TWI699205B - 用於預防或治療青光眼之藥物療法 - Google Patents
用於預防或治療青光眼之藥物療法 Download PDFInfo
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- TWI699205B TWI699205B TW104141511A TW104141511A TWI699205B TW I699205 B TWI699205 B TW I699205B TW 104141511 A TW104141511 A TW 104141511A TW 104141511 A TW104141511 A TW 104141511A TW I699205 B TWI699205 B TW I699205B
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- Prior art keywords
- glaucoma
- intraocular pressure
- brimonidine
- isoquinolinesulfonyl
- fluoro
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Abstract
本發明提供一種眼壓下降作用強力並具有即效性且其持續時間經延長之用於預防青光眼或者預防或治療高眼壓症之藥物療法。
本發明係一種用於預防或治療青光眼之(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之組合。
Description
本發明係關於一種用於預防或治療青光眼或者高眼壓症之藥物療法。
所謂青光眼，係指因各種病因而導致眼壓上升，視神經受到障礙而萎縮，從而導致視野異常、視力逐漸降低之疾病。由於發生過一次萎縮之視神經不會恢復，故而若忽視青光眼，則會導致失明，並且即便治療成功，亦只會停留在維持現狀而無法期望恢復之難治性之疾患。又，雖然不會伴隨視野異常但長時間下來發展成青光眼之可能性較高之高眼壓症亦蘊藏著同樣之危險性。
青光眼被分成先天性青光眼、繼發性青光眼、原發性青光眼之3種類型。先天性青光眼係自出生起因房角發育不良、房水之排出受到阻礙所引起之青光眼。繼發性青光眼係因炎症或損傷等明確之原因所引起之青光眼，除葡萄膜炎或眼睛之損傷等眼睛之原因以外，亦會因糖尿病所導致之出血、其他疾病之治療所使用之類固醇激素之長期使用等而導致發病。原發性青光眼係不明原因之青光眼之總稱，且常見於中老年者中，係青光眼中最多之類型。原發性青光眼與繼發性青光眼根據房水流動之阻塞方式而進一步被分成開角型青光眼與閉角型青光眼之2種類型。又，亦大量存在發病為未伴隨眼壓之上升之正常眼壓青光眼之患者，總而言之，青光
眼治療之第一目標為降低眼壓。
關於青光眼之治療方法，於利用藥物無法控制眼壓時或閉角型青光眼患者發作成急性青光眼之情形時，進行雷射治療法(雷射纖維柱帶形成術)或手術療法(纖維柱帶切除術及纖維柱帶切開術)等，但首選使用藥物療法。青光眼之藥物療法使用交感神經興奮劑(腎上腺素等非選擇性興奮劑、阿可樂定(Apraclonidine)、溴莫尼定(Brimonidine)等α2興奮劑)、交感神經阻斷劑(噻嗎洛爾(Timolol)、苯呋洛爾(Befunolol)、卡替洛爾(Carteolol)、尼普地洛(Nipradilol)、倍他洛爾(Betaxolol)、左旋布諾洛爾(Levobunolol)、美替洛爾(Metipranolol)等β阻斷劑、鹽酸布那唑嗪等α1阻斷劑)、副交感神經促效劑(匹魯卡品(Pilocarpine)等)、碳酸脫水酵素抑制劑(乙醯唑胺等)、前列腺素類(異丙基烏諾前列酮、拉坦前列素(Latanoprost)、曲伏前列素(Travoprost)、比馬前列素(Bimatoprost)、他氟前列素(Tafluprost)等)等。
該等藥劑之中，溴莫尼定係藉由房水產生之抑制及經由葡萄膜鞏膜流出路徑之房水流出之促進而降低眼壓之類型之藥劑，亦廣泛用於臨床(非專利文獻1)。
另一方面，作為新穎之基於作用機制之青光眼治療藥之候補，發現有Rho激酶抑制劑(專利文獻1~2)。暗示Rho激酶抑制劑係藉由促進來自纖維柱帶流出路徑之房水流出而降低眼壓(非專利文獻2)，進而其作用取決於纖維柱帶細胞中之細胞骨架之變化(非專利文獻2、非專利文獻3)。
