TWI568456B - Containing transdermal absorption preparations of oxybutynin - Google Patents
Containing transdermal absorption preparations of oxybutynin Download PDFInfo
- Publication number
- TWI568456B TWI568456B TW101139715A TW101139715A TWI568456B TW I568456 B TWI568456 B TW I568456B TW 101139715 A TW101139715 A TW 101139715A TW 101139715 A TW101139715 A TW 101139715A TW I568456 B TWI568456 B TW I568456B
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- Prior art keywords
- oxybutynin
- cholesterol
- patch
- acid
- mass
- Prior art date
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Description
本發明係關於含有奧昔布寧(oxybutynin)的經皮吸收製劑,尤其減低奧昔布寧所引起之皮膚刺激之含有奧昔布寧(oxybutynin)的經皮吸收製劑及其製造方法、以及減低含有奧昔布寧(oxybutynin)的經皮吸收製劑所引起皮膚刺激之方法。
奧昔布寧(oxybutynin)係於治療急尿感或頻尿等之症狀「膀胱過動」所使用之藥物。傳統上,奧昔布寧(oxybutynin)主要係經口投與,已知因肝臟首渡效應之代謝物所引起之口內乾燥或便秘、嗜睡等之副作用。為減輕經口投與所引起之副作用,提出含有奧昔布寧(oxybutynin)的經皮吸收製劑(專利文獻1)。
然而,由皮膚投與奧昔布寧(oxybutynin)時,很少發生搔癢、紅斑、出疹、疼痛、濕疹、皮膚炎等之皮膚刺激的情況。
另一方面,即使經皮投與奧昔布寧(oxybutynin)以外之藥物,有時亦因藥物本身的結構而於皮膚發生紅斑等之刺激,為減低如此的皮膚刺激,至今實施減低經皮吸收製劑中之藥物濃度、或添加皮膚刺激減低劑。減低藥物濃度,因為是減低所投與的皮膚接觸藥物的量,所以對減低皮膚刺激常常有效,但另一方面,因為一般藥物的吸收量
係與經皮吸收製劑中之藥物濃度成比例,所以有不能確保治療所需吸收量之問題點。
另外,有許多皮膚刺激減低劑被進行檢討,已知對特定藥物所引起之皮膚刺激有效之皮膚刺激減低劑。例如已知作為選擇性血清素再吸收抑制成份之皮膚刺激減低劑之氫醌配糖體、泛酸、傳明酸及卵磷脂(專利文獻2)、作為非類固醇系消炎鎮痛藥之皮膚刺激減低劑之氧化鈦及氫氧化鋁(專利文獻3)。然而,此等皮膚刺激減低劑之效果並不充份,並且有只對特定藥物顯示效果等之問題,希望有可有效地減低奧昔布寧(oxybutynin)刺激皮膚之新穎的皮膚刺激減低劑。
固醇類係已知摻混於經皮吸收製劑。例如揭示藉由使固醇與含有5.0%以上之γ-亞麻酸之植物油脂肪酸或其酯進行反應所得之固醇衍生物係作為具有抗炎症效果之藥效成份(專利文獻4)。然而,此抗炎症效果係記載為減低日曬所引起之「灼熱感」,並非減低藥物所引起之皮膚刺激。
膽固醇係不具有抗炎症活性(專利文獻5)。並且,已知膽固醇係作為活性氧去除劑而摻混於經皮吸收製劑(專利文獻6及7)。雖有膽固醇對於含雙磷酸鹽之貼布型製劑,具有抑制皮膚刺激性之效果之報告(專利文獻8),但未確認對含其他藥物之經皮吸收製劑之皮膚刺激減低效果。
專利文獻1:特開2004-83519號公報
專利文獻2:特開2007-284378號公報
專利文獻3:特開2007-45738號公報
