TWI482645B - 含有待克菲那（ｄｉｃｌｏｆｅｎａｃ）羥乙基吡咯啶之外用油性敷貼劑 - Google Patents
含有待克菲那（ｄｉｃｌｏｆｅｎａｃ）羥乙基吡咯啶之外用油性敷貼劑 Download PDFInfo
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- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明有關具有優異的藥物經皮吸收性及安定性以及對於皮膚之刺激性低的含待克菲那羥乙基吡咯啶之油性貼片。
待克菲那羥乙基吡咯啶為待克菲那鹽類中的一種，其具有比待克菲那鈉低之熔點，且為適於經皮吸收性製劑的藥劑(專利文件1)。再者，由於待克菲那羥乙基吡咯啶具有優於待克菲那鈉之水溶性以及與水性基質材料之優異相容性，故已開發有含待克菲那羥乙基吡咯啶之泥罨劑(專利文件2)。然而，通常該泥罨劑具有諸如藥物之經皮吸收性不足以及對於皮膚之黏著性低等問題。
專利文件1：日本專利公告A 63-152372
專利文件2：日本專利公告A 6-305958
本發明目的係解決上述問題及提供具有優異的藥物經皮吸收性和對於皮膚之刺激性低以及優異藥物安定性的含待克菲那羥乙基吡咯啶之外用貼片。
本發明人對於解決上述問題進行廣泛硏究，結果證實藉由結合藥物與特定助溶劑形成油性外用貼片解決了該等問題，且最終完成本發明。
更明確地說，本發明有關一種含有待克菲那羥乙基吡咯啶之貼片，其係藉由將黏著層層壓於撐體而製備，其中該黏著層之特徵係包含5-50重量%之苯乙烯-異戊二烯-苯乙烯嵌段共聚物，20-50重量%之增黏樹脂，5-70重量%之柔軟劑，0.5-20重量%之選自N-甲基-2-吡咯啶酮、丙二醇及二甲亞碸之一或多種助溶劑作為基本成分，以及0.5-20重量%之待克菲那羥乙基吡咯啶作為活性成分。
由於本發明之外用貼片包含上述組成物，所以本發明具有提供具優異之待克菲那羥乙基吡咯啶經皮吸收性及對皮膚之低刺激性及另外之保存安定性之貼片的效果。
實施本發明之最佳模式
本發明可包含0.5-20重量%之待克菲那羥乙基吡咯啶，較佳為1-10%。當包含0.5重量%或更少之待克菲那羥乙基吡咯啶時，藥理功效不足；而當包含20重量%或更多時，對於該製劑之物理性質有負面影響，諸如藥物結晶。
作為本發明之待克菲那羥乙基吡咯啶的助溶劑，可使用選自N-甲基-2-吡咯啶酮、丙二醇及二甲亞碸中之一或多者。其中，以丙二醇為佳。其組成為0.5-20重量%，較佳為1-10重量%。當包含0.5重量%或更少時，顯示藥物之溶解性不充分，因此對於物理性質造成負面影響，諸如經皮吸收性降低或藥物結晶。而且當包含20重量%或更多時，其對於物理性質亦具有負面影響，諸如皮膚刺激提高以及基質材料之凝聚作用降低。
本發明黏著層中所使用之苯乙烯-異戊二烯-苯乙烯嵌段共聚物的量為5-50重量%，較佳為10-30重量%。當包含5重量%或更少時，會產生黏著層之凝聚作用不足導致基質材料殘留在皮膚上的問題，而當包含50重量%或更多時，過度凝聚會造成黏著作用減低或降低在捏揉程序中的功效。
通常，增黏樹脂係與苯乙烯-異戊二烯-苯乙烯嵌段共聚物混合以提供對於皮膚之黏著性，且其組成為20-50重量%，更佳為20-35重量%。當增黏樹脂之量少於20重量%時，外用貼片之黏著性質變差，而當包含多於50重量%時，顯示出過高膠黏性而造成在從皮膚剝離該貼片時的物理性皮膚刺激性。本發明中之增黏樹脂的實例為選自松脂樹脂、萜烯樹脂、石油樹脂、酚樹脂、二甲苯樹脂及類似物中之一或多者，尤其以經氫化之松脂甘油酯及飽和脂環烴樹脂為佳。
該黏著層可另外包含脂肪及油(包括液態石蠟、凡士林)、柔軟劑諸如液態橡膠(包括聚丁烯、聚異丁烯、聚異戊二烯)及類似物，且其量為5-70重量%，更佳為20-60重量%。尤其是，以液態石蠟及聚丁烯為佳。
本發明可另外含有經皮吸收性促進劑，以提高待克菲那羥乙基吡咯啶之經皮吸收性。該經皮吸收性提高劑可包括脂肪酸酯，諸如肉豆蔻酸異丙酯、己二酸二異丙酯；高脂肪酸，諸如異硬脂酸酯、油酸酯、肉豆蔻酸酯；胺，諸如二異丙醇胺、三乙醇胺；及界面活性劑，諸如去水山梨醇單油酸酯、聚月桂醇(lauromacrogol)。