進而，於青光眼或高眼壓症中，為了增強眼壓下降作用，亦進行有將具有眼壓下降作用之藥劑組合使用。例如於非專利
文獻4中記載有將多種作用機制之眼壓降低劑組合使用。又，雖有利用小鼠對Rho抑制劑K-115與α2興奮劑溴莫尼定之併用所帶來之眼壓降低作用進行評價之報告(非專利文獻5)，但在投予溴莫尼定1.5小時後併用K-115之條件下並未確認到相對於單獨投予K-115之明顯之眼壓下降作用。
青光眼或高眼壓症之治療劑或治療方法於眼壓下降效果之作用強度或持續時間之方面仍然難以說滿意。尤其是於閉角型青光眼患者之青光眼發作、新生血管青光眼或手術後等特殊之狀態下存在成為極高之眼壓之情況，為了抑制視神經細胞之障礙而必須儘早降低眼壓。根據此種背景，要求更具即效性且眼壓下降作用強力之青光眼治療劑。
[專利文獻1]國際公開第00/09162號
[專利文獻2]日本專利特開平11-349482號公報
[非專利文獻1]Arch. Ophthalmol., 113 (12), 1514-1517 (1995)
[非專利文獻2]IOVS, 42(1), 137-144 (2001)
[非專利文獻3]IOVS, 42(5), 1029-1037 (2001)
[非專利文獻4]Exp. Opin. Emer. Drugs, 12(2), 313-327(2007)
[非專利文獻5]第27屆日本眼藥理學會主旨集，總則18,59(2007)
本發明係關於提供一種眼壓下降作用強力並具有即效性且其持續時間經延長之用於預防或治療青光眼或者高眼壓症之藥物療法。
本發明者等人為了解決上述問題而反覆進行努力研究，結果發現藉由組合投予(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
(以下有時稱為化合物1)或者其鹽或其等之溶劑合物與作為α2興奮劑之溴莫尼定，可發揮強力並具有即效性之眼壓下降作用且可延長其持續時間。據稱於兔子中，於α2興奮劑發揮滴眼側之眼壓降低作用之前，首先會產生基於存在於末梢神經突觸之α1腎上腺素受體興奮之短暫性之眼壓上升作用，繼而藉由經由眼睛局部之腎上腺素α2受體之房水產生之抑制或來自葡萄膜鞏膜流出路徑之房水流出量之增加而降低眼壓(Current eye research,5(9),665-676(1986)、Ann N Y Acad Sci,763,78-95(1995))。因此，於將溴莫尼定與化合物1組合之情形時，於短時間內表現出強眼壓降低作用係完全出乎意料。
即，本發明係關於以下之發明。
1)一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之組合，其用於預防或治療青光眼。
2)如上述1)之組合，其中，α2興奮劑為溴莫尼定或者其鹽或其等之溶劑合物。
3)如上述1)或2)之組合，其係調配劑。
4)如上述1)或2)之組合，其係包含含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
而成之藥劑與含有α2興奮劑而成之藥劑之套組。
5)一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之組合，其用於預防或治療高眼壓症。
6)如上述5)之組合，其中，α2興奮劑為溴莫尼定或者其鹽或其等之溶劑合物。
7)如上述5)或6)之組合，其係調配劑。
8)如上述5)或6)之組合，其係包含含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
而成之藥劑與含有α2興奮劑而成之藥劑之套組。
9)如上述5)或6)之組合，其係包含如下順序之套組：投予含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
而成之製劑作為第1藥劑，接下來投予含有α2興奮劑而成之製劑作為第2藥劑。
10)一種青光眼預防或治療方法，其特徵在於組合投予(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑。
11)一種高眼壓症預防或治療方法，其特徵在於組合投予(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑。