專利文獻4:特開2006-96703號公報
專利文獻5:特開平4-501415號公報
專利文獻6:特開2009-143900號公報
專利文獻7:特開2006-348035號公報
專利文獻8:國際公開2009/075258號
本發明係以提供減低皮膚刺激性之含有奧昔布寧(oxybutynin)的經皮吸收製劑為課題。
本發明者等為解決前述課題,重複努力研究中,發現膽固醇抑制奧昔布寧(oxybutynin)所引起之兔子皮膚刺激性,可作為皮膚刺激減低劑使用,而達成完成本申請書發明。
本發明係提供含有選自奧昔布寧(oxybutynin)及其藥學上所容許的鹽之1種以上的藥物,以及經皮吸收製劑之總量基準之0.05質量%以上之選自膽固醇、膽固醇衍生物及膽固醇類似物之固醇類之經皮吸收製劑。可提供藉由
前述經皮吸收製劑,使用於皮膚時,避免經口投與的副作用,同時亦減低奧昔布寧(oxybutynin)所引起之皮膚刺激之經皮吸收製劑。
一種實施型態,經皮吸收製劑係貼附劑。為貼附劑時,經過24小時或其以上的時間,可提供治療上所需足夠量之奧昔布寧(oxybutynin)之皮膚滲透,同時亦與提升服藥遵從性相關。進一步的實施形態,經皮吸收製劑係具備支持體、及支持體之至少一面上所層合之藥物層,該藥物層係含選自奧昔布寧(oxybutynin)及其藥學上所容許的鹽之1種以上的藥物、選自膽固醇、膽固醇衍生物及膽固醇類似物之固醇類、以及黏著基劑之貼附劑。
其他實施型態,經皮吸收製劑中,固醇類含量係經皮吸收製劑之總量基準之0.05~15質量%。
依據本發明,可提供使用皮膚時,避免經口投與之副作用,同時亦減低奧昔布寧(oxybutynin)所引起之皮膚刺激性之經皮吸收製劑。另外,若固醇類之含量係經皮吸收製劑之總量基準之0.05質量%以上,可發揮皮膚刺激減低效果,該皮膚刺激減低效果係濃度依賴性。
本發明之含有奧昔布寧(oxybutynin)的經皮吸收製劑係含有選自奧昔布寧(oxybutynin)及其藥學上所容許
的鹽之1種以上的藥物,以及經皮吸收製劑之總量基準之0.05質量%以上之選自膽固醇、膽固醇衍生物及膽固醇類似物之固醇類。
奧昔布寧(oxybutynin)係化學名為α-環己基-α-羥基-苯乙酸-4-二乙胺基-2-丁炔酯。所使用之藥物係可為自由體之奧昔布寧,亦可為藥學上所容許的奧昔布寧鹽,亦可為此等之組合。奧昔布寧之藥學上所容許的鹽,可為無機酸鹽,亦可為有機酸鹽,至今已知例如鹽酸鹽、溴酸鹽及矽酸鹽等之無機酸鹽,以及醋酸鹽、檸檬酸鹽、富馬酸鹽及馬來酸鹽等之有機酸鹽。其中,以鹽酸鹽及醋酸鹽尤佳。
經皮吸收製劑中藥物含量係只要為治療有效量即可,雖依經皮吸收製劑之種類而異,但通常經皮吸收製劑之總量基準為4~50質量%,5~30質量%,6~15質量%,進而10~15質量%亦可。若為此含量時,可得到經皮吸收製劑所需充份量之奧昔布寧之皮膚滲透量,同時亦可減低奧昔布寧所引起之皮膚刺激。另外,本說明書中,所謂經皮吸收製劑之總量係指含有藥物部份之總質量。軟膏劑、乳霜劑、凝膠劑、膠狀乳霜劑、藥膏劑及乳液劑等之劑型時,係指其總質量,糊劑及貼布劑等之劑型時,係指去除支持體部份及依狀況之剝離被覆物部份之質量,通常為黏著劑層部份之質量。另外,噴霧劑及氣溶膠劑等之劑型時,係指去除容器部份的部份之質量。
作為藥物發生皮膚刺激之機制之一,對表皮細胞之免
疫反應,進行各種研究。表皮細胞釋出細胞激素(cytokine)、趨化素(Chemokine)、炎症介質(inflammatory mediators)及細胞生長因子等之許多炎症誘發物質於細胞外,或於細胞上發生細胞激素受體、黏附因子及MHC-Ⅱ類,扮演皮膚免疫的中心角色(皮膚免疫手冊(中外醫藥社))。
