JP6632810B2 - Topical pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition for external use. More specifically, the present invention relates to a pharmaceutical composition for external use which exhibits an excellent anti-inflammatory and analgesic action.

  In the modern society, people who 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 are increasing. Conventionally, for such stiff shoulders, muscle and joint pains and the like, measures have been taken to apply an anti-inflammatory analgesic to suppress inflammation occurring in the affected area and improve symptoms.

  Conventionally, non-steroidal anti-inflammatory drugs such as diclofenac, felbinac, indomethacin, ibuprofen and the like have been known as anti-inflammatory analgesics. Among these non-steroidal anti-inflammatory drugs, diclofenac is known to have a high inhibitory activity against cyclooxygenase and to exert an excellent anti-inflammatory and analgesic action, and many external pharmaceutical compositions containing diclofenac have been put to practical use. . Diclofenac, when administered orally or rectally, may cause gastrointestinal, renal or liver damage as a side effect, and in particular, may have serious side effects on the gastrointestinal tract. I have. However, diclofenac has a drawback that transdermal absorbability is low and, when applied transdermally, the anti-inflammatory and analgesic effects inherent to diclofenac cannot be sufficiently exhibited.

  Until now, various studies have been made on formulation techniques for improving the transdermal absorbability of diclofenac and improving its drug efficacy. For example, Patent Document 1 discloses that a topical pharmaceutical composition contains diclofenac or a pharmaceutically acceptable salt thereof in a proportion of 0.5 to 1.5% by weight and a cooling agent in a proportion of 5 to 15% by weight. It is disclosed that the analgesic effect is thereby improved.

  However, with the increase in the number of people suffering from stiff shoulders, muscle pain, joint pain, etc., there has been a growing demand for external preparations capable of exhibiting better anti-inflammatory and analgesic effects, and formulation technology for further improving the anti-inflammatory and analgesic effects of diclofenac. Expectations for the development of are increasing.

JP 2011-074032 A

  An object of the present invention is to provide, in an external pharmaceutical composition containing diclofenac and / or a pharmaceutically acceptable salt thereof, a formulation technique for improving the anti-inflammatory effect of diclofenac and / or a pharmaceutically acceptable salt thereof. And

  The present inventors have made intensive studies to solve the above-mentioned problems, and found that in a topical pharmaceutical composition, together with diclofenac and / or a pharmaceutically acceptable salt thereof, a cellulose-based water-soluble polymer compound and a nonionic It has been found that when used in combination with a surfactant, the anti-inflammatory effect is significantly improved, and the anti-inflammatory and analgesic effect can be significantly improved. The present invention has been completed by further study based on such knowledge.

That is, the present invention provides the following aspects of the invention.
Item 1. An external pharmaceutical composition comprising (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) a cellulosic water-soluble polymer compound, and (C) a nonionic surfactant. .
Item 2. Item 2. The topical pharmaceutical composition according to Item 1, wherein the component (B) is hydroxypropylcellulose.
Item 3. Item 3. The topical pharmaceutical composition according to Item 1 or 2, wherein the component (C) is a polyoxyalkylene hydrogenated castor oil and / or a polyoxyalkylene sorbitan fatty acid ester.
Item 4. Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, wherein the component (C) is polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan oleate.
Item 5. Item 5. The topical pharmaceutical composition according to any one of Items 1 to 4, which is a gel or a liquid.
Item 6. (A) Diclofenac and / or a method for improving the anti-inflammatory analgesic effect of an externally applied pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, wherein the externally applied pharmaceutical composition, (B) a cellulose-based water-soluble polymer compound, And (C) a method for improving an anti-inflammatory and analgesic action, which comprises mixing a nonionic surfactant.
Item 7. Item 7. The method for improving an anti-inflammatory and analgesic effect according to Item 6, wherein the component (B) is hydroxypropyl cellulose.
Item 8. Item 9. The method for improving an anti-inflammatory and analgesic effect according to Item 7 or 8, wherein the component (C) is polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan oleate.