12)一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之組合，其用於製造青光眼預防或治療劑。
13)一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之組合，其用於製造高眼壓症預防或治療劑。
根據本發明，可提供一種眼壓下降作用強力並具有即效性且其持續時間經延長之青光眼或者高眼壓症之預防或治療方法。
圖1係表示各投予群組之眼壓之經時變化之曲線圖。眼壓係以與初始眼壓之變化值(平均值±標準誤差)表示。□：溴莫尼定單獨投予群組，○：(S)-(-)-化合物1單獨投予群組，●：溴莫尼定與化合物1之併用投予群組，統計解析：#p<0.05，##p<0.01vs.化合物1群組，$$$ p<0.001vs.溴莫尼定群組。
本發明所使用之(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
(化合物1)係具有P物質拮抗作用、白三烯素D4拮抗作用及Rho激酶抑制作用之化合物，可利用公知之方法、例如國際公開第99/20620號所記載之方法進行製造。
作為化合物1之鹽，例如可列舉與鹽酸、硫酸、硝酸、氫氟酸、氫溴酸等無機酸之鹽或與乙酸、酒石酸、乳酸、檸檬酸、富馬酸、馬來酸、琥珀酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸、樟腦磺酸等有機酸之鹽，尤佳為鹽酸鹽。
化合物1或其鹽不僅能以未溶劑合型之形式存在，亦能以水合物或溶劑合物之形式存在。較佳為水合物，於本發明中為
包含全部結晶型及水合或者溶劑合物者。
另一方面，作為α2興奮劑，只要為具有眼壓下降作用而對青光眼治療有用者即可。作為具有眼壓下降作用之α2興奮劑之具體例，可列舉：可樂定、阿可樂定、溴莫尼定等。例如溴莫尼定可利用Bioorganic & Medicinal Chemistry Letters(1995),5(19),2255-8等所記載之公知之方法進行製造。
作為溴莫尼定之鹽，例如可列舉與鹽酸、硫酸、硝酸、氫氟酸、氫溴酸等無機酸之鹽或與乙酸、酒石酸、乳酸、檸檬酸、富馬酸、馬來酸、琥珀酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸、樟腦磺酸等有機酸之鹽，尤佳為酒石酸。
溴莫尼定或其鹽不僅能以未溶劑合型之形式存在，亦能以水合物或溶劑合物之形式存在。較佳為水合物，於本發明中為包含全部結晶型及水合或者溶劑合物者。
於組合使用(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物(化合物1)與α2興奮劑之情形時，如下述實施例所示，可於投藥後立刻確認到強力且協同之眼壓下降作用。又，該強力之眼壓下降作用係持續數小時。因此，該等之組合作為青光眼或高眼壓症之預防或治療劑有用，該等之組合投予作為用於預防或治療青光眼或高眼壓症之藥物療法有用。此處，作為青光眼，例如可列舉：原發性開角型青光眼、正常眼壓青光眼、房水產生過多青光眼、高眼壓症、急性閉角型青光眼、慢性閉角型青光眼、高原型虹膜症候群(plateau iris syndrome)、混合型青光眼、類固醇青光眼、水晶體之囊性青光眼、色素青光眼、澱粉樣蛋白青光眼、血管新生青光眼、惡性青光眼等。又，所謂高眼壓
症，亦稱為眼性高血壓症，係指雖然未於視神經中確認到明確之病變但仍顯示出異常高之眼壓之症狀，包含術後之高眼壓表現等大量高眼壓狀態。
本發明之用於預防或治療青光眼或者高眼壓症之(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物(化合物1)與α2興奮劑之組合作為調配劑(青光眼預防或治療劑、高眼壓症之預防或治療劑)，既可為於適當之調配比中將各自之有效量製劑化成一種劑型而成者，又，亦可為以可同時地或隔開間隔分別使用將含有各自之有效量之藥劑單獨製劑化而成者之方式製成之套組。