例如,表皮細胞釋出的炎症誘發物質有介白素(IL)-1 α、1L-10、1L-12、1L-18、TNF-α、GM-CSF、1L-6、1L-7、1L-15、TGF-α、雙向調節因子、HB-EGF、bFGF、VEGF、PDGF、SCF、IFN-β、IFN-γ、TGF-β、MIP-3 α、IP-9、IP-10、Mig、IL-8、GRO α、RANTEs(T細胞表達和分泌因子)、MCP-1、TARC、前列腺素、白三烯、P物質、活性氧分子及氮氧化物,種類非常多,各種複雜地相互作用以調節免疫反應。
因此,本說明書中,所謂減低皮膚刺激係指於使用表皮細胞之in vitro(體外)試驗中,減少藥物所引起之前列腺素E2(PGE2)、1L-1 α、1L-6、1L-8等之所謂的皮膚刺激介質產生,及/或於in vivo(體內)中,減低藥物所引起之皮膚紅斑、痂皮及浮腫形成等之皮膚刺激。皮膚刺激係可依據例如皮一次刺激指數(Primary Irritation Index,PII)所評估。
作為本發明之含有奧昔布寧(oxybutynin)的經皮吸收製劑之皮膚刺激減低劑,可使用選自膽固醇、膽固醇衍生物及膽固醇類似物之固醇類,其添加量係經皮吸收製劑
之總量基準之0.05質量%以上。
固醇類係選自膽固醇、膽固醇衍生物及膽固醇類似物之具有類固醇骨架之醇。狹義的膽固醇係(3 β)-cholest-5-en-3-ol,cholest-5-en-3-3 β-ol(膽甾-5-烯-3β-醇),已知為高等動物之細胞膜之必要成份。所謂膽固醇衍生物,係指例如來自動植物或微生物、菌類之天然或合成的膽固醇衍生物,可列舉於羥基部份鍵結脂肪酸之酯體之醯基膽固醇。另外,所謂膽固醇類似物係指天然或合成之膽固醇類似物,可列舉來自植物細胞之穀固醇、豆固醇、岩藻固醇、菠菜固醇、菜油固醇及菜子固醇等之植物固醇、來自真菌之麥角固醇等。可使用此等中之單獨一種,亦可混合2種以上使用。
其中係以膽固醇為宜,以來自羊毛的膽固醇尤佳。膽固醇、膽固醇衍生物及膽固醇類似物皆分類於類固醇,其中亦屬於稱為膽固醇之亞類。經皮吸收製劑係含有此等固醇類中任一種,或亦可組合2種以上。此等固醇類因具有減低奧昔布寧所引起的皮膚刺激之作用,所以藉由摻混此等化合物,可減低奧昔布寧所引起的皮膚刺激。
固醇類之摻混量係經皮吸收製劑之總量基準之0.05質量%以上,例如可為0.05~30質量%,0.1~25質量%,0.5~20質量%,1~15質量%。但是,雖依經皮吸收製劑的種類而異,若摻混超過15質量%之固醇類摻混量時,會有明顯地改變製劑特性的情況。例如貼附劑時,固醇類摻混量若超過15質量%時,因為有不能得到充份的貼附劑黏
著性之虞,所以若為貼附劑時,以15%以下之摻混量為宜。另外,作為本發明之貼附劑,雖可列舉糊劑及貼布劑等,但實質上以不含水份的貼布劑尤佳。
經皮吸收製劑可再含有經皮吸收促進劑。作為可使用之經皮吸收促進劑,可為傳統上認為具有於皮膚之經皮吸收促進作用之化合物中任一種。可舉例如有機酸類、碳數6~20之脂肪酸、脂肪醇、脂肪酸酯、醯胺、醚類、芳香族系有機酸、芳香族系醇、芳香族系有機酸酯及醚(上述可為飽和、不飽和中任一種,另外,亦可環狀、直鏈狀、支鏈狀中任一種)、乳酸酯類、醋酸酯類、單萜烯類化合物、倍半萜烯類化合物、氮酮(azone)、氮酮(azone)衍生物、1-[2-(癸硫基)乙基]-2-吡咯烷酮(Pirotiodecane)、甘油脂肪酸酯類、丙二醇脂肪酸酯類、山梨糖醇酐脂肪酸酯類(Span系)、聚山梨醇酯類(Tween類)、聚乙二醇脂肪酸酯類、聚氧乙烯硬化萞麻油類(HCO系)、聚氧乙烯烷基醚類、蔗糖脂肪酸酯類及植物油等。
作為相關的有機酸類,可列舉脂肪族(單、二或三)羧酸(醋酸、丙酸、檸檬酸(含檸檬酸酐)、異丁酸、己酸、辛酸、乳酸、馬來酸、丙酮酸、草酸、琥珀酸、酒石酸等)、芳香族羧酸(苯二甲酸、水楊酸、苯甲酸、乙醯水楊酸等)、烷基磺酸(甲烷磺酸、乙烷磺酸、丙烷磺酸、丁烷磺酸、聚氧乙烯烷基醚磺酸等)、烷基磺酸衍生物(N-2-羥乙基哌啶-N'-2-乙烷磺酸)、膽酸衍生物(去氫膽酸等)、或此等的鹽(例如鈉鹽等之鹼金屬鹽)等。
此等有機酸類中,以羧酸類及此等的鹽為宜,以醋酸、醋酸鈉及檸檬酸尤佳。此等有機酸類係可使用單獨1種,亦可組合2種以上使用。
