JP2016193850A - External pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a formulation technique for improving the anti-inflammatory analgesic action of an external pharmaceutical composition comprising diclofenac and/or salt thereof.SOLUTION: An external pharmaceutical composition comprises diclofenac and/or salt thereof and additionally comprises capsaicinoid, tocopherol and/or derivative thereof, and ester derivative of nicotinic acid, and also has a pH controlled at 6.1 or more, so that anti-inflammatory action is significantly improved for dramatic improvement of anti-inflammatory analgesic action.SELECTED DRAWING: None

Description

  The present invention relates to an external pharmaceutical composition. More specifically, the present invention relates to an external pharmaceutical composition that exhibits an excellent anti-inflammatory analgesic action.

  In modern society, an increasing number of people suffer from stiff shoulders, muscle pain, joint pain, etc. due to the same posture for a long time, excessive stress, lack of exercise, etc. due to the spread of OA equipment. Conventionally, for such stiff shoulders, muscle and joint pains, etc., countermeasures have been taken to apply anti-inflammatory analgesics in order to suppress inflammation occurring in the affected area and improve symptoms.

  Conventionally, non-steroidal anti-inflammatory drugs such as diclofenac, felbinac, indomethacin and ibuprofen are known as anti-inflammatory analgesics. Among these non-steroidal anti-inflammatory drugs, diclofenac is known to have a high inhibitory activity against cyclooxygenase and exhibit excellent anti-inflammatory analgesic action, and many external pharmaceutical compositions containing diclofenac have been put into practical use. . Diclofenac, when administered orally or rectally, may cause gastrointestinal, renal or hepatic damage as a side effect, especially for the gastrointestinal tract. Yes. However, diclofenac has a low percutaneous absorbability and has a drawback in that when it is applied transdermally, it cannot fully exert its anti-inflammatory analgesic action.

  So far, various investigations have been made on preparation techniques for improving the transdermal absorbability of diclofenac and improving its medicinal effect. For example, Patent Document 1 includes diclofenac or a pharmaceutically acceptable salt thereof in a proportion of 0.5 to 1.5% by weight and a refreshing agent in a proportion of 5 to 15% by weight in an external pharmaceutical composition. Thus, it is disclosed that the analgesic effect is improved.

JP 2011-074032 A

  With the increase in the number of people suffering from stiff shoulders, muscle pain, joint pain, etc., there is an increasing demand for an external pharmaceutical composition capable of exerting an excellent anti-inflammatory analgesic effect, and an external pharmaceutical composition containing diclofenac and / or a salt thereof. There is a high expectation for the development of pharmaceutical technology that further improves anti-inflammatory analgesic activity.

  On the other hand, it is known that blood flow improvement in the affected area is also effective for relieving stiff shoulders, muscle pain, joint pain, etc., and the present inventor has obtained diclofenac and / or a salt thereof and capsaicinoid which is a blood circulation promoter. As a result of evaluating the anti-inflammatory analgesic action of the externally used pharmaceutical composition, a new problem was found that the anti-inflammatory action was reduced in the external pharmaceutical composition, and as a result, the anti-inflammatory analgesic action was attenuated.

  Then, one of the objectives of this invention is providing the formulation technique which improves an anti-inflammatory analgesic effect in the external pharmaceutical composition containing a diclofenac and / or its salt. Another object of the present invention is to provide a preparation technique for improving anti-inflammatory analgesic action in an external pharmaceutical composition containing diclofenac and / or a salt thereof and capsaicinoid.

  As a result of diligent studies to solve the above-mentioned problems, the inventor of the present invention, in a pharmaceutical composition for external use, together with diclofenac and / or a salt thereof, capsaicinoid, tocopherol and / or a derivative thereof, and (D) an ester of nicotinic acid When a derivative is used in combination and the pH is set to 6.1 or higher, the anti-inflammatory effect is remarkably improved and the anti-inflammatory analgesic action is dramatically improved despite the combined use of diclofenac and / or its salt and capsaicinoid. It has been found that it can be improved. The present invention has been completed by further studies based on this finding.

