[實施發明之形態] [0009] 本發明之外用組成物為含有菸鹼酸之酯衍生物、與洛索洛芬或其藥學上可容許之鹽(洛索洛芬類)的組成物，其係含有相對於組成物全體為0.005～0.1質量%的該菸鹼酸之酯衍生物。 [0010] 1.菸鹼酸之酯衍生物 本發明之外用組成物係含有菸鹼酸之酯衍生物作為溫感作用之有效成分。 [0011] 就菸鹼酸之酯衍生物而言，係以藥學上可容許為限而不特別限制，可廣泛使用。可舉出例如菸鹼酸苯甲酯、菸鹼酸β-丁氧基乙酯及菸鹼酸甲酯等。此等菸鹼酸之酯衍生物可單獨使用1種，亦可組合使用2種以上。菸鹼酸之酯衍生物當中，較佳為菸鹼酸苯甲酯。 [0012] 本發明之外用組成物係含有相對於組成物全體為0.005～0.1質量%的菸鹼酸之酯衍生物。透過菸鹼酸之酯衍生物的含有比例相對於組成物全體為0.005質量%以上，可獲得充分的溫熱效果。透過菸鹼酸之酯衍生物的含有比例相對於組成物全體為0.1質量%以下，可顯著抑制皮膚塗佈後的發紅。依此觀點，菸鹼酸之酯衍生物的左述含有比例較佳為0.05質量%以下。 [0013] 2.洛索洛芬及其藥學上可容許之鹽(洛索洛芬類) 本發明之外用組成物係含有洛索洛芬類。本發明之外用組成物，透過與菸鹼酸之酯衍生物組合洛索洛芬類，可發揮抑制發紅之效果；此發紅係塗佈於皮膚後由菸鹼酸之酯衍生物所引起而產生於皮膚者。 [0014] 再者，本發明之外用組成物，透過與菸鹼酸之酯衍生物組合洛索洛芬類，亦可發揮抑制組成物全體的褐變之效果；此褐變係隨時間經過由洛索洛芬類所引起而產生者。 [0015] 雖不特別限定，惟洛索洛芬類亦可作為選自由解熱、鎮痛及消炎作用所成群組的至少一種作用之有效成分而摻混。 [0016] 洛索洛芬(2-[4-(2-側氧基環戊基甲基)苯基]丙酸)為一種具有解熱、鎮痛及消炎作用的丙酸系非類固醇性解熱鎮痛消炎劑(NSAID)。 [0017] 於本發明中，除洛索洛芬本身以外，亦可使用其藥學上可容許之鹽。所述鹽亦包含洛索洛芬或其藥學上可許容之鹽與水或醇等的溶劑合物。此等為周知之化合物，除可藉由周知之方法來製造外，亦可使用市售品。 [0018] 於本發明中，作為洛索洛芬或其藥學上可容許之鹽，較佳為洛索洛芬鈉水合物。 [0019] 洛索洛芬類的含量，只要是效能上有效的量即可，不特別限制。就其含量，相對於本發明之外用組成物全體，以無水洛索洛芬鈉換算，例如可取0.1～10質量%，較佳為0.5～5質量%，更佳為0.5～3質量%。 [0020] 此外，洛索洛芬類的比例，亦可考量其相對於外用組成物中所含之菸鹼酸之酯衍生物的比例來設定。具體而言，相對於外用組成物中所含之菸鹼酸之酯衍生物1質量份，洛索洛芬類的比例通常設定為10～1000質量份的範圍，較佳為10～500質量份，更佳為10～300質量份。 [0021] 3.碳數1～4之醇(低級醇) 本發明之外用組成物亦可進一步包含低級醇。低級醇不特別限定，只要是可發揮作為對上述有效成分屬有效之基劑的機能者則可廣泛使用。 [0022] 作為低級醇，具體而言可舉出例如甲醇、乙醇、丙醇及異丙醇等，較佳為乙醇。 [0023] 本發明之外用組成物較佳含有相對於組成物全體為55質量%以上的低級醇。藉此，本發明之外用組成物便可抑制歷時褐變。 [0024] 本發明之外用組成物，基於抑制皮膚刺激之觀點，較佳含有相對於組成物全體為90質量%以下的低級醇，更佳含有80質量%以下。 [0025] 本發明之外用組成物，基於歷時褐變的抑制效果之觀點，較佳含有相對於組成物全體為60質量%以上的低級醇。 [0026] 從而，本發明之外用組成物透過含有相對於組成物全體為55～90質量%的低級醇，不僅可抑制皮膚刺激，還可抑制外用組成物的歷時褐變；依此觀點，較佳含有相對於組成物全體為60～90質量%的低級醇，更佳含有60～80質量%。 [0027] 4.其他成分 本發明之外用組成物中，只要不妨害本發明之效果，則除了上述成分外，還可摻混其他的溫感作用劑。 [0028] 其他的溫感作用劑不特別限定，可廣泛使用。可單獨使用1種其他的溫感作用劑，亦可組合使用2種以上。作為其他的溫感作用劑，可舉出例如辣椒素類似物等。 [0029] 作為辣椒素類似物，可使用N-醯基香草基醯胺。N-醯基香草基醯胺為周知作為血液循環促進劑的化合物。 [0030] N-醯基香草基醯胺中的醯基可為直鏈狀或分支狀任一種。又，就N-醯基香草基醯胺中的醯基的碳數，不特別限制，可採用例如5～15，較佳為6～11等。 [0031] 作為N-醯基香草基醯胺，具體而言可舉出壬酸香草醯胺以及；辣椒素、二氫辣椒素、正二氫辣椒素、高辣椒素及高二氫辣椒素(homodihydrocapsaicin)等的辣椒素類等。 [0032] 於本發明中，辣椒素類似物可使用純化物，惟亦可使用除辣椒素類似物以外尚含有其他成分的混合物。作為此種包含辣椒素類似物的混合物，具體而言可舉出辣椒萃取物、辣椒酊及辣椒粉末等辣椒類。 [0033] 於本發明中，就辣椒素類似物而言，可單獨使用1種辣椒素類似物，亦可組合使用2種以上。辣椒素類似物當中，基於藉由與乙醇組合而更容易發揮歷時褐變的抑制效果之觀點，較佳為壬酸香草醯胺。 [0034] 本發明中的辣椒素類似物的含量，只要是效能上有效的量即可，不特別限制。就其含量，相對於本發明之外用組成物全體，可取例如0.002～0.2質量%；而基於歷時褐變的抑制效果之觀點，較佳可取0.003～0.05質量%，更佳可取0.01～0.015質量%。 [0035] 本發明之外用組成物中，只要不妨害本發明之效果，則除了上述成分外，還可摻混冷卻劑。 [0036] 作為所述冷卻劑，可舉出l-薄荷醇、d-薄荷醇、dl-薄荷醇、d-樟腦、dl-樟腦、d-龍腦、dl-龍腦、薄荷烷、乳酸薄荷酯、香葉醇、桉油、萜烯油、佛手柑油、茴香油、薄荷油(peppermint)、玫瑰油及COOL MINT等。此等冷卻劑可單獨使用1種，亦可任意地組合使用2種以上。 [0037] 本發明之外用組成物所含之冷卻劑較佳為l-薄荷醇、d-薄荷醇、dl-薄荷醇、d-龍腦、dl-龍腦、薄荷烷、薄荷油(peppermint)及COOL MINT，更佳為薄荷醇，特佳為l-薄荷醇。 [0038] 本發明之外用組成物中，只要不妨害本發明之效果，則除了上述成分外，還可摻混藥效助劑。 [0039] 作為所述藥效助劑，可舉出甘草次酸、甘草酸二鉀、甘草酸銨、甘草酸硬脂酯等抗炎症劑或皮膚保護劑；二苯基咪唑、苯海拉明及其藥學上可容許之鹽、順丁烯二酸氯苯那敏等抗組織胺劑；乙酸生育酚酯等血液循環促進劑；山金車花酊、黃柏萃取物、山梔子萃取物、西洋七葉樹萃取物、東莨菪萃取物、顛茄浸膏、當歸萃取物、紫根萃取物、山椒萃取物等生藥等。 [0040] 本發明之外用組成物中，除上述成分外，尚可適宜摻混可併用之活性成分、pH調節劑、防腐劑、保存劑、抗氧化劑、穩定劑等一般使用於外用組成物的添加劑。 [0041] 5.形態及製造方法 本發明之外用組成物，不特別限制其形態，惟較佳為液劑(含洗劑、噴霧劑、氣膠劑、及乳液劑)。 [0042] 本發明之外用組成物可按所述製劑形態，依循常用方法來調製。可舉出例如將菸鹼酸之酯衍生物、洛索洛芬類、或視需求而用之其他成分，與如下述所說明之用於外用製劑的廣用基劑混合而使其溶解或分散，並調整成所要之pH的方法。此外，就pH而言，只要是對皮膚無不良影響的範圍則不予限制，通常調整成pH3.5～8.5，較佳為pH4～8，更佳為4～7.5。 [0043] 例如，要將本發明之外用組成物調製成液劑時，可藉由將菸鹼酸之酯衍生物、洛索洛芬類、及進一步視需求而用之其他成分，與基劑混合來調製。基劑可採用例如以低級醇為主成分，並對其摻混選自二醇類、水及乳化劑的至少一種而成者。 [0044] 作為二醇類，不特別限定，可舉出例如甘油、丙二醇、1,3-丁二醇、辛二醇、乙二醇、聚乙二醇、D-山梨醇等。較佳為甘油、丙二醇及1,3-丁二醇。二醇類可單獨使用一種，亦可組合使用多種。 [0045] 作為乳化劑，不特別限定，可舉出例如去水山梨醇脂肪酸酯、甘油脂肪酸酯、聚氧乙烯去水山梨醇脂肪酸酯、聚乙二醇硬脂酸酯、聚桂醇等非離子性界面活性劑等。乳化劑可單獨使用一種，亦可組合使用多種。 [0046] 本發明之外用組成物較佳調製成塗佈形態之外用劑，而能夠局部地外用投予。本發明之外用組成物的投予量係由待治療症狀的程度來掌控；其中所含之有效成分的洛索洛芬類的每日塗佈投予量可調成100mg以下的量。 [0047] 本發明之外用組成物，作為外用消炎鎮痛劑，可針對伴隨肩酸之肩痛、關節痛、腰痛、肌肉痛、腱鞘炎(手、手腕之疼痛)、肘之疼痛(網球肘等)、撞傷疼痛、挫傷痛、骨折痛、神經痛等疼痛，以鎮痛為目的而合宜地使用。 [實施例] [0048] 以下，舉出實施例來說明本發明，惟本發明不受此等實施例等所限定。此外，表中的單位係表示組成物每100g的質量(g)(即質量%)。 [0049] 試驗例1 如表1～3所記載，按各分量量取各成分，加以攪拌使其溶解而調製成液狀組成物(實施例1及2、比較例1～6)。 [0050][0051][0052][0053] 調製上述製劑後，取0.2g塗佈於手腕成2.5cm見方的四方形，塗佈後每隔10分鐘以ANTERA 3D (Gadelius Medical股份有限公司)測定發紅度(a值)至50分鐘為止。 [0054] 評定方法如下。算出由塗佈後50分鐘之a值減去剛塗佈後之a值所得的值(Δa值)作為肌膚發紅指標，如下式，以僅含有等量的菸鹼酸苯甲酯之製劑(相對於實施例1、2及比較例6，分別為比較例1、2及5)為基準而設定，分別算出發紅抑制效果。 發紅抑制效果=100-((Δa值)/(基準之Δa值)×100) [0055] 就僅含有菸鹼酸苯甲酯之製劑，可看出肌膚發紅(比較例1、2及5)。 [0056] 使比較例2含有水楊酸二醇酯或甘草酸二鉀時，無法充分抑制發紅(比較例3、4)。 [0057] 又，摻混0.5質量%的菸鹼酸苯甲酯時，即使含有洛索洛芬鈉水合物也無法抑制發紅(比較例6)。 [0058] 另一方面，菸鹼酸苯甲酯取0.01～0.1質量%且含有洛索洛芬鈉水合物時，可充分抑制發紅(實施例1、2)。 [0059] 試驗例2 如表4所記載，按各分量量取各成分，加以攪拌使其溶解而調製成液狀組成物(實施例3～6、比較例7)。 [0060][0061] 將所得各組成物裝入螺旋蓋小瓶(Maruemu製，No.5，直徑27mm、高度55mm)中，於60℃保存1個月，觀察其性質狀態。將以目視呈透明者評為「◎」、褐變傾向最強者評為「×」，依「×～◎」此4等級(差～良好之順序為「×」、「△」、「○」、「◎」)加以評定。將結果示於表4。圖1表示「◎」與「×」各者之照片。此係面向讀者左側為「◎」、右側為「×」的照片。 [0062] 如表4所示，就乙醇中含有洛索洛芬鈉水合物之製劑，可隨時間經過看出褐變傾向(比較例7)。 [0063] 然而，與洛索洛芬鈉水合物共同含有菸鹼酸苯甲酯時，可看出褐變傾向獲抑制，為高透明性之性質狀態(實施例3～6)。[Modes for Implementing the Invention] [0009] The external composition of the present invention is a composition containing an ester derivative of nicotinic acid, and loxoprofen or a pharmaceutically acceptable salt (loxoprofen), which It contains 0.005 to 0.1% by mass of the nicotinic acid ester derivative with respect to the entire composition. [0010] 1. Nicotinic acid ester derivatives The external composition of the present invention contains nicotinic acid ester derivatives as an effective ingredient for temperature sensing. [0011] As far as the ester derivatives of nicotinic acid are concerned, they are pharmaceutically acceptable and not particularly limited, and can be widely used. Examples include benzyl nicotinate, β-butoxyethyl nicotinate, methyl nicotinate, and the like. These nicotinic acid ester derivatives may be used singly, or two or more of them may be used in combination. Among the ester derivatives of nicotinic acid, benzyl nicotinate is preferred. [0012] The external composition system of the present invention contains 0.005 to 0.1% by mass of an ester derivative of nicotinic acid with respect to the entire composition. The content of the ester derivative of permeate nicotinic acid is 0.005% by mass or more with respect to the entire composition, and