JP2014196372A - Pharmaceutical composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an analgesic pharmaceutical composition for external use including diclofenac or a salt thereof as an anti-inflammatory ingredient, and exhibiting excellent analgesic effects by improving the analgesic effects thereof.SOLUTION: The pharmaceutical composition for external use is prepared by formulating 0.5 to 1.5 wt.% of diclofenac or pharmaceutically acceptable salt thereof, and 5 to 15 wt.% of a refreshing agent in the composition.

Description

  The present invention relates to an external pharmaceutical composition, specifically, an external pharmaceutical composition used for anti-inflammatory analgesia. More specifically, the present invention relates to an external pharmaceutical composition excellent in analgesic effect comprising diclofenac, which is a nonsteroidal anti-inflammatory analgesic component, or a pharmaceutically acceptable salt thereof as an active ingredient.

  Diclofenac and its pharmaceutically acceptable salts are excellent non-steroidal anti-inflammatory analgesics. Previously, it was used as an internal preparation or suppository, but when administered orally or rectally, gastrointestinal, renal or liver damage may occur as a side effect, and especially serious problems related to the gastrointestinal tract. Recently, application as an external preparation is increasing.

  However, diclofenac and its pharmaceutically acceptable salts are poorly absorbed from the skin, and the therapeutic effect over the internal use is not obtained. By combining various ingredients, for example, transdermal absorption is possible. Attempts to improve the analgesic effect have been studied.

  For example, Patent Document 1 discloses diclofenac or a pharmaceutically acceptable salt thereof by combining diclofenac or a pharmaceutically acceptable salt thereof with a gel base obtained by neutralizing a gelling agent with an alkylamine. It is described that the transdermal absorbability is improved, and that menthol is further used to further improve the transdermal absorbability.

  In Patent Document 2, non-steroidal anti-inflammatory components such as diclofenac sodium are mixed with essential oils such as bergamot and warming-inducing components such as nonylic acid vanillylamide to apply to shoulder and neck stiffness. It is described that the effect can be immediately realized and a high therapeutic effect can be exhibited.

  Patent Document 3 discloses a non-steroidal anti-inflammatory agent, 0.0001 to 5% by weight of a warming-imparting substance, and 0.1% by weight or more of a refreshing agent. The effect of the external pharmaceutical composition used in combination at a ratio of 1: 0.1 to 1: 0.0001 can be realized with a smaller blending amount than when the warming substance and the refreshing agent are used alone. Since this can reduce skin irritation, it is described that it is excellent in use feeling and safety.

  Patent Document 4 discloses that non-steroidal anti-inflammatory agent selected from indomethacin, ketoprofen and flurbiprofen is 0.1 to 5% by weight, capsaicin and / or nonyl acid vanillylamide is 0.001 to 0.1% by weight. It is described that the therapeutic effect on inflammation is drastically improved by combining%, and that menthol may be added thereto.

JP-A-7-267854 JP 2004-175723 A JP-A-11-199522 JP-A-5-1065628

  The present invention relates to an external pharmaceutical composition for analgesia containing diclofenac or a pharmaceutically acceptable salt as an active ingredient, and the external pharmaceutical composition exhibiting an excellent analgesic effect by improving the analgesic effect. The purpose is to provide.

  The present inventor made extensive studies to solve the above problems, and as an external pharmaceutical composition using a specific amount of a diclofenac or a pharmaceutically acceptable salt thereof in combination with a specific amount of a cooling agent, By preparing as a liquid agent, the analgesic effect of diclofenac or a pharmaceutically acceptable salt thereof is further improved, and further by adding a warming component to the composition at a specific ratio, diclofenac or a pharmaceutical thereof can be further added. It was found that the analgesic effect of a salt allowed to be further improved, and the present invention was completed. In particular, the external pharmaceutical composition of the present invention containing a specific amount of a cooling agent and a warming component in diclofenac or a pharmaceutically acceptable salt thereof has a cooling sensation immediately after application, and then gradually has a burning sensation. In this way, a sense of effectiveness can be realized.

  The present invention has been completed based on such findings and has the following aspects.

