TWI419718B - 含有凱妥普洛芬離胺酸鹽之水性貼附劑 - Google Patents
含有凱妥普洛芬離胺酸鹽之水性貼附劑 Download PDFInfo
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- TWI419718B TWI419718B TW098109317A TW98109317A TWI419718B TW I419718 B TWI419718 B TW I419718B TW 098109317 A TW098109317 A TW 098109317A TW 98109317 A TW98109317 A TW 98109317A TW I419718 B TWI419718 B TW I419718B
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- Prior art keywords
- polyethylene glycol
- weight
- ketoprofen
- paste
- aqueous patch
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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Description
本發明為有關含有活性成分凱妥普洛芬(ketoprofen)離胺酸鹽之水性貼附劑，詳言之，以對水之溶解度高之凱妥普洛芬之離胺酸鹽為活性成分，使用膏體基劑其平均分子量1000以下之聚乙二醇之水性貼附劑。
已知若干含有活性成分為具有抗炎症活性之凱妥普洛芬之水性貼附劑(專利文獻1及2)。但活性成分凱妥普洛芬本身對水之溶解度低，故作為水性貼附劑混合於膏體基劑中時，使用溶解劑或分散劑來溶解或分散膏體中。
如此溶解劑可為已知作為難溶解性藥物之溶解劑之克羅他米通(crotamiton)、脂肪酸、脂肪酸酯、精油類、多價醇、界面活性劑、N-取代-鄰甲苯胺衍生物等特定之溶解劑(專利文獻3)。又作為使用分散劑之方法，有採用將凱妥普洛芬分散於液狀之分散劑後，與酸性黏著劑基劑混合之手段(專利文獻4)。
這些製造方法因凱妥普洛芬本身對水之溶解性低，故其製造法必要有所加工夫，有製造作業效率低之基本缺點。
即為使凱妥普洛芬溶解使用之這些特定之溶解劑一般以親油性之溶解劑較多，於水性貼附劑之製造時，將這些溶解劑添加於其他膏體成分之際不注意施行，則親
水性高分子之不溶或親油性之溶劑之分離等對貼附劑之物性有不良影響之可能性。
又作為基劑成分將甘油高濃度混合之習知含有凱妥普洛芬的水性貼附劑之場合，對基劑之凱妥普洛芬之溶解性不充分，故經皮吸收性低、加上分子中具有羧酸基之凱妥普洛芬與具有羥基之多價醇(例如甘油)、低級醇、薄荷醇等溶解劑之間，水性貼附劑之基劑成分之有機酸、聚丙烯酸等弱酸成為觸媒，即使較低溫也進行酯化反應，有保存安定性低之問題。
於專利文獻5提案將含有分子中具有羧酸基之凱妥普洛芬之非類固醇消炎鎮痛劑溶解或分散於甘油及碳數3~30之乙二醇來安定化。但即使為專利文獻5記載之習知之貼附劑，作為活性成分混合凱妥普洛芬場合，作為基劑成分使用甘油，故考慮長期安定性時，擔心由酯化反應之保存安定性之降低。
又一般而言，貼附劑膏體中藥物以分散狀態存在，則其保存安定性雖昇高，但其反面，藥物本身之經皮吸收性降低。故殷望含有活性成分凱妥普洛芬其保存安定性和經皮吸收性皆良好之更改良品。
專利文獻1：特開昭58-083623號公報
專利文獻2：特開昭61-275212號公報
專利文獻3：國際公開W096/11022號公報
專利文獻4：特開2006-104170號公報
專利文獻5：特開2002-193793號公報
本發明之課題為解決上述問題者，於含有凱妥普洛芬之水性貼附劑，不僅改善製造之作業效率，且提供凱妥普洛芬之保存安定性及經皮吸收性優異之水性貼附劑。