a sufficient warming effect can be obtained. The content of the ester derivative of permeable nicotinic acid is 0.1% by mass or less with respect to the entire composition, and redness after skin application can be significantly suppressed. From this point of view, the content of the ester derivative of nicotinic acid described on the left is preferably 0.05% by mass or less. [0013] 2. Loxoprofen and its pharmaceutically acceptable salts (Loxoprofen) The external composition system of the present invention contains loxoprofen. The composition for external use of the present invention can exert the effect of suppressing redness by combining loxoprofen with nicotinic acid ester derivatives; this redness is caused by the nicotinic acid ester derivatives after being applied to the skin And those that arise from the skin. [0014] Furthermore, the composition for external use of the present invention can also exert the effect of inhibiting the browning of the whole composition by combining loxoprofen with nicotinic acid ester derivatives; this browning is caused by the passage of time Those caused by loxoprofen. [0015] Although not particularly limited, loxoprofen can also be blended as an active ingredient of at least one action selected from the group consisting of antipyretic, analgesic and anti-inflammatory effects. [0016] Loxoprofen (2-[4-(2-oxocyclopentylmethyl)phenyl] propionic acid) is a kind of non-steroidal antipyretic, analgesic and anti-inflammatory properties of propionic acid with antipyretic, analgesic and anti-inflammatory effects Agent (NSAID). [0017] In the present invention, in addition to loxoprofen itself, pharmaceutically acceptable salts thereof can also be used. The salt also includes a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water or alcohol. These are well-known compounds, and in addition to being produced by well-known methods, commercially available products can also be used. [0018] In the present invention, loxoprofen or a pharmaceutically acceptable salt thereof is preferably loxoprofen sodium hydrate. [0019] The content of loxoprofen is not particularly limited as long as it is an effective amount in terms of efficacy. Regarding the content, it can be, for example, 0.1 to 10% by mass, preferably 0.5 to 5% by mass, and more preferably 0.5 to 3% by mass in terms of anhydrous loxoprofen sodium relative to the entire composition for external use of the present invention. [0020] In addition, the ratio of loxoprofen can also be set in consideration of the ratio of the ester derivative of nicotinic acid contained in the external composition. Specifically, relative to 1 part by mass of the nicotinic acid ester derivative contained in the external composition, the ratio of loxoprofen is usually set in the range of 10 to 1000 parts by mass, preferably 10 to 500 parts by mass , More preferably 10 to 300 parts by mass. [0021] 3. Alcohols with 1 to 4 carbons (lower alcohols) The