另外,作為其他經皮吸收促進劑,可舉例如月桂酸、肉豆蔻酸、棕櫚酸、硬脂酸、異硬脂酸、油酸、亞油酸、亞麻酸、月桂醇、肉豆蔻醇、油醇、異硬脂醇、十六烷基醇、月桂酸甲酯、月桂酸己酯、月桂酸二乙醇醯胺、肉豆蔻酸異丙酯、肉豆蔻酸肉豆蔻基酯、肉豆蔻酸辛基十二烷基酯、棕櫚酸十六烷基酯、水楊酸甲酯、水楊酸乙二醇酯、肉桂酸、肉桂酸甲酯、甲酚、乳酸十六烷基酯、乳酸月桂基酯、醋酸乙酯、醋酸丙酯、香葉醇、百里酚、丁香酚、松油醇、1-薄荷醇、莰烷醇、d-檸檬烯、異丁香酚、異莰烷醇、橙花醇、dl-樟腦、甘油單辛酸酯、甘油單癸酸酯、甘油單月桂酸酯、甘油單油酸酯、山梨醇酐單月桂酸酯、蔗糖單月桂酸酯、聚山梨醇酯20(polysorbate 20)、丙二醇、丙二醇單月桂酸酯、聚乙二醇單月桂酸酯、聚乙二醇單硬脂酸酯、聚氧乙烯月桂基醚、HCO-60、1-[2-(癸硫基)乙基]-2-吡咯烷酮(Pirotiodecane)及橄欖油。其中係以油醇、月桂醇、異硬脂醇、月桂酸二乙醇醯胺、甘油單辛酸酯、甘油單癸酸酯、甘油單油酸酯、山梨醇酐單月桂酸酯、丙二醇單月桂酸酯、聚氧乙烯月桂基醚、1-[2-(癸硫基)乙基]-2-吡咯烷酮(Pirotiodecane)為宜。其中以碳數6~20之脂肪酸為宜,以油酸尤佳。如此的經皮吸收促進劑亦可混合2種以上使用。
經皮吸收製劑中,藥物與固醇類之質量比可為400:1~1:10、300:1~1:5、150:1~1:1,進而,15:1~1:1。若為此質量比,不對奧昔布寧之皮膚滲透性造成影響而可減低皮膚刺激。
經皮吸收製劑之劑型並無特別限制,可列舉軟膏劑、乳霜劑、凝膠劑、膠狀乳霜劑、藥膏劑、乳液劑、噴霧劑、氣溶膠劑、糊劑及貼布劑等。其中,就附著性及吸收性之觀點,以實質上不含有水之劑型之貼布劑或油性軟膏劑為宜。但是,藥物含有組成物係容許含有來自原料或製造環境之1質量%以下之微量水份。
後述係列舉貼附劑作為1種實施型態之經皮吸收製劑。貼附劑係具備支持體、及支持體之至少一面上所層合之藥物層。藥物層係含選自奧昔布寧及其藥學上所容許的鹽之1種以上的藥物、皮膚刺激減低劑、以及黏著基劑。作為皮膚刺激減低劑係以選自膽固醇、膽固醇衍生物及膽固醇類似物之1種以上的固醇類為宜。
貼附劑之藥物層係以實質上不含有水為宜。所謂實質上不含有水係指藥物層係由非水系材料所構成。但是,藥物層係容許含有來自原料或製造環境之1質量%以下之微量水份。
作為黏著基劑,可列舉丙烯酸系黏著基劑、橡膠系黏著基劑、矽膠系黏著基劑等。作為丙烯酸系黏著基劑,適合使用烷基之碳數4~18之(甲基)丙烯酸烷基酯之單獨聚合物或共聚物、或前述(甲基)丙烯酸烷基酯與其他官
能性單體之共聚物。另外,(甲基)丙烯基係指丙烯基或甲基丙烯基。
作為具體的黏著基劑,可使用例如醫藥品添物事典2000(日本醫藥品添加劑協會編集)中作為黏著劑所收錄之丙烯酸.丙烯酸辛酯共聚物、丙烯酸2-乙基己酯.乙烯吡咯烷酮共聚物溶液、丙烯酸酯.乙酸乙烯共聚物、丙烯酸2-乙基己酯.甲基丙烯酸2-乙基己酯.甲基丙烯酸十二烷基酯共聚物、丙烯酸甲酯.丙烯酸2-乙基己酯共聚樹脂乳劑、於丙烯酸樹脂烷醇胺液中含有丙烯酸系高分子等之黏著劑、或DURO-TAK丙烯酸黏著劑系列(Henkel)、EUDRAGIT系列(Evonik Industries)等。
作為丙烯酸系黏著基劑,只要是含有含2-乙基己基丙烯酸酯、丙烯酸甲酯、丙烯酸丁酯、羥乙基丙烯酸酯及2-乙基己基甲基丙烯酸酯等所代表之(甲基)丙烯酸衍生物中至少一種之共聚物者即可,其並無特別限定,但以含有50%以上之2-乙基己基丙烯酸酯者為宜。
作為橡膠系黏著基劑,可列舉苯乙烯-異戊二烯-苯乙烯嵌段共聚物(SIS)、異戊二烯膠、聚異丁烯(PIB)、苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-丁二烯橡膠(SBR)及聚矽氧烷等,其中以SIS、PIB及聚矽氧烷類為宜,以SIS及PIB尤佳。