於將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物(化合物1)與α2興奮劑分別製劑化之情形時，可分別依據公知之方法製備製劑。例如(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物之製劑能以上述專利文獻1及國際公開第97/23222號所記載之製劑例為參考而進行製備。又，於α2興奮劑為溴莫尼定之情形時，能以國際公開第92/13855號等所記載之製劑例為參考而進行製備。關於溴莫尼定，亦可使用市售之製劑。
於製備調配有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之製劑之情形時，亦可依據公知之方法進行製備。例如滴眼劑可視需要使用等張劑、緩衝劑、界面活性劑、防腐劑等而進行製備。pH值只要處於眼科製劑所容許之範圍內即可，較佳為pH值4~8之範圍。
上述製劑較佳為眼科用製劑、尤其是作為滴眼用而使
用者，該滴眼劑可為水性滴眼劑、非水性滴眼劑、懸浮性滴眼劑、乳濁性滴眼劑、眼軟膏等之任一者。此種製劑作為適合投予形態之組成物，可視需要調配藥學上容許之載體，例如等張劑、螯合劑、穩定劑、pH值調節劑、防腐劑、抗氧化劑、溶解輔助劑、黏稠化劑等，並利用業者公知之(製劑)方法進行製造。
於製備滴眼劑之情形時，例如可藉由使所需之上述成分溶解或懸浮於滅菌純化水、生理食鹽水等水性溶劑或棉籽油、大豆油、芝麻油、花生油等植物油等非水性溶劑中，調整為既定之浸透壓力並實施過濾滅菌等滅菌處理而進行。再者，於製備眼軟膏劑之情形時，除上述各種成分以外，亦可包含軟膏基劑。作為上述軟膏基劑，並無特別限定，可較佳地列舉：凡士林、流動石蠟、聚乙烯等油性基劑；藉由界面活性劑等使油相與水相乳化而成之乳劑性基劑；及包含羥丙基甲基纖維素、羧甲基纖維素、聚乙二醇等之水溶性基劑等。
於將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌或者其鹽或其等之溶劑合物與α2興奮劑之組合製成用於預防或治療青光眼或者高眼壓症之套組之情形時，能以如下方式設計：將以如上方式製劑化之含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物而成之藥劑與含有前列腺素類而成之藥劑分別單獨包裝，於投予時自各個包裝中取出各個醫藥品製劑並使用。又，亦可將各個醫藥品製劑以適合每次併用投予之形態預先包裝。
於將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑組合用於預防或治療
青光眼或者高眼壓症之情形時，其投予量因患者之體重、年齡、性別、症狀、投予形態及投予次數等而有所不同，通常相對於成人，作為(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物，可列舉每天0.025~10000μg、較佳為0.025~2000μg、更佳為0.1~2000μg之範圍，作為α2興奮劑，可列舉每天3~10000μg、較佳為30~3000μg之範圍。若針對α2興奮劑列舉具體例，則例如於溴莫尼定之情形時，通常每天使用30~300μg。再者，於作為調配有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之製劑投予之情形時，只要以每天之投予量成為上述各成分之量或其以下之方式，製備適當選擇了調配比例之製劑即可。
又，投予次數並無特別限定，較佳為1次或分成數次投予，於液體滴眼劑之情形時，每次滴眼1~數滴即可。於製成套組之情形時，可分別同時投予單獨之製劑，亦可隔開5分鐘~24小時之間隔投予。於隔開間隔投予之情形時，較佳為設為如下順序：投予含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
而成之製劑作為第1藥劑，接下來投予含有α2興奮劑而成之製劑作為第2藥劑。以下，對本發明更詳細地進行說明，但本發明並不限定於該等。
實施例1為了研究(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
(化合物1)與α2興奮劑之組合所帶來之有用性，而針對對實驗動物單獨或併用投予兩種藥物時之眼壓下降效果進行了比較研究。
1.被試驗化合物溶液之製備
A.化合物1之溶液之製備
於將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