That is, this invention provides the invention of the aspect hung up below.
Item 1. (A) Diclofenac and / or a pharmaceutically acceptable salt thereof, (B) capsaicinoid, (C) tocopherol and / or a derivative thereof, and (D) an ester derivative of nicotinic acid, having a pH of 6.1 or more A pharmaceutical composition for external use characterized by the above.
Item 2. Item 6. The external pharmaceutical composition according to Item 1, wherein the pH is 6.1 to 7.1.
Item 3. Item 3. The external pharmaceutical composition according to Item 1 or 2, wherein the component (B) is nonanoic acid vanillylamide.
Item 4. Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, wherein the component (C) is tocopherol acetate.
Item 5. Item 5. The external pharmaceutical composition according to any one of Items 1 to 4, wherein (D) is nicotinic acid benzyl ester.
Item 6. Item 6. The external pharmaceutical composition according to any one of Items 1 to 5, further comprising menthol.
Item 7. (A) A method for improving the anti-inflammatory analgesic effect of an external pharmaceutical composition comprising diclofenac and / or a pharmaceutically acceptable salt thereof,
(B) capsaicinoid, (C) tocopherol and / or a derivative thereof, and (D) an ester derivative of nicotinic acid are blended with the external pharmaceutical composition, and the pH is set to 6.1 or more. How to improve anti-inflammatory and analgesic action.
Item 8. (A) Diclofenac and / or a pharmaceutically acceptable salt thereof, and (B) a method for improving the anti-inflammatory analgesic effect of an external pharmaceutical composition comprising capsaicinoid,
(C) Tocopherol and / or a derivative thereof and (D) an ester derivative of nicotinic acid are blended into the external pharmaceutical composition, and the pH is set to 6.1 or more, and the anti-inflammatory analgesic action How to improve.

  According to the pharmaceutical composition for external use of the present invention, although it contains diclofenac and / or a salt thereof and capsaicinoid, the anti-inflammatory action is remarkably improved, and an excellent anti-inflammatory analgesic action can be exhibited. Therefore, the pharmaceutical composition for external use of the present invention can exhibit an excellent effect in the relief or healing of stiff shoulders, muscle pain, joint pain and the like.

In Experiment 1, it is a figure which shows the result of having calculated | required the foot edema suppression rate after apply | coating each external pharmaceutical composition to the rat right hind paw and causing acute inflammation. In Experiment 2, it is a figure which shows the result of having applied each external pharmaceutical composition and evaluating the anti-inflammatory analgesic effect (degree of shoulder stiffness).

1. External pharmaceutical composition The external pharmaceutical composition of the present invention comprises (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) capsaicinoid, (C) tocopherol and / or a derivative thereof, and (D) nicotinic acid. It is characterized by having an ester derivative of pH 6.1 or higher. Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.

(A) Diclofenac and / or salt thereof The external pharmaceutical composition of the present invention contains diclofenac and / or a salt thereof (hereinafter sometimes referred to as “component (A)”) as an anti-inflammatory analgesic component.

  Diclofenac is a known nonsteroidal compound also called 2- (2- (2,6-dichlorophenylamino) phenyl) acetic acid.

  The salt of diclofenac is not particularly limited as long as it is pharmaceutically acceptable; for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; salt with ammonia; Salts with primary, secondary or tertiary alkylamines such as amine, diethylamine, trimethylamine, triethylamine; primary such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, And salts with secondary or tertiary alkanolamines. Among these, an alkali metal salt is preferable, and a sodium salt is more preferable. These diclofenac salts may be used alone or in combination of two or more.

  In the pharmaceutical composition for external use of the present invention, as the component (A), one kind selected from diclofenac and a salt thereof may be used alone, or two or more kinds may be used in combination. Among the components (A), a salt of diclofenac is preferable, an alkali metal salt of diclofenac is more preferable, and diclofenac sodium is particularly preferable.

  The content of the component (A) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.2 to 2% by weight, preferably 0.5 to 1.5% by weight, more preferably 0.7. -1.3% by weight.