作為聚矽氧烷系黏著基劑,可使用以聚有機矽氧烷、聚二甲基矽氧烷為主要成份者。
前述之黏著基劑係可混合2種以上使用,黏著基劑之
摻混量係考慮藥物層之形成及充份的奧昔布寧的皮膚滲透性,通常為總量基準之5~90質量%,亦可為10~70質量%,10~50質量%,進而10~30質量%。
藥物層亦可再含有可塑劑。作為可塑劑,可列舉鏈烷烴系加工處理油、環烷系加工處理油及芳香族系加工處理油等之石油系油;角鯊烷;角鯊烯;橄欖油、椿油、蓖麻油、妥爾油及花生油等之植物系油;矽油;苯二甲酸二丁酯及苯二甲酸二辛酯等之二元酸酯;聚丁烯及液狀異戊二烯膠等之液狀橡膠;肉豆蔻酸異丙酯、月桂酸己酯、癸二酸二乙酯及癸二酸二異丙酯等之液狀脂肪酸酯類;二乙二醇;聚乙二醇;水楊酸乙二醇酯;丙二醇;二丙二醇;三醋精;檸檬酸三乙酯;克羅米通(Crotamiton)等。此等中係以流動鏈烷烴、液狀聚丁烯、肉豆蔻酸異丙酯、癸二酸二乙酯及月桂酸己酯為宜,以液狀聚丁烯、肉豆蔻酸異丙酯及流動鏈烷烴尤佳。此等可塑劑亦可混合2種以上使用。
可塑劑之摻混量係考慮充份的奧昔布寧之皮膚滲透性及維持作為經皮吸收製劑之充份的凝聚力,通常為總量基準之10~70質量%,亦可為10~60質量%,進而10~50質量%。
藥物層亦可再含有賦予黏著的樹脂。作為賦予黏著的樹脂,可列舉松香、松香之甘油酯、氫化松香、氫化松香之甘油酯及松香之季戊四醇酯等之松香衍生物、Alcon P100(商品名,荒川化學工業)等之脂環族飽和烴樹脂、
Quintone B170(商品名,日本Zeon)等之脂肪族系烴樹脂、Clearon P-125(商品名,YASUHARA CHEMICAL)等之萜烯樹脂、馬來酸樹脂等。此等中,以氫化松香之甘油酯、脂環族飽和烴樹脂、脂肪族系烴樹脂及萜烯樹脂尤佳。
賦予黏著的樹脂之摻混量係考慮作為經皮吸收製劑之充份的黏著力及剝離時對皮膚之刺激性,通常為總量基準之5~70質量%,亦可為5~60質量%,進而10~50質量%。
支持體係只要適合於支持藥物層者即可,並無特別限定,可使用伸縮性或非伸縮性者。可使用聚乙烯、聚丙烯、聚丁二烯、乙烯-醋酸乙烯共聚物、聚氯化乙烯、聚酯、尼龍、聚胺基甲酸乙酯等之薄膜、薄片、此等之積層體、多孔體、發泡體、布及不織布、以及此等之層合品等。貼附劑之藥物層之接觸支持體面及另一側的面,亦可具備使用於患部前剝離而使用之剝離被覆物。作為剝離被覆物,可使用聚乙烯、聚丙烯、聚酯、聚對苯二甲酸乙二醇酯、及將此等以矽氧烷進行離型處理者或剝離紙等。
接著,說明貼附劑之製造方法。使用丙烯酸系黏著基劑之貼附劑時,使藥物、固醇類、因應需要之其他添加劑、及黏著基劑,溶解或分散於溶劑,將所得之溶液或分散液直接塗抹於支持體表面後乾燥,形成厚度為30~200μm之藥物層、或將前述之溶液或分散液,塗抹於經施加剝離處理的紙或薄膜上,將乾燥後所得之藥物層,加壓
轉印到支持體。接著,將藥物層之接觸支持體面及另一側的面,以剝離被覆物覆蓋,裁切成適當大小,得到貼附劑。另外,前述製造方法中各成份之摻混順序係僅敍述其一例而已,並非受此摻混順序所限定者。此製造方法所使用之溶劑係只要對全部的黏著基劑及藥物等之摻混成份,具有相溶性即可,並無特別限定,可使用例如甲苯、苯及二甲苯等之芳香族烴類、醋酸乙酯等之酯類、四氯化碳、氯仿及二氯甲烷等之鹵化烴類。
使用橡膠系黏著基劑之貼附劑時,使用捏和機、攪拌器等之混合機,將黏著基劑及因應需要之可塑劑及賦與黏著的樹脂加熱混合。接著,加入藥物、固醇類、因應需要之其他添加劑,使均勻分散,直接延展於支持體,或延展於經施加剝離處理的紙或薄膜,之後,加壓層合於支持體。接著,將藥物層之接觸支持體面及另一側的面,以剝離被覆物覆蓋,裁切成適當大小,得到貼附劑。另外,前述製造方法中各成份之摻混順序係僅敍述其一例己而,並非受此摻混順序所限定者。
