TWI486180B - 丙炔基胺基氫茚經皮組成物 - Google Patents
丙炔基胺基氫茚經皮組成物 Download PDFInfo
- Publication number
- TWI486180B TWI486180B TW100115008A TW100115008A TWI486180B TW I486180 B TWI486180 B TW I486180B TW 100115008 A TW100115008 A TW 100115008A TW 100115008 A TW100115008 A TW 100115008A TW I486180 B TWI486180 B TW I486180B
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- TW
- Taiwan
- Prior art keywords
- transdermal
- transdermal composition
- propynylaminohydroquinone
- composition
- copolymer
- Prior art date
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Description
根據35U.S.C. §119(e),此申請案係請求於2010黏8月30日申請之美國臨時申請案連續案號61/330,018申請日之優先權;該申請案之揭露內容係以參考方式併於本文中。
提供丙炔基胺基氫茚(例如雷沙吉蘭(Rasagiline))的經皮組成物。該經皮組成物之方面包括於包含羧化聚合物壓敏黏著劑內的丙炔基胺基氫茚之基質。在一些例子中,該基質進一步包含陽離子丙烯酸共聚物。亦提供利用該經皮組成物的方法以及含該經皮組成物的套組。
單胺氧化酶(MAOs)為催化單胺例如單胺能神經遞質包括多巴胺(dopamine)氧化的酵素。由於MAOs扮演去活化神經遞質的角色,因此MAO功能異常(例如過高或過低MAO活性)被認為將導致許多的神經性疾病。例如,體內過高或過低的MAOs通常與憂鬱症、精神分裂症、濫用藥物、注意力缺乏症、偏頭痛以及不規則性成熟有關。
已發現MAOs有兩種類型,即A型MAO(MAO-A)和B型MAO(MAO-B)。MAO-B更常見於腦內,其在釋入突觸之後負責多巴胺的分解。巴金森氏症的特徵為利用多巴胺傳遞信號的細胞死亡,其導致整體突觸信號強度的降低以及增加伴隨巴金森氏症的症狀。
雷沙吉蘭(rasagiline)(即(R)-N-(丙-2-炔基)-2,3-二氫-1H-茚-1-胺或R(+)-N-炔丙基-1-胺基氫茚(商品名))係一種單胺氧化酶(MAO)的不可逆抑制劑,以及選擇性被用於B型MAO而非A型MAO。雷沙吉蘭於突觸內藉由抑制多巴胺的分解而使傳遞信號神經元再吸收更多釋放多巴胺以供日後再使用,其可補償大量被消耗的已產生多巴胺。
人體內經常需要投與生理活性劑,例如抗巴金森氏劑(如雷沙吉蘭)。口服投藥由於較簡單易行,因此為最常見的使用方法。然而,口服投藥途徑經常因胃腸道的刺激以及肝臟內的藥物代謝而變得複雜化。經皮投藥(經皮藥物傳遞)係一種另類的口服投藥途徑,以及具有避免首過(first pass)代謝、控制傳遞、更簡單的投藥法和較佳病人順應性的優點。經皮途徑的主要缺點為可被傳遞通過皮膚的藥物量受到限制。為了增加藥物通過皮膚的量,用於經皮途徑的藥物一般使用游離鹼型分子。游離鹼型的藥物之安定性通常不如鹽型的藥物。因此,藥物的安定性通常為主要的考量。增加皮膚穿透率的另一種方法為於配製物內使用化學促進劑。使用促進劑雖然可增加經皮膚的傳遞,但是經常造成皮膚的刺激。
經皮投與雷沙吉蘭具有其優點。雷沙吉蘭具有極高的效力和短的半生期。口服投藥可能產生峰-谷型的血漿濃度型態。巴金森氏症患者通常不易藉由口服投藥。經皮傳遞雷沙吉蘭可形成相當中等的吸收度而可避免或減少伴隨口服投藥的副作用,並且投藥頻率可從每天減少至每3天或甚至每週。
提供丙炔基胺基氫茚(例如雷沙吉蘭)的經皮組成物。該經皮組成物方面包括於包含羧化聚合物壓敏黏著劑內的丙炔基胺基氫茚之基質。在一些實例中,該基質進一步包含陽離子丙烯酸共聚物。亦提供利用該經皮組成物的方法以及含該經皮組成物的套組。
本發明的具體實施例提供顯示所欲活性劑傳遞性質的經皮雷沙吉蘭貼片。如技藝中所習知,雷沙吉蘭必須以游離鹼型穿透皮膚而於持續時間內傳遞治療有效劑量,例如高達7天。雷沙吉蘭游離鹼於室溫下不安定並且於室溫貯藏期間迅速分解。因此,雷沙吉蘭游離鹼用於經皮配製物內並非可行之選項。針對此分解議題,由於雷沙吉蘭鹽類一般具有較高的熔點及更為安定,因此經皮配製物內應使用鹽型雷沙吉蘭如甲磺酸雷沙吉蘭。然而,鹽型藥物具有極低的皮膚穿透率。