composition for external use of the present invention may further contain lower alcohols. The lower alcohol is not particularly limited, and it can be widely used as long as it can function as a base effective for the above-mentioned active ingredient. [0022] As the lower alcohol, specific examples include methanol, ethanol, propanol, and isopropanol, and ethanol is preferred. [0023] The composition for external use of the present invention preferably contains 55% by mass or more of lower alcohol with respect to the entire composition. Thereby, the composition for external use of the present invention can suppress browning over time. [0024] From the viewpoint of suppressing skin irritation, the composition for external use of the present invention preferably contains 90% by mass or less of lower alcohol relative to the entire composition, and more preferably contains 80% by mass or less. [0025] The composition for external use of the present invention preferably contains a lower alcohol in an amount of 60% by mass or more with respect to the entire composition from the viewpoint of the effect of inhibiting browning over time. [0026] Therefore, the composition for external use of the present invention can not only suppress skin irritation but also inhibit the chronological browning of the composition for external use by containing 55 to 90% by mass of the lower alcohol relative to the entire composition; from this point of view, more The lower alcohol is preferably contained in an amount of 60 to 90% by mass relative to the entire composition, and more preferably 60 to 80% by mass. [0027] 4. Other components In the composition for external use of the present invention, as long as it does not harm the effects of the present invention, in addition to the above-mentioned components, other temperature-sensitive agents may be blended. [0028] Other temperature-sensitive agents are not particularly limited, and can be widely used. One kind of other temperature-sensitive agents may be used alone, or two or more kinds may be used in combination. Examples of other temperature-sensitive agents include capsaicin analogs and the like. [0029] As the capsaicin analogue, N-vanillylamide can be used. N-acylvanillylamide is a compound known as a blood circulation promoter. [0030] The amide in the N-vanillylamide can be either linear or branched. In addition, the carbon number of the acyl group in the N-anisylvanillylamide is not particularly limited, and, for example, 5-15, preferably 6-11, etc. can be used. [0031] As N-vanillylamide, specific examples include vanillylnonanoate and capsaicin, dihydrocapsaicin, dihydrocapsaicin, percapsaicin, and homodihydrocapsaicin (homodihydrocapsaicin) And other capsaicins and so on. [0032] In the present invention, the capsaicin analog may be purified, but it is also possible to use a mixture containing other ingredients in addition to the capsaicin analog. Specific examples of