  According to the external pharmaceutical composition of the present invention, diclofenac and / or a pharmaceutically acceptable salt thereof coexist with a cellulosic water-soluble polymer compound and a nonionic surfactant, so that the anti-inflammatory effect is remarkable. And can exhibit excellent anti-inflammatory and analgesic effects. Therefore, the pharmaceutical composition for external use of the present invention can show an excellent effect on alleviation or cure of stiff shoulder, muscle pain, joint pain and the like.

In Test Example 1, after applying each external pharmaceutical composition to the right hind paw of a rat to cause acute inflammation, the figure shows the result of measuring the rate of increase in paw volume. In Test Example 2, it is a figure which shows the result of having evaluated each anti-inflammatory effect (the degree of shoulder stiffness) by applying each external pharmaceutical composition.

1. External pharmaceutical composition The external pharmaceutical composition of the present invention comprises (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) a cellulosic water-soluble polymer compound, and (C) a nonionic surfactant. It is characterized by containing. Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.

(A) Diclofenac and / or a pharmaceutically acceptable salt thereof The topical pharmaceutical composition of the present invention comprises diclofenac and / or a salt thereof (hereinafter, sometimes referred to as “(A) component”) 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 amines, diethylamine, trimethylamine and triethylamine; primary salts such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine and triisopropanolamine; And salts with secondary or tertiary alkanolamines. Among them, preferred are alkali metal salts, and more preferred are sodium salts. One of these diclofenac salts may be used alone, or two or more of them may be used in combination.

  In the external pharmaceutical composition of the present invention, as the component (A), one kind may be selected from diclofenac and salts thereof and used alone, or two or more kinds may be used in combination. Among the components (A), diclofenac salts are preferable, alkali metal salts of diclofenac are 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, and more preferably 0.7% by weight. To 1.3% by weight.

(B) Cellulose-based water-soluble polymer compound The external pharmaceutical composition of the present invention is a cellulose-based water-soluble polymer compound (hereinafter, may be referred to as "component (B)" in order to improve the anti-inflammatory and analgesic effect. ). In the external pharmaceutical composition of the present invention, the component (C) described below is integrally contained together with the component (B), thereby dramatically improving the anti-inflammatory analgesic effect of diclofenac and / or a salt thereof, and an excellent anti-inflammatory analgesic effect. Can be demonstrated.

  The cellulose-based water-soluble polymer compound is a compound in which water-insoluble cellulose is converted to water-soluble by modifying a part of the hydroxyl groups of cellulose with alkylene oxide or the like. The cellulosic water-soluble polymer compound used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (alias: hypromellose), Hydroxyethyl cellulose and carboxymethyl cellulose can be mentioned. These cellulose-based water-soluble polymer compounds may be used alone or in a combination of two or more. Among these cellulose-based water-soluble polymer compounds, hydroxypropyl cellulose is preferably used from the viewpoint of further improving the anti-inflammatory effect.

  The molecular weight of the cellulosic water-soluble polymer compound used in the present invention is not particularly limited, and may be appropriately set according to the type of the cellulosic water-soluble polymer compound used.

  The viscosity of the hydroxypropylcellulose is not particularly limited. For example, the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) is about 2 to 5000 mPa · s. Such hydroxypropylcellulose is commercially available as NISSO HPC (L, M, H, SL, SSL) (Nippon Soda Co., Ltd.) or the like.

  The viscosity of hydroxyethylmethylcellulose is not particularly limited, and for example, a viscosity of about 7000 to 10000 mPa · s as the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) can be used. Such hydroxyethyl methylcellulose is commercially available as Mecellose 80H (Tome Industry Co., Ltd.) or the like.

  The viscosity of the hydroxypropylmethylcellulose is not particularly limited, and for example, a viscosity of about 2 to 10000 mPa · s as the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) can be mentioned. Such hydroxypropyl methylcellulose is commercially available as Metrose 65SH-400, 65SH-1500, 65SH-4000, 90SH-400, 90SH-4000 (Shin-Etsu Chemical Co., Ltd.) and the like.