具有如前述組成之經皮吸收製劑係可藉由通常已知之任一種方法所製造。例如使含奧昔布寧之黏著基劑熱融解,塗抹於離型紙或支持體後,得到與支持體或離型紙互貼之本劑。另外,使含奧昔布寧之黏著基劑成份溶解於甲苯、己烷或醋酸乙酯等之溶劑,延展於離型紙或支持體上,乾燥去除溶劑後,可得到與支持體或離型紙互貼之本劑。
作為其他的實施型態,可列舉後述之經皮吸收製劑之軟膏劑。軟膏劑係含選自奧昔布寧及其藥學上所容許的鹽之1種以上的藥物,以及皮膚刺激減低劑。作為皮膚刺激減低劑,以選自膽固醇、膽固醇衍生物及膽固醇類似物之1種以上的固醇類為宜。
軟膏劑係以實質上不含有水為宜。所謂實質上不含有水係指軟膏劑係由非水系材料所構成。但是,軟膏劑係容許含有來自原料或製造環境之5質量%以下,以1質量%以下之微量水份為宜。
軟膏劑係除了藥物及固醇類之外,亦包含肉豆蔻酸等之高級脂肪酸或其酯、鯨蠟等之蠟類、聚氧乙烯等之界面活性劑、親水凡士林等之烴類。軟膏劑係加入以總量基準,5~15質量%之高級脂肪酸或其酯、1~10質量%之界面活性劑、0.1~30質量%之藥物、0.05~30質量%之固醇類、4~10質量%之蠟類及50~90質量%之烴類後加熱,全部成份成為透明溶解液後,以勻化器均勻混合,於攪拌下降低至室溫而可製造。
此等經皮吸收製劑係於不損及本發明目的之範圍,可添加藥理上所容許之各種添加劑,例如可添加安定劑、抗氧化劑、香料、填充劑及經皮吸收製劑。
本發明之其他實施型態係提供包含於經皮吸收製劑摻混選自奧昔布寧及其藥學上所容許的鹽之1種以上的藥物,以及經皮吸收製劑之總量基準之0.05質量%以上之選自膽固醇、膽固醇衍生物及膽固醇類似物之固醇類之步驟
之減低皮膚刺激之含有奧昔布寧的經皮吸收製劑之製造方法,及減低經皮吸收製劑之皮膚刺激之方法。
後述係表示實施例及比較例,具體地說明本發明,但本發明並非受後述實施例所限定者。
製造含有奧昔布寧之貼附劑。依據表1記載之各成份及摻混量,將材料溶解於甲苯,作為塗抹溶液。將塗抹溶液塗抹於離型薄膜(矽離型處理之PET薄膜)上,以80℃乾燥15分鐘,層合支持體(PET布帛)。之後,隨意裁切成實施例1~14及比較例1~5之含有奧昔布寧之貼附劑。另外,表1記載之比率係含有奧昔布寧之貼附劑之黏著層(含藥物)之總量基準(質量%)。
將19週齡之JW雌性兔子供與釋出實驗。將經剃毛處理之兔子背部狀態,平均地分組,於各個體之背部皮膚,貼附1.5cm×1.5cm之實施例5及比較例1之製劑,於24小時後剝離(第1次投與)。剝離後設有24小時之停藥期間,與第1次投與相同部份,貼附同樣大小的製劑於同一組,於其24小時後剝離(第2次投與)。將剝離後回收之貼附劑之鹽酸奧昔布寧量,以HPLC進行分析,求出每單位面積之奧昔布寧之釋出量及釋出率。結果如表2所示。由表2可知添加膽固醇幾乎不影響奧昔布寧釋出。
接著,於裸鼠(Hr-,雌性,8週齡)皮膚滲透試驗,經時地測定實施例5及比較例1之貼附劑。不使用相同個體的皮膚於相同試驗製劑,將取出之裸鼠皮膚,貼附各3枚製劑於取出皮膚。將此皮膚安置於縱型之Franz型擴散槽,於槽內裝滿生理食鹽水,以滾輪式幫浦及分液收集器及管子連接。接著,以管子連接擴散槽循環相與設定成37℃之恆溫循環槽,以多杯攪拌器攪拌下,每隔2小時,進行接受液回收。該結果可知摻混膽固醇之奧昔布寧製劑之皮膚滲透性係與未摻混膽固醇者大致相同。
將19週齡之JW雌性兔子供與釋出實驗。將經剃毛處理之兔子背部狀態,平均地分組,於各個體之背部皮膚,貼附1.5cm×1.5cm之含有15%之鹽酸奧昔布寧製劑於相同部位2次(貼附時間:24小時,投與間隔:24小時停
藥)。第2次投與結束後,於剝離1、24、48小時後,依據Draize等之判定基準(參考文獻:Draize Jh等,J Pharmacol Exp Ther.1944;82:377-390),評估使用部位之紅斑及浮腫,由剝離1、24、48小時後之3點之評分平均值,算出皮膚一次刺激指數(PII)。各製劑之PII相對於比較例1(含有0%之膽固醇/15%之鹽酸奧昔布寧製劑)之相對值作為抑制率,如後述之等級所示。結果如表3所示。由表3可知,膽固醇含量為0.05%以上時,認為對於奧昔布寧所引起之兔子皮膚一次刺激,有高的減低效果,並且,隨著膽固醇的濃度依賴性而減低效果變高。