本發明者為解決如此課題反復致力研究之結果，發現作為活性成分(有效成分)，於凱妥普洛芬之鹽或衍生物之中選擇對水溶解度高之凱妥普洛芬離胺酸鹽，且不使用甘油而溶解於以相互作用小之平均分子量1000以下之聚乙二醇為基劑成分含有之膏體中，獲得製造上之作業效率高，不損凱妥普洛芬之經皮吸收性，又因不含有甘油而保存安定性良好之水性貼附劑，終於完成本發明。
故本發明之基本態樣為具備支持體和積層於支持體之黏著劑(膏體)層之貼附劑，其特徵為於不含甘油而混合平均分子量1000以下之聚乙二醇之膏體中，將作為活性成分之凱妥普洛芬離胺酸鹽以完全溶解之狀態混合之含有凱妥普洛芬離胺酸鹽之水性貼附劑。
更較佳為平均分子量1000以下之聚乙二醇為由聚乙二醇200、聚乙二醇400、聚乙二醇600及聚乙二醇1000而成之群選擇之1種或2種以上之聚乙二醇之含有凱妥普洛芬離胺酸鹽之水性貼附劑。
尤宜平均分子量1000以下之聚乙二醇之混合量為2~30%之含有凱妥普洛芬離胺酸鹽之水性貼附劑，更較佳本發明為膏體成分為由凱妥普洛芬離胺酸鹽0.1~5重量%、水30~80重量%、平均分子量1000以下之聚乙二醇2~30重量%、水溶性高分子3~20重量%、保濕劑10~30重量%、多價金屬化合物0.001~1重量%而成之含有凱妥普洛芬離胺酸鹽之水性貼附劑。
最佳本發明之貼附劑為膏體成分不含有甘油，而由平均分子量1000以下之聚乙二醇2~30重量%、水溶性高分子3~20重量%、保濕劑10~30重量%、多價金屬化合物0.001~1重量%及水30~80重量%而成，混合活性成分凱妥普洛芬離胺酸鹽0.1~5重量%之含有凱妥普洛芬離胺酸鹽之水性貼附劑。
本發明提供活性成分使用對水溶解度高之凱妥普洛芬離胺酸鹽，膏體成分不含有甘油而溶解於混合平均分子量1000以下之聚乙二醇之膏體中，使製造作業簡便，且安定地混合凱妥普洛芬離胺酸鹽之水性貼附劑。
依本發明可提供習知之溶解型或分散型之水性貼附劑無法獲得之高含凱妥普洛芬之兼備經皮吸收性及保存安定性之水性貼附劑。
本發明提供之含有凱妥普洛芬離胺酸鹽之水性貼附劑即使40℃以上高溫之苛酷條件也長期保存安定性優異。且凱妥普洛芬之經皮吸收性也優異。
獲得如此優異之效果之理由雖未明，但與混合作為膏體成分使用之平均分子量1000以下之聚乙二醇為其他多價醇等保濕劑之製劑比較，膏體中生成之自由體(分子型)之凱妥普洛芬溶解能力高，即使為pH3.5~6.5之酸性領域也對凱妥普洛芬之反應性低，故使凱妥普洛芬安定化。
即本發明無混合一般於水性貼附劑使用之甘油，而於含有聚乙二醇之酸性黏著劑基劑混合凱妥普洛芬離胺酸鹽，則可將凱妥普洛芬以溶解狀態安定地混合，其結果使保存安定性優異。
本發明提供之水性貼附劑中，作為活性成分使用之凱妥普洛芬離胺酸鹽為凱妥普洛芬之分子內之羧基與鹼性之離胺酸來鹽結合者，與凱妥普洛芬比較，對水溶解性非常高，能於水直接溶解，故有製造之作業效率高之特徵。
於本發明之水性貼附劑，凱妥普洛芬離胺酸鹽之混合量以0.1~5.0重量%較佳，更較佳為0.3~3.0重量%。即混合量0.1重量%未滿，則無法得充分藥效、他方面若混合量超過5.0重量%，則由於過剩投與而呈現皮膚刺激等之弊害和經濟面之不適當。
本發明之水性貼附劑中為溶解凱妥普洛芬離胺酸鹽，以水較佳使用。對於膏體重量，水之含有量為30~80重量%，宜為40~70重量%。若含水量超過80重量%時
，因膏體黏度降低而保形性劣化，及呈現黏答現象。又黏著力顯著降低，對貼附部位之接著性不充分而不良。他方面若30重量%未滿，則膏體黏度過高而將膏體展延於支持體及襯層來貼附劑化時之作業性惡化。又因黏著力過強，故剝離時發生疼痛或皮膚刺激而不良。
本發明中為使活性成分凱妥普洛芬離胺酸鹽於水溶性基劑中安定地混合，使用平均分子量1000以下之聚乙二醇單獨或2種以上之組合。
如此平均分子量1000以下之聚乙二醇以聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇1000較佳。更較佳為聚乙二醇300、聚乙二醇400、聚乙二醇600。
本發明中作為膏體成分不使用甘油，而使用平均分子量1000以下之聚乙二醇為一特徵。混合平均分子量大於1000之聚乙二醇時，因其熔點超過40℃，故不能使作為膏體成分混合之水溶性高分子充分分散，有於膏體中發生粉團等之問題而不良。
