TW201609200A - 含水型貼劑 - Google Patents
含水型貼劑 Download PDFInfo
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- TW201609200A TW201609200A TW103143983A TW103143983A TW201609200A TW 201609200 A TW201609200 A TW 201609200A TW 103143983 A TW103143983 A TW 103143983A TW 103143983 A TW103143983 A TW 103143983A TW 201609200 A TW201609200 A TW 201609200A
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- dexmedetomidine
- salt
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Abstract
本發明提供一種右美托咪定的吸收性足夠高且皮膚刺激性小的貼劑。本發明是一種含水型貼劑，其含有右美托咪定或其鹽及水溶性高分子。
Description
本發明是有關於一種含有作為鎮靜劑有用的右美托咪定(dexmedetomidine)或其鹽的貼劑。
右美托咪定或其鹽是α2腎上腺素受體(alpha-2 adrenaline receptor)的促效劑(agonist)，具有鎮靜作用、鎮痛作用、交感神經抑制作用，被用作鎮靜劑。目前，在日本被用於集中治療中的人工呼吸過程中及脫離後的鎮靜，在海外被廣泛用作鎮靜劑、鎮痛劑。作為該右美托咪定的投與形態，僅使用靜脈內投與(intravenous administration)。
另一方面，作為右美托咪定的投與形態，亦進行了經皮吸收製劑的研究。例如，報告有如下貼劑：由襯裏層(backing layer)/固定接著劑層/多孔性中間層/接觸接著劑層/剝離襯墊(release liner)構成的非水系貼劑(專利文獻1)、儲藥(reservoir)型貼劑(專利文獻2)、使用環糊精(cvclodextrin)衍生物的貼劑(專利文獻3)、及以與羧酸的鹽的形式調配有右美托咪定的貼劑(專利文獻4)。
[現有技術文獻]
[專利文獻]
[專利文獻1]日本專利第3043064號公報
[專利文獻2]日本專利第3011459號公報
[專利文獻3]日本專利第3734267號公報
[專利文獻4]日本專利第3483881號公報
然而，該些先前的含右美托咪定的貼劑為了獲得高吸收性而使用複雜的製劑構成或釋放機制，或者將右美托咪定製成特殊的鹽。因此，產生對皮膚的刺激性或出現皮疹等問題的可能性變高。
因此，本發明的課題在於提供一種右美托咪定的吸收性足夠高且皮膚刺激性小的貼劑。
因此，本發明者使用各種基劑而製造含右美托咪定的貼劑，並研究其經皮吸收性，結果完全意外地發現，若製成調配有右美托咪定或其鹽及水溶性高分子且含有大量水的含水型貼劑，則可獲得右美托咪定的經皮吸收性優異且皮膚刺激小的貼劑，從而完成本發明。
即，本發明提供以下[1]~[8]。
[1]一種含水型貼劑，其含有右美托咪定或其鹽及水溶性高分子。
[2]如[1]所述的含水型貼劑，其中水溶性高分子的含量於膏體中為5質量%~25質量%，水的含量於膏體中為25質量%~70質量%。
[3]如[1]或[2]所述的含水型貼劑，其中水溶性高分子包含聚丙烯酸或其鹽及羧基甲基纖維素(carboxymethyl cellulose)或其鹽。
[4]如[1]至[3]中任一項所述的含水型貼劑，其中膏體的pH值為6~7。
[5]如[1]至[4]中任一項所述的含水型貼劑，其更含有選自多元醇(polyhydric alcohol)及脂肪酸酯(fatty acid ester)系吸收促進劑中的一種或兩種以上。
