TWI411452B - 用於投與活性成分布普雷諾芬(buprenorphine)之經皮治療系統 - Google Patents
用於投與活性成分布普雷諾芬(buprenorphine)之經皮治療系統 Download PDFInfo
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Description
本發明係關於一種經皮治療系統,具有至少一種決定布普雷諾芬(buprenorphine)在基質層內之溶解且同樣可吸收的羧酸;該系統係用於疼痛療法,具有明顯增加的活性成分利用性。
活性成分布普雷諾芬(17-(環丙基-甲基)-α-(1,1-二甲基乙基)-4,5-環氧基-18,19-二氫-3-羥基-6-甲氧基-α-甲基-6,14-乙烯橋嗎啡喃-7-甲醇)係一種部分合成鴉片劑(opiate),其相較於此類物質的其他化合物之優點在於具有更高的活性。此意指在具有非常不利的診斷之癌症或腫瘤患者,在最後階段,用約1毫克之每日劑量可達到疼痛解脫。布普雷諾芬在此範疇中超過合成的類鴉片劑(opioid)酚太尼(fentanyl)及其類似物之特點在於布普雷諾芬之潛在成癮性低於此等化合物。其缺點為,由於布普雷諾芬之高分子量,即467.64道耳吞(dalton),其難於達成其經皮吸收。
儘管有此點,含有布普雷諾芬的經皮系統(例如Transtec®或Norspan®)業已可從商場上取得。德國專利DE 39 39 376 C1述及彼等的功能化。該活性成分係在聚丙烯酸酯基質中呈均勻溶液,以羧酸用為滲透促進劑及助溶劑。
活性成分係在均勻溶液中之系統常以低活性物質利用率為其特色。此特色的理由在於決定活性成分遞送的活性成分熱力學活性在投藥過程中因為遞降的活性成分裝載而減低。活性成分在整個投藥時間內之一致性遞送僅能透過比要遞送之量相對高的活性成分裝載而達到。在歐洲銷售的Transtec® 35產品之公開數據表示,例如,在投藥期間僅有17%之活性成分利用率。在布普雷諾芬係一種昂貴的活性成分之下,從成本觀點上看,更高的活性成分利用率為一實質優點。再者,布普雷諾芬(其係一種麻醉劑,且在施用後於所用系統中生成最低殘留含量)之非常低系統裝載量,從安全性觀點看係非常合意者。
因此,本發明之一目的為開發一種經皮治療系統(TTS),其可使難以達成經皮吸收的活性成分布普雷諾芬可用於經皮投藥,具有明顯增加的活性成分利用率。
此目的係根據本發明,且以意外的方式,利用投與布普雷諾芬至皮膚之經皮治療系統而達到,該TTS包括活性成分不透性背層,至少一層壓力敏感性黏著劑基質層(其包含活性成分布普雷諾芬及至少一種羧酸),及,於需要時,一保護層(其在使用前要拆離)。
該基質層係基於聚矽氧烷或聚異丁烯而構成。該布普
雷諾芬係在一種羧酸或多種羧酸內之溶液中,且此溶液係以小滴形式分散於基質層內。從布普雷諾芬已知的物理化學性質,更特別者其不良的溶解性,其所具216℃的比較高之熔點,及,如已提及者,其高分子量,等來考慮,布普雷諾芬會輕易地傾向於結晶化之事實來看,此係更出人意外者。為此理由,使用具有至少一個酸性基的溶劑以在劑型之貯存期間防止布普雷諾芬結晶化。布普雷諾芬本身及羧酸兩者在聚矽氧烷或聚異丁烯中具有極低溶解度,因此,可將布普雷諾芬溶解於羧酸中且將此溶液以小滴形式分散在根據下述物質作為基礎聚合物所製備成的基質層中:聚異丁烯或聚矽氧烷,較佳地為耐胺性二甲基聚矽氧烷,更佳為耐胺性及非耐胺性二甲基聚矽氧烷之混合物,該非耐胺二甲基聚矽氧烷的含量為不高於40重量%,較佳地2至20重量%。於此情況中,重要者為布普雷諾芬及羧酸或多種羧酸之混合物係液體形式。
所用該等羧酸在黏著劑的有機溶劑中典型地具有微溶性。因此布普雷諾芬及羧酸之液體混合物可分散在黏著劑溶液中,而在溶劑移除後,仍保留該分散液。在此類型的基質層中,布普雷諾芬之溶解度事實上僅決定於羧酸或多種羧酸之量。該分散溶液之量可為至高達40重量%,其較佳地不超過20重量%。該小滴的尺寸本身應當較佳地不超過50微米。再者,較佳尺寸係決定於基質層之厚度。