(B) Capsaicinoid The external pharmaceutical composition of the present invention contains a capsaicinoid (hereinafter sometimes referred to as “component (B)”) in order to improve anti-inflammatory analgesia. Capsaicinoid, when used in combination with diclofenac and / or a salt thereof, attenuates the anti-inflammatory action of diclofenac and / or a salt thereof. Moreover, when the pH is set to 6.1 or more, it is possible to dramatically improve the anti-inflammatory action and to exert an excellent anti-inflammatory analgesic action.

  Capsaicinoid is N-acyl vanillylamide and is a known compound as a blood circulation promoter. The acyl group in capsaicinoid may be either linear or branched. Moreover, although it does not restrict | limit especially about carbon number of the acyl group in a capsaicinoid, For example, 5-15, Preferably 6-11 is mentioned.

  Specific examples of capsaicinoids include nonanoic acid vanillylamide; capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin.

  In this external pharmaceutical composition, a purified product may be used as the capsaicinoid, but a mixture containing other components in addition to capsaicinoid may be used. Specific examples of such a mixture containing capsaicinoids include capsicinoids such as chili pepper extract, chili pepper tincture and chili powder.

  In the external pharmaceutical composition of the present invention, as the component (B), one type of capsaicinoid may be used alone, or two or more types may be used in combination. Among the components (B), nonanoic acid vanillylamide is preferable from the viewpoint of more effectively exerting anti-inflammatory analgesic action.

  The content of the component (B) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.002 to 0.2% by weight, preferably 0.003 to 0.05% by weight, and more preferably 0. 0.01 to 0.015% by weight.

  Further, in the external pharmaceutical composition of the present invention, the ratio of the component (B) to the component (A) is determined based on the content range of each component, but exhibits an anti-inflammatory analgesic action more effectively. In view of the above, the range in which the component (B) is 0.1 to 100 parts by weight, preferably 0.2 to 10 parts by weight, more preferably 0.7 to 2 parts by weight per 100 parts by weight of the component (A). Can be mentioned.

(C) Tocopherol and / or its derivative The pharmaceutical composition for external use of the present invention may be referred to as tocopherol and / or its derivative (hereinafter referred to as “component (C)”) together with the above-mentioned component in order to enhance the anti-inflammatory analgesic action. Contains).

  Tocopherol is a known compound known as vitamin E. The tocopherol may be any of d-form, l-form, and dl-form, and preferably a dl-form. In addition, the tocopherol may be any of α-form, β-form, γ-form, and δ-form, and preferably α-form.

  The tocopherol derivative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include ester forms with carboxylic acids such as acetic acid, nicotinic acid and succinic acid, and diester forms with phosphoric acid. Among these tocopherol derivatives, an ester with a carboxylic acid is preferable, and tocopherol acetate is more preferable.

  The tocopherol derivative may be any of d-form, l-form, and dl-form, and preferably a dl-form. Furthermore, the derivative of tocopherol may be any of α-form, β-form, γ-form, and δ-form, and preferably α-form.

  In the external pharmaceutical composition of the present invention, as the component (C), one may be selected from tocopherol and derivatives thereof and used alone, or two or more may be used in combination. Among the components (C), a derivative of tocopherol, preferably an ester of tocopherol with a carboxylic acid, more preferably a tocopherol acetate, particularly preferably d-α-tocopherol acetate, 1-α-tocopherol acetate, dl acetate -Α-tocopherol.

  The content of the component (C) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.01 to 2% by weight, preferably 0.05 to 1.50% by weight, and more preferably 0.08. Up to 1% by weight.

  Further, in the external pharmaceutical composition of the present invention, the ratio of the component (C) to the component (A) is determined based on the content range of each component, but exhibits an anti-inflammatory analgesic action more effectively. In view of the above, a range in which the component (C) is 5 to 1000 parts by weight, preferably 3 to 300 parts by weight, more preferably 5 to 150 parts by weight per 100 parts by weight of the component (A).