[6]如[1]至[4]中任一項所述的含水型貼劑，其更含有選自多元醇、高級脂肪酸烷基酯(higher fatty acid alkyl ester)、二元酸二烷基酯(dibasic acid dialkyl ester)及多元醇脂肪酸酯(polyhydric alcohol fatty acid ester)中的一種或兩種以上。
[7]如[1]至[4]中任一項所述的含水型貼劑，其更含有選自丙二醇(propylene glycol)、甘油(glycerin)、糖醇(sugar alcohol)、肉豆蔻酸異丙酯(isopropyl myristate)及丙二醇單辛酸酯(propylene glycol monocaprylate)中的一種或兩種以上。
[8]如[1]至[7]中任一項所述的含水型貼劑，其中該貼劑為鎮靜劑。
本發明的貼劑由於右美托咪定的經皮吸收性優異且皮
膚刺激性小，故而可長時間穩定地獲得右美托咪定的作為鎮靜劑的效果。
本發明的貼劑的有效成分是右美托咪定或其鹽。右美托咪定的化學名為(+)-(S)-4-[1-(2,3-二甲基苯基)乙基]-1H-咪唑，為中樞性α2腎上腺素受體的促效劑。該右美托咪定的鹽可列舉酸加成鹽(acid addition salt)，較佳為鹽酸、硫酸、硝酸、磷酸等的無機酸加成鹽，尤佳為鹽酸鹽。
就經皮吸收性、皮膚刺激性、製劑穩定性的方面而言，右美托咪定或其鹽的含量較佳為於貼劑的膏體中為0.1質量%~10質量%、進而0.1質量%~7質量%。
本發明的貼劑中所使用的水溶性高分子可列舉：明膠(gelatin)、澱粉(starch)、瓊脂(agar)等水溶性天然高分子；羧基甲基纖維素或其鹽、羥基丙基纖維素、羥基丙基甲基纖維素、甲基纖維素、乙基纖維素等水溶性纖維素衍生物；丙烯酸澱粉等加工澱粉；聚丙烯酸、聚丙烯酸鹽、聚丙烯酸部分中和物、交聯型聚丙烯酸、羧基乙烯基聚合物(carboxy vinyl polymer)、聚乙烯醇、N-乙烯基乙醯胺．聚丙烯酸鈉共聚物等水溶性合成高分子等。其中，較佳為明膠、聚丙烯酸、聚丙烯酸鹽、聚丙烯酸部分中和物、交聯型聚丙烯酸、羧基乙烯基聚合物、羧基甲基纖維素或其
鹽、羥基丙基纖維素、羥基丙基甲基纖維素。該些水溶性高分子可使用一種或組合使用兩種以上。
該些水溶性高分子之中，就右美托咪定或其鹽的經皮吸收性、皮膚刺激性及製劑穩定性的方面而言，進而較佳為將聚丙烯酸或其鹽與羧基甲基纖維素或其鹽組合使用。該聚丙烯酸或其鹽與羧基甲基纖維素或其鹽之中，進而較佳為聚丙烯酸部分中和物、聚丙烯酸鈉及羧基甲基纖維素鈉的組合。此處，聚丙烯酸或其鹽(PA)與羧基甲基纖維素或其鹽(CMC)的含有質量比(PA：CMC)較佳為1：5~5：1，更佳為1：3~3：1，進而較佳為1：2~2：1。另外，在使用聚丙烯酸部分中和物(PA)、聚丙烯酸鈉(PANa)及羧基甲基纖維素鈉(CMCNa)的情況下，該些的含有質量比(PA+PANa)：(CMCNa)較佳為1：5~5：1，更佳為1：3~3：1，進而較佳為1：2~2：1。
就經皮吸收性、皮膚刺激性、製劑穩定性的方面而言，水溶性高分子的含量較佳為於貼劑的膏體中為5質量%~25質量%、進而5質量%~20質量%。
本發明的貼劑為含水型貼劑，就右美托咪定或其鹽的經皮吸收性及皮膚刺激性的方面而言，重要的是含有相對大量的水。就經皮吸收性、皮膚刺激性及製劑穩定性的方面而言，該水的含量較佳為於貼劑的膏體中為25質量%~70質量%、進而30質量%~60質量%、進而30質量%~55質量%。
就提高右美托咪定或其鹽的經皮吸收性的方面而言，本
發明的貼劑較佳為調配選自多元醇及脂肪酸酯系吸收促進劑中的一種或兩種以上。
多元醇可列舉：乙二醇、丙二醇、二丙二醇、1,3-丁二醇、聚乙二醇(分子量1000以下)、聚丙二醇(分子量1000以下)等二醇類；甘油、二甘油、聚甘油等甘油類；山梨糖醇、麥芽糖醇等糖醇等。該些多元醇可使用一種或組合使用兩種以上。其中，較佳為丙二醇、甘油、糖醇。尤其是就防止膏體中的右美托咪定或其鹽的結晶化的方面而言，較佳為添加丙二醇。此外，如下所述，即便於製劑中右美托咪定或其鹽產生結晶，亦幾乎不會影響皮膚透過性，但就製劑的外觀的方面而言，較佳為無結晶。