  The viscosity of the hydroxyethylcellulose is not particularly limited. For example, the viscosity of a 1% aqueous solution (20 ° C., B-type viscometer) is about 60 to 6000 mPa · s. Such hydroxyethylcellulose is commercially available as HEC DAICEL (SP200, SP600, SP850, SP900, SE550, SE850, SE900, EP850, EE820) (Daicel FineChem Ltd.) and the like.

  The viscosity of carboxymethylcellulose is not particularly limited. For example, the viscosity of a 1% aqueous solution (20 ° C., B-type viscometer) is about 10 to 18000 mPa · s. Such carboxymethyl cellulose is commercially available as CMC Daicel (1120, 1180, 1250, 1330, 2260) (Daicel Chemical Co., Ltd.) or the like.

  The content of the component (B) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.01 to 10% by weight, preferably 0.1 to 8% by weight, and more preferably 0.3 to 5% by weight. % By weight.

  In the external pharmaceutical composition of the present invention, the ratio of the component (B) to the component (A) is determined based on the range of the content of each component, but more effectively exerts an anti-inflammatory analgesic effect. From the viewpoint, the range of 0.5 to 5000 parts by weight, preferably 6 to 1600 parts by weight, more preferably 23 to 715 parts by weight of the component (B) per 100 parts by weight of the component (A) is exemplified.

(C) Nonionic surfactant The topical pharmaceutical composition of the present invention, together with the component (A) and the component (B), comprises a nonionic surfactant (hereinafter, referred to as "(C ) Component).

  The nonionic surfactant (component (C)) used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, polyoxyalkylene hydrogenated castor oil, polyoxyalkylene sorbitan fatty acid ester, Polyoxyalkylene fatty acid ester, alkylene glycol fatty acid ester, polyoxyalkylene alkyl ether, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyalkylene fatty acid glyceryl, glycerin alkyl ether, alkyl glucoside and the like can be mentioned.

  As the polyoxyalkylene hydrogenated castor oil, specifically, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) Hardened castor oil, polyoxyethylene (40) hardened castor oil, polyoxyethylene (50) hardened castor oil, polyoxyethylene (60) hardened castor oil, polyoxyethylene (80) hardened castor oil, polyoxyethylene (100) And polyoxyethylene hydrogenated castor oil such as hydrogenated castor oil.

  Examples of the polyoxyalkylene sorbitan fatty acid ester include a polyoxyethylene sorbitan fatty acid ester having a fatty acid having 10 to 26 carbon atoms. More specifically, polyoxyethylene sorbitan monostearate (polysorbate 60), oleic acid Polyoxyethylene sorbitan (polysorbate 80), polyoxyethylene sorbitan monopalmitate (polysorbate 40) and the like.

  Examples of the polyoxyalkylene fatty acid ester include a polyoxyethylene fatty acid ester having 10 to 26 carbon atoms of a fatty acid and a polyoxypropylene fatty acid ester having 10 to 26 carbon atoms of a fatty acid.

  Examples of the alkylene glycol fatty acid ester include an ethylene glycol fatty acid ester having 10 to 26 carbon atoms of a fatty acid and a propylene glycol fatty acid ester having 10 to 26 carbon atoms of a fatty acid, and specifically, propylene glycol monostearate. And the like.

  Examples of the polyoxyalkylene alkyl ether include a polyoxyethylene alkyl ether having an alkyl group having 10 to 26 carbon atoms, a polyoxypropylene alkyl ether having an alkyl group having 10 to 26 carbon atoms, and specifically, And polyoxyethylene cetyl ether.

  Examples of the glycerin fatty acid ester include glycerin fatty acid esters having 10 to 26 carbon atoms in the fatty acid, and specific examples include glyceryl monostearate and glyceryl malate monostearate.

  Examples of the polyglycerin fatty acid ester include a polyglycerin fatty acid ester having 10 to 26 carbon atoms in the fatty acid, and specifically, polyglyceryl monoisostearate, polyglyceryl diisostearate and the like.