(I) External pharmaceutical composition (I-1). An external pharmaceutical composition comprising 0.5 to 1.5% by weight of diclofenac or a pharmaceutically acceptable salt thereof and 5 to 15% by weight of a refreshing agent.
(I-2). The pharmaceutical composition for external use described in (I-1), which comprises 3 to 20 parts by weight of a refreshing agent with respect to 1 part by weight of diclofenac or a pharmaceutically acceptable salt thereof.
(I-3). The external pharmaceutical composition described in (I-1) or (I-2), wherein the refreshing agent is menthol.
(I-4). The external pharmaceutical composition according to any one of (I-1) to (I-3), which is used for analgesic use.
(I-5). The pharmaceutical composition for external use according to any one of (I-1) to (I-4), which is a liquid.
(I-6). The pharmaceutical composition for external use described in (I-1), further comprising a warming component.
(I-7). The pharmaceutical composition for external use described in (I-6), which contains a warm sensation component in a proportion of 0.002 to 0.2% by weight, preferably 0.003 to 0.1% by weight.
(I-8). The external pharmaceutical composition as described in (I-6) or (I-7), wherein the refreshing agent is l-menthol.
(I-9). The pharmaceutical composition for external use according to any one of (I-6) to (I-8), wherein the warming component is nonanoic acid vanillylamide.
(I-10). The external pharmaceutical composition according to any one of (I-6) to (I-9), which is used for analgesic use.
(I-11). The pharmaceutical composition for external use according to any one of (I-6) to (I-10), which is a liquid agent.
(I-12). The pharmaceutical composition for external use according to any one of (I-1) to (I-11), which has an application form.

(II) Method for improving analgesic action of external pharmaceutical composition (II-1). A method for improving the analgesic effect of an external pharmaceutical composition comprising diclofenac or a pharmaceutically acceptable salt thereof as an active ingredient, wherein 0.5 to 0.5% of diclofenac or a pharmaceutically acceptable salt thereof is added to the external pharmaceutical composition. A method comprising blending 1.5% by weight of a refreshing agent in a proportion of 5 to 15% by weight.
(II-2). The method according to (II-1), further comprising a warming component.
(II-3). (II-1) or (II), wherein the warming ingredient is blended in the external pharmaceutical composition in a proportion of 0.002 to 0.2% by weight, preferably 0.003 to 0.1% by weight. -2) The method described in any one of the above.
(II-4). The method according to any one of (II-1) to (II-3), wherein the refreshing agent is l-menthol.
(II-5). The method according to any one of (II-2) to (II-4), wherein the warming sensation component is nonanoic acid vanillylamide.
(II-6). The method according to any one of (II-1) to (II-5), wherein the external pharmaceutical composition is a liquid.
(II-7). The method according to any one of (II-1) to (II-6), wherein the external pharmaceutical composition has a coating form.

  According to the pharmaceutical composition for external use of the present invention comprising a specific amount of diclofenac or a pharmaceutically acceptable salt thereof and a specific amount of a refreshing agent in combination, in particular, by preparing it as a solution, diclofenac or a pharmaceutical agent thereof Can be provided as a pharmaceutical composition for external use that can improve the analgesic effect of a salt that is acceptable to the skin and exhibits excellent analgesic effect on stiff shoulders, low back pain, muscle pain and the like.

  Moreover, the analgesic effect of diclofenac or a pharmaceutically acceptable salt thereof can be further improved by further adding a warming component to the composition at a specific ratio. Such an external pharmaceutical composition has a refreshing sensation immediately after application and then gradually a burning sensation, thereby reducing analgesic feeling and allowing the user to feel a sense of effectiveness both in terms of immediate effect and sustainability. It is a pharmaceutical composition for external use with excellent use feeling.

I. External pharmaceutical composition and method for preparing the same The external pharmaceutical composition of the present invention comprises (a) diclofenac or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “component (a)”), and (b) a cooling agent. (Hereinafter also referred to as “component (b)”) at a specific ratio.

(A) Diclofenac or a pharmaceutically acceptable salt thereof Diclofenac [2- (2- (2,6-dichlorophenylamino) phenyl) acetic acid] contained as an active ingredient in the externally applied pharmaceutical composition of the present invention has anti-inflammatory analgesic action. It is a non-steroidal compound having

  In the present invention, in addition to diclofenac itself, pharmaceutically acceptable salts thereof can also be used. Such salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium; salts with ammonia; primary, secondary or tertiary such as dimethylamine, diethylamine, trimethylamine and triethylamine. And salts with primary, secondary or tertiary alkanolamines such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine and triisopropanolamine. Alkali metal salts such as sodium salt and potassium salt are preferable, and sodium salt is more preferable. These salts can be used in any combination.