就經皮吸收性、皮膚刺激性的方面而言，多元醇的含量較佳為於貼劑中的膏體中為10質量%~60質量%、進而20質量%~55質量%、進而25質量%~55質量%。
脂肪酸酯系吸收促進劑可列舉：肉豆蔻酸異丙酯、棕櫚酸異丙酯、硬脂酸丁酯、肉豆蔻酸丁酯等高級脂肪酸烷基酯(較佳為C8-C24脂肪酸C1-C6烷基酯)；癸二酸二異丙酯、癸二酸二乙酯、己二酸二異丙酯等二元脂肪酸二烷基酯(較佳為二元酸二C1-C6烷基酯)；丙二醇單辛酸酯、丙二醇二辛酸酯、丙二醇二癸酸酯、甘油單辛酸酯、四甘油單辛酸酯、去水山梨糖醇六辛酸酯等多元醇脂肪酸酯(較佳為多元醇C8-C24脂肪酸酯)等。
其中，較佳為高級脂肪酸烷基酯、多元醇脂肪酸酯、二元脂肪酸二烷基酯，尤佳為高級脂肪酸烷基酯、多元醇脂肪酸酯，進
而就除高吸收促進效果以外，亦容易維持所期望的鎮痛程度(level)的方面而言，較佳為肉豆蔻酸異丙酯、丙二醇單辛酸酯。
該些脂肪酸酯系吸收促進劑亦可不添加，但較佳為於貼劑的膏體中含有0.01質量%~15質量%、進而0.1質量%~10質量%、進而0.1質量%~5質量%。
該些多元醇、所述吸收促進劑之中，較佳為使用選自丙二醇、甘油、糖醇、高級脂肪酸烷基酯及多元醇脂肪酸酯中的一種或組合使用兩種以上，較佳為使用選自丙二醇、甘油、糖醇、肉豆蔻酸異丙酯及丙二醇單辛酸酯中的一種或組合使用兩種以上。
具體而言，較佳為將甘油與糖醇組合，進而較佳為將甘油、糖醇、高級脂肪酸烷基酯組合，進而較佳為將甘油、糖醇、高級脂肪酸烷基酯、丙二醇組合使用，進而較佳為將甘油、糖醇、高級脂肪酸烷基酯、多元醇脂肪酸酯、丙二醇組合使用。此處，糖醇尤佳為山梨糖醇。另外，高級脂肪酸烷基酯尤佳為肉豆蔻酸異丙酯。多元醇脂肪酸酯尤佳為丙二醇單辛酸酯。此處，若調配多元醇脂肪酸酯，則貼劑的長期保存穩定性提高。
此外，本發明的貼劑中亦可調配其他吸收促進劑。該吸收促進劑可列舉：辛酸、癸酸、己酸、月桂酸、肉豆蔻酸、棕櫚酸、硬脂酸等C8~C18脂肪酸；辛醇、癸醇、月桂醇、肉豆蔻醇、鯨蠟醇、油醇等C8~C18高級醇；聚氧化乙烯烷基醚、烷基硫酸鹽、N-甲基-2-吡咯啶酮等。
除所述成分以外，本發明的貼劑中亦可調配交聯劑、pH值調整劑、螯合劑(chelate)、界面活性劑、其他添加劑。
交聯劑是使水溶性高分子交聯而形成凝膠(gel)的成分，較佳為鋁化合物。該鋁化合物可列舉：氫氧化鋁、氯化鋁、合成矽酸鋁、乾燥氫氧化鋁凝膠、氫氧化鋁鎂、硫酸鋁、二羥基胺基乙酸鋁(dihydroxyaluminum aminoacetate)等。
就經皮吸收性及製劑穩定性的方面而言，交聯劑的含量較佳為於貼劑的膏體中含有0.001質量%~1質量%、進而0.01質量%~1質量%。
pH值調整劑可使用乳酸、酒石酸、檸檬酸、乙酸及該些的鹽等。pH值調整劑的含量較佳為於貼劑的膏體中為0.001質量%~1質量%、進而0.01質量%~1質量%。就提高右美托咪定或其鹽的經皮吸收性而言，較佳為使含水型貼劑的膏體pH值成為6~7。
螯合劑可列舉：乙二胺四乙酸(Ethylene Diamine Tetraacetic Acid，EDTA)鈉、葡萄糖酸-δ-內酯(glucono delta lactone)、偏磷酸鈉等聚磷酸鈉等。螯合劑的含量較佳為於貼劑的膏體中為0.001質量%~1質量%、進而0.01質量%~1質量%。
界面活性劑可列舉：聚氧化乙烯去水山梨糖醇脂肪酸酯(polyoxyethylene sorbitan fatty acid ester)、去水山梨糖醇脂肪酸酯、甘油脂肪酸酯、聚氧化乙烯甘油脂肪酸酯、聚甘油脂肪酸酯、聚氧化乙烯氫化蓖麻油、聚氧化乙烯烷基醚等。該些界面活性劑
亦可不添加，但較佳為於貼劑的膏體中含有0.01質量%~5質量%、進而0.01質量%~3質量%。
其他添加劑可列舉：丙烯酸系共聚物(甲基丙烯酸．丙烯酸．正丁基共聚物、丙烯酸甲酯．丙烯酸2-乙基己酯共聚物)、防腐劑、抗氧化劑、穩定劑、賦形劑(高嶺土(kaolin)、無水矽酸、氧化鈦、滑石(talc)等)、香料、著色劑、油成分(克羅米通(crotamiton)、蓖麻油)等。