  Examples of sorbitan fatty acid esters include, for example, sorbitan fatty acid esters having 10 to 26 carbon atoms of fatty acids, and specifically, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, Diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate, and the like.

  Examples of the polyoxyalkylene fatty acid glyceryl include polyoxyethylene fatty acid glyceryl having 10 to 26 carbon atoms in the fatty acid, and specific examples include polyoxyethylene monococo oil fatty acid glyceryl.

  Examples of the glycerin alkyl ether include a glycerin alkyl ether having an alkyl group having 2 to 100 carbon atoms.

  Examples of the alkyl glucoside include an alkyl glucoside having an alkyl group having 2 to 100 carbon atoms.

  Among these nonionic surfactants, for the nonionic surfactant containing a polyoxyalkylene group, the number of moles of the polyoxyalkylene is not particularly limited, but is, for example, 20 to 80 mol, preferably 40 mol. To 60 mol.

  Among these nonionic surfactants, from the viewpoint of further improving the anti-inflammatory effect, preferably polyoxyalkylene-hardened castor oil, polyoxyalkylene sorbitan fatty acid ester; more preferably polyoxyethylene-hardened castor oil, polyoxy Ethylene sorbitan fatty acid ester; more preferably polyoxyethylene hydrogenated castor oil; polyoxyethylene sorbitan fatty acid ester having 5 to 200 carbon atoms of fatty acid; particularly preferably polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan oleate (polysorbate 80) ); Most preferably, polyoxyethylene hydrogenated castor oil.

  These nonionic surfactants may be used alone or in a combination of two or more.

  When two or more nonionic surfactants are used as the component (C), the mode of combination is not particularly limited, but as an example of a suitable combination, two or more polyoxyethylene cured castors are used. A combination of oils, particularly preferably polyoxyethylene (40) hydrogenated castor oil (hereinafter sometimes referred to as the (Ca) component) and polyoxyethylene (60) hydrogenated castor oil (hereinafter referred to as the (Cb) component) In some cases). When the component (B) is used in combination with the component (Ca) and the component (Cb), the mixing ratio is not particularly limited, but as an example, the component (Cb) is 100 parts by weight per 100 parts by weight of the component (Ca). To 1000 parts by weight, preferably 200 to 400 parts by weight.

  The content of the component (C) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.1 to 20% by weight, preferably 1 to 15% by weight, and more preferably 3 to 10% by weight. Can be

  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 more effectively exerts an anti-inflammatory analgesic effect. From the viewpoint, the range of 5 to 10,000 parts by weight, preferably 66 to 3000 parts by weight, more preferably 230 to 1430 parts by weight, per 100 parts by weight of the component (A) is exemplified.

Other Ingredients The external pharmaceutical composition of the present invention may contain a pharmacological component, if necessary, in addition to the aforementioned components, as long as the effects of the present invention are not hindered. The pharmacological components that can be added to the external pharmaceutical composition of the present invention are not particularly limited. For example, anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and the like Pharmaceutically acceptable salts, antihistamines such as chlorpheniramine maleate; lidocaine and its pharmaceutically acceptable salts, dibucaine and its pharmaceutically acceptable salts, local anesthetics such as ethyl aminobenzoate; nicotine Blood circulation promoters such as benzyl acid ester, tocopherol acetate, and pepper tincture; Arnica tincture, oak extract, sanshishi extract, horse chestnut extract, funnel extract, belladonna extract, touki extract, sicon extract, sanshoe Herbal medicines such as vinegar and the like.

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

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

  Examples of the oil base include non-polar oils and polar oils. Specific examples of the nonpolar oil include hydrocarbons such as paraffin and isoparaffin; squalane and wax. Specific examples of the polar oil 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 esters include, for example, isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, isotridecyl isononanoate, isononyl isononanoate, cetyl 2-ethylhexanoate, myristyl myristate, hexadecyl isostearate, octanoic acid Cetyl, cetyl isooctanoate and the like can be mentioned. These aliphatic monocarboxylic acid esters may be used alone or in a 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- Palmitooleoyl-2-stearoyl-3-linoleoylglycerol, 1-linoleoyl-2-palmitooleoyl-3-stearoylglycerol, and the like. One of these triglycerides may be used alone, or two or more thereof may be used in combination.