  If the proportion of the component (a) contained in 100% by weight of the external pharmaceutical composition of the present invention is less than 0.5% by weight, the analgesic effect of the composition itself is weakened and exceeds 1.5% by weight. And since the synergistic improvement of the analgesic effect by mix | blending a (b) component will not be seen, it is 0.5 to 1.5 weight% normally. Preferably it is 0.5-1.2 weight%, More preferably, it is 0.5-1.0 weight%.

(B) Refreshing agent In the pharmaceutical composition for external use of the present invention, the refreshing agent used in combination with the above-mentioned diclofenac or a pharmaceutically acceptable salt thereof includes 1-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, menthanum, menthyl lactate, geraniol, eucalyptus oil, terpene oil, bergamot oil, fennel oil, peppermint oil (peppermint), rose oil, cool mint, etc. be able to. These cooling agents may be used alone or in any combination of two or more.

  Preferred are l-menthol, d-menthol, dl-menthol, d-borneol, dl-borneol, menthane, peppermint oil (peppermint), and cool mint, and more preferred is menthol, particularly l-menthol.

  If the proportion of the component (b) contained in 100% by weight of the external pharmaceutical composition of the present invention is less than 5% by weight, a synergistic improvement in the analgesic effect can be seen even when combined with a specific amount of the component (a). Moreover, when it exceeds 15% by weight, the analgesic effect per blending unit amount of the refreshing agent is suppressed or skin irritation becomes strong, so the amount is usually 5 to 15% by weight. In particular, from the viewpoint of the balance between analgesic effect and skin irritation, it is preferably 5 to 10% by weight, more preferably 6 to 8% by weight.

  In addition, it is preferable to set the ratio of the said (b) component in consideration of the ratio with respect to the said (a) component contained in an external pharmaceutical composition. Specifically, the ratio of the component (b) is usually set in the range of 3 to 20 parts by weight with respect to 1 part by weight of the component (a) contained in the external pharmaceutical composition, preferably 4 -15 parts by weight, more preferably 5-10 parts by weight.

(C) Warm sensation component In the pharmaceutical composition for external use of the present invention, in addition to the above-mentioned diclofenac or a pharmaceutically acceptable salt thereof (component (a)) and a cooling agent (component (b)), further a warm sensation component (Hereinafter also referred to as “component (c)”).

  Examples of the warming component used in the present invention include capsaicins such as capsicoside, capsaicin, capsaicinoside, dihydroxycapsaicin, and capsaicin; capsicum such as capsicum extract, capsicum tincture, and capsicum powder; benzyl nicotinate, nicotinic acid β -Butoxyethyl, N-acylvanylamide, nonanoic acid vanillylamide and the like can be mentioned. These warm feeling components may be used alone or in any combination of two or more. Nonanoic acid vanillylamide is preferable.

  The proportion of the component (c) contained in 100% by weight of the external pharmaceutical composition of the present invention varies depending on the proportion of the component (a) and the component (b) contained in the external pharmaceutical composition, but is usually 0.002 to 0. .2% by weight, preferably 0.003 to 0.1% by weight, more preferably 0.003 to 0.05% by weight, still more preferably 0.005 to 0.02% by weight. Particularly preferred is 0.01 to 0.015% by weight. Within this range, a particularly excellent analgesic effect can be exhibited in an external pharmaceutical composition containing specific amounts of the component (a) and the component (b).

  In addition, the ratio of the said (c) component can also be set in consideration of the ratio with respect to the said (a) component contained in an external pharmaceutical composition. Specifically, the proportion of the component (c) is usually set in the range of 0.002 to 0.2 parts by weight with respect to 1 part by weight of the component (a) contained in the external pharmaceutical composition. , Preferably 0.003 to 0.1 parts by weight, more preferably 0.003 to 0.05 parts by weight, still more preferably 0.005 to 0.02 parts by weight, particularly preferably 0.01 to 0.015 parts by weight. Part.

