TWI383811B - 具有黏著層之經皮治療系統，將該系統之支撐層加以聚矽氧化的方法以及該支撐層的用途 - Google Patents
具有黏著層之經皮治療系統，將該系統之支撐層加以聚矽氧化的方法以及該支撐層的用途 Download PDFInfo
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Description
本發明係關於含有支撐層、與支撐層接觸且包含聚矽氧黏著劑的聚合物層以及與聚合物層接觸的可分離式保護層之經皮治療系統，加以聚矽氧化之系統支撐層的製造方法及該支撐層的用途。
經皮治療系統(TTS)或活性成份貼片目前已成為經建立之藥物型式。雖然如此，但是與該藥物型式有關連的特定問題迄今尚未解決至令人滿意。這些問題之一特別關於所謂的基質系統或具有與基質系統有關的裝配之系統。該種類的基質系統或基質TTS係由最簡單的支撐層、活性成份基質層(以自黏式較佳)及希望在使用之前移除的保護層所構成。在配戴TTS期間，在特定的時間之後常在皮膚上發現在貼片周圍形成或多或少的微黑色邊緣，及/或在移除TTS時在皮膚上留下黏著劑殘餘物。在適合貼用數天的TTS之例子中，該現象出現的程度特別顯著。該兩種現象的原因係貼片基質與系統的支撐層不當的黏著性。該不當的黏著性及在貼用位置的身體移動引起在系統邊緣露出黏著劑，並使露出的黏著劑可與衣服接觸。與衣服接觸的結果使織物纖維以露出的黏著劑維持停住不動，並在大部分的例子中使其成為深暗的外觀。在移除TTS之後，露出的黏著劑以深暗的痕跡形式留在皮膚上。如果與支撐層
的黏著性特別弱時，則也可能自支撐層分離出大塊的基質區域且可能留在皮膚上。特別容易引起該現象的是以聚矽氧為主之黏著劑。該理由係聚矽氧黏著劑非常不具有極性，因此與或高或低極性的支撐層表面具有相對差的黏著性，在大部分的例子中，該支撐層係由聚對苯二甲酸乙二醇酯(PET)所組成。其它因素為聚矽氧黏著劑具有低的內聚力，因此使彼等具有特別強力顯著自系統露出的傾向。
聚矽氧黏著劑因此具有像是黏稠液體的行為，並擴散於相對大的面積，於是也稱為”冷流”。
因此，本發明的目的係改進在經皮治療系統中的支撐層與含有至少一種聚矽氧黏著劑的活性成份聚合物層的黏著性，而且主要係阻止聚矽氧黏著劑自系統露出。
該目的係根據本發明以最初所述之經皮治療系統達成，其係藉由提供具有以聚矽氧化所獲得的黏著層之支撐層接觸表面。
在本發明的具體實施例中，黏著層為有機聚矽氧烷層。黏著層特別包含含有乙烯基之有機聚矽氧烷及含有Si-H基團之有機聚矽氧烷。
在較佳的方式中，支撐層為選自聚酯，尤其為聚對苯二甲酸乙二醇酯、聚丙烯、聚乙烯、聚胺基甲酸酯、與聚
酯組合之EVA(乙烯-乙酸乙烯酯共聚物)層、PVDC(聚偏二氯乙烯)、聚芳香醯胺及乙烯-(甲基)丙烯酸酯共聚物之聚合物膜材料。
自申請專利範圍5至9之特色明白本發明進一步的具體實施例。
使本發明的方法(即在經皮治療系統中所使用的支撐層之製造方法)以包含將與具備微貯庫之聚合物層接觸的支撐層表面加以聚矽氧化的事實予以突顯。該方法較佳地係藉由含有乙烯基團之有機聚矽氧烷與含有Si-H官能基團之有機聚矽氧烷混合及在觸媒的存在下以混合物塗佈支撐層表面予以完成。然後將經塗佈之支撐層表面以熱處理，直到形成堅牢地固定在支撐層上的有機聚矽氧烷層為止。所使用的觸媒為例如鉑觸媒。熱處理發生在熱烘箱中或熱隧道中。溫度為約80至100℃，並也可以小於80℃。