由於羧酸同樣可透過皮膚吸收,因此彼等在系統中之量會在施用期間下降,且因此也會使布普雷諾芬的飽和溶
解度降低。因此,布普雷諾芬之熱力學活性的減少,如因遞送引起者,會受到補償。羧酸之選擇係由透過皮膚吸收所引導,與布普雷諾芬相較下,該吸收係同等快速的,且較佳者為更為快速。較佳地是使用在皮膚溫度下係液體的羧酸。該羧酸或多種羧酸係選自油酸、乙醯丙酸(laevulinic acid)、亞麻油酸及次亞麻油酸組成之群組。於一適當具體實例中,在施用期間,其可能達到超飽和狀態。在超飽和系統中,活性成分之熱力學活性及因此每單位面積之滲透速率係根據超飽和因素而增加。結果,有利地,可使遞送面積及系統之面積最小化。在貯存期間,布普雷諾芬及酸兩者都保留在聚合物基質中,使得在此時間內,該系統不超過飽和,且可排除活性成分之再結晶化。
本發明之另一方面關係到此種系統之效果,若酸的遞送太快,則熱力學活性之上升可能導致在施用後滲透速率的過度增加。其後果為TTS會因活性成分的過度快速遞送而變成過早耗盡。頃發現此類型的效果可藉由添加另一基於聚丙烯酸酯的層而防止。此層較佳地是位於含有活性成分的聚合物基質層與皮膚之間,或者在基質層與背層之間。此附加的層較佳地係具體化成自黏性皮膚接觸層。
布普雷諾芬在聚丙烯酸酯內的溶解度明顯地高於在聚矽氧烷或聚異丁烯內者,且取決於具體的組成,其範圍至高達約10重量%。由於整體系統對於布普雷諾芬具有更高的飽和溶解度,因此經由酸的遞送引起的超飽和程度會因
為布普雷諾芬從基質層進入聚丙烯酸酯層內的再分配而降低。結果活性成分之遞送更一致,且可防止系統之過早耗盡。業經發現者,在一較佳具體實例中,在基質層裝載約0.4毫克之布普雷諾芬且所用羧酸為乙醯丙酸之下,每平方公分具有15-30克/平方米的塗層重量之皮膚接觸層即足以達到所欲效果。
對於製造聚丙烯酸酯黏著劑所用的單體基本上沒有限制。
不過,基於理論考量,較佳者為沒有游離羧基之黏著劑,因為彼等不能透過鹽的形成固定鹼性布普雷諾芬。
圖2顯示出此類別系統之示意圖;其製造係在實施例1中說明。基質層及皮膚接觸層之厚度在每一情況下與基質層中所選活性成分濃度及,分別地,每單位面積的活性成分量的關係都必須予以最佳化。基質層內酸之量或濃度係取決於其對布普雷諾芬之溶解力。於乙醯丙酸之較佳使用中,布普雷諾芬及酸係以相同的重量比例使用。兩種物質之所選7至9重量%的濃度,業經證明為適當者,不過也可以有不同的選擇,在選擇塗層重量時,給予恰當的考慮,以不影響TTS之性能。
將根據實施例1之經皮治療系統與已存在於市場上的TTS(作為參考系統)進行人體內藥物動力學(pharmacokinetics)研究的比較。經發現根據實施例1有6.3毫克布普雷諾芬含量的17平方公分系統係相當於有20毫克活性成分含量之25平方公分參考TTS。基於參
考產品所述35微克/小時TTS遞送速率,此對參考產品給出17%的活性成分利用率而對根據實施例1的TTS給出53%的活性成分利用率。此清楚地顯示,使用根據實施例1之經皮系統,已經達到實質改良活性成分利用率之目的。據此,使用本發明含有作為活性成分的布普雷諾芬之TTS,可達到在活體內(in vivo)至少30%,較佳地至少40%,更佳地至少50%之活性成分利用率。所產生的另一項優點為,因為更高的滲透速率,此等系統能以比參考系統小約30%之表面積使用。
一項特別的優點在於此種改良的活性成分利用率可讓系統的麻醉劑布普雷諾芬之裝載率進一步的降低,其結果為讓使用後的廢系統中之殘留布普雷諾芬含量進一步減到最小。
本發明經皮治療系統可提供成具有不同釋放變化(release profiles)及不同的劑量強度。如上面已敘述者,例如,活性成分釋放變化可利用,例如,含活性成分的基質及/或皮膚接觸層之層厚度之適當改變,或經由變更基質中活性成分之濃度,予以影響。本發明TTS之劑量強度可經由,例如,變更含活性成分的基質之表面積、同時將基質及皮膚接觸層之組成和層厚度保持相同,而予以修改,以達到不同的劑量強度。以此方式,可較佳地獲得具有可與市場上已存在之經皮治療系統相比的性質之經皮治療系統。