  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 diesters may be used alone or in combination of two or more.

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

  Examples of the higher fatty acids 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, linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, and the like. . 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, as necessary, other additives usually used in the external pharmaceutical composition, in addition to the components described above. Such additives include, for example, pH adjusters, surfactants (other than nonionic surfactants), emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, Examples include a thickener, a fragrance, and a coloring agent.

  The surfactant (other than the nonionic surfactant) that can be incorporated into the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include an anionic surfactant, a cationic surfactant, and a zwitterionic surfactant. Surfactants. One of these surfactants may be used alone, or two or more thereof may be used in combination.

  The thickener that can be added to the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include hyaluronic acid and xanthan gum.

pH
The pH of the pharmaceutical composition for external use of the invention is set to 6.1 or more. By including the components (A) to (D) and setting the pH to 6.1 or more, the anti-inflammatory effect can be dramatically improved, and an excellent anti-inflammatory and analgesic effect can be exhibited.

  The pH of the externally applied pharmaceutical composition of the present invention is preferably 6.1 to 7.4, more preferably 6.1 to 7.1, particularly preferably 6 from the viewpoint of exhibiting an anti-inflammatory and analgesic effect more effectively. .1 to 6.6.

  The pH of the external pharmaceutical composition of the present invention is adjusted 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. You can do this by doing

Formulation The formulation of the external pharmaceutical composition of the present invention is not particularly limited as long as it can be applied transdermally, and examples thereof include liquids (including lotions, sprays, aerosols, and emulsions), Foams, ointments, creams, gels, patches and the like can be mentioned. Among these, a liquid agent or a gel agent is preferable. Preparation into these dosage forms can be carried out by formulating with an additive according to the dosage form according to a known method described in the 16th Revised Japanese Pharmacopoeia General Rules for Preparations and the like.

The pharmaceutical composition for external use of the invention is used by external application to a topical (skin) where antiphlogistic analgesia is required. The dose of the external pharmaceutical composition of the present invention is appropriately set depending on the site to be administered, the degree of the symptom to be treated, and the like, but per 1 cm ^{2 of} the local site to be administered, diclofenac and / or its pharmaceutically acceptable amount. It is desirable that the dose per dose of the salt be about 10 to 500 mg.

  The topical pharmaceutical composition of the present invention is used as an anti-inflammatory analgesic for external use, such as shoulder pain, joint pain, lower back pain, muscle pain, tendonitis (hand / wrist pain), elbow pain (tennis elbow, etc.), bruise pain associated with stiff shoulders , Sprain pain, bone fracture pain, neuralgia, osteoarthritis, arthritis and the like.

2. Method for improving anti-inflammatory analgesic effect As described above, in the external pharmaceutical composition containing the component (A), the components (B) to (C) are added to improve the anti-inflammatory analgesic effect of the external pharmaceutical composition. be able to. Accordingly, the present invention further provides (A) a method for improving the anti-inflammatory and analgesic effect of an external pharmaceutical composition comprising diclofenac and / or a pharmaceutically acceptable salt thereof, wherein the external pharmaceutical composition comprises (B) Disclosed is a method for improving an anti-inflammatory and analgesic action, which comprises mixing a cellulosic water-soluble polymer compound and (C) a nonionic surfactant.

  In these methods for improving anti-inflammatory analgesic action, the types and amounts of components used, pH and formulation of the topical pharmaceutical composition, and the like are as described in the above-mentioned “1. .

  Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Test Example 1: Relationship between combination of each component and anti-inflammatory effect (pharmacological test)
An external pharmaceutical composition (gel) having the composition shown in Table 1 was prepared. The following tests were performed to evaluate the anti-inflammatory effect of each topical pharmaceutical composition. In addition, the measurement of the pH of the pharmaceutical composition for external use of the following Examples and Comparative Examples was performed under a temperature condition of 25 ° C.