such a mixture containing capsaicin analogs include capsicum extracts, capsicum tinctures, and capsicum powder. [0033] In the present invention, for capsaicin analogs, one capsaicin analog may be used alone, or two or more of them may be used in combination. Among the capsaicin analogs, based on the viewpoint that the effect of inhibiting browning over time can be more easily exhibited by combining with ethanol, vanillamide pelargonate is preferred. [0034] The content of the capsaicin analog in the present invention is not particularly limited as long as it is an effective amount in terms of efficacy. With respect to the content, it can be, for example, 0.002 to 0.2% by mass relative to the entire composition for external use of the present invention; and from the viewpoint of the effect of inhibiting browning over time, it is preferably 0.003 to 0.05% by mass, and more preferably 0.01 to 0.015% by mass. . [0035] In the composition for external use of the present invention, as long as the effect of the present invention is not impaired, in addition to the above-mentioned components, a coolant may be blended. [0036] Examples of the cooling agent include l-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, menthane, and menthol lactate. Esters, geraniol, eucalyptus oil, terpene oil, bergamot oil, fennel oil, peppermint, rose oil and COOL MINT, etc. These coolants may be used individually by 1 type, and may be used in combination of 2 or more types arbitrarily. [0037] The cooling agent contained in the composition for external use of the present invention is preferably l-menthol, d-menthol, dl-menthol, d-borneol, dl-borneol, menthane, peppermint (peppermint) And COOL MINT, more preferably menthol, particularly preferably l-menthol. [0038] In the composition for external use of the present invention, as long as the effects of the present invention are not impaired, in addition to the above-mentioned components, medicinal adjuvants may also be blended. [0039] As the medicinal effect auxiliary agent, glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate and other anti-inflammatory agents or skin protectants; diphenylimidazole, diphenhydramine And its pharmaceutically acceptable salts, antihistamines such as chlorpheniramine maleate; blood circulation promoters such as tocopheryl acetate; arnica tincture, cork extract, mountain gardenia extract, quinoa Leaf tree extract, scopole extract, belladonna extract, angelica extract, purple root extract, sansho pepper extract and other crude drugs. [0040] In the external composition of the present invention, in addition to the above-mentioned components, active ingredients, pH adjusters, preservatives, preservatives, antioxidants, stabilizers, etc. generally used in external compositions can be appropriately blended. additive. [0041] 5. Form and manufacturing method The external composition of the present invention is not particularly limited in form, but is