(D) Ester Derivative of Nicotinic Acid The pharmaceutical composition for external use of the present invention has an ester derivative of nicotinic acid (hereinafter sometimes referred to as “(D) component”) together with the above-mentioned components in order to enhance anti-inflammatory analgesic action. Containing. Thus, by containing the components (A) to (D) as one body, by satisfying the pH described later, it is possible to dramatically improve the anti-inflammatory effect and to exert an excellent anti-inflammatory analgesic effect Become.

  The ester derivative of nicotinic acid is not particularly limited as long as it is pharmaceutically acceptable, and 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.

  In the pharmaceutical composition for external use of the present invention, as the component (D), one kind selected from ester derivatives of nicotinic acid may be used alone, or two or more kinds may be used in combination. Among the components (D), nicotinic acid benzyl ester is preferable.

  The content of the component (D) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.002 to 0.2% by weight, preferably 0.003 to 0.05% by weight, and more preferably 0. 0.008 to 0.015% by weight.

  Further, in the external pharmaceutical composition of the present invention, the ratio of the component (D) to the component (A) is determined based on the range of the content of each component, but exhibits an anti-inflammatory analgesic action more effectively. In view of the above, the range in which the component (D) is 0.1 to 100 parts by weight, preferably 0.2 to 10 parts by weight, more preferably 0.5 to 2 parts by weight per 100 parts by weight of the component (A). Can be mentioned.

(E) Menthol The external pharmaceutical composition of the present invention may contain menthol (hereinafter sometimes referred to as “component (E)”) as necessary. By containing menthol, the anti-inflammatory analgesic action can be further improved, or a refreshing feeling can be imparted to the applied skin, thereby improving the feeling of use.

  Menthol may be any of d-form, l-form, and dl-form, and preferably 1-form.

  In addition, the external pharmaceutical composition of the present invention may use an essential oil containing menthol as the component (E). The essential oil containing menthol can be appropriately selected from known ones, and examples thereof include peppermint oil, peppermint oil, spearmint oil, and the like.

  Although there is no restriction | limiting in particular about content of (E) component in the external pharmaceutical composition of this invention, For example, 1-15 weight%, Preferably it is 2-10 weight%, More preferably, 3-7 weight% is mentioned.

  In the external pharmaceutical composition of the present invention, the ratio of the component (E) to the component (A) is determined based on the range of the content of each component. Specifically, it is 100 parts by weight of the component (A). The range which becomes (E) component 50-7500 weight part per part, Preferably it is 130-2000 weight part, More preferably, it is 230-1000 weight part, Most preferably, it is 300-700 weight part.

Other components The pharmaceutical composition for external use of the present invention may contain a pharmacological component, if necessary, in addition to the components described above, as long as the effects of the present invention are not hindered. The pharmacological component that can be blended in the external pharmaceutical composition of the present invention is not particularly limited. For example, anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and its Pharmaceutically acceptable salts, antihistamines such as chlorpheniramine maleate; lidocaine and pharmaceutically acceptable salts thereof, dibucaine and pharmaceutically acceptable salts thereof, local anesthetics such as ethyl aminobenzoate; heparin Blood circulation promoters such as similar substances; herbal medicines such as arnica tincture, agaric extract, sanshi extract, horse chestnut extract, funnel extract, belladonna extract, toki extract, shikon extract, salamander extract and the like.

  In addition, the external pharmaceutical composition of the present invention can contain a base such as an aqueous base or an oil base in order to obtain a desired pharmaceutical form.

  Examples of the aqueous base include water; lower alcohols such as ethanol, propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and butylene glycol. Is mentioned.

  Examples of oily bases include nonpolar oils and polar oils. Specific examples of the nonpolar oil include hydrocarbons such as paraffin and isoparaffin; squalane and wax. Specific examples of polar oils include aliphatic monocarboxylic acid esters, triglycerides, aliphatic dicarboxylic acid diesters, aliphatic dicarboxylic acid alkylene glycol esters, and higher fatty acids.

  Examples of the aliphatic monocarboxylic acid ester include isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, isotridecyl isononanoate, isononyl isononanoate, cetyl 2-ethylhexanoate, myristyl myristate, hexadecyl isostearate, octanoate Examples include cetyl and cetyl isooctanoate. These aliphatic monocarboxylic acid esters may be used alone or in combination of two or more.

