TWI519323B - 含有聯苯乙酸之外用貼附劑 - Google Patents
含有聯苯乙酸之外用貼附劑 Download PDFInfo
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- TWI519323B TWI519323B TW100139701A TW100139701A TWI519323B TW I519323 B TWI519323 B TW I519323B TW 100139701 A TW100139701 A TW 100139701A TW 100139701 A TW100139701 A TW 100139701A TW I519323 B TWI519323 B TW I519323B
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- biphenylacetic acid
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Classifications
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Description
本發明係有關一種經皮吸收性外用消炎鎮痛製劑，詳言之，係有關一種顯示良好的藥物釋放性、皮膚刺激性低且具有高藥物穩定性之含有聯苯乙酸之消炎鎮痛外用貼附劑。
聯苯乙酸(Felbinac：4-聯苯乙酸)係非類固醇系消炎鎮痛藥芬布芬(fenbufen，聯苯丁酮酸)的活性代謝物，是一種顯示強力消炎鎮痛作用的藥物。若經口投予聯苯乙酸，則會對消化系統產生副作用而有發生胃腸損傷的問題，由此便對經皮吸收型製劑進行探討，迄今市售有凝膠劑、液劑等外用製劑。
然而，如凝膠劑、液劑之劑形存有難以進行定量投予、生物學上之利用率低，及製劑沾附於衣服上等問題。
為改善此種凝膠劑、液劑之問題，以聯苯乙酸為首，既已開發有含各種消炎鎮痛藥的水性貼附劑(泥罨劑(cataplasm))、油性貼附劑(硬膏劑(plaster))。特別是油性貼附劑(硬膏劑)因未有貼附時的冰冷感等原因，業已成為非類固醇系消炎鎮痛貼附劑的主流，而具組合有橡膠系基劑與增黏樹脂之配方者亦經廣泛使用。
在非類固醇系消炎鎮痛貼附劑中，一般為了提高藥物的經皮吸收性而摻混有各種添加劑。特別是L-薄荷醇係有用於作為聯苯乙酸的溶解劑，是一種與多數市售含有聯苯乙酸之貼附劑摻混的添加劑。惟，另一方面已知聯苯乙酸與L-薄荷醇反應會生成作為分解生成物的L-薄荷醇酯體，摻混L-薄荷醇茲認為係貼附劑中聯苯乙酸的穩定性惡化的原因之一。
此外，多數人亦對伴隨L-薄荷醇的昇華而生之刺激性臭味感到不適，且市場上對未摻混有L-薄荷醇、或可抑制L-薄荷醇臭味之貼附製劑的需求高漲同為實情。
其他，為提高聯苯乙酸的經皮吸收性，自昔至今已對摻混克羅他命酮、脂肪酸、脂肪酸酯、單萜烯類、多元醇類、吡咯啶酮類等經皮吸收促進劑進行探討。
舉例而言，專利文獻1中提出有一種具備黏著劑層的含有聯苯乙酸之貼附劑，該黏著劑層含有對聯苯乙酸的溶解能力優良的克羅他命酮為主要成分。然而，克羅他命酮有容易由黏著劑層表面滲出而使黏著力歷時性下降的問題。