本發明的具體實施例包括含有弱鹼如丙烯酸樹脂(Eudragit)或二甲基三胺的經皮配製物,以加速將雷沙吉蘭鹽轉化成鹼。為了進一步平衡從鹽至鹼的轉化,例如避免突發(burst)傳遞,本發明具體實施例運用含有羧化官能度的壓敏黏著劑。本發明的某些具體實施例中,壓敏黏著劑內該弱鹼原料、藥物和羧化基團之間的相互作用可使雷沙吉蘭產生經皮最適傳遞效果,例如下文中所詳述。
提供丙炔基胺基氫茚(例如雷沙吉蘭)的經皮組成物。該經皮組成物之方面包括於包含羧化聚合物之壓敏黏著劑內的丙炔基胺基氫茚之基質。在一些實例中,該基質進一步包含陽離子丙烯酸共聚物。亦提供利用該經皮組成物的方法以及含該經皮組成物的套組。
在更詳細說明本發明之前,應瞭解本發明並非僅侷限於所述的特定具體例,因此其必然有許多不同的變化。亦應瞭解此處所使用之術語僅為說明特定具體實施例之目的而非限制,因此本發明的範圍僅侷限於申請專利範圍附件。
當提供一範圍內之值時,應瞭解除非另外明述該範圍上下限間之值及該陳述範圍內的任何其他陳述值或居間值,否則其居間值之單位下限的十位數仍被包含於本發明的範圍內。這些較小範圍的上下限值可被獨立包含於較小範圍內,以及亦屬於本發明的範圍而其陳述範圍並無任何特殊的排除限制。當陳述範圍包含一或兩種限制值時,不包含其一或兩種限制值的範圍亦包含於本發明的範圍內。
此處以數值表示的某些範圍被冠以"約"的不定冠詞。此處"約"一詞被用於提供其所前導之確實數目的字面上支持,以及接近或大約該前導數目的數目。在決定一數目是否接近或大約一特定引用數目時,該接近或大約的未引用數目可為一於本文中出現的數目而實質上相等於該特定的引用數目。
除非另有界定,否則此處使用之全部技術和科學名詞與熟習本領域之技術者通常所瞭解的意義相同。雖然此處所述之任何類似或相同的方法和材料亦可被應用於本發明之實務或試驗中,但仍於下文中詳述其代表性方法和材料。
此專利說明書所引述的全部出版品及專利係以參考方式併於本文中,如同各獨立出版品或專利係明確及獨立地指明以參考方式併入且藉由以參考揭露及敘述與被引述出版品相關之方法及/或材料而被併入於本文中。任何引用之出版品已揭示於本申請日之前不應被解釋為承認本發明喪失先於因先前發明的此類公開之權利。此外,所述之公告日期可能和實際之公告日期有所不同,因此必需自行加以確認。
應注意除非本文中另有明述否則此處及申請專利範圍附件內所使用的單數型"a"、"an"和"the"皆包括複數的涵意。其進一步應注意申請專利範圍已排除任何選擇性的元件。依此,此聲明可做為所述專利申請元件有關之"專屬"、"唯一"等專有名詞之使用的前置基礎,或做為否定性的限制。
熟習此技術的人士研讀此揭示內容時將瞭解,此處所述和說明的各別具體例具有不同的組件和特性,其可輕易地和任何其他具體例分開或組合而不偏離本發明的範圍或精神。可依敘述事件的順序或以任何其他邏輯上可行的順序執行任何所引述的方法。
在進一步描述本發明的各種具體實施例之前,首先更詳細地討論該經皮組成物的特徵,接著詳細地說明利用該經皮傳遞系統的具體實施例以及討論包含該經皮傳遞系統的套組。
如上所述,提供丙炔基胺基氫茚經皮組成物。本發明的經皮組成物係為配置為當局部施用於個體皮膚表面時可經皮傳遞活性劑(特別是丙炔基胺基氫茚)至個體的配製物。本發明組成物包含丙炔基胺基氫茚的活性劑層,其中該丙炔基胺基氫茚活性劑層被配製成當組成物被局部施用於個體時可多日傳遞治療有效量的丙炔基胺基氫茚活性劑至該個體。多日傳遞意指該層被配製成當組成物被局部施用於個體時可長期傳遞治療有效量藥物至一個體,其可為1天或更長,例如2天或更長如3天或更長,如5天或更長,包括7天或更長例如10天或更長的時間。治療有效劑量意指當組成物被施用至個體皮膚部位一段所欲時間,例如7天內時,可提供具有所需治療活性之全身性治療量的丙炔基胺基氫茚。在一些具體實施例中,該組成物在一週期間(即7天或168小時)內可傳遞0.5 mg/天,包括在一週或多於一週期間內傳遞1.0 mg/天或更多,例如10 mg/天的目標劑量活性劑。