  Examples of the triglyceride include triacylglycerol, tripalmitin, glyceryl tripalmitate, glyceryl triisooctanoate, 1-palmitoyl-2,3-dioleoylglycerol, 1,3-dioleoyl-2-palmitoylglycerol, 1- Examples include palmitooleoyl-2-stearoyl-3-linoleoylglycerol, 1-linoleoyl-2-palmioleoyl-3-stearoylglycerol, and the like. These triglycerides may be used individually by 1 type, and may be used in combination of 2 or more type.

  Examples of the aliphatic dicarboxylic acid diester include diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diethyl adipate, diisopropyl adipate, dibutyl adipate, diisobutyl adipate, dioctyl adipate, and the like. These aliphatic dicarboxylic acid diesters may be used individually by 1 type, and may be used in combination of 2 or more type.

  Examples of the aliphatic dicarboxylic acid alkylene glycol ester include neopentyl glycol dioctanoate, propylene glycol dicaprate, ethylene glycol dioleate, and ethylene glycol distearate. These aliphatic dicarboxylic acid alkylene glycol esters may be used alone or in combination of two or more.

  Examples of the higher fatty acid include fatty acids having 12 to 26 carbon atoms. Specific examples of such higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid. . These higher fatty acids may be used alone or in combination of two or more.

  Furthermore, the external pharmaceutical composition of the present invention may contain other additives usually used in the external pharmaceutical composition, if necessary, in addition to the components described above. Examples of such additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, and coloring agents. Is mentioned.

  The surfactant that can be blended in the external pharmaceutical composition of the present invention is not particularly limited. For example, glyceryl fatty acids such as glyceryl monostearate and glyceryl monostearate; polyglyceryl monoisostearate, polyglyceryl diisostearate Polyglycerin fatty acids: sorbitan fatty acids such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate Esters; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, poly Cured castor oil derivatives such as oxyethylene hydrogenated castor oil 60 and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60) , Polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polyoxyethylene (20) sorbitan (polysorbate 80) monooleate; other polyoxyethylene monococonut oil fatty acid glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene Examples thereof include cetyl ether, stearylamine, oleylamine and the like. Preferably, surfactants used in the preparation of ointments, such as sorbitan monostearate, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (20) sorbitan monostearate, and the like. Can be mentioned. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  Although it does not restrict | limit especially about the thickener which can be mix | blended with the external pharmaceutical composition of this invention, For example, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a carboxy vinyl polymer, a hyaluronic acid, a xanthan gum etc. are mentioned.

pH
The pH of the external pharmaceutical composition of the invention is set to 6.1 or higher. By including the components (A) to (D) and setting the pH to 6.1 or higher, it is possible to dramatically improve the anti-inflammatory action and to exert an excellent anti-inflammatory analgesic action.

  The pH of the external pharmaceutical composition of the invention is preferably 6.1 to 7.4, more preferably 6.1 to 7.1, and particularly preferably 6 from the viewpoint of more effectively exerting anti-inflammatory analgesic action. .1 to 6.6.

  The adjustment of pH in the external pharmaceutical composition of the present invention is performed by adding a pharmaceutically acceptable acid such as hydrochloric acid, acetic acid, lactic acid or citric acid, or a pharmaceutically acceptable alkali such as sodium hydroxide or potassium hydroxide. Can be done.

Formulation Form The formulation form of the external pharmaceutical composition of the present invention is not particularly limited as long as it can be applied transdermally. For example, liquids (including lotions, sprays, aerosols, and emulsions), Examples include foams, ointments, creams, gels, patches and the like. Among these, Preferably a liquid agent or a gel agent is mentioned. These preparation forms can be prepared by formulating with additives according to the preparation form according to a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.

