingredient of the at least 1 sort (s) of action selected from the group which consists of an antipyretic, analgesic, and anti-inflammatory action.

  Loxoprofen (2- [4- (2-oxocyclopentylmethyl) phenyl] propionic acid) is a propionic acid-based nonsteroidal antipyretic analgesic / antiinflammatory agent (NSAID) having antipyretic, analgesic and anti-inflammatory effects.

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

  In the present invention, loxoprofen sodium hydrate is preferred as loxoprofen or a pharmaceutically acceptable salt thereof.

  The content of loxoprofen is not particularly limited as long as it is effective in terms of efficacy. Content is 0.1-10 mass% in conversion of loxoprofen sodium anhydride with respect to the whole external composition of this invention, for example, Preferably it is 0.5-5 mass%, More preferably, it is 0.5-3. It can be made into the mass%.

  In addition, the ratio of loxoprofen can also be set in consideration of the ratio with respect to the ester derivative of nicotinic acid contained in the composition for external use. Specifically, the ratio of loxoprofen is usually in the range of 10 to 1000 parts by mass with respect to 1 part by mass of the nicotinic acid ester derivative contained in the external composition, preferably 10 to 500 parts by mass. Parts, more preferably 10 to 300 parts by mass.

3. C1-C4 alcohol (lower alcohol)
The composition for external use of the present invention may further contain a lower alcohol. The lower alcohol is not particularly limited and can be widely used as long as it functions as an effective base for the above active ingredients.

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

  The composition for external use of the present invention preferably contains 55% by mass or less of the lower alcohol with respect to the whole composition. Thereby, the composition for external use of the present invention is one in which browning with time is suppressed.

  From the viewpoint of suppressing skin irritation, the external composition of the present invention preferably contains 90% by mass or less, and more preferably 80% by mass or less of the lower alcohol with respect to the entire composition.

  It is preferable that the external composition of this invention contains 60 mass% or more of lower alcohol with respect to the whole composition from a viewpoint of the suppression effect of browning with time.

  Therefore, the composition for external use of the present invention contains 55 to 90% by mass of the lower alcohol with respect to the whole composition, thereby suppressing skin irritation and temporal browning of the composition for external use. In this respect, it is preferable that the lower alcohol is contained in an amount of 60 to 90% by mass, and more preferably 60 to 80% by mass with respect to the entire composition.

4). Other Components In the composition for external use of the present invention, another warming agent can be blended in addition to the above components as long as the effects of the present invention are not hindered.

  Another warming sensation agent is not particularly limited and can be widely used. One type of another warming agent may be used alone, or two or more types may be used in combination. Examples of other warming agents include capsaicinoids.

  As the capsaicinoid, N-acyl vanillylamide can be used. N-acyl vanillylamide is a known compound as a blood circulation promoter.

  The acyl group in N-acyl vanillyl amide may be linear or branched. Moreover, it does not restrict | limit especially about carbon number of the acyl group in N-acyl vanillyl amide, For example, it can be set to 5-15, Preferably it is 6-11.

  Specific examples of N-acyl vanillyl amide include nonanoic acid vanillyl amide and capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin.

  In the present invention, a purified product may be used as the capsaicinoid, but a mixture containing other components in addition to the capsaicinoid may be used. Specific examples of such a mixture containing capsaicinoid include peppers such as pepper extract, pepper tincture, and pepper powder.

  In the present invention, as a capsaicinoid, one kind of capsaicinoid may be used alone, or two or more kinds may be used in combination. Among capsaicinoids, nonanoic acid vanillylamide is preferable from the viewpoint that it is easier to exhibit the effect of suppressing browning with time by combining with ethanol.

  The capsaicinoid content in the present invention is not particularly limited as long as it is an effective amount in terms of efficacy. Content can be 0.002-0.2 mass% with respect to the whole external composition of this invention, Preferably it is 0.003-0.05 from a viewpoint of the inhibitory effect of a time-dependent browning. It can be made into the mass%, More preferably, it is 0.01-0.015 mass%.

  In the composition for external use of the present invention, a cooling agent can be blended in addition to the above components as long as the effects of the present invention are not hindered.

  As such a refreshing agent, l-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, menthane, lactate menthyl, geraniol, eucalyptus oil, terpene oil, bergamot oil , Fennel oil, peppermint oil (peppermint), rose oil, cool mint and the like. These cooling agents may be used alone or in any combination of two or more.

  The refreshing agent contained in the composition for external use of the present invention is preferably l-menthol, d-menthol, dl-menthol, d-borneol, dl-borneol, menthane, peppermint oil (peppermint) and cool mint, Menthol is more preferable, and l-menthol is particularly preferable.

  In the composition for external use of the present invention, a medicinal aid can be blended in addition to the above components as long as the effects of the present invention are not hindered.

  Such pharmaceutical adjuvants include anti-inflammatory agents and skin protectants such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, chlorpheny maleate, Examples include antihistamines such as lamin; blood circulation promoters such as tocopherol acetate; herbal medicines such as arnica tincture, agaric extract, sushi extract, horse chestnut extract, funnel extract, belladonna extract, toki extract, chicory extract, and salamander extract.