又，專利文獻2中揭示有一種以苯乙烯-異戊二烯-苯乙烯嵌段共聚物為黏著劑，且組合摻混有L-薄荷醇與各種吸收促進劑之聯苯乙酸摻混消炎鎮痛貼布。然而，與該貼布摻混之L-薄荷醇係如前述，可能與聯苯乙酸反應而生成分解生成物，更有組合摻混L-薄荷醇與吸收促進劑時引起基劑物性的惡化及皮膚刺激性之虞。
同樣專利文獻3中揭示有一種摻混有萜烯、癸二酸酯、烷基甘油醚的含有聯苯乙酸之貼附劑，其與專利文獻2相同的是，對於藥物穩定性、基劑物性及皮膚刺激性仍有改善的空間。
其他，既已探討組合摻混有N-甲基-2-吡咯啶酮與聚乙二醇的聯苯乙酸貼附劑(專利文獻4)、摻混硬化油者(專利文獻5)等摻混有各種經皮吸收促進劑的貼附劑，但仍未發現兼備高藥物經皮吸收性與安全性、及優良之藥物穩定性的經皮吸收製劑。
另一方面，亦已嚐試利用摻混經皮吸收促進劑之方法以外的手段來提高藥物之經皮吸收性。
例如，專利文獻6揭示一種在以苯乙烯-異戊二烯-苯乙烯嵌段共聚物為基材之黏著劑基劑中摻混羊毛脂，並使羊毛脂保持水分的含水型硬膏劑。
此為擬透過製劑中所含之水分來提高聯苯乙酸之溶解性，由此提升經皮吸收性之試行，然，使水分含於油性貼附劑中會使製造步驟複雜化，且無法完全排除保存中之製劑的物性降低的可能性。
再者，其有相較於使用經皮吸收促進劑之硬膏劑，經皮吸收性方面略差的問題。
專利文獻7中提出一種貼附劑，其未使用克羅他命酮，而是以苯乙烯-異戊二烯-苯乙烯嵌段共聚物為主基劑，並使聯苯乙酸均勻分散於摻混有松香系樹脂等的黏著基劑中。
然而，與該貼附劑摻混之松香系樹脂已知其作用為皮膚過敏(cutaneous sensitization)成分，予以摻混時較不理想。所謂「皮膚過敏」係指延遲性過敏反應的一種，乃由化學物質引起過剩的免疫反應而使皮膚發生腫癢等的現象。
[專利文獻1]日本特開平4-321624號公報
[專利文獻2]日本特開平10-218793號公報
[專利文獻3]日本特開2008-13494號公報
[專利文獻4]日本特開2001-342130號公報
[專利文獻5]日本特開2007-8927號公報
[專利文獻6]日本特開2001-97857號公報
[專利文獻7]國際公開WO98/24423號
本發明係用於解決上述問題，課題在於提供一種即便未摻混作為聯苯乙酸之優良溶解劑的L-薄荷醇亦顯示高藥物釋放性，且皮膚刺激性低、可發揮高藥物穩定性之含有聯苯乙酸之外用貼附劑。
本發明者為解決前述課題而戮力進行多次研究的結果發現，在含有苯乙烯-異戊二烯-苯乙烯嵌段共聚物、脂環族飽和烴樹脂、軟化劑及癸二酸二乙酯而未含有L-薄荷醇之黏著劑基劑中分散摻混平均粒徑為5μm以上且小於100μm的聯苯乙酸，便可製成皮膚刺激性低、兼備聯苯乙酸的優良藥物釋放性與藥物穩定性的外用貼附劑，本發明即臻完成。
因此本發明之基本形態為一種以在不含有L-薄荷醇，而包含苯乙烯-異戊二烯-苯乙烯嵌段共聚物、脂環族飽和烴樹脂、軟化劑及癸二酸二乙酯之黏著基劑中分散摻混有平均粒徑為5μm以上且小於100μm的聯苯乙酸為特徵之含有聯苯乙酸之外用貼附劑。
更具體之本發明為一種以在不含有L-薄荷醇，而包含苯乙烯-異戊二烯-苯乙烯嵌段共聚物10~30重量%、脂環族飽和烴樹脂10~50重量%、軟化劑10~75重量%、癸二酸二乙酯0.1~10重量%之黏著劑基劑中分散摻混有平均粒徑為5μm以上且小於100μm的聯苯乙酸0.1~10重量%為特徵之含有聯苯乙酸之外用貼附劑。