在使用之前，必須將任何自黏式系統(不論其為經皮治療系統、非活性成份貼片(石膏)、標籤或黏著膠帶)以可再分離之保護層保護。保護層可由各種材料所組成，例如，PET、聚乙烯或聚丙烯，尤其將黏著劑上的接觸面加以處理，以便於可使其儘可能輕易地自黏著層分離。為了與不以聚矽氧為主之黏著劑組合使用，故該表面處理經常由聚矽氧化作用所組成。該聚矽氧化作用包含將例如在混合物中的含有乙烯基團之有機聚矽氧烷與含有SiH官能基團之有機聚矽氧烷在鉑觸媒的存在下以塗佈操作塗佈在以熱處理的處理膜上，得以形成堅固地黏著於基板的有機
聚矽氧烷層。反之，例如不以聚矽氧為主之黏著劑(如聚丙烯酸酯黏著劑)與因此處理的表面連接極差，聚矽氧黏著劑與這些表面的連接極完好。在石膏配戴試驗中，頃發現以聚矽氧黏著劑為主之非活性成份貼片及以該方式處理的支撐層在移除之後在皮膚上留下相當少/更少的黏著劑殘餘物，並使在貼片周圍形成”黑色”邊緣的傾向減低不少。
在以聚矽氧黏著劑為主之TTS的例子中，以外加的熱施予貼用的TTS使活性成份經由皮膚的穿透率增加。在例如US 6,488,599 A1及US 6,261,595 A1中詳細說明該種類的系統。就此點而論，由於可輕易爬升至約45℃之溫度，故以冷流使聚矽氧黏著劑擴散的傾向大量增加。在這些條件下更有可能在移除貼片之後在貼片周圍形成深暗的邊緣且使黏著劑殘餘物留在皮膚上。在這些系統中，最大的優點屬於使支撐層加以聚矽氧化，因為儘管有加熱，但主要是阻止黏著劑擴散。
支撐層的聚矽氧化作用同樣證實對已知為以聚矽氧黏著劑及兩性溶劑為主之微貯庫系統的系統種類有關連的活性成份特別重要。在EP 1 191 927 B1中詳細說明該種類的微貯庫系統。在製造這些系統時，將活性成份溶解在兩性溶劑中，例如，二丙二醇或1,3-丁二醇，並將溶液分散在黏著劑溶液中。然後將分散液塗佈在後續TTS的保護層上，移除黏著劑的溶劑，並將乾燥膜壓疊於支撐層上。目前顯示未加以聚矽氧化之支撐層實際上未展現任何與該等
膜之黏著性。其理由係在乾燥的活性成份膜表面上形成非常薄的兩性溶劑膜。改變製造方法(例如，直接塗佈在支撐層上)不會改進乾燥膜的黏著性。但是，在與微貯庫層接觸之後，加以聚矽氧化之支撐層立即產生非常好的黏著性，與膜材料本身的化學本性無關。雖然經由使用較低惰性之材料(例如，乙烯與醋酸乙烯酯之共聚物)於這些系統的支撐層也可以達成改進的黏著性，但是該種材料具有吸收活性成份與溶劑的缺點。因此使用聚酯或類似的惰性材料所製之加以聚矽氧化之支撐層最可實現如上述之微貯庫系統。
唯一的圖形展示經皮治療系統5，其包含支撐層1、堅牢地固定在支撐層上的黏著層4、聚合物層2及可分離式保護層3。黏著層4為有機聚矽氧烷層，其包含含有乙烯基團之有機聚矽氧烷及含有Si-H官能基團之有機聚矽氧烷。支撐層1係由聚合物膜材料所構成。適合的聚合物為聚酯，尤其為聚對苯二甲酸乙二醇酯、聚丙烯、聚乙烯、聚胺基甲酸酯、與聚酯組合之EVA層、PVDC、聚芳香醯胺及乙烯-(甲基)丙烯酸酯共聚物。更多適合的材料為乙基纖維素、纖維素醋酸酯、玻璃紙、紙、金屬-聚合物複合物及乙烯-醋酸乙烯酯共聚物。
在聚合物層2中的聚矽氧黏著劑係選自例如聚矽氧烷及聚矽氧烷混合物。
在聚合物層2中存在的是微貯庫，其包括至少一種在兩性溶劑中成為溶液的活性成份。適合的兩性溶劑為1,3-
丁二醇、二乙二醇單甲醚、二乙二醇單乙醚、二乙二醇二甲醚、二丙二醇、丙二醇、四氫糠醇、二乙二醇單丁醚、三乙二醇和二乙二醇之羧酸酯、6-18個碳原子之聚氧乙基化脂肪醇、及其混合物。
保護層3懸於聚合物層2的兩面上，所以可將其黏牢且分離而沒有問題。
加以聚矽氧化之支撐層的使用對微貯庫系統的製造毫無任何影響。甚至在已銷售之TTS的例子中，自純粹技術的觀點而言，有可能以聚矽氧化之支撐層置換未加以聚矽氧化之支撐層而沒有問題。關於活性成份輸送的TTS的特性在該等置換例子中保持不受影響，因為所施加之厚度小於10微米之聚矽氧層實際上不吸收任何活性成份。