本發明之黏著層可另外含有酸性聚合物。當添加酸性聚合物至本發明之油性貼片時，部分或全部的待克菲那羥乙基吡咯啶鹽係脫鹽而形成游離形式之待克菲那，因此改善該藥物之經皮吸收性。作為本發明中所使用之酸性聚合物，以聚丙烯酸較佳且其量為0.1-10重量%，更佳為0.1-5重量%。
此外，作為本發明中所使用之基質材料，可隨意地選擇貼片之製備中慣用的材料且適當地添加以控制該基質材料的黏著性及安定性。特別是，可隨意地含有適當量之吸水性聚合物，諸如聚乙烯吡咯啶酮或聚乙烯吡咯啶酮/乙酸乙烯酯共聚物；無機填料，諸如二氧化鈦、矽酸鹽；或抗氧化劑，諸如二丁基羥甲苯。
本發明油性貼片的撐體較佳為撓性且可拉伸材料，其包括但不限於聚酯織物、不織布、低密度聚合物膜及類似物，且該材料可隨意地選擇。
本發明中所使用之脫離襯層包括諸如聚對苯二甲酸乙二酯、聚丙烯、紙及類似物。該脫離襯層可隨意地滲矽以調整剝離強度。
本發明之油性貼片係藉由例如以下方法製備。該藥物溶液係藉由加溫而將待克菲那羥乙基吡咯啶溶解在上述助溶劑中而製備。在攪拌加熱之下分別混合苯乙烯-異戊二烯-苯乙烯嵌段共聚物、柔軟劑(例如聚丁烯或液態石蠟)及增黏樹脂，以及隨意的抗氧化劑及酸性聚合物等。於該黏著基質材料中添加該藥物溶液，且攪拌該混合物直到該溶液變均勻為止。然後藉由習知方法將如此形成的黏著層展布在該襯層上，且層壓於撐體上。藉由將該貼片裁切成適當大小及形狀，獲得本發明之外用貼片。待塗覆之黏著層的適當量為50-400g/m2
，較佳為100-200g/m2
。
實施例
下文中將藉由以下實施例更具體解釋本發明，不過本發明絕對不侷限於該等實施例。除非另有說明，否則實施例中之數值為「重量%」。
根據上述方法及表1中之處方，製備各實施例之油性貼片。
比較實例1
使用專利文件2之實例1作為參考，以表2之處方製備比較實例1之外用貼片(黏著性皮膚泥罨劑)。
試驗實例1：大鼠之活體外經皮滲透性試驗
為硏究本發明油性貼片上之待克菲那羥乙基吡咯啶的經皮吸收性，對實施例1-4及比較實例1進行大鼠的活體外經皮滲透性試驗。將切下的Wister大鼠腹部皮膚置於Franz擴散槽，且將切成圓形(φ 14 mm)的各試驗樣本施加於切下的Wister大鼠腹部皮膚。在接受側填充磷酸鹽緩衝鹽水，且令37℃之熱水在水夾套中循環。在該時間期間的每一時間點取樣接受側的溶液且藉由液態層析術(LC)測量滲透該皮膚的待克菲那羥乙基吡咯啶之量。
結果示於圖1。
試驗實例2：對兔子皮膚的一次性刺激試驗
藉由Draize法使用兔子對實施例1-4及比較實例1進行一次性皮膚刺激性試驗。在兔子的健康及損傷背部皮膚上施加各樣本24小時，然後予以移除。在移除該貼片之後1、24及48小時，根據表3之評估標準進行觀察，且計算各樣本的刺激性評分。刺激性評分之評估標準係示於表3-1，而測量結果示於表3-2。
試驗實例3：安定性試驗
對實施例1-4評估貼片中之藥物安定性。每一試驗樣本在40℃下貯存6個月之後，藉由LC測量所收集樣本的藥物濃度。以該硏究前的待克菲那羥乙基吡咯啶(初始量：100%)之量計算貯存之後各樣本剩餘的藥物比(對初始量之%)。結果示於表4。
從上述各試驗的結果可看出，本發明油性貼片與比較實例的泥罨劑一樣安全，且該貼片顯示經皮吸收性遠高於該泥罨劑。該貼片亦顯示非常優異的藥物安定性。也就是說，本發明之含待克菲那羥乙基吡咯啶的油性貼片為具有優異藥物吸收性、安全性及安定性之外用貼片。
圖1顯示試驗實例1之大鼠活體外經皮滲透性試驗的結果。
Claims (2)
- 一種含有待克菲那(diclofenac)羥乙基吡咯啶之油性外用貼片，其係藉由層壓黏著層於撐體而製備，其中該黏著層包含5-50重量%之苯乙烯-異戊二烯-苯乙烯嵌段共聚物，20-50重量%之增黏樹脂，5-70重量%之柔軟劑，及0.5-20重量%之選自N-甲基-2-吡咯啶酮、丙二醇及二甲亞碸之至少一種助溶劑作為基本成分，以及0.5-20重量%之待克菲那羥乙基吡咯啶作為活性成分。
- 如申請專利範圍第1項之含有待克菲那羥乙基吡咯啶的外用貼片，其中該黏著層另外含有酸性聚合物。
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