前述聚乙二醇於膏體組成中之含有量以2~30重量%較佳，更較佳為5~20重量%。即若含有量為2重量%未滿，則無法使水性貼附劑中發生之自由體之凱妥普洛芬充分溶解。他方面若超過30重量%，則於凝膠表面無法保持之聚乙二醇引起浮出現象，貼附時發生黏答之問題。
將這些聚乙二醇特以上述混合量使用，則可不使用甘油，使凱妥普洛芬於水溶性基劑中安定地溶解，且膏
體之流動性昇高，可形成展延性優異之初期黏著力良好之含有凱妥普洛芬離胺酸鹽之水性貼附劑。
構成本發明提供之含有凱妥普洛芬離胺酸鹽之含水性貼附劑之基劑成分，只要為一般製造含水性貼附劑時使用之基劑成分則無特限，可將例如水溶性高分子、保濕劑、賦形劑、安定化劑、交聯劑、抗氧化劑、清涼化劑等適宜混合。
水溶性高分子可為將例如明膠、水解明膠、聚丙烯酸、聚丙烯酸鈉、聚丙烯酸部分中和物、聚丙烯酸澱粉、聚乙烯醇、聚乙烯吡咯啶酮、羥丙基纖維素、羥丙基甲基纖維素、羥乙基纖維素、甲基纖維素、羧甲醚纖維素鈉、羧乙烯聚合物、甲氧亞乙基馬來酸酐共聚物、N-乙烯乙醯胺共聚物、呫噸樹膠、阿拉伯膠等單獨或2種以上之組合使用。
前述水溶性高分子之膏體組成中含有量以3~20重量%較佳，更較佳為5~15重量%。含有量為3重量%未滿，則膏體黏度過低而發生膏體之滴液現象，作為貼附劑難成形。他方面若超過20重量%，則水溶性高分子於膏體中不能均勻地溶解，不能形成良好之膏體而不良。
又作為保濕劑將甘油除外，可將例如D-山梨糖醇液、吡咯啶酮羧酸鹽等單獨或以2種以上之組合使用，其含有量於10~30重量%較佳。
賦形劑可將例如高嶺土、氧化鈦、矽酸酐、氧化鋅、皂土等單獨或以2種以上組合使用。
安定化劑可例如將乙二胺四乙酸鹽、酒石酸、檸檬酸、亞硫酸氫鈉等單獨或以2種以上之組合使用。
膏體組成之pH由皮膚刺激性之點以pH3.5~6.5之範圍較佳，尤以pH4.0~5.5之範圍更較佳。
交聯劑可為將例如乾燥氫氧化鋁凝膠、合成矽酸鋁、二羥胺基乙酸鋁、合成水滑石、偏矽酸鋁酸鎂、矽酸鋁酸鎂等多價金屬化合物等單獨或2種以上之組合使用。其含有量依其種類而異，以0.001~1重量%較佳。
抗氧化劑可為例如將乙酸生育酚、抗壞血酸、丁羥基甲苯、生育酚等單獨或2種以上組合使用。
清涼化劑可為樟腦、百里酚、1-薄荷醇、N-乙基-對薄荷烷-羧醯胺，對薄荷烷-3,8-二醇、1-異長葉薄荷醇、1-薄荷甘油醚等1-薄荷醇衍生物等，這些可以1種單獨或2種類以上適宜組合使用。又必要時可將防腐劑、可塑劑、乳化劑、界面活性劑等混合。
本發明提供之水性貼附劑之膏體之厚度以250~1400μm較佳，更較佳為300~1000μm。前述膏體之厚度為250μm未滿，則有黏著性或附著性之持續性減低之傾向，他方面若前述膏體之厚度超過1400μm，則有凝集力或保型性減低之傾向。
被覆膏體組成表面之塑膠薄膜可用聚乙烯、聚丙烯、聚酯、聚氯乙烯、剝離紙等單獨或貼合者，更可用於這些表面施行矽酮處理、電暈放電處理、凹凸處理、電漿處理等者。
一方面含水性貼附劑之支持體可用聚乙烯、聚丙烯、聚氯乙烯、聚酯、尼龍、聚胺甲酸酯、嫘縈等之多孔體、發泡體、織布，不織布，更可用薄膜或片與多孔體、發泡體、織布，不織布之積層品等。
本發明提供之水性貼附劑之製造方法無特限，可將公知之製造方法製造。例如將由前述構成組成之膏體組成於支持體上展延，將膏體組成表面以塑膠薄膜被覆，則可成形含有凱妥普洛芬離胺酸鹽之水性貼附劑。
以下列示實施例及比較例來更具體說明本發明，但本發明不受這些實施例限定。
基於如下表1記載之實施例1之膏體組成，依如下之手法製作實施例1之貼附劑。
將羥丙基纖維素0.5g、對羥苯甲酸甲酯0.15g、乙二胺四乙酸鈉0.06g、二羥胺基乙酸鋁0.06g、酒石酸0.5g、羧甲醚纖維素鈉4.5g、20%聚丙烯酸水溶液20g、聚丙烯酸部分中和物4g、聚山梨酸酯80 0.2g、70%D-山梨糖醇液25g、聚乙二醇200 15g、薄荷醇0.5g、乙酸生育酚0.5g、聚乙烯醇0.5g、精製水適量均勻地混合來調製含水凝膠。