因此，可以概括說明使用加以聚矽氧化之支撐層毅然改進以聚矽氧黏著劑為主之TTS的配戴特性，並使特殊的系統目前在技術上可行，例如以聚矽氧黏著劑及兩性溶劑為主之微貯庫系統。
1‧‧‧支撐層
2‧‧‧聚合物層
3‧‧‧可分離式保護層
4‧‧‧黏著層
5‧‧‧經皮治療系統
圖1展示根據本發明的經皮治療系統。
1‧‧‧支撐層
2‧‧‧聚合物層
3‧‧‧可分離式保護層
4‧‧‧黏著層
5‧‧‧經皮治療系統
Claims (13)
- 一種經皮治療系統，其包含支撐層、與該支撐層接觸且包含聚矽氧黏著劑的聚合物層以及與該聚合物層接觸的可分離式保護層，其中該支撐層的接觸面具備以聚矽氧化作用所獲得的黏著層，此黏著層堅牢地固定於該支撐層並且包含含有乙烯基團之有機聚矽氧烷及含有Si-H基團之有機聚矽氧烷。
- 如申請專利範圍第1項之經皮治療系統，其中該支撐層為選自聚酯(尤其為聚對苯二甲酸乙二醇酯)、聚丙烯、聚乙烯、聚胺基甲酸酯、與聚酯組合之EVA(乙烯-乙酸乙烯酯共聚物)層、PVDC(聚偏二氯乙烯)、聚芳香醯胺及乙烯-(甲基)丙烯酸酯共聚物之聚合物膜材料。
- 如申請專利範圍第1項之經皮治療系統，其中該支撐層係由選自乙基纖維素、纖維素醋酸酯、玻璃紙(cellophane)、紙、金屬-聚合物複合物及乙烯-醋酸乙烯酯共聚物之材料所構成。
- 如申請專利範圍第1項之經皮治療系統，其中該聚合物層包含以聚矽氧聚合物為主之聚矽氧黏著劑及樹脂。
- 如申請專利範圍第1項之經皮治療系統，其中聚矽氧黏著劑係選自聚矽氧烷及聚矽氧烷混合物。
- 如申請專利範圍第1項之經皮治療系統，其中該聚合物層包含在兩性溶劑中成為溶液的活性醫藥成份之微 貯庫。
- 如申請專利範圍第1項之經皮治療系統，其中該兩性溶劑係選自1,3-丁二醇、二乙二醇單甲醚、二乙二醇單乙醚、二乙二醇二甲醚、二丙二醇、丙二醇、四氫糠醇、二乙二醇單丁醚、三乙二醇和二乙二醇之羧酸酯、6-18個碳原子之聚氧乙基化脂肪醇及其混合物。
- 一種製造在經皮治療系統中所使用之支撐層的方法，其包含把將與具備微貯庫之聚合物層接觸的支撐層表面加以聚矽氧化。
- 如申請專利範圍第8項之方法，其中將含有乙烯基團之有機聚矽氧烷與含有Si-H官能基團之有機聚矽氧烷混合及在觸媒的存在下將該支撐層表面以該混合物塗佈。
- 如申請專利範圍第9項之方法，其中將該支撐層之塗佈表面熱處理，直到形成堅牢地固定在該支撐層上的有機聚矽氧烷層為止。
- 一種經聚矽氧化之支撐層在經皮治療系統中的用途。
- 如申請專利範圍第11項之支撐層的用途，其中在該支撐層上以聚矽氧化作用堅牢地固定了一層有機聚矽氧烷層。
- 如申請專利範圍第12項之支撐層的用途，其中該系統之含有微貯庫及至少一種溶解在其中的活性成份以及至少一種聚矽氧黏著劑的聚合物層係以自黏式連結於該 有機聚矽氧烷層。
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| TW585789B (en) * | 1997-09-16 | 2004-05-01 | Teijin Ltd | Gel adhesive, adhesive material containing same, and adhering pharmaceutical preparation |
| CN1356895A (zh) * | 1999-07-02 | 2002-07-03 | Lts勒曼治疗系统股份公司 | 以聚硅氧烷及亲两性溶剂为基础的微贮存系统 |
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