根據本發明某些具體實施例的經皮組成物顯示長期時間內實質上恒定流量的丙炔基胺基氫茚活性劑。實質上恒定的流量意指長期時間內流量變化的幅度為100%或更低的任何流量變化,例如80%或更低的流量變化以及包含50%或更低的流量變化,例如40%或更低的流量變化,30%或更低的流量變化,25%或更低的流量變化,例如20%或更低的流量變化,包含15%或更低的流量變化,例如10%或更低的流量變化。觀察實質上恒定流量之長期時間可能不同,以及在一些實例中為24小時或更長,例如48小時或更長,包括72小時或更長,例如96小時或更長。組成物的實際流量雖然可能不同,但是在一些實例中(例如使用下文實驗部分報告的皮膚穿透檢測而測定)為0.5 μg/cm2
/小時或更高的皮膚滲透率,例如1 μg/cm2
/小時或更高,包括10 μg/cm2
/小時或更高。在一些實例中,本發明的配製物,例如與其中不含羧化官能度之壓敏黏著劑的對照組配製物比較(例如下文實驗部分中使用的對照壓敏黏著劑),在施用配製物至皮膚之後立即顯示藥物之實質上降低的突發傳遞。實質上降低之突發傳遞意指降低10%或更低,例如20%或更低,如25%或更低,33%或更低,40%或更低,50%或更低,包括66%或更低,75%或更低,包括90%或更低。在一些實例中,該配製物被配置成提供實質上活性劑之零級傳遞。
該經皮組成物具有不同的尺寸(即面積)。在某些具體實施例中,依據該活性劑和目標劑量的所欲經皮流率選擇該組成物的尺寸。例如,若經皮流量為3.4 μg/cm2
/小時及目標劑量為5 mg/天時,選擇具有約43 cm2
面積的經皮組成物。或者例如,若經皮流量為3.4 μg/cm2
/小時及目標劑量為10 mg/天時,則選擇具有約87 cm2
的經皮貼片。在某些具體實施例中,所選擇該組成物的尺寸可覆蓋皮膚面積為從10至200,例如20至150,包括40至140 cm2
的皮膚區域。
該組成物的丙炔基胺基氫茚活性劑層具有不同的厚度。在一些實例中,該活性劑層(即基質)的厚度為從25至250,例如50至200,包括100至150微米的厚度。
在一些具體實施例中,本發明的組成物包括丙炔基胺基氫茚的活性劑層、襯底層(backing layer)及釋放襯墊(release liner)。例如,第1圖根據本發明一具體實施例的組成物1,該組成物1包括襯底層2、丙炔基胺基氫茚活性劑層3(即基質),以及釋放襯墊4。現在更詳細說明這些層中的每一層。
如上所述,本發明的經皮組成物包括於襯底層表面上含活性劑的基質。感興趣的基質層包括存在於壓敏黏著劑內一定量的丙炔基胺基氫茚活性劑。感興趣的丙炔基胺基氫茚包括下式的化合物:
其中R1係H、-OR2
,或
其中R2
係C1-
C4
烷基,以及R3
係H或C1
-C4
烷基。在一些實例中,該丙炔基胺基氫茚係N-炔丙基-1-胺基氫茚(即雷沙吉蘭)。
存在於基質內的該丙炔基胺基氫茚活性劑可為游離鹼或鹽。醫藥上可接受鹽包括,但不侷限於甲磺酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、鹽酸鹽、溴酸鹽、乙磺酸鹽、對甲苯磺酸鹽、苯甲酸鹽、醋酸鹽、磷酸鹽和硫酸鹽。此外,該丙炔基胺基氫茚存在消旋混合物或純鏡像異構物,例如該活性劑的R或L鏡像異構物。
在一些實例中,基質內的該丙炔基胺基氫茚為完全的R(+)-N-炔丙基-1-胺基氫茚游離鹼。在一些實例中,該丙炔基胺基氫茚為完全的甲磺酸R(+)-N-炔丙基-1-胺基氫茚。
基質內存在不同含量的丙炔基胺基氫茚。在一些實例中,丙炔基胺基氫茚的含量為從5至50 mg,例如10至40 mg以及包括15至30 mg。
如上綜述,該基質含有壓敏黏著劑。所謂"壓敏黏著劑"、"自黏劑"和"自黏黏著劑"意指當黏著劑與一表面施予壓力時可形成鍵結的黏著劑。在一些實例中,該黏著劑係一種不需溶劑、水或熱的黏著劑。就壓敏黏著劑而言,其鍵結強度與施予黏著劑至表面的壓力大小成比例。
重要的壓敏黏著劑包括,但不侷限於羧化聚合物例如羧化丙烯酸共聚物。重要的丙烯酸酯共聚物包括各種單體的共聚物,其可為"軟"單體、"硬"單體,以及任選的"官能性"單體。亦可為此類共聚物的滲合物。該丙烯酸共聚物的組成可為二聚物(即由兩種單體組成)、三聚物(即由三種體組成)或四聚物(即由四種單體組成)的共聚物,或甚至更多單體所構成的共聚物。該丙烯酸共聚物包括交聯和非交聯聚合物。可藉由已知方法交聯該聚合物以獲得所欲聚合物。
製成丙烯酸酯共聚物的單體包括選自下列群組的至少二或多種範例成分包括丙烯酸、烷基丙烯酸酯、甲基丙烯酸酯、可共聚合第二單體或具有官能基的單體。重要的單體("軟"和"硬"單體)包括,但不侷限於丙烯酸甲氧乙酯、丙烯酸乙酯、丙烯酸丁酯、甲基丙烯酸丁酯、丙烯酸己酯、甲基丙烯酸己酯、丙烯酸2-乙丁酯、甲基丙烯酸-2-乙丁酯、丙烯酸異辛酯、甲基丙烯酸異辛酯、丙烯酸-2-乙基己酯、甲基丙烯酸-2-乙基己酯、丙烯酸癸酯、丙烯酸十二酯、甲基丙烯酸十二酯、丙烯酸十三酯、甲基丙烯酸十三酯、丙烯腈、甲基丙烯酸甲氧乙酯等。丙烯酸黏著劑單體的其他實例已述於Satas,壓敏膠黏技術之"丙烯酸膠黏劑"手冊第二版,396~456(D. Satas編輯),紐約Van Nostrand Reinhold市(1989)。