The external use pharmaceutical composition of use aspect invention is used by administering to an area | region (skin) for which anti-inflammatory analgesia is calculated | required externally. The dosage of the external pharmaceutical composition of the present invention is appropriately set according to the site to be administered, the degree of symptoms to be treated, etc., but per 1 cm ^{2 of} the local site to be administered, diclofenac and / or its pharmaceutically acceptable. It is desirable that the dose per salt of the salt is about 10 to 500 mg.

  The external pharmaceutical composition of the present invention is used as an external 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 used for the treatment of pain, fracture pain, neuralgia, osteoarthritis, arthritis and the like.

2. To enhance the method described above for anti-inflammatory analgesic effect, in the pharmaceutical composition for external application comprising the component (A), by the (B) is contained ~ (D) component, and sets the pH 6.1 or more, The anti-inflammatory and analgesic action of the external pharmaceutical composition can be improved. Therefore, the present invention further relates to a method for improving anti-inflammatory analgesic action of an external pharmaceutical composition comprising (A) diclofenac and / or a pharmaceutically acceptable salt thereof, wherein the external pharmaceutical composition comprises (B) Provided is a method for improving anti-inflammatory analgesia, comprising capsaicinoid, (C) tocopherol and / or a derivative thereof, and (D) an ester derivative of nicotinic acid, wherein the pH is set to 6.1 or higher. .

  Further, as described above, in the external pharmaceutical composition containing the components (A) and (B), the anti-inflammatory action is attenuated as compared with the case where the component (A) is used alone, but further (C ) And (D) components, and by setting the pH to 6.1 or more, the anti-inflammatory action can be dramatically improved and the excellent anti-inflammatory analgesic action can be exhibited. Therefore, the present invention further provides a method for improving anti-inflammatory analgesic action of an external pharmaceutical composition comprising (A) diclofenac and / or a pharmaceutically acceptable salt thereof, and (B) capsaicinoid, the external pharmaceutical composition (C) Tocopherol and / or a derivative thereof, and (D) an ester derivative of nicotinic acid, and a pH is set to 6.1 or higher. provide.

  In these methods for improving the anti-inflammatory analgesic effect, the types and amounts of components used, the pH and formulation of the external pharmaceutical composition, and the like are as described in the section of “1. External pharmaceutical composition”. .

  EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Test Example 1: Relationship between combinations of components and anti-inflammatory action An external pharmaceutical composition (liquid) having the composition shown in Table 1 was prepared. In order to evaluate the anti-inflammatory effect of each external pharmaceutical composition, the following tests were conducted. In addition, the measurement of the pH of the external pharmaceutical composition of a following example and a comparative example was performed on 25 degreeC temperature conditions.

  After the habituation of rats (Slc: Wistar strain, male, 7 weeks old after habituation), the right hind paw volume was measured with a paw volume measuring device (MK-101 CMP, Muromachi Kikai Co., Ltd.), and the right hind paw of each group The group was divided into 6 groups (8 animals per group) so that the average value of the volume was uniform.

  220 μL of each topical pharmaceutical composition was applied to the right hind paw of each group of rats, and immediately after that, 100 μL of 1 wt% carrageenan solution was administered into the right hind paw skin without anesthesia to induce acute inflammation. . 2, 4, and 6 hours after administration, the right hind paw volume was measured with a paw volume measuring device (MK-101 CMP, Muromachi Kikai Co., Ltd.). As a control, the right hind paw volume was measured under the same conditions as described above, except that the external pharmaceutical composition was not administered. The measured rate of each right hind paw volume was used to evaluate the foot edema inhibition rate according to the following calculation formula. In addition, since the degree of induced acute inflammation is reflected in the degree of foot edema, the higher the foot edema suppression rate, the stronger the anti-inflammatory effect.