preferably a liquid (including lotion, spray, aerosol, and emulsion). [0042] The composition for external use of the present invention can be prepared according to the described formulation form and according to common methods. For example, the ester derivatives of nicotinic acid, loxoprofen, or other ingredients used as required can be mixed with the general bases for external preparations as described below to dissolve or disperse them. , And adjust to the required pH method. In addition, the pH is not limited as long as it has no adverse effects on the skin, and it is usually adjusted to pH 3.5 to 8.5, preferably pH 4 to 8, and more preferably 4 to 7.5. [0043] For example, when the composition for use outside of the present invention is prepared into a liquid, it is possible to combine nicotinic acid ester derivatives, loxoprofen, and other components as required, and a base Mix to modulate. As the base, for example, a lower alcohol is used as the main component, and at least one selected from glycols, water, and emulsifiers is blended with it. [0044] The glycols are not particularly limited, and examples include glycerin, propylene glycol, 1,3-butanediol, octanediol, ethylene glycol, polyethylene glycol, and D-sorbitol. Preferred are glycerin, propylene glycol and 1,3-butanediol. The glycols may be used singly, or multiple types may be used in combination. [0045] The emulsifier is not particularly limited, and examples thereof include sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol stearate, and cassia Nonionic surfactants such as alcohols, etc. One kind of emulsifier may be used alone, or multiple kinds may be used in combination. [0046] The composition for external use of the present invention is preferably prepared as an external agent in a coating form, and can be administered locally for external use. The dosage of the composition for external use of the present invention is controlled by the degree of the symptoms to be treated; the daily coating dosage of loxoprofen contained in the active ingredient can be adjusted to be less than 100 mg. [0047] The composition for external use of the present invention, as a topical anti-inflammatory analgesic, can be used for shoulder pain, arthralgia, low back pain, muscle pain, tenosynovitis (pain in hands and wrists), elbow pain (tennis elbow, etc.) associated with shoulder pain , Bruise pain, contusion pain, fracture pain, neuralgia and other pains, suitable for the purpose of analgesia. [Examples] [0048] Hereinafter, examples are given to illustrate the present invention, but the present invention is not limited by these examples. In addition, the unit in the table indicates the mass (g) (that is, mass %) per 100 g of the composition. [0049] Test Example 1 As described in Tables 1 to 3, each component was measured for each component, stirred and dissolved to prepare a liquid composition (Examples 1 and 2, Comparative Examples 1 to 6). [0050] 