重要的丙烯酸酯共聚物含有極性官能基單體殘基。特別重要者為具有-COOH官能基的單體殘基。具有-COOH官能基的有用羧酸單體含有從約3至約6個碳原子以及其中一些包括丙烯酸、甲基丙烯酸、伊康酸(itaconic)等。在某些具體實施例中的酸係使用丙烯酸、甲基丙烯酸及其混合物。該官能基單體於某些共聚物具體實施例中的含量為2重量%或更高,例如介於3~10重量%之間。
在一些具體實施例中,該黏著劑具有與87-2852(紐澤西州Bridgewater市Henkel公司)相同或實質上相同的組成物。此處"實質上相同"一詞意指具有此處所述官能度的有機溶劑溶液內丙烯酸-醋酸乙烯酯共聚物。在一些具體實施例中,該丙烯酸壓敏黏著劑係87-2852。
在一些實例中,該壓敏黏著劑的含量為從50至95,例如60至90以及包括65至85%重量比的基質。
當使用丙炔基胺基氫茚游離鹼時,該基質係由活性劑和壓敏黏著劑所構成,例如87-2852壓敏黏著劑。
在一些實例中,例如使用丙炔基胺基氫茚鹽時,該基質進一步含有一弱鹼,例如陽離子丙烯酸共聚物。重要的陽離子丙烯酸共聚物為二或多種不同單體殘基的聚合物,該至少一種殘基為丙烯酸殘基例如丙烯酸酯或甲基丙烯酸酯,以及至少一種殘基為陽離子懸垂基例如胺基懸垂基,這些特性為含有構成該共聚物的相同或不同單體殘基。需要時,該陽離子丙烯酸共聚物可為胺化甲基丙烯酸酯共聚物。該胺化甲基丙烯酸酯共聚物可為甲基丙烯酸二乙胺基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的共聚物。重要的胺化甲基丙烯酸共聚物為實質上與E100相同的胺化甲基丙烯酸共聚物。如此處所述,實質上相同一詞意指該胺化甲基丙烯酸共聚物與E100胺化甲基丙烯酸共聚物對組成物具有相同的官能度影響。在一些實例中,該胺化甲基丙烯酸共聚物係E100胺化甲基丙烯酸共聚物。若存在時,該陽離子丙烯酸共聚物之量可為以基質重量計之從1至15、例如2至10以及包括4至8%範圍之量存在。同樣感興趣者為作為弱鹼之例如三乙醇胺之試劑。若存在時,三乙醇胺可以基質重量計之從1至15、例如2至10以及包括4至8%之量存在。
此處所述的基質可含有經皮吸收促進劑。該經皮吸收促進劑有助於活性劑被個體的皮膚所吸收。由於該經皮吸收促進劑不僅可經由皮膚吸收活性劑亦有助於個體通過皮膚經皮滲透該活性劑,因此亦被稱為經皮滲透促進劑。
該經皮吸收促進劑包括但不侷限於下列:脂族醇,例如但不侷限於具有12至22個碳原子的飽和或不飽和高級醇,例如油醇和月桂醇;脂肪酸,例如但不侷限於亞麻仁酸、油酸、次亞麻仁酸、硬脂酸、異硬脂酸和棕櫚酸;脂肪酸酯,例如但不侷限於肉豆蔻酸異丙酯、己二酸二異丙酯和棕櫚酸異丙酯;醇胺,例如但不侷限於三乙醇胺、三乙醇胺鹽酸鹽和二異丙醇胺;多元醇烷基醚,例如但不侷限於多元醇如甘油、乙二醇、丙二醇、1,3-丁二醇、雙甘油、聚合甘油、二乙二醇、聚乙二醇、二丙二醇、聚丙二醇、去水山梨糖醇、山梨糖醇、異山梨酯、甲基葡糖苷、寡糖和還原寡糖的烷基醚,該多元醇烷基醚內烷基部分的碳原子數目較佳為6至20;聚氧乙烯烷基醚,例如但不侷限於烷基部分的碳原子數目為6至20的聚氧乙烯烷基醚,以及聚氧乙烯鏈的重複單位(如-O-CH2
CH2
-)數目為1至9,例如但不侷限於聚氧乙烯月桂基醚、聚氧乙烯鯨蠟基醚、聚氧乙烯硬脂基醚和聚氧乙烯油基醚;甘油酯(即甘油的脂肪酸酯),例如但不侷限於具有6至18個碳原子的脂肪酸甘油酯,該甘油酯可為單酸甘油酯(即經由一酯鍵共價鍵地連接至一脂肪酸鏈的甘油分子)、二酸甘油酯(即經由酯鍵共價鍵地連接至二條脂肪酸鏈的甘油分子)、三酸甘油酯(即經由酯鍵共價鍵地連接至三條脂肪酸鏈的甘油分子),或其組合,形成甘油酯的脂肪酸成分包括,但不侷限於辛酸、癸酸、十二烷酸、十四烷酸、十六烷酸、十八烷酸(即硬脂酸)和油酸;多元醇的中鏈脂肪酸酯;乳酸烷基酯;二元酸烷基酯;醯化胺基酸;吡咯啶酮;吡咯啶酮衍生物;及其組合。
其他類型的經皮吸收促進劑包括,但不侷限於乳酸、酒石酸、1,2,6-己三醇、苯甲醇、羊毛脂、氫氧化鉀(KOH)和三(羥甲基)甲胺。
經皮吸收促進劑的特定實例包括,但不侷限於單油酸甘油酯(GMO)、山梨醇酐單月桂酸酯(SML)、山梨醇單油酸酯(SMO)、月桂醇聚醚(laureth)-4(LTH),及其組合。