  Moreover, it can also set in consideration of the mixture ratio with (b) component contained in an external pharmaceutical composition. Specifically, the ratio (weight ratio) of the component (b) and the component (c) contained in the external pharmaceutical composition is set in the range of 25: 1 to 7500: 1, preferably 100 : 1 to 3500: 1, more preferably 400: 1 to 800: 1.

(D) Other components In the pharmaceutical composition for external use of the present invention, a medicinal aid can be blended as another component in addition to the above components as long as the effects of the present invention are not hindered. Such medicinal aids 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, sanshi extract, horse chestnut extract, funnel extract, belladonna extract, toki extract, shikon extract, and salamander extract.

  In addition to the above-mentioned components, the external pharmaceutical composition of the present invention can be applied to normal external pharmaceutical compositions such as appropriate active ingredients, pH regulators, preservatives, preservatives, antioxidants and stabilizers. Additives used can be blended as appropriate.

(E) Form and Production Method The form of the external pharmaceutical composition of the present invention is not particularly limited, but the analgesic effect obtained by combining the component (a) with the component (b) and further the component (c). From the point of synergistic effect, it should have a coating form such as liquid (including lotions, sprays, aerosols, and emulsions), foams, ointments, creams, or gels, not patches. Is preferred. More preferably, it is a liquid agent.

  The pharmaceutical composition for external use of the present invention can be prepared according to a conventional method depending on the formulation form. For example, (a) diclofenac or a pharmaceutically acceptable salt thereof, and (b) a refreshing agent, or in addition to these components, (c) a warming component is used in an external preparation as described below. An example is a method in which a general-purpose base is added and dissolved or dispersed to adjust to a desired pH. 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 preparing the pharmaceutical composition for external use of the present invention as a liquid preparation, in addition to (b) a cooling agent, or (b) component in addition to (b) a component, Lower alcohols having 1 to 6 carbon atoms (for example, aliphatic alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and the like, preferably ethanol), glycols (for example, glycerin, propylene glycol, 1,3-butylene glycol, octanediol, ethylene glycol, polyethylene glycol, D-sorbitol, preferably glycerin, propylene glycol or 1,3-butylene glycol), water, and optionally an emulsifier (Sorbitan fatty acid ester, glycerin fatty acid ester, poly Nonionic surfactants such as oxyethylene sorbitan fatty acid ester, polyoxyl stearate and lauromacrogol are preferred).

  Moreover, when setting it as a gel agent, in addition to (b) refreshing agent or (b) component in addition to (a) component, (c) warm feeling component is mix | blended, This is a C1-C6 lower alcohol ( Examples thereof include aliphatic alcohols such as methanol, ethanol, propyl alcohol and isopropyl alcohol, preferably ethanol), glycols (for example, glycerin, propylene glycol, 1,3-butylene glycol, octanediol) , Ethylene glycol, polyethylene glycol, D-sorbitol, preferably glycerin, propylene glycol or 1,3-butylene glycol), water, and optionally cellulose-based water-soluble polymer compound Can be prepared.

  In addition, in the case of a cream or ointment, (b) a cooling agent or (c) a warming component in addition to (b) a component is added to (a) component, and a liquid oily substance (for example, fluid A cream base comprising a hydrocarbon such as paraffin, a higher fatty acid ester such as isopropyl myristate, a higher alcohol such as octyldodecanol, glycols (same as described above), an emulsifier (same as described above), and water. It can be prepared by blending.

  The blending amount of the other components other than the components (a) to (c) in the external pharmaceutical composition of the present invention is not particularly limited as long as it can be formulated. For example, the blending ratio of the lower alcohol is the external pharmaceutical 0 to 90% by weight, preferably 25 to 80% by weight, more preferably 50 to 80% by weight in 100% by weight of the composition; the blending ratio of glycols is 0 to 30% by weight in 100% by weight of the external pharmaceutical composition, Preferably 5 to 15% by weight; The mixing ratio of water can be 0 to 75% by weight, preferably 5 to 50% by weight in 100% by weight of the external pharmaceutical composition.