透過具有不同劑量之TTS的提供,可以個別地給一患
者其所需的活性成分之量。而且,也可以對該患者建立活性成分遞送,其方式為以原則上已知的方式,利用恰當的投藥方案給該患者其所需的活性成分之量。在此類方案中,投與患者的活性成分之量係藉由,例如,依序投予具有不同劑量強度之經皮治療系統而相應地增加。活性成分劑量的依序增加得以進一步減少活性成分布普雷諾芬投藥過程中可能產生的已知副作用。利用恰當的投藥方案對患者的活性成分遞送之依序調整之例子經載於,例如,專利申請WO 2006/030030 A2及EP 1572167之中。本發明因而也涵蓋包括二或更多種具有不同劑量強度的本發明TTS之系統,例如套組。
本發明經皮治療系統所採取的形式可為諸如可將TTS分成不同次單位者。此可分性得以針對患者之個別活性成分需求對TTS作進一步修改,或使用TTS實施恰當的投藥方案。在此情況中,該可分的TTS有利地含有複數個聚合物基質區域,彼等在空間上係藉由不含活性成分之區域予以分開。TTS可隨後沿著不含活性成分之區域,藉由例如切割,予以分開使得一或更多個聚合物基質區域與TTS其餘部分分開。可分的TTS變異形式的構造之例子經載於,例如,專利申請WO 2003/079962 A2及WO 02/41878 A2之中。
本發明經皮治療系統可經修改且使用不同的投藥期間。本發明TTS可施用例如至少12小時或24小時。不過,較佳地,個別的本發明TTS亦可使用至少72小時、
84小時或96小時之個別施用期間。不過,也可能有更長的施用期間,諸如120小時、144小時或168小時。
本發明係藉由下列實施例闡明,但不因此限定本發明之範圍。
A在一不鏽鋼容器中,將3.65公斤之布普雷諾芬懸浮在3.65公斤之乙醯丙酸及2.6公斤之乙醇中。於攪拌下,加入呈在正庚烷中具有74重量%固體含量的溶液形式的60.6公斤之聚矽氧烷黏著劑及9.72公斤之庚烷。攪拌該混合物直到布普雷諾芬鹼完全溶解為止,得到80.22公斤之含布普雷諾芬的黏著劑溶液,其具有4.55%之布普雷諾芬,固體含量為64.8%(黏著劑溶液1)。
B用於皮膚接觸層者,係使用從丙烯酸2-乙基己酯、醋酸乙烯酯和丙烯酸2-羥基乙酯製備的聚丙烯酸酯黏著劑。將31.87公斤具有51重量%固體含量之此黏著劑溶液,與6.5公斤之醋酸乙酯及1.91公斤呈純形式或與其他羧酸之混合物的形式之油酸摻合,在勻化之後,得到約40公斤之無活性成分的聚丙烯酸酯溶液(黏著劑溶液2)。
C使用熟諳此技者已知的輔助手段將一膜(該膜業經處理以對所選黏著劑呈黏著性)塗上含布普雷諾芬的黏著劑溶液1。塗層厚度係經選擇使得移除溶劑會得到55克/平方米的基質層塗層重量。布普雷諾芬和乙醯丙酸在此層中之濃度係7至9重量%。隨後將後續系統之背層層積
在“乾燥”基質層上。同樣地將黏著劑溶液2塗覆在經黏著處理的膜上(使用系統前要移除的後設保護膜)且移除有機溶劑。所得皮膚接觸層之塗層厚度,在溶劑移除之後,應該有約20克/平方米之量。然後從最先產生的基質層移除該經黏著處理的膜,且將基質層層積在該皮膚接觸層上。
至此可從所得總積層體沖孔出個別系統。
在具體的實例中,上述TTS可裝設具更大表面積之超熟石膏(over-plaster),較佳地具有圓角者,包括不含活性成分的壓力敏感性黏著劑基質層且較佳地具有膚色背層。當皮膚接觸層,僅基於其物理特性,不會充足地黏附至皮膚之時及/或當含布普雷諾芬的基質層,為避免浪費之目的,具有明顯的角(方形或長方形)之時,此係有利者。
以實施例1的相同方式進行製造,不同處在於基質層之濃度及層厚度係根據表1而變異。
於實施例6中,使用得自Grünenthal GmbH的商品Transtec®。
使用此等TTS,用諳於此技者所知的Franz擴散單元,使用得自完整人類皮膚之表皮,進行試管內(in vitro)實驗。為此目的,從積層體沖出具有2.54平方公分的面積之模切片(diecuts),且針對商品Transtec®之模切片分別進行試驗。Transtec®在商場上可取得三種不同的劑量強度,不過,這些劑量強度都與彼等的表面積成比例。測量在Franz單元的接收器介質中之布普雷諾芬濃度(表2)。此外,實驗後,分析TTS的布普雷諾芬及乙醯丙酸之含量。實施例1的分析結果與其他實施例一起顯示於表及圖形中。