根據本發明，可提供一種在含有聯苯乙酸之經皮吸收製劑中顯示優良的藥物釋放性、皮膚刺激性低並顯示高藥物穩定性之含有聯苯乙酸之外用貼附劑。
本發明所提供之含有聯苯乙酸之外用貼附劑可因聯苯乙酸的優良消炎鎮痛效果，如有用於預防、治療退化性關節炎、慢性類風濕性關節炎、腰痛、肩關節周圍炎、腱鞘炎、腱周圍炎、肱骨外上髁炎(網球肘等)、肌肉痛、外傷後的腫脹、疼痛等。
本發明係如上述，其基本形態為一種以在不含有L-薄荷醇，而包含苯乙烯-異戊二烯-苯乙烯嵌段共聚物、脂環族飽和烴樹脂、軟化劑及癸二酸二乙酯之黏著基劑中分散摻混有平均粒徑為5μm以上且小於100μm的聯苯乙酸為特徵之含有聯苯乙酸之外用貼附劑。
即，本發明之特徵為，作為有效成分之聯苯乙酸特別係使用平均粒徑為5μm以上且小於100μm的聯苯乙酸，並使之分散於黏著基劑層中。
本發明中，只要可製劑化，作為有效成分之聯苯乙酸於製劑中的摻混量則未特別限定，較佳為相對黏著劑重量，宜於0.1~10重量%，更佳為0.5~6重量%之範圍內摻混。
若黏著劑中的聯苯乙酸摻混量小於0.1重量%時，經皮吸收性便不充分而無法確認出效果，又即使摻混超過10重量%，亦無法確認出進一步之效果，經濟上較不利而不佳。
又，就本製劑中所摻混之聯苯乙酸而言，若考量在黏著劑中之分散性、或製造步驟之作業性，則以使用其平均粒徑為5μm以上且小於100μm，較佳為10μm以上且小於70μm，特佳為15μm以上且小於40μm之範圍者為佳。
其平均粒徑若小於5μm，則於製造步驟中聯苯乙酸原藥會發生二次凝聚而有分散不均勻之虞，導致藥物之經皮吸收性降低。反之平均粒徑若為100μm以上，藥物在黏著劑中可能分散不均勻。特別是當粒徑較大時，遑論藥物之經皮吸收性降低，在製造步驟，特別是塗布黏著劑成剝離膜之步驟中亦發現不良影響。即，有時聯苯乙酸原藥在製造時發生凝聚，而可見由此所生之黏著劑表面的凹凸。
本發明所摻混之苯乙烯-異戊二烯-苯乙烯嵌段共聚物(以下有簡記為SIS)係作為黏著劑之基本骨架的合成橡膠，其摻混量係於10~30重量%，較佳為10~20重量%之範圍內摻混。若SIS之摻混量低於10重量%時，黏著劑之凝聚力會降低，另一方面若上述摻混量摻混超過30重量%時則導致黏著力下降及製造時的作業性降低。
本發明中，若考量增黏樹脂對皮膚的安全性，可較佳使用脂環族飽和烴樹脂。作為此種脂環族飽和烴樹脂可例舉如ARKON P90、P100、P115(荒川化學工業公司製)等。
只要可製劑化，其摻混量則未特別限定，較佳為相對黏著劑重量，宜於10~50重量%之範圍內摻混。
黏著劑中的脂環族飽和烴樹脂含量若低於10重量%時黏著力弱，而摻混超過50重量%時則製劑之黏著力增強，存在剝離時伴有痛感的問題。
本發明中所使用之癸二酸二乙酯係發揮作為聯苯乙酸之皮膚吸收促進劑的功能。只要可製劑化，該癸二酸二乙酯之摻混量則未特別限定，較佳為相對黏著劑重量，宜於0.1~10重量%，較佳為1~7重量%之範圍內摻混。
黏著劑中的癸二酸二乙酯摻混量若低於0.1重量%時，聯苯乙酸之皮膚穿透性會不充分，摻混超過10重量%時則發生皮膚刺激等問題而不佳。
本發明中，顯然聯苯乙酸與癸二酸二乙酯之摻混比對於經皮吸收性亦為重要之因素。即，可知以重量%言，宜於聯苯乙酸：癸二酸二乙酯=1：0.1~1：15之範圍，較佳為聯苯乙酸：癸二酸二乙酯1：0.5~1：10之範圍。