本發明的含水型貼劑通常是將含有所述成分的膏體塗敷於支持體上，並使被覆膜(film)(剝離片(sheet))附著於該膏體面而製造。
支持體較佳為不透水性(water impermeable)的支持體，較佳為於聚對苯二甲酸乙二酯、聚乙烯、聚丙烯等聚烯烴系膜上積層不織布而成者。
被覆膜可使用聚乙烯膜、聚丙烯膜等聚烯烴膜及聚酯膜。另外，對於該些膜，亦可實施矽剝離處理、電暈放電處理(corona discharge treatment)、及壓紋處理(embossing treatment)。
膏體的塗佈量較佳為40g/m2~400g/m2，進而較佳為50g/m2~300g/m2。
本發明的貼劑的尺寸(size)較佳為大小為10cm2~100cm2，且設為方形、圓形、橢圓形等形狀。
本發明的含水型貼劑由於為貼劑，故而在貼附等時，可在不把手弄髒的情況下簡便地投與一定量的右美托咪定或其鹽。
進而，由於含有有效量的右美托咪定或其鹽，皮膚刺激性小，經皮吸收性良好，故而即便不進行靜脈內投與，藉由一天重複貼附1次~3次，亦可期待連日持續的效果，可快速達到所期望的鎮靜程度，從而獲得穩定的鎮靜作用。
此外，穩定的鎮靜作用是指在依據鎮靜程度評估表(Richmond Agitation-Sedation Scale，RASS)進行評估時，可獲得評分(score)0~-2的鎮靜程度。
為了快速獲得穩定的鎮靜效果，本發明的含水型貼劑的經皮吸收速度較佳為在使用無毛小鼠(hairless mouse)腹部摘出皮膚進行評估時，右美托咪定鹽酸鹽的皮膚透過速度為3.40μg/cm2/hr以上、進而4.45μg/cm2/hr以上。另外，用於人類(human)時的經皮吸收速度較佳為0.2μg/kg/hr以上。
[實施例]
其次，列舉實施例對本發明進行更詳細的說明，但本發明並不限定於該些實施例。
實施例1~實施例10
依據表1~表3的配方，製造含水型貼劑。
(1)於純化水中添加明膠、酒石酸、乙二胺四乙酸鈉及右美托咪定鹽酸鹽並使該些溶解。將在多元醇中加入聚丙烯酸
部分中和物、聚丙烯酸鈉、羧基甲基纖維素鈉(CMC-Na)、二羥基胺基乙酸鋁及視需要的肉豆蔻酸異丙酯、聚山梨醇酯80、丙二醇單辛酸酯並使該些分散而成者另外添加至該溶液中，進行攪拌而製成膏體。
(2)將膏體以膏體的塗佈量成為160g/m2的方式於支持體上延展，進而以黏著面經矽剝離處理的聚酯膜覆蓋後，裁斷成預定的大小，獲得右美托咪定的含水型貼劑。
(3)支持體是使用於聚酯膜上積層聚酯不織布而成者。
試驗例1<皮膚透過試驗>
試驗方法
將無毛小鼠(7週齡，雄性)的腹部摘出皮膚裝於附水套(water jacket)的側向擴散池(lateral diffusion cell)。對角質層側應用預定的貼劑，對接收(receiver)側應用pH值6.8的磷酸緩衝液2.5mL。使32℃的溫水於水套中循環而將其保持為固定溫度。一面利用攪拌子攪拌接收側溶液，一面經時性地採取接收側的溶液0.5mL而製成試樣溶液。此外，採取接收液後立即補充新的磷酸緩衝液0.5mL。試樣溶液中的右美托咪定鹽酸鹽的量是利用高效液相層析法(high performance liquid chromatography，HPLC)進行定量，求出右美托咪定鹽酸鹽自製劑向接收側的累積透過量。另外，根據右美托咪定鹽酸鹽的累積透過量的經時變化，計算試驗開始後第6小時~第9小時的右美托咪定鹽酸鹽的透過速度。將結果示於表4~表6。
進而，於表4~表6中記載各製劑的pH值。製劑的pH值是將膏體1質量份加溫溶解於純化水9質量份中，溶解液成為20℃~25℃後，使用pH計(pH meter)進行測定。
根據表4~表6的結果判明，藉由將右美托咪定或其鹽製成調配有水溶性高分子且水分量多的含水型貼劑，而使經皮吸收性變得良好。另外亦判明，藉由調配多元醇(丙二醇、甘油、山梨糖醇)或/及高級脂肪酸烷基酯(肉豆蔻酸異丙酯)，而使經皮吸收性提高。此外，亦確認，所述實施例1~實施例10的貼劑無皮膚刺激性且穩定。