在一些實例中,基質內該經皮吸收促進劑的含量為從2至25%(w/w),例如從5至20%(w/w),以及包括從5至15%(w/w)。在某些實例中,基質內該經皮吸收促進劑的含量為約5%(w/w),約10%(w/w),約15%(w/w),或約20%(w/w)。
在一些具體實施例中,該基質層不溶於水。不溶於水一詞意指該基質層在浸入水中1天或更長的一段時間之後呈現極低或無觀察到(若有任何溶解時)的溶解度,例如1週或更長,包括1個月或更長。
如上所述,本發明的經皮組成物包括一襯底(即支持層)。該襯底可彈性延伸而被緊密貼牢於個體的所欲局部位置。該襯底係由不吸收活性劑並且不易從支持層滲漏出活性劑的材料所製成。該襯底包括,但不侷限於不織布、編織布、薄膜(包括薄片)、多孔體、泡沫體、紙、藉由層合一薄膜於不織布或織布上所獲得的複合材料,以及其組合。
不織布包括,但不侷限於下列:聚烯烴樹脂例如聚乙烯和聚丙烯;聚酯樹脂例如聚對苯二甲酸乙酯、聚對苯二甲酸丁酯和聚萘二甲酸乙二酯;人造纖維(rayon)、聚醯胺、聚(酯醚)、聚胺基甲酸酯、聚丙烯酸樹脂、聚乙烯醇、苯乙烯-異戊二烯-苯乙烯共聚物,以及苯乙烯-乙烯-丙烯-苯乙烯共聚物;及其組合。織布包括,但不侷限於綿、人造纖維、聚丙烯樹脂、聚酯樹脂、聚乙烯醇,及其組合。薄膜包括,但不侷限於下列:聚烯烴樹脂例如聚乙烯和聚丙烯;聚丙烯酸樹脂例如聚甲基丙烯酸甲酯和聚乙基丙烯酸甲酯;聚酯樹脂例如聚對苯二甲酸乙酯、聚對苯二甲酸丁酯和聚萘二甲酸乙二酯;此外玻璃紙、聚乙烯醇、乙烯-乙烯醇共聚物、聚氯化乙烯、聚苯乙烯、聚胺基甲酸酯、聚丙烯腈、氟樹脂、苯乙烯-異戊二烯-苯乙烯共聚物、苯乙烯-丁二烯橡膠、聚丁二烯、乙烯-醋酸乙烯酯共聚物、聚醯胺和聚碸;及其組合。紙類包括,但不侷限於浸漬紙、塗佈紙、道林紙、牛皮紙、和紙、蠟油紙、合成紙,及其組合。複合材料包括,但不侷限於上述不織布或織布上層合上述薄膜所獲得的複合材料。
該襯底可有不同的尺寸,以及在一些實例中該襯底的大小可覆蓋所欲的局部目標位置。在一些具體實施例中,該襯底具有從2至100 cm,例如4至60 cm的長度以及從2至100 cm,例如4至60 cm的寬度。
在一些具體實施例中,該襯底層係不溶於水。不溶於水一詞意指該基質層在浸入水中1天或更長的一段時間之後呈現極低或無觀察到(若有何溶解十)的溶解度,例如1週或更長,包括1個月或更長。
在一些具體實施例中,於活性劑層(即基質)上以及特別於離襯底層遠側(反側)的活性劑層表面提供一釋放襯墊。該釋放襯墊係用於保護活性劑層。該釋放襯墊的製備係藉由矽酮處理單側的聚乙烯塗佈道林紙、聚烯烴塗佈蠟油紙、聚對苯二甲酸乙二酯(聚酯)薄膜、聚丙烯薄膜等。
可使用任選的一或多種黏著劑塗層以增加當被施用於皮膚時組成物的黏性。黏著劑塗層包括置於襯底例如多孔、無孔、封閉或透氣襯底材料上的黏著劑層。選擇可達到所欲功能的該黏著劑塗層尺寸,在一些實例中選擇該黏著劑塗層尺寸使其覆蓋於活性劑配製物上時可延伸超過該活性劑配製物一或多邊的距離。在一些實例中,該黏著劑塗層的面積超過活性劑配製物面積的5%或更多,例如10%或更多,包括20%或更多。病人、照護者可於使用時施用該黏著劑塗層,或被整合入套組內。
使用該經皮組成物產品的方法包括投與有效量的丙炔基胺基氫茚組成物至個體以治療該個體的重要目標症狀,例如述於下文中實用性部分者。"處理"或"治療"意指至少抑制或緩和與影響該個體之病症有關的症狀,該抑制和緩和廣義上指至少降低其參數例如與被治療病症有關之症狀的幅度。依此,治療亦包括完全抑制該病症如預防其再發生,或阻止如中止該病症而使該個體不再經歷該病症的狀態。依此,治療包括預防及處理一病症。
執行本方法時,將此處揭示的經皮組成物局部地投與至一個體,即將該經皮組成物投與於任何適當的局部位置(例如皮膚部位)。重要的局部位置包括黏膜部位和角質化皮膚部位,以及因此包括,但不侷限於:口腔、鼻內、眼睛、直腸、陰道、手臂、腿部、軀幹、頭部等。組成物局部覆蓋的表面積足以提供所欲劑量的藥物,以及在一些具體實施例中係從1至200 cm2
,例如從10至180 cm2
,以及包括從100至150 cm2
,如140 cm2
。
該經皮組成物可於其已施用之局部位置維持一段所欲的時間,而可傳遞所欲劑量的活性劑。在一些實例中,組成物於貼附部位維持的一段時間為24小時或更長,例如48小時或更長,如72小時或更長,例如96小時或更長。
執行本方法時,在一已知的一段時間內,例如於被治療疾病症狀的過程中,可投與單次或複數次的一已知劑量經皮組成物,該於已知期間內投與複數次組成物的投藥方法可為每天、每週、每兩週、每個月等。