摻混比例若小於1：0.1時便無法獲得癸二酸二乙酯所產生的吸收促進效果，未得充分的藥物吸收性。又摻混比例超過1：15時，則聯苯乙酸會溶於過量的癸二酸二乙酯中而形成藥物穩定性低之製劑。
本發明所摻混之軟化劑可賦予黏著劑柔軟性，可例舉液態聚丁烯、液態聚異戊二烯、液態聚異丁烯等液態橡膠；流動石蠟等石蠟油；肉豆蔻酸異丙酯、己二酸二異丙酯等脂肪酸酯類；辛基十二醇等高級醇；矽油；羊毛脂；鯊烷；鯊烯；蓖麻油等，而較佳為液態聚丁烯及流動石蠟。
相對黏著劑重量，軟化劑之摻混量宜於10~75重量%，較佳為15~60重量%，更佳為20~50重量%之範圍內摻混。
其他，就本發明外用貼附劑而言，只要未造成其他影響，則可使用一般外用製劑所使用的各種基劑成分。作為所述基劑成分並未特別限定，可例舉如苯乙烯-丁二烯-苯乙烯嵌段共聚物、苯乙烯‧丁二烯橡膠、天然橡膠、異戊二烯橡膠等橡膠系彈性體；聚丙烯酸系聚合物、矽氧橡膠等疏水性高分子；二丁基羥基甲苯、新戊四醇-四-[3-(3,5-二-三級丁基-4-羥苯基)丙酸酯]、生育酚(維生素E)乙酸酯等抗氧化劑；氫氧化鋁、含水矽酸鋁、氧化鈦、氧化鋅、矽酸酐、矽酸鎂等無機填充劑等。可進一步視需求添加吸收促進劑、防腐劑、清涼劑、殺菌劑、芳香劑、著色劑等。
就本發明貼附劑之支持物(support)而言，只要未造成其他影響，則可使用一般外用製劑所使用的各種支持物。作為所述支持物並未特別限定，可使用與例如聚乙烯、聚丙烯、聚氯乙烯、聚酯、尼龍、聚胺基甲酸酯、嫘縈(rayon)等多孔體、發泡體(foam body)、織布、不織布之積層品等。
就本發明貼附劑所使用之釋離襯墊(release liner)而言，只要未造成其他影響，則可使用一般外用製劑所使用的各種襯墊。作為所述釋離襯墊並未特別限定，可採用例如聚對苯二甲酸乙二酯薄膜、聚丙烯薄膜、紙等，特佳為聚對苯二甲酸乙二酯薄膜。為使來自黏著劑層的剝離力最佳化，釋離襯墊可視需求而實施有矽氧處理。
本發明所提供之外用貼附劑例如可由以下方式來製造。
亦即，加熱使構成黏著劑層的SIS、軟化劑、及脂環族飽和烴樹脂、抗氧化劑溶解。次之，將有效成分聯苯乙酸、與癸二酸二乙酯添加至前述黏著基劑混合物中並攪拌、混合，來調製貼附劑中的黏著劑。
其次，將調製之黏著劑(膏狀物)塗布於經矽氧處理的聚對苯二甲酸乙二酯薄膜上，形成厚50~300μm的黏著劑層。於所得之黏著劑層上積層支持物聚酯製織布或不織布後，裁切成適當的大小暨形狀，即可製得本發明外用貼附劑。
以下舉出具體實施例來更具體地說明本發明，惟本發明並未受限於以下實施例。
此外，實施例及比較例之各表中的摻混成分的摻混量只要未予特別事先說明，則以「重量%」表示之。
在170℃加熱條件下揉合(knead)SIS、聚丁烯、流動石蠟、二丁基羥基甲苯使其溶融後，進一步添加脂環族飽和烴樹脂，並在130℃加熱條件下予以揉合、混合來製作黏著基劑。
另外，一面攪拌平均粒徑為5μm以上且小於100μm的聯苯乙酸，一面使其均勻分散於混有癸二酸二乙酯與適量流動石蠟的液體中，來調製聯苯乙酸分散液。將該聯苯乙酸分散液添加至上述黏著基劑中，揉合至均勻分散為止來調製黏著劑。將黏著劑塗布於經矽氧處理的聚對苯二甲酸乙二酯薄膜上成100μm厚之後，與聚酯織布積層即得試驗製劑。