-鹽酸鹽.二水合物溶解於生理食鹽水後，添加磷酸二氫鈉、氫氧化鈉對溶液進行中和(pH值6.0)，而製備所需濃度之化合物1之溶液。
B. α2受體促效劑類之製備
直接使用市售之溴莫尼定(千壽製藥股份有限公司，Aiphagan滴眼液0.1%)。
2.試驗方法
對併用投予化合物1與溴莫尼定時之眼壓下降效果進行了研究。作為比較對照，亦對單獨投予化合物1或單獨投予溴莫尼定時之眼壓下降效果進行了研究。
A.試驗所使用之藥劑及動物
化合物1之溶液：0.4%溶液(滴眼量：50μL)
溴莫尼定：0.1%滴眼液(滴眼量：50μL)
實驗動物：白色兔子(性別：雄性，一群組10隻)
B.投予方法及測定方法
(1)兩種藥劑之併用投予
1)於實驗動物之兩眼中滴眼一滴4%鹽酸奧布卡因滴眼液(商品名：Benoxil0.4%液)進行局部麻醉(資料僅為滴眼側)。
2)於將要投予被試驗化合物溶液之前測定眼壓並設為初始眼壓。
3)將化合物1之溶液滴眼至實驗動物之單眼中，接下來將溴莫尼定溶液滴眼至同一眼中。
4)於滴眼兩種藥劑0.5小時、1小時、2小時、3小時、4小時及5小時後將0.4%鹽酸奧布卡因滴眼液逐滴滴眼至兩眼中進行局部麻醉後，測定眼壓。
(2)化合物1之單獨投予
進行化合物1之單獨滴眼，並於與上述併用投予試驗相同之測定時間內進行試驗。
(3)溴莫尼定之單獨投予
將上述化合物1之單獨投予之受檢溶液替換成溴莫尼定，除此以外，以與上述單獨投予試驗相同之方法進行試驗。
3.結果及考察
將試驗之結果示於表1及圖1。再者，眼壓表示與初始眼壓之變化值。又，統計處理係使用Stat Preclinica Client 1.1、參數Tukey型多重比較。
由表1可知，藉由化合物1與溴莫尼定之併用確認到即效性之眼壓降低作用。尤其是於滴眼後0.5小時內，雖然單獨投予溴莫尼定並無眼壓降低作用，但是藉由併用2劑而表現出協同且
強力之眼壓降低作用。又，由圖1可知，化合物1與溴莫尼定之併用群組表現出較藥劑單獨投予群組、即化合物1投予群組或溴莫尼定投予群組更優異之眼壓下降作用，又，其作用之持續性亦提高。由以上可知，藉由將化合物1與溴莫尼定組合，可自早期獲得較強之眼壓下降效果、以及持續效果之提高。
本發明之(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌
或者其鹽或其等之溶劑合物與α2興奮劑之組合具有優異之眼壓下降效果、以及即效性與持續效果，從而作為用於預防或治療青光眼或者高眼壓症之醫藥有用。
Claims (4)
- 一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌或者其鹽或其等之溶劑合物與溴莫尼定之組合，其用於預防或治療青光眼，且係製劑化成一種劑型而成之調配劑。
- 如請求項1之組合，其用於預防或治療高眼壓症。
- 一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌或者其鹽或其等之溶劑合物與溴莫尼定之組合，其用於預防或治療青光眼，或者用於預防或治療高眼壓症，且係以藥劑單獨製劑化並同時使用之方式製成之套組。
- 一種(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌或者其鹽或其等之溶劑合物與溴莫尼定之組合，其用於預防或治療青光眼，或者用於預防或治療高眼壓症，且係包含如下順序之套組：投予含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌而成之製劑作為第1藥劑，接下來投予含有溴莫尼定而成之製劑作為第2藥劑。
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| Title |
|---|
| Lee AJ,et al."Emerging drugs for ocular hypertension." Expert Opin Emerg Drugs. 2011 Mar;16(1):137-161. * |
| 佐伯忠男朗ら,マウス眼圧に対するROCK阻害剤K115とブリモニジンの併用効果,日本眼薬理学会プログラム・講演抄録集, 2007, Vol.27, p.59. * |
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