  The external pharmaceutical composition of the present invention is preferably prepared as an external preparation (solution, foam, gel, cream, or ointment) in the above-described application form, and can be locally administered externally. The dosage of the external pharmaceutical composition of the present invention depends on the degree of the symptom to be treated, but (a) diclofenac or a pharmaceutically acceptable salt thereof which is an active ingredient contained therein It is desirable that the applied dose per unit be about 0.2 to 5 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 preferably used for the purpose of analgesia against pains such as pain, fractures, and neuralgia.

II. Method for improving analgesic action of external pharmaceutical composition The method of the present invention comprises (a) 0.5 to 1.5% by weight of diclofenac or a pharmaceutically acceptable salt thereof in the external pharmaceutical composition, a cooling agent Can be carried out by blending 5 to 15% by weight.

  The target component (a) and component (b) are as described in (I) above. A preferred pharmaceutically acceptable salt of diclofenac is diclofenac sodium or potassium, more preferably diclofenac sodium. The component (b) is preferably menthol, particularly l-menthol.

  The proportion of the component (a) to be blended in the external pharmaceutical composition is as described above, preferably 0.5 to 1.2% by weight, more preferably 0.5 to 1% by weight. Moreover, although the ratio of the component (b) mix | blended with an external pharmaceutical composition is also as above-mentioned, Preferably it is 5 to 10 weight%, More preferably, it is 6 to 8 weight%.

  In addition, it is preferable to set the ratio of the said (b) component in consideration of the ratio with respect to the said (a) component contained in an external pharmaceutical composition. Specifically, the ratio of the component (b) is usually set in a range of more than 3 parts by weight and less than 20 parts by weight with respect to 1 part by weight of the component (a) contained in the external pharmaceutical composition. The Preferably it is 4-15 weight part, More preferably, it is 5-10 weight part.

  In addition, in the method of the present invention, a method that can achieve a higher effect is a method in which, in addition to the components (a) and (b) described above, (c) a warming component is added to the external pharmaceutical composition. . The component (c) is also as described in the above (I), and the preferred (c) warming component is nonanoic acid vanillylamide.

  The proportion of the component (c) to be blended in the external pharmaceutical composition varies depending on the proportion of the component (a) and the component (b) contained in the external pharmaceutical composition, but is usually in the range of 0.002 to 0.2% by weight. Preferably 0.003 to 0.1% by weight, more preferably 0.003 to 0.05% by weight, still more preferably 0.005 to 0.02% by weight, particularly preferably 0.01. -0.015 wt%.

  Moreover, it can also set in consideration of the mixture ratio with the (a) component contained in an external pharmaceutical composition. Specifically, the proportion of the component (c) is usually set in the range of 0.002 to 0.2 parts by weight with respect to 1 part by weight of the component (a) contained in the external pharmaceutical composition. , Preferably 0.003 to 0.1 parts by weight, more preferably 0.003 to 0.05 parts by weight, still more preferably 0.005 to 0.02 parts by weight, particularly preferably 0.01 to 0.015 parts by weight. Part.

  Moreover, it can also set in consideration of the mixture ratio with (b) component contained in an external pharmaceutical composition. Specifically, the ratio (weight ratio) of the component (b) and the component (c) contained in the external pharmaceutical composition is set in the range of 25: 1 to 7500: 1, preferably 100 : 1 to 3500: 1, more preferably 400: 1 to 800: 1.

  According to the method of the present invention, the analgesic effect of the component (a) can be synergistically improved by using the component (a) and the component (b) in combination at the specific blending ratio. Moreover, in addition to said (a) component and (b) component, by using (c) component in combination, the analgesic effect obtained when combining (b) component with (a) component is improved further. be able to. Therefore, the method of the present invention can be effectively used to provide an external pharmaceutical composition excellent in analgesic effect, particularly an external pharmaceutical composition having an application form, preferably a liquid form.

  Hereinafter, although an example of an experiment and an example are given and the present invention is explained, the present invention is not limited to these examples. In the table, the unit represents “% by weight”.

Experimental Example 1 Analgesic Evaluation Test Using Rats The components described in Tables 1 to 3 were mixed and the pH was adjusted to 7, thereby preparing a liquid external pharmaceutical composition (total 100% by weight) (Example 1 and 2, Comparative Examples 1-7). For comparison experiments, as shown in Tables 2 and 3, solutions were prepared in the same manner using indomethacin and felbinac in place of diclofenac sodium (Comparative Examples 2 to 7).