在將表2的累積通量速率互相比較時,可看出本發明TTS之所有滲透速率皆與商品Transtec®在相同數量級。即使Franz單元不能作為代替物用於臨床試驗。但卻可用來區別不同的TTS配方,表2中所呈現的結果可經評定而顯示,在試管內條件下,實施例1之TTS遞送與Transtec®同樣多的布普雷諾芬。如上面已述者,在人體內的藥物動力學研究中,將實施例1之TTS,與做為參考系統的市場上已有之此TTS相比較,該參考產品展現出17% TTS之活性成分利用率,而相較下實施例1的TTS則有53%之活性成分利用率。
在滲透研究後,分析所有本發明實施例TTS之殘留乙醯丙酸含量。乙醯丙酸的殘留量及相對遞送量,如從殘留量計算出者,都顯示在表3中。
表3示出,根據本發明之教導,在使用期間TTS變成耗盡乙醯丙酸,因此發生出人意外的活性成分布普雷諾芬之高利用率。
1‧‧‧背層
2‧‧‧以聚矽氧烷為基之基質層,有分散的布普雷諾芬/羧酸溶液小滴
3‧‧‧保護層,在使用前移除
4‧‧‧皮膚接觸層,以聚丙烯酸酯黏著劑為基
5‧‧‧沒有布普雷諾芬之壓力敏感性黏著劑層
6‧‧‧背層(例如皮膚色者)
圖1顯示本發明一層式自黏系統之示意圖。圖2繪示出一種具有皮膚接觸層之系統;圖3顯示出一種具有頂部貼片(patch)之多層系統。在此等圖中,指示數字之意義如下:
1‧‧‧背層
2‧‧‧以聚矽氧烷為基之基質層,有分散的布普雷諾芬/羧酸溶液小滴
3‧‧‧保護層,在使用前移除
Claims (15)
- 一種用於投與布普雷諾芬(buprenorphine)至皮膚之經皮治療系統,其包括:活性成分不透性背層;至少一層壓力敏感性黏著劑基質層,此層包含活性成分布普雷諾芬及至少一種羧酸;及,於需要時,一保護層,此保護層在使用前要拆離,該系統的特徵在於該基質層係以聚矽氧烷或聚異丁烯為基礎所構成,該布普雷諾芬係在該羧酸或多種羧酸中之溶液中,且此溶液係以小滴形式分散在該基質層內。
- 根據申請專利範圍第1項之經皮治療系統,其中該聚矽氧烷係耐胺性二甲基聚矽氧烷。
- 根據申請專利範圍第1項之經皮治療系統,其中該聚矽氧烷係一種耐胺性及非耐胺性二甲基聚矽氧烷之混合物,其中該非耐胺性二甲基聚矽氧烷的含量至高達40重量%。
- 根據申請專利範圍第1項之經皮治療系統,其中該羧酸比活性成分布普雷諾芬更快地擴散到皮膚中。
- 根據申請專利範圍第1項之經皮治療系統,其中該分散溶液之量係至高達40重量%。
- 根據申請專利範圍第5項之經皮治療系統,其中該分散溶液之量係至高達20重量%。
- 根據申請專利範圍第1項之經皮治療系統,其中該羧酸在皮膚溫度下係液體。
- 根據申請專利範圍第7項之經皮治療系統,其中該 羧酸係選自油酸、乙醯丙酸(laevulinic acid)、亞麻油酸及次亞麻油酸所組成之群組。
- 根據申請專利範圍第7或8項之經皮治療系統,其中布普雷諾芬和乙醯丙酸係以相同的重量比例存在。
- 根據申請專利範圍第1項之經皮治療系統,其中該基質層係與以聚丙烯酸酯為基的層呈可擴散性接觸。
- 根據申請專利範圍第10項之經皮治療系統,其中該聚丙烯酸酯層係具體化為自黏性皮膚接觸層。
- 根據申請專利範圍第11項之經皮治療系統,其中該聚丙烯酸酯黏著劑不具有游離羧基。
- 根據申請專利範圍第1項之經皮治療系統,其中在活體內(in vivo)條件下的活性物質利用率達到至少30%。
- 根據申請專利範圍第13項之經皮治療系統,其中在活體內(in vivo)條件下的活性物質利用率達到至少40%。
- 根據申請專利範圍第14項之經皮治療系統,其中在活體內(in vivo)條件下的活性物質利用率達到至少50%。
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