次於適量精製水溶解凱妥普洛芬離胺酸鹽1.5g後，於先前調製之含水凝膠中均勻地混合，得貼附劑用膏體。
將此膏體於由聚乙烯薄膜與嫘縈纖維之積層不織布而成之支持體塗布成膏體重量為300g/m2
，黏著面以聚酯薄膜被覆，打穿成7×10cm之長方形來製作貼附劑。
基於如下表1記載之組成，仿實施例1，製作實施例2~4及比較例1~3之貼附劑。
比較例1~3之貼附劑，則以濃甘油取代聚乙二醇。
聚乙二醇1500因疏水性高，故不能混合於貼附劑。
將依上述實施例1~4及比較例1~3調製之各貼附劑，以5片為一袋而密封於鋁袋後，於40℃及50℃之條件
下保存1個月，將保存後之各製劑中凱妥普洛芬含有量，及分解生成物凱妥普洛芬甘油酯之比率，以高速液體層析來測定。
所得結果如下表2及表3。
由表2及表3之結果得知，使用聚乙二醇之本發明之水性貼附劑(實施例1~4)，比使用甘油之貼附劑(比較例1~3)，於苛酷條件下之保存安定性顯著優異。
參考特開2002-193793號公報(專利文獻5)記載之實施例2，使每單位面積之凱妥普洛芬含量為30mg/140cm2
(凱妥普洛芬之換算量依凱妥普洛芬離胺酸鹽為47mg/140cm2
)，基於表4記載之組成，仿實施例1製作貼附劑。
使用混合有效成分凱妥普洛芬(含有0.3重量%)之塗布重量為714g/m2
之水性貼附劑(市售品)。
與比較例4及5同樣，使每單位面積之凱妥普洛芬含量為30mg/140cm2
(凱妥普洛芬之換算量依凱妥普洛芬離胺酸鹽含量為47mg/140cm2
)，將實施例5及6之膏體基於表4記載之組成，仿實施例1製作，將此膏體塗布於由聚乙烯薄膜與嫘縈纖維之積層不織布而成之支持體，將黏著面以聚酯薄膜被覆，打穿成10×14cm之長方形，來製作各貼附劑。
將Wistar系雄性大鼠(6~7週齡)之腹部摘出皮膚裝著於Franz型擴散胞，將實施例5和6，及比較例4和5之製品各打穿成直徑16mm之圓形(按凱妥普洛芬含有0.43mg)之試驗片貼付於擴散胞之大鼠皮膚上部。
於受體側使用磷酸緩衝生理食鹽水，於每一定時間採集受體液，使用HPLC測定採集液中之凱妥普洛芬濃度，求出通過大鼠皮膚之藥物量。
試驗結果如第1圖。
由其結果判明，實施例5及6之水性貼附劑比市售之貼布劑之比較例5呈示更高藥物透過量，認定同等以上之良好藥物放出之持續性。
如以上記載，依本發明提供以對水溶解度高之凱妥普洛芬離胺酸鹽為活性成分，不含有甘油而溶解於混合平均分子量1000以下之聚乙二醇之膏體中，使製造作業簡便，且安定地混合凱妥普洛芬離胺酸鹽之水性貼附劑。
本發明提供之水性貼附劑為習知之溶解型或分散型之水性貼附劑無法達成高凱妥普洛芬之兼備經皮吸收性及保存安定性者，其醫療上頗多有用性。
第1圖表示依本發明試驗例2之活體外凱妥普洛芬之皮膚透過量之圖。
Claims (5)
- 一種含有凱妥普洛芬(ketoprofen)離胺酸鹽之水性貼附劑，其特徵為於不含有甘油之混合平均分子量1000以下，且pH為3.5~6.5之聚乙二醇之膏體中，將活性成分凱妥普洛芬離胺酸鹽以溶解狀態混合。
- 如申請專利範圍第1項之含有凱妥普洛芬離胺酸鹽之水性貼附劑，其中平均分子量1000以下之聚乙二醇為由聚乙二醇200、聚乙二醇400、聚乙二醇600及聚乙二醇1000而成之群選擇之1種或2種以上之聚乙二醇。
- 如申請專利範圍第1項之含有凱妥普洛芬離胺酸鹽之水性貼附劑，其中平均分子量1000以下之聚乙二醇之混合量為2~30%。
- 如申請專利範圍第2項之含有凱妥普洛芬離胺酸鹽之水性貼附劑，其中平均分子量1000以下之聚乙二醇之混合量為2~30%。
- 如申請專利範圍第1至4項中任一項之含有凱妥普洛芬離胺酸鹽之水性貼附劑，其中膏體成分不含有甘油，而由平均分子量1000以下之聚乙二醇2~30重量%、水溶性高分子3~20重量%、保濕劑10~30重量%、多價金屬化合物0.001~1重量%及水30~80重量%而成，並混合活性成分凱妥普洛芬離胺酸鹽0.1~5重量%。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008078486A JP4879928B2 (ja) | 2008-03-25 | 2008-03-25 | ケトプロフェンリジン塩を含有する水性貼付剤 |