(1) Test method The obtained liquid preparation was subjected to the Randall Cerit analgesia test described below, and the analgesic action of each liquid preparation was evaluated.

<Randal Cerit analgesia test>
Using a pressure-stimulated analgesic effect measuring device (TK-201, Muromachi Kikai Co., Ltd.) on the right hind footpad of a rat, a pressure load was applied and an avoidance reaction threshold pressure was measured.

  Yeast as a flame retardant was administered to the right hind footpad subcutaneously in Wistar male rats (Japan SLC Co., Ltd., 8 animals / group) in a volume of 0.1 mL / animal.

  Immediately thereafter, 110 μL (approx. 100 mg equivalent) of the external pharmaceutical composition of Examples 1 and 2 and Comparative Examples 1 to 7 was applied to the same footpad using a micropipette, and then immediately covered with a wrap film and sealed. Protect clothes with elastic bandages, and attach plastic necklaces (Elizabeth Color, Bioresearch Center Co., Ltd.) to avoid ingestion and store them in individual cages.

  The avoidance reaction threshold pressure was measured three times 4 hours after administration of yeast driven, and the average value was calculated. It was judged that the analgesic effect was high if the measured pressure was large, and the analgesic effect was low if the measured pressure was small.

  When diclofenac sodium was used as the anti-inflammatory analgesic component, the measured value of Comparative Example 1 was measured, the measured value of Comparative Example 2 was used when indomethacin was used, and the measured value of Comparative Example 4 was used when felbinac was used. %), The relative values of the measured values of each Example and Comparative Example were calculated, and each analgesic action was evaluated according to the following criteria.

<Evaluation criteria>
○: 150% or more ×: less than 150%

(2) Test results The results are shown in Tables 1 to 3.

  In Table 1, from the comparison between Comparative Example 1 and Example 1, diclofenac sodium was added to 1% by weight by adding 6% by weight of 1-menthol to 1% by weight of diclofenac sodium. Thus, it was found that the analgesic effect was remarkably improved as compared with the liquid preparation of Comparative Example 1 containing 1-menthol at a ratio of 3% by weight.

  As can be seen from the results of Comparative Examples 2 and 3 shown in Table 2 and Comparative Examples 4 to 7 shown in Table 3, the effect of diclofenac sodium is that a specific amount of l-menthol is used in combination with a specific amount of diclofenac sodium. It is a peculiar thing obtained by.

  Further, from the results of Examples 1 and 2, Example 2 in which 1% by weight of diclofenac sodium and 6% by weight of l-menthol was further mixed with vanillylamide nonanoic acid was 1% by weight of diclofenac sodium and 6% by weight of l-menthol. It was found that the analgesic effect was remarkably improved as compared with Example 1 containing at a ratio of%.

Experimental Example 2 Analgesic Evaluation Test Using Rats In the same manner as in Experimental Example 1, the results of Experimental Example 1 were received, and the ratio of the refreshing agent to diclofenac sodium blended in the external pharmaceutical composition (total 100% by weight) was changed. Thus, the analgesic action of each solution was evaluated.

  Specifically, the components listed in Table 4 were mixed and the pH was adjusted to 7, thereby preparing liquid external pharmaceutical compositions (Examples 3 to 6, Comparative Examples 1 and 8). These were subjected to the Randall Cerit analgesia test in the same manner as in Experimental Example 1, and from the obtained results, the measured values of each Example and Comparative Example when the measured value of Comparative Example 1 was “100” (%) The relative value for was calculated. Further, the calculated value was divided by the blending amount of 1-menthol, and the analgesic effect per 1% by weight of the refreshing agent was calculated as “the analgesic effect per unit amount of menthol”. The results are also shown in Table 4.

  From this result, when 5 to 15% by weight of 1-menthol is added to 1% by weight of diclofenac sodium, it exhibits a very excellent analgesic effect, and the analgesic effect per unit amount of l-menthol is greatly improved. There was found. From the results of the analgesic effect per unit amount of l-menthol, the analgesic effect is further improved by adjusting the blending ratio of 1-menthol to 5 to 10% by weight with respect to 1% by weight of diclofenac sodium. There was found. On the other hand, Comparative Example 1 in which 3% by weight of l-menthol was blended with 1% by weight of diclofenac sodium had a low analgesic effect and was not satisfactory in practical use. Further, it was found that when the amount of l-menthol exceeds 15% by weight, the analgesic effect per 1% by weight of l-menthol is suppressed, and it is difficult to improve the analgesic effect, and the skin irritation becomes strong.