局部組成物可有不同的覆蓋面積。在一些實例中,該局部組成物的皮膚覆蓋面積為從1至200 cm2
,例如10至180 cm2
,以及包括100至150 cm2
。
該經皮活性劑組成物被施用於皮膚一段所欲時間(即足夠傳遞目標劑量活性劑至該個體的一段時間)之後,可從皮膚部位移除該組成物。可將新的經皮組成物施用於相同或不同的皮膚部位。該新的經皮組成物可被施用於不同的皮膚部位以避免造成皮膚刺激及/或於先前施用部位產生皮膚過敏。
在某些具體實施例中,本發明方法包括一診斷步驟。可利用任何簡易的方法診斷需要本發明方法的個體。此外,已知需要本發明方法的個體為例如罹患巴金森氏症者。可利用任何簡易的診斷方法執行目標症狀的診斷或評估。
本發明的方法可進一步包括判定該治療方法的功效,包括投與局部性麻醉乳液組成物。可利用任何習知方法執行治療效果的評估。
在一些實例中,經皮組成物可配合一或多種用於該目標症狀的其他治療劑共同投與。依此,可單獨使用該經皮組成物以治療目標疾病,或者,在巴金森氏症的例子中可配合習知的L-DOPA治療劑。
本發明的經皮組成物可被投與至不同種類的個體。重要的個體包括,但不侷限於:人或非人的哺乳類,包括食肉目(例如犬和貓)、囓齒目(例如小白鼠、天竺鼠和大鼠)、兔形目(例如兔子)和靈長目(例如人、黑猩猩和猴子)。在某些具體實施例中,該個體例如病人為人類。
本發明的經皮組成物可被用於能使個體受益於經皮投與丙炔基胺基氫茚,例如雷沙吉蘭的任何應用上。雷沙吉蘭及/或其鹽類可用於各種不同疾病症狀的治療,例如但不侷限於:巴金森氏症、阿茲海默症、記憶力障礙、中風及其他疾病,例如述於美國專利案號5,387,612;5,453,446;5,457,133;5,668,181;5,576,353;5,532,415;5,599,991;5,786,390;5,519,061,5,891,923;5,744,500和6,316,504,藉由引述將其內容併入於此。治療意指達到至少緩和影響該個體之病症有關症狀的目標,該緩和廣義上指至少降低其參數例如與被治療病症有關之症狀的幅度。依此,治療亦包括完全抑制該病理性疾病或至少其伴隨症狀例如預防其再發生,或中止該病症而使該個體不再罹患該疾病,或至少不發生該疾病的特徵性症狀。
亦提供用於執行此處所述某些方法的套組。在某些具體實施例中,該套組包含一或多種上述的經皮組成物。在某些具體實施例中,該套組包含上述的黏著劑塗層。在一些具體實施例中,該套組包含多層,例如一層含有藥物及另一層含或不含任何藥物以及其他賦形劑。在一已知套組中包含二或多種組成物,該組成物可被分別包裝或被置於共同容器內。
在某些具體實施例中,該套組進一步包含用於執行本發明方法或獲得其之手段(例如指引使用者至提供說明書之網頁的URL網站)的說明書,這些說明書可被印刷於一基片上,該基片可為一或多種的:包裝附頁、包裝本身、試劑容器等。本發明的套組中,該一或多種成分視方便性或需要被置於相同或不同的容器內。
下列非限制性實例僅提供作為說明的用途。明確而言,下列實例係用於執行本發明的特定具體實施例。該實例僅提供做為說明的用途,以及無論如何本發明均非僅侷限於該範圍。
於有機溶劑(一般為醋酸乙酯、甲醇及/或乙醇內30~60重量%固體含量)內藉由混合各混合物成分的儲備液繼之藉由一混合過程製備配製物。於形成均質混合物之後,將溶液澆鑄於一釋放襯墊(2~3 mils的矽化聚酯片)上以及於65~85℃乾燥10~90分鐘。該膠膜被層合至一PET襯底。
使用人類屍皮以及從全厚度皮膚分離表皮層作為皮膚黏膜(角質層和表皮層)。樣本以弧形壓模沖切成約2.0 cm2
的終直徑。移除釋放襯墊及以藥物黏著層面向角質層的方式將貼片置於表皮/角質層上。輕壓使膠黏層和角質層之間有良好的接觸效果。將經皮吸收系統(Franz cell)的供體和受體邊夾在一起以及將含pH6.5磷酸鹽的受體溶液加入該經皮吸收系統。實驗期間將該槽保持在33℃。定期採取受體溶液的樣本以及藉由HPLC測量活性劑的濃度。以新鮮溶液更換被移除受體溶液以維持槽內條件。從接受室之藥物累積量曲線的斜率計算其流量的時間曲線圖。
利用先前所述的一般方法製備詳列於下表1中裝載於87-2852內之含不同雷沙吉蘭鹼的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第2圖。可觀察到大量雷沙吉蘭鹼的裝載效應。於開始時亦存在突發流量,接著流量明顯降低。由於1 mg雷沙吉蘭的每日劑量係一種強效藥物,因此不希望產生高流量率的突發流量。