A:51%以上之抑制率
B:21~50%之抑制率
C:1~20%之抑制率
D:無抑制效果
對於含有10%之鹽酸奧昔布寧製劑,亦進行與實驗2相同的評估。該結果如表4所示。由表4可知,膽固醇含量為1%以上時,認為對於含有10%之鹽酸奧昔布寧之貼附劑所引起之皮膚刺激,有高的減低皮膚刺激效果。
將製劑之黏著面向下放置的樣品之下方,以5mm/秒的速度,使探針接近,接觸1秒後,於下方以一定的速度,使探針移動,將自黏著面剝離探針所需的力(gF),使用探針黏力測試器(理學工業)進行測定。每1個製劑進行此操作3次,算出平均值。該結果如表5所示。由表5可知,膽固醇含量若超過15%時,黏著力變得極弱,有不能確保作為貼附劑機能之虞。
依據後述表6之配方,與製造例之方法同樣地製造不含有奧昔布寧之貼附劑a~e。之後,隨意裁切,供與附著性試驗。另外,表6記載之含量係含有奧昔布寧之貼附劑之黏著層之總量基準(質量%)。
附著性(黏著性)試驗係如後述進行。對於各個貼附劑,貼附貼附劑a~e於約20名之健康成人試驗者的下腹部24小時後,將各貼附劑之附著狀態,依據後述基準,判定評分。對於各貼附劑,合計所得之附著狀態之評分,各個貼附劑a~e之合計值除以貼附劑d(對照)之合計值的值作為附著性(%)。試驗結果係如後述表7所示。
評分0:貼附劑剝落
評分2:貼附劑面積之1/2以上剝離
評分4:貼附劑面積之約1/3剝離
評分6:貼附劑面積之約1/5剝離
評分8:貼附劑面積之約1/10剝離
評分10:幾乎無剝離的部份
由表7可知,與不含有膽固醇之對照組的貼附劑d相比,含有5%之膽固醇之貼附劑a及貼附劑e之附著性降
低。然而,將黏著基劑由僅SIS(貼附劑a及貼附劑e),改變成SIS+PIB(貼附劑b及貼附劑c),明白附著性恢復與對照組相同程度。因此,可知於摻混膽固醇之貼附劑,藉由更含有作為黏著基劑之PIB(聚異丁烯),可比不含有PIB之貼附劑更改善附著性。此種情況即使是含有藥物之奧昔布寧之貼附劑,仍可說相同。
依據本發明,可提供使用於皮膚時,避免經口投與之副作用,同時亦減低奧昔布寧所引起之皮膚刺激性之經皮吸收製劑。另外,若固醇類之含量係經皮吸收製劑之總量基準之0.05質量%以上,可發揮減低皮膚刺激之效果,該減低皮膚刺激之效果係濃度依賴性的。
Claims (4)
- 一種貼附劑,其特徵係含有選自奧昔布寧(oxybutynin)及其藥學上所容許的鹽之1種以上的藥物,以及貼附劑之總量基準之0.05質量%~15質量%之膽固醇。
- 如申請專利範圍第1項之貼附劑,其中藥物的含有量係貼附劑之總量基準之5質量%~30質量%。
- 如申請專利範圍第1項或第2項之貼附劑,其中膽固醇含量係貼附劑之總量基準之1質量%~15質量%。
- 如申請專利範圍第1項或第2項之貼附劑,其具備支持體、及前述支持體之至少一面上所層合之藥物層,前述藥物層係含選自前述奧昔布寧(oxybutynin)及其藥學上所容許的鹽之1種以上的藥物、前述膽固醇、以及黏著基劑之貼附劑。
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EP (1) | EP2772252B1 (zh) |
JP (1) | JP5462421B2 (zh) |
ES (1) | ES2786504T3 (zh) |
TW (1) | TWI568456B (zh) |
WO (1) | WO2013061969A1 (zh) |
Families Citing this family (6)
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CN103919754B (zh) * | 2013-01-15 | 2018-11-06 | 江苏康倍得药业股份有限公司 | 奥昔布宁药物组合物及其应用 |