X: right hind paw volume after acute inflammation in the control group-right hind paw volume before acute inflammation in the control group Y: right hind paw volume after acute inflammation in the group administered with the external pharmaceutical composition-external medicine Right hind paw volume before acute inflammation in the group receiving the composition

  The obtained results are shown in FIG. From this result, when diclofenac sodium and nonanoic acid vanillylamide were used in combination (Comparative Example 2), the anti-inflammatory action was remarkably attenuated as compared with the case where diclofenac sodium was contained alone (Comparative Example 1). Moreover, even when diclofenac sodium is used in combination with nicotinic acid benzyl ester or tocopherol acetate (Comparative Examples 3 and 4), the anti-inflammatory action tends to be lower than when diclofenac sodium is contained alone (Comparative Example 1). It was. On the other hand, in the case where nonanoic acid vanillylamide, nicotinic acid benzyl ester, and tocopherol acetate are used in combination with diclofenac sodium (Example 1), the anti-inflammatory effect is much higher than when diclofenac sodium is contained alone (Comparative Example 1). Was recognized.

Test Example 2: Relationship between pH and anti-inflammatory action An external pharmaceutical composition (liquid) having the composition shown in Table 2 was prepared. In order to evaluate the anti-inflammatory effect of each external pharmaceutical composition, the following tests were conducted.

  Appropriate amounts (about 5 reciprocations) of each external pharmaceutical composition were applied to the shoulders of 4 subjects who were experiencing stiff shoulders. Next, for 6 hours after application, VAS (Visual Analogue Scale) evaluation was performed with 10 points for “feeling stiff shoulder” and 0 point for “not feeling stiff shoulder” over time. The degree of shoulder stiffness by application was scored, and the average value of the score of shoulder stiffness was calculated for each external pharmaceutical composition.

  The obtained results are shown in FIG. From this result, in the case of using an external pharmaceutical composition having a pH of 6.1 or more (Examples 1 to 5), compared to the case of an external pharmaceutical composition having a pH of 6.02 (Comparative Example 5), It was confirmed that the degree of shoulder stiffness was remarkably improved. From the above results, it is clear that excellent anti-inflammatory analgesic action can be obtained for the first time by using nonanoic acid vanillylamide, nicotinic acid benzyl ester, and tocopherol acetate together with diclofenac sodium and setting the pH to 6.1 or higher. It became. Moreover, among the external pharmaceutical compositions of Examples 1 to 5, it was revealed that even more excellent anti-inflammatory analgesic action can be obtained when the pH is 7.1 or lower (Examples 1 to 4).

Formulation Example An external pharmaceutical composition (liquid or gel) having the composition shown in Tables 3 and 4 was prepared. When the anti-inflammatory action of each of the obtained external pharmaceutical compositions was tested by the same method as in Test Example 2, all of them exhibited an excellent anti-inflammatory action.

Claims (8)

  (A) Diclofenac and / or a pharmaceutically acceptable salt thereof, (B) capsaicinoid, (C) tocopherol and / or a derivative thereof, and (D) an ester derivative of nicotinic acid, having a pH of 6.1 or more A pharmaceutical composition for external use characterized by the above.   The pharmaceutical composition for external use according to claim 1, which has a pH of 6.1 to 7.1.   The external pharmaceutical composition according to claim 1 or 2, wherein the component (B) is nonanoic acid vanillylamide.   The external pharmaceutical composition according to any one of claims 1 to 3, wherein the component (C) is tocopherol acetate.   The external pharmaceutical composition according to any one of claims 1 to 4, wherein the (D) is nicotinic acid benzyl ester.   Furthermore, the external pharmaceutical composition in any one of Claims 1-5 containing a menthol. (A) A method for improving the anti-inflammatory analgesic effect of an external pharmaceutical composition comprising diclofenac and / or a pharmaceutically acceptable salt thereof,
(B) capsaicinoid, (C) tocopherol and / or a derivative thereof, and (D) an ester derivative of nicotinic acid are blended with the external pharmaceutical composition, and the pH is set to 6.1 or more. How to improve anti-inflammatory and analgesic action. (A) Diclofenac and / or a pharmaceutically acceptable salt thereof, and (B) a method for improving the anti-inflammatory analgesic effect of an external pharmaceutical composition comprising capsaicinoid,
(C) Tocopherol and / or a derivative thereof and (D) an ester derivative of nicotinic acid are blended into the external pharmaceutical composition, and the pH is set to 6.1 or more, and the anti-inflammatory analgesic action How to improve.