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

  Each topical pharmaceutical composition (220 mg) was applied to the right hind paw of each group of rats, and immediately thereafter, 100 μl of a 1% by weight carrageenin solution was intradermally administered to the right hind footpad under anesthesia to induce acute inflammation. . Two, four, and six hours after the administration, the right hind paw volume was measured by a paw volume measurement device (MK-101 CMP, Muromachi Kikai Co., Ltd.). In addition, as a control, the volume of the right hind paw was measured under the same conditions as above except that the administration of the external pharmaceutical composition was not performed. Using the measured value of the right hind paw volume, the paw volume increase rate was evaluated according to the following formula. Since the degree of the induced acute inflammation is reflected in the degree of increase in foot volume, the lower the rate of increase in foot volume, the stronger the anti-inflammatory effect.

Foot volume relative increase rate (%) = X / Y × 100
X: value at each measurement time point after carrageenin administration Y: value before carrageenin administration

  The results obtained are shown in FIG. From these results, when hydroxypropylcellulose and polyoxyethylene hydrogenated castor oil were used together with diclofenac sodium (Example 1), the quenching was significantly higher than when diclofenac sodium was used alone (Comparative Example 1). An effect was observed.

Test Example 2: Relationship between combination of each component and anti-inflammatory effect (human test)
An external pharmaceutical composition (liquid) having the composition shown in Table 2 was prepared. The following tests were performed to evaluate the anti-inflammatory effect of each topical pharmaceutical composition.

  An appropriate amount (0.5 g) of each pharmaceutical composition for external use was applied to the shoulders of four subjects experiencing stiff shoulders. Then, during 2 hours after application, a VAS (Visual Analogue Scale) evaluation was performed with the time “10” for “feeling shoulder stiffness” and the point “0 for no feeling stiff shoulder”. The degree of shoulder stiffness due to application was scored, and the average value of the scores of shoulder stiffness was calculated for each of the externally applied pharmaceutical compositions.

  FIG. 2 shows the obtained results. From these results, when an external pharmaceutical composition containing a cellulose-based water-soluble polymer compound and a nonionic surfactant together with diclofenac sodium (Examples 2 and 3), the cellulose-based water-soluble polymer compound or non-cellulose was used. When only one of the ionic surfactants was used (Comparative Examples 2 and 3), it was confirmed that the degree of shoulder stiffness was significantly improved as compared with the case where diclofenac sodium was solely contained (Comparative Example 4). Was done. From the above results, it was clarified that an excellent anti-inflammatory analgesic effect was obtained for the first time by using a cellulose-based water-soluble polymer compound and a nonionic surfactant together with diclofenac sodium. In addition, in the topical pharmaceutical compositions of Examples, when polyoxyethylene hydrogenated castor oil was used as the nonionic surfactant (Example 2), it was clear that a more excellent anti-inflammatory and analgesic effect was obtained. It became.

Formulation Examples Pharmaceutical compositions for external use (gels) having the compositions shown in Tables 3 and 4 were prepared. The anti-inflammatory action of each of the obtained external pharmaceutical compositions was tested in the same manner as in Test Example 2 above, and all excellent anti-inflammatory actions were observed.

Claims (4)

An external pharmaceutical composition comprising (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) hydroxypropylcellulose, and (C) polyoxyalkylene hydrogenated castor oil .   The external pharmaceutical composition according to claim 1, which is a gel or a liquid.   The composition for external use according to claim 1 or 2, wherein the content of the component (C) is 5 to 20% by weight. (A) A method for improving the anti-inflammatory and analgesic effect of an externally applied pharmaceutical composition comprising diclofenac and / or a pharmaceutically acceptable salt thereof,
A method for improving an anti-inflammatory and analgesic effect, comprising blending (B) hydroxypropylcellulose and (C) polyoxyalkylene-hardened castor oil into the external pharmaceutical composition.