試驗例2(皮膚透過速度及長期穩定性)
製造實施例1、實施例6、實施例8、實施例9及實施例10的含水型貼劑，並對長期保存穩定性(有無結晶析出及右美托咪定鹽酸鹽的穩定性)進行評估。另外，針對實施例1的含水型貼劑，以與試驗例1相同的方式亦進行長期保存後的皮膚透過試驗。
(結晶的確認方法)
將製劑(10cm2)包裝於鋁袋中，在室溫下保管8個月後，目視確認製劑中有無右美托咪定鹽酸鹽的結晶，依據下述評分進行評估。
[表7]
(右美托咪定鹽酸鹽的穩定性試驗)
將製劑1片(10cm2，以右美托咪定鹽酸鹽計為160mg)包裝於鋁袋中，在60℃下保管3週。利用甲醇將保管後的製劑中的右美托咪定鹽酸鹽加熱回流萃取。利用高效液相層析法(HPLC)定量萃取液中的右美托咪定鹽酸鹽的量，求出保管後的右美托咪定鹽酸鹽相對於初始值(initial value)的殘存率(%)。
根據表8可知，藉由亦添加多元醇脂肪酸酯，而即便長期保存，亦無結晶析出，穩定性提高。另外，根據表9可知，即便是因長期保存而導致結晶析出的貼劑，亦幾乎不會影響右美托咪定鹽酸鹽的皮膚透過速度。但是，自製劑的外觀考慮，較佳為
無結晶析出。
Claims (8)
- 一種含水型貼劑，其含有右美托咪定或其鹽及水溶性高分子。
- 如申請專利範圍第1項所述的含水型貼劑，其中水溶性高分子的含量於膏體中為5質量%~25質量%，水的含量於膏體中為25質量%~70質量%。
- 如申請專利範圍第1項所述的含水型貼劑，其中水溶性高分子包含聚丙烯酸或其鹽及羧基甲基纖維素或其鹽。
- 如申請專利範圍第1項所述的含水型貼劑，其中膏體的pH值為6~7。
- 如申請專利範圍第1項所述的含水型貼劑，其更含有選自多元醇及脂肪酸酯系吸收促進劑中的一種或兩種以上。
- 如申請專利範圍第1項所述的含水型貼劑，其更含有選自多元醇、高級脂肪酸烷基酯、二元酸二烷基酯及多元醇脂肪酸酯中的一種或兩種以上。
- 如申請專利範圍第1項所述的含水型貼劑，其更含有選自丙二醇、甘油、糖醇、肉豆蔻酸異丙酯及丙二醇單辛酸酯中的一種或兩種以上。
- 如申請專利範圍第1項至第7項中任一項所述的含水型貼劑，其中所述貼劑為鎮靜劑。
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| JPS60163811A (ja) * | 1984-02-06 | 1985-08-26 | Watanabe Yakuhin Kogyo Kk | プロプラノロ−ル含有外用貼付剤 |
| EP0303445A1 (en) * | 1987-08-13 | 1989-02-15 | Walton S.A. | Clebopride transdermal patch |
| US5124157A (en) | 1989-08-18 | 1992-06-23 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
| US5217718A (en) * | 1989-08-18 | 1993-06-08 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
| JP2849937B2 (ja) | 1990-04-18 | 1999-01-27 | 日東電工株式会社 | 医療用貼付剤 |
| GB9111732D0 (en) | 1991-05-31 | 1991-07-24 | Orion Yhtymae Oy | The use of certain salts of medetomidine and its optically active enantiomers to regulate the rate of transdermal administration of the drugs |