利用先前所述的一般方法製備詳列於下表2中裝載於PIB內之含不同雷沙吉蘭鹼的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第3圖。以6:6:1比例的PIB Oppanol B10、Oppanol B30和聚丁烯H1900配製該PIB黏著劑。
利用先前所述的一般方法製備詳列於下表3中於矽膠黏劑(Bio-PSA 7-4101)內之含雷沙吉蘭鹼的經皮貼片。測量通過人類屍皮的流量。發現其穩態流量為約0.1 μg/hr.cm2
。Bio-PSA 7-4101係供應自道康寧(Dow Corning)公司。其係具有65/35樹脂對聚合物比例的胺相容壓敏黏著劑。其係以庚烷內60%固體含量溶液的形式被供應。
利用先前所述的一般方法製備詳列於下表4中裝載於丙烯酸黏著劑內之含不同Eudragit E100的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第4圖。此處數據證明甲磺酸雷沙吉蘭與弱鹼Eudragit之間的相互作用。於利用甲磺酸雷沙吉蘭的貼片中使用Eudragit E100在增加穿透皮膚通量上扮演重要角色。
利用先前所述的一般方法製備詳列於下表5中含不同丙烯酸黏著劑的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第5圖。這些三種丙烯酸黏著劑之間的主要差異在於COOH官能基的含量。87-4287不含COOH基,然而87-2100和87-2852則含有不同數量的COOH基。此處數據證明黏著劑內甲磺酸雷沙吉蘭、Eudragit E100和COOH基之間的相互作用。無COOH基之黏著劑的貼片亦發現開始時有突發傳遞的現象,但是其與含雷沙吉蘭的貼片相比較不明顯。利用含COOH基的黏著劑可明顯減少此突發傳遞的現象。樣本3具有最高的COOH濃度以及呈現平坦的傳遞作用。控釋傳遞中較佳為接近零級的傳遞曲線。
利用先前所述的一般方法製備詳列於下表6中含不同丙烯酸黏著劑的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第6圖。此處數據證明黏著劑內甲磺酸雷沙吉蘭、Eudragit E100和COOH基之間的相互作用。
利用先前所述的一般方法製備詳列於下表7中含不同丙烯酸黏著劑以及不同設計的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第7圖。甲磺酸雷沙吉蘭和E100均被裝載於藥物層內。使用黏著層可作為控制皮膚黏性的用途。
利用先前所述的一般方法製備詳列於下表8中含不同丙烯酸黏著劑以及不同鹼性賦形劑的一系列經皮貼片。測量通過人類屍皮的流量以及將結果繪圖說明於第8圖。此處數據顯示Eudragit E100可被具有類似性質的其他弱鹼所取代。
為清礎瞭解之目的上述發明雖然已藉由圖表及實(施)例進行詳細說明,但熟習本技藝之人士極明顯可藉由本發明之提示而進行某種程度的變化和修改,而其仍未偏離本發明之申請專利範圍附件的精神或範圍。
因此,前述內容僅說明本發明的原理。將瞭解熟習本領域之技術者可想出各種的安排其,雖然未明確描述或示於此,但可具體化本發明的原理及仍在其精神和範圍內。另外,此處所引述的全部實例和條件語句主要擬幫助讀者瞭解本發明之發明者所提供的原理和概念以進一步瞭解本領域,以及被認為非僅侷限於此類特別引述的實例和條件。再者,此處所引述本發明的原理、態樣和具體實施例以及其特定實例的全部陳述均屬於其構造和功能上的相等物。此外,此類相等物擬包括目前已知相等物和將發展出的相等物,即不論構造而可執行相同功能的任何元件。因此,本發明的範圍非僅侷限於此處所示及描述的該舉例性具體實施例。反之,藉由下列的申請專利範圍附件更具體化本發明的範圍和精神。
1...組成物
2...襯底層
3...活性劑層
4...釋放襯墊
第1圖係此處所述經皮活性劑配製物一具體實施例的橫剖面圖。
第2至8圖係各種配製物依時間函數的流動之圖(中點介於兩處採樣時間點之間)。
1...組成物
2...襯底層
3...活性劑層
4...釋放襯墊
Claims (14)
- 一種經皮組成物,該組成物包含:一基質,其包含:丙炔基胺基氫茚;一弱鹼,其選自陽離子丙烯酸共聚物及三乙醇胺,其中該弱鹼係為以基質重量計之從1%至15%範圍之量存在;以及包含羧化聚合物的壓敏黏著劑,該羧化聚合物包含-COOH官能基,其中該壓敏黏著劑係為以基質重量計之從50%至95%範圍之量存在;以及一襯底,其中該經皮組成物顯示於長期時間內30%或更低的流量變化之丙炔基胺基氫茚。