Experimental Example 3 Analgesic Evaluation Test Using Rats According to the results of Experimental Example 2 above, each solution was prepared in the same manner as in Experimental Example 1, except that the proportion of diclofenac sodium to be added to the external pharmaceutical composition (total 100% by weight) was changed. The analgesic action of was evaluated.

  Specifically, the components listed in Table 5 were mixed and the pH was adjusted to 7, thereby preparing liquid external pharmaceutical compositions (Examples 1, 7-8, Comparative Examples 9-15). These were subjected to the Randall Cerit analgesia test in the same manner as in Experimental Example 1, and from the obtained results, the measured values obtained for the liquid preparations containing only diclofenac sodium (Comparative Examples 9-12, 14) were “100” (% ), Relative values for the measured values of the respective compositions (Examples 1, 7, 8 and Comparative Examples 13 and 15) were calculated, and each analgesic action was evaluated according to the above criteria. The results are also shown in Table 5.

  From this result, it was confirmed that when the blending amount of diclofenac sodium in the external pharmaceutical composition is 0.5 to 1.5% by weight, the synergistic effect of the analgesic effect by the l-menthol blending is remarkable (implementation) Example 1, Examples 7 and 8). On the other hand, when the compounding amount of diclofenac sodium in the external pharmaceutical composition exceeds 1.5% by weight, the analgesic effect due to diclofenac sodium alone increases in a concentration-dependent manner, but the synergistic effect of the analgesic effect by l-menthol formulation Was not recognized (Comparative Examples 13 and 15). Although the results are not shown, it was judged that when the compounding amount of diclofenac sodium in the external pharmaceutical composition was reduced to less than 0.5% by weight, the analgesic effect itself was low and impractical.

Experimental Example 4 Analgesic Evaluation Test Using Humans The components described in Table 6 were mixed, and the pH was adjusted to 7, thereby preparing a liquid external pharmaceutical composition (100% by weight in total) (Examples 1, 2, 9-17).

  What was packed in a roll-type container was applied to the shoulders of 10 subjects with a stiff shoulder, and the analgesic effect on the stiff shoulder after application was evaluated in the following five stages. The evaluation points of 10 subjects for each composition were added together, and the value was taken as the analgesic effect for each composition. The results are also shown in Table 6.

<Analgesic effect>
5 points: There was an analgesic effect 4 points: There was a little analgesic effect 3 points: Neither could be said 2 points: There was not much analgesic effect 1 point: There was no analgesic effect.

  From this result, in addition to diclofenac sodium and the refreshing agent of the external pharmaceutical composition, the analgesic effect obtained by the combined use of diclofenac sodium and the refreshing agent is further improved by adding a warming ingredient. It has been found. In particular, the effect of improving the analgesic effect obtained by using diclofenac sodium and l-menthol in combination by adding 0.003 to 0.1% by weight of the warming ingredient in the external pharmaceutical composition is remarkable. (Examples 10 to 17). In addition, there was no analgesic effect in the external pharmaceutical composition which does not mix | blend l-menthol and / or nonanoic acid vanillylamide.

Formulation Examples 1-48 (Liquid), Formulation Examples 49-53 (Gel) and Formulation 54 (Ointment)
According to the formulation examples described in Tables 7 to 11, they were prepared as usual. In these cases as well, good analgesic effects were shown as in the examples.

Claims (5)

  An external pharmaceutical composition comprising 0.5 to 1.5% by weight of diclofenac or a pharmaceutically acceptable salt thereof and 5 to 15% by weight of a refreshing agent.   The external pharmaceutical composition according to claim 1, wherein the composition comprises 3 to 20 parts by weight of a refreshing agent with respect to 1 part by weight of diclofenac or a pharmaceutically acceptable salt thereof.   The external pharmaceutical composition according to claim 1 or 2, wherein the refreshing agent is menthol.   The external pharmaceutical composition according to any one of claims 1 to 3, which is used for analgesia.   The external pharmaceutical composition according to any one of claims 1 to 4, which is a liquid preparation.