以與實施例1相同的步驟，根據表1~表3所示的成分組成來製作目標本發明貼附劑。
除改為下述表4所示的成分組成以外，係以與實施例1相同的步驟來製作各比較例的外用貼附劑。
此外，比較例7之製劑在製造時(調製黏著劑時)因聯苯乙酸原藥發生凝聚，製劑表面可見凹凸，無法進行以下的製劑評定試驗。
將實施例1~2與比較例1~2之製劑各衝切成φ25mm，並貼附於15名健全男子的上臂內側24小時，判定剝離後1小時及24小時的皮膚刺激性。
其結果係示於下述表5。
由表5所示之結果可知，相較於比較例1~2，本發明外用貼附劑之實施例1~2之製劑其皮膚刺激性較低。
將實施例1與比較例3~4之製劑各衝切成5cm×7cm，並貼附於6名健全男子的背部12小時，萃取回收之製劑中所殘留的藥物並以HPLC測定藥物量。
由貼附0小時之藥物量減去殘留藥物量來計算藥物消失量。其結果係示於下述表6。
由表6所示之結果可知，相較於比較例3~4，本發明貼附劑之實施例1之製劑係藥物消失量高、經皮吸收性高的製劑。
以40℃保存實施例1、比較例2及比較例5之樣本(7cm×10cm)3個月後，萃取試驗製劑中的藥物並測定聯苯乙酸含量。
對比試驗前之各樣本的聯苯乙酸含量(初始值)，以相對初始值(%)算出。其結果係示於表7。
由表7所示之結果可知，相較於比較例2或比較例5，本發明外用貼附劑之實施例1其藥物穩定性優良。
將實施例1、實施例16及比較例6之各製劑各衝切成φ20mm，在容量100mL的燒杯內側側面，使用雙面膠以黏著劑面面向燒杯內側的方式貼附之。
製劑的貼附位置係調整成製劑最下端的部分為燒杯底部算起約30mm的位置。其後，對燒杯內側注入100mL的釋放溶液(PBS緩衝溶液)，並以磁性定子(magnetic stator)攪拌釋放溶液。爾後以高效液相層析法測定試驗開始90分鐘後之釋放溶液中的聯苯乙酸含量，並算出主藥之釋放率。其結果係示於表8。
由表8所示之結果可知，相較於比較例6之製劑，本發明外用貼附劑之實施例1及實施例16其主藥之釋放性格外優異。
根據本發明，可提供一種顯示良好的藥物釋放性、皮膚刺激性低並具有高藥物穩定性之含有聯苯乙酸之消炎鎮痛外用貼附劑。
本發明之外用貼附劑係有用於預防、治療如退化性關節炎、慢性類風濕性關節炎、腰痛、肩關節周圍炎、腱鞘炎、腱周圍炎、肱骨外上髁炎(網球肘等)、肌肉痛、外傷後的腫脹、疼痛等，其利用性極廣。
Claims (2)
- 一種含有聯苯乙酸之外用貼附劑，其特徵為在不含有L-薄荷醇，而包含苯乙烯-異戊二烯-苯乙烯嵌段共聚物、脂環族飽和烴樹脂、軟化劑及癸二酸二乙酯之黏著基劑中分散摻混有平均粒徑為5μm以上且小於100μm的聯苯乙酸，且進一步使聯苯乙酸與癸二酸二乙酯之摻混比例為1：0.1~1：15之範圍內。
- 一種含有聯苯乙酸之外用貼附劑，其特徵為在不含有L-薄荷醇，而包含苯乙烯-異戊二烯-苯乙烯嵌段共聚物10~30重量%、脂環族飽和烴樹脂10~50重量%、軟化劑10~75重量%、癸二酸二乙酯0.1~10重量%之黏著基劑中分散摻混有平均粒徑為5μm以上且小於100μm的聯苯乙酸0.1~10重量%，且進一步使聯苯乙酸與癸二酸二乙酯之摻混比例為1：0.1~1：15之範圍內。
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