| US5352456A (en) | 1991-10-10 | 1994-10-04 | Cygnus Therapeutic Systems | Device for administering drug transdermally which provides an initial pulse of drug |
| GB2290964A (en) | 1994-07-08 | 1996-01-17 | Arto Olavi Urtti | Transdermal drug delivery system |
| US7001609B1 (en) | 1998-10-02 | 2006-02-21 | Regents Of The University Of Minnesota | Mucosal originated drug delivery systems and animal applications |
| EP1170020A4 (en) * | 1999-12-27 | 2009-05-06 | Teikoku Seiyaku Kk | EXTERNAL USE PADS |
| US6761900B2 (en) * | 2001-03-12 | 2004-07-13 | Teikoku Pharma Usa, Inc. | Topical patch preparation containing a delayed-type hypersensitivity inducer and methods for using the same |
| JP5243158B2 (ja) * | 2008-09-12 | 2013-07-24 | 日東電工株式会社 | 貼付材並びに貼付製剤 |
| TWI629066B (zh) | 2013-10-07 | 2018-07-11 | 帝國製藥美國股份有限公司 | 使用右美托咪啶經皮組成物用於治療注意力不足過動症、焦慮及失眠的方法及組成物 |
-
2014
- 2014-12-17 JP JP2015553566A patent/JP6469587B2/ja active Active
- 2014-12-17 US US15/102,605 patent/US9974754B2/en active Active
- 2014-12-17 TW TW103143983A patent/TW201609200A/zh unknown
- 2014-12-17 WO PCT/JP2014/083335 patent/WO2015093503A1/ja active Application Filing
- 2014-12-17 EP EP14872467.7A patent/EP3087985B1/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113874011A (zh) * | 2019-05-27 | 2021-12-31 | 救急药品工业株式会社 | 外用制剂 |
| WO2024037545A1 (zh) * | 2022-08-17 | 2024-02-22 | 宜昌人福药业有限责任公司 | 右美托咪定经皮组合物、透皮贴剂及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6469587B2 (ja) | 2019-02-13 |
| JPWO2015093503A1 (ja) | 2017-03-23 |
| US20160310441A1 (en) | 2016-10-27 |
| EP3087985A1 (en) | 2016-11-02 |
| EP3087985B1 (en) | 2018-10-17 |
| US9974754B2 (en) | 2018-05-22 |
| WO2015093503A1 (ja) | 2015-06-25 |
| EP3087985A4 (en) | 2017-07-19 |
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