  In the composition for external use of the present invention, in addition to the above-mentioned components, active ingredients that can be used in combination, pH adjusters, preservatives, preservatives, antioxidants, stabilizers, etc., which are used for usual external compositions An agent can be appropriately blended.

5. Form and Production Method The composition for external use of the present invention is not particularly limited in form, but is preferably a liquid (including lotions, sprays, aerosols, and emulsions).

  The composition for external use of the present invention can be prepared according to a conventional method depending on the form of the preparation. For example, nicotinic acid ester derivatives, loxoprofen, or other ingredients, if necessary, are mixed with general-purpose bases used in external preparations as described below, dissolved or dispersed, and adjusted to the desired pH The method of doing can be mentioned. 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 4 to 7.5.

  For example, when the composition for external use of the present invention is prepared as a liquid, it can be prepared by mixing an ester derivative of nicotinic acid, loxoprofen, and other components as necessary with a base. The base can be, for example, a mixture containing a lower alcohol as a main component and at least one selected from glycols, water and an emulsifier.

  The glycols are not particularly limited, and examples thereof include glycerin, propylene glycol, 1,3-butylene glycol, octanediol, ethylene glycol, polyethylene glycol, and D-sorbitol. Glycerin, propylene glycol and 1,3-butylene glycol are preferred. A glycol may be used individually by 1 type and may be used in combination of multiple types.

  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. An emulsifier may be used individually by 1 type and may be used in combination of multiple types.

  The external composition of the present invention is preferably prepared as an external preparation in a coating form and can be locally administered externally. The dosage of the composition for external use of the present invention depends on the degree of symptoms to be treated, but the amount of loxoprofen that is an active ingredient contained therein is 100 mg or less per day. You can also

  The composition for external use of the present invention is a topical anti-inflammatory analgesic, such as shoulder pain associated with stiff shoulders, joint pain, low back pain, muscle pain, tendonitis (hand / wrist pain), elbow pain (tennis elbow etc.), bruise pain, It can be suitably used for the purpose of analgesia against pains such as pain, fractures, and neuralgia.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples etc. In the table, the unit represents mass (g) (that is, mass%) per 100 g of the composition.

Test example 1
As described in Tables 1 to 3, a liquid composition was prepared by dissolving each component in an amount, weighing, stirring and dissolving (Examples 1 and 2, Comparative Examples 1 to 6).

  After preparing the above preparation, 0.2 g is applied to a 2.5 cm square shape with an arm, and redness (a value) is measured every 10 minutes by Antera 3D (Gadelius Medical Co., Ltd.) until 50 minutes after application. did.

The evaluation method was as follows. A value (Δa value) obtained by subtracting the a value immediately after application from the a value 50 minutes after application (Δa value) as a skin redness index, and a formulation containing only the same amount of nicotinic acid benzyl ester (Example) For Comparative Examples 1, 2, and 6, Comparative Examples 1, 2, and 5) were set as references, and redness suppression effects were calculated.
Redness suppression effect = 100 − ((Δa value) / (reference Δa value) × 100)

  In the preparation containing only nicotinic acid benzyl ester, redness of the skin was seen (Comparative Examples 1, 2 and 5).

  When Comparative Example 2 contained glycol salicylate or dipotassium glycyrrhizinate, redness could not be sufficiently suppressed (Comparative Examples 3 and 4).

  Moreover, when 0.5 mass% of benzyl nicotinate was blended, redness could not be suppressed even when loxoprofen sodium hydrate was contained (Comparative Example 6).

  On the other hand, when the amount of benzyl nicotinate was 0.01 to 0.1% by mass and loxoprofen sodium hydrate was contained, redness could be sufficiently suppressed (Examples 1 and 2).

Test example 2
As described in Table 4, each component was weighed and weighed and dissolved by stirring to prepare a liquid composition (Examples 3 to 6, Comparative Example 7).

  Each composition obtained was put into a screw tube (manufactured by Maruemu, No. 5, diameter 27 mm, height 55 mm), stored at 60 ° C. for 1 month, and the properties were observed. Visually transparent one is “◎”, the one with the strongest browning tendency is “×”, and “X to ◎” is four stages (“X”, “△”, “○”, “◎” in order of worse). It was evaluated with. The results are shown in Table 4. FIG. 1 shows photographs of “◎” and “×”. The photo on the left side is “◎” and the right side is “×”.

  As shown in Table 4, in the preparation containing loxoprofen sodium hydrate in ethanol, a browning tendency was observed over time (Comparative Example 7).

  However, when nicotinic acid benzyl ester was contained together with loxoprofen sodium hydrate, suppression of the browning tendency was observed, and the properties were highly transparent (Examples 3 to 6).

Claims (5)

  A composition comprising an ester derivative of nicotinic acid and loxoprofen or a pharmaceutically acceptable salt thereof, wherein the ester derivative of nicotinic acid is added in an amount of 0.005 to 0.1% by mass based on the entire composition. An external composition to contain.   The composition for external use according to claim 1, wherein the ester derivative of nicotinic acid is benzyl nicotinate.   Furthermore, the composition for external use of Claim 1 or 2 containing a C1-C4 alcohol.   The external composition as described in any one of Claims 1-3 used for an analgesic use.   The composition for external use as described in any one of Claims 1-4 which is a liquid agent.