- 如申請專利範圍第1項之經皮組成物,其中該丙炔基胺基氫茚係N-炔丙基-1-胺基氫茚。
- 如申請專利範圍第1項之經皮組成物,其中該羧化聚合物為丙烯酸羧化聚合物。
- 如申請專利範圍第3項之經皮組成物,其中該丙烯酸羧化聚合物包含丙烯酸酯-醋酸乙烯酯共聚物。
- 如申請專利範圍第4項之經皮組成物,其中該弱鹼係一種陽離子丙烯酸共聚物。
- 如申請專利範圍第5項之經皮組成物,其中該陽離子丙烯酸共聚物為胺化甲基丙烯酸酯共聚物,其係甲基丙烯酸二乙胺基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的 共聚物。
- 如申請專利範圍第1項之經皮組成物,其中該弱鹼為三乙醇胺。
- 如申請專利範圍第1項之經皮組成物,其中該基質係由下列組成:(a)R(+)-N-炔丙基-1-胺基氫茚游離鹼、三乙醇胺和丙烯酸酯-醋酸乙烯酯共聚物;或(b)R(+)-N-炔丙基-1-胺基氫茚甲磺酸鹽、胺化甲基丙烯酸酯共聚物和丙烯酸酯-醋酸乙烯酯共聚物。
- 如申請專利範圍第1項之經皮組成物,其中該基質包含一促進劑。
- 如申請專利範圍第1項之經皮組成物,其中該經皮組成物顯示於長期時間內恒定流量的丙炔基胺基氫茚。
- 一種方法,其包含:以足以達到於長期時間內30%或更低的流量變化之流量的丙炔基胺基氫茚之方式,將如申請專利範圍第1至9項中任一項之組成物施用於一個體皮膚表面上。
- 如申請專利範圍第11項之方法,其中該長期時間係72小時或更長。
- 一種套組,其包含:二或多種根據申請專利範圍第1至10項中任一項之經皮組成物。
- 如申請專利範圍第1至10項中任一項之經皮組成 物,其中該丙炔基胺基氫茚係N-炔丙基-1-胺基氫茚鹽。
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CN102985082A (zh) | 2013-03-20 |
NZ602274A (en) | 2014-05-30 |
US20110268785A1 (en) | 2011-11-03 |
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ES2608782T3 (es) | 2017-04-17 |
AP3030A (en) | 2014-11-30 |
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EA023786B1 (ru) | 2016-07-29 |
CN108186611A (zh) | 2018-06-22 |
WO2011139420A2 (en) | 2011-11-10 |
AU2011248904B2 (en) | 2014-02-27 |
SG184547A1 (en) | 2012-11-29 |
EP2563347A4 (en) | 2013-04-10 |
US9017723B2 (en) | 2015-04-28 |
AP2012006462A0 (en) | 2012-10-31 |
UA103851C2 (en) | 2013-11-25 |
JP5820469B2 (ja) | 2015-11-24 |
MY153762A (en) | 2015-03-13 |
EA201290775A1 (ru) | 2013-04-30 |
US9597301B2 (en) | 2017-03-21 |
ZA201206676B (en) | 2014-01-29 |
CA2793571C (en) | 2015-10-13 |
AU2011248904A1 (en) | 2012-09-27 |
CO6561765A2 (es) | 2012-11-15 |
IL221959A (en) | 2016-11-30 |
EP2563347A2 (en) | 2013-03-06 |
EP2563347B1 (en) | 2016-10-12 |
CA2793571A1 (en) | 2011-11-10 |
WO2011139420A3 (en) | 2012-01-12 |
KR20120137373A (ko) | 2012-12-20 |
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JP2013525432A (ja) | 2013-06-20 |
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