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| TW200942275A TW200942275A (en) | 2009-10-16 |
| TWI419718B true TWI419718B (zh) | 2013-12-21 |
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|---|---|
| US (1) | US9861598B2 (zh) |
| EP (1) | EP2266556B1 (zh) |
| JP (1) | JP4879928B2 (zh) |
| KR (1) | KR101606950B1 (zh) |
| CN (1) | CN101977598B (zh) |
| CA (1) | CA2718755C (zh) |
| TW (1) | TWI419718B (zh) |
| WO (1) | WO2009119601A1 (zh) |
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| JP5622410B2 (ja) | 2010-03-12 | 2014-11-12 | 帝國製薬株式会社 | ケトプロフェン含有水性貼付剤 |
| GB201120908D0 (en) * | 2011-12-06 | 2012-01-18 | Reckitt Benckiser Healthcare | Patch containing non-steroidal anti-inflammatory drug |
| EP3406239B1 (en) * | 2017-05-22 | 2021-10-20 | Epifarma Srl | Palatable ketoprofen lysine salt solutions |
| TWI827775B (zh) * | 2018-12-27 | 2024-01-01 | 日商小林製藥股份有限公司 | 貼附劑 |
| KR102022336B1 (ko) * | 2019-03-12 | 2019-09-18 | 주식회사 우신라보타치 | 국소 통증 완화 카타플라즈마 패치 |
| CN114007594A (zh) * | 2019-06-24 | 2022-02-01 | 帝国制药株式会社 | 水性贴剂 |
| CN115337289A (zh) * | 2020-07-29 | 2022-11-15 | 湖南九典制药股份有限公司 | 含有右酮洛芬或其药用盐的凝胶贴膏基质及其制备方法 |
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| US5614171A (en) * | 1991-03-06 | 1997-03-25 | Domp e Farmaceutici SpA | Hydrophilic pharmaceutical composition containing ketoprofen lysine salt for topical use |
| US6455067B1 (en) * | 2000-05-24 | 2002-09-24 | Sang-A Pharmaceutical Co., Ltd. | Transdermal patch for nonsteroidal antiinflammatory drug(s) |
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| KR100209469B1 (ko) | 1994-10-05 | 1999-07-15 | 나까도미 히로다카 | N-치환-o-톨루이딘유도체로 이루어진 약용배합제 및 경피흡수형 제제 |
| AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
| JP4346696B2 (ja) * | 1996-05-28 | 2009-10-21 | 久光製薬株式会社 | 経皮治療用装置 |
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| JP2002193793A (ja) | 2000-12-26 | 2002-07-10 | Teikoku Seiyaku Co Ltd | 非ステロイド系消炎鎮痛貼付剤 |
| KR100612070B1 (ko) * | 2003-02-12 | 2006-08-11 | 알앤피코리아주식회사 | 용출률이 향상된 난용성 약제의 용매 시스템 및 이를 함유한 제약학적 제제 |
| DK1611884T3 (da) * | 2003-03-18 | 2012-12-10 | Hisamitsu Pharmaceutical Co | Plaster, indeholdende diclofenac |
| ES2408007T3 (es) * | 2004-04-28 | 2013-06-17 | Hisamitsu Pharmaceutical Co., Inc. | Material adhesivo |
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| JP5010834B2 (ja) * | 2006-02-20 | 2012-08-29 | 帝國製薬株式会社 | 貼付剤 |
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| US5614171A (en) * | 1991-03-06 | 1997-03-25 | Domp e Farmaceutici SpA | Hydrophilic pharmaceutical composition containing ketoprofen lysine salt for topical use |
| US6455067B1 (en) * | 2000-05-24 | 2002-09-24 | Sang-A Pharmaceutical Co., Ltd. | Transdermal patch for nonsteroidal antiinflammatory drug(s) |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101606950B1 (ko) | 2016-03-28 |
| US9861598B2 (en) | 2018-01-09 |
| CA2718755A1 (en) | 2009-10-01 |
| JP2009227640A (ja) | 2009-10-08 |
| US20110184066A1 (en) | 2011-07-28 |
| KR20100126826A (ko) | 2010-12-02 |
| EP2266556B1 (en) | 2018-11-14 |
| JP4879928B2 (ja) | 2012-02-22 |
| CN101977598A (zh) | 2011-02-16 |
| TW200942275A (en) | 2009-10-16 |
| WO2009119601A1 (ja) | 2009-10-01 |
| CN101977598B (zh) | 2012-07-18 |
| EP2266556A1 (en) | 2010-12-29 |
| CA2718755C (en) | 2016-05-10 |
| AU2009230011A1 (en) | 2009-10-01 |
| EP2266556A4 (en) | 2013-10-23 |
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