US10149828B2 (en) | 2015-01-09 | 2018-12-11 | Chase Pharmaceuticals Corporation | Oxybutynin transdermal therapeutic system combination |
WO2018070370A1 (ja) * | 2016-10-11 | 2018-04-19 | 久光製薬株式会社 | オキシブチニン含有経皮吸収製剤 |
KR102201003B1 (ko) | 2017-08-01 | 2021-01-08 | 히사미쓰 세이야꾸 가부시키가이샤 | 첩부제 |
JP6480630B1 (ja) | 2018-09-26 | 2019-03-13 | アサヒグループホールディングス株式会社 | 脂肪蓄積抑制剤および血中脂質改善剤 |
US20220133643A1 (en) * | 2019-01-31 | 2022-05-05 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
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- 2012-10-23 ES ES12844042T patent/ES2786504T3/es active Active
- 2012-10-23 US US14/354,151 patent/US20140271796A1/en not_active Abandoned
- 2012-10-23 EP EP12844042.7A patent/EP2772252B1/en active Active
- 2012-10-23 WO PCT/JP2012/077367 patent/WO2013061969A1/ja active Application Filing
- 2012-10-23 JP JP2013534879A patent/JP5462421B2/ja active Active
- 2012-10-26 TW TW101139715A patent/TWI568456B/zh active
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JPS63280006A (ja) * | 1987-05-12 | 1988-11-17 | Yakult Honsha Co Ltd | 皮膚刺激感抑制剤及びこれを配合してなる化粧料 |
CN1708269A (zh) * | 2002-11-01 | 2005-12-14 | 华生实验室公司 | 用于奥昔布宁经皮治疗的组合物和方法 |
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Also Published As
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EP2772252A1 (en) | 2014-09-03 |
TW201328729A (zh) | 2013-07-16 |
JP5462421B2 (ja) | 2014-04-02 |
US20140271796A1 (en) | 2014-09-18 |
ES2786504T3 (es) | 2020-10-13 |
JPWO2013061969A1 (ja) | 2015-04-02 |
EP2772252A4 (en) | 2015-06-03 |
EP2772252B1 (en) | 2020-03-18 |
WO2013061969A1 (ja) | 2013-05-02 |
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