TWI643619B - 一種用於預防或治療青光眼或高眼壓症、或降低眼壓之醫藥組合物及其用途 - Google Patents
一種用於預防或治療青光眼或高眼壓症、或降低眼壓之醫藥組合物及其用途 Download PDFInfo
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- TWI643619B TWI643619B TW102124846A TW102124846A TWI643619B TW I643619 B TWI643619 B TW I643619B TW 102124846 A TW102124846 A TW 102124846A TW 102124846 A TW102124846 A TW 102124846A TW I643619 B TWI643619 B TW I643619B
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- Prior art keywords
- compound
- glaucoma
- intraocular pressure
- solution
- ocular hypertension
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Abstract
本發明之課題係發現作為青光眼或高眼壓症之預防或治療劑為有用之青光眼或高眼壓症之預防或治療藥的組合。
本發明之解決手段係藉由組合(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥,而相互地輔助及/或增強降眼壓作用。作為投予之形態,可為合併投予、亦可作為合劑投予。
Description
本發明係關於一種組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它青光眼或高眼壓症之預防或治療藥的青光眼或高眼壓症之預防或治療劑、或降眼壓劑。
青光眼係由於種種病因而眼壓上升、眼球的內部組織(網膜、視神經等)受到障礙而有導致失明的危險性之難治性的眼疾病。作為青光眼之治療方法,一般而言為降眼壓療法,作為其代表者有藥物療法、雷射治療法、手術療法等。
藥物療法係使用有交感神經促效藥(地匹福林(dipivefrine)等之非選擇性刺激藥、溴莫尼定(brimonidine)等之α2受體促效藥)、交感神經阻斷藥(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)、左布諾洛爾(levobunolol)或美替洛爾(Metipranolol)等之β受體阻斷藥、鹽酸布那唑嗪(bunazosin hydrochloride)等之α1受體阻斷藥)、副交感神經促效藥(毛果芸香鹼(pilocarpine)等)、碳酸酐酶抑制劑(乙醯唑胺(acetazolamide)等)、前列腺素類(異丙基烏諾前列酮
(isopropyl unoprostone)、拉坦前列腺素(latanoprost)、曲伏前列腺素(travoprost)或比馬前列腺素(bimatoprost)等)之藥物。又,Rho激酶抑制劑(SNJ-1656等)、腺核苷促效藥(INO-8875等)、血清素阻斷藥(BVT-28949)等作為新藥物開發中。又,除了該等以外,已知前列腺素E2受體亞型(subtype)2促效劑(EP2促效劑)有降眼壓作用,且於國際公開第2010/113957號(專利文獻1)報告有具有高EP2受體選擇性與強效之EP2促效劑作用之磺醯胺化合物用作為青光眼之治療藥有其希望。
因此,已有多數報告,以治療青光眼之目的,組合具有降眼壓作用之藥劑來使用。例如:於日本專利第2726672號公報(專利文獻2)報告有投予交感神經阻斷藥與前列腺素類之組合。又,於國際公開第2002/38158號(專利文獻3)揭示有組合數種具有降眼壓作用之藥劑而投予眼之青光眼的治療方法。進而,於國際公開第2004/019951號(專利文獻4)報告有投予Rho激酶抑制劑與前列腺素類之組合,於國際公開第2004/045644號(專利文獻5)報告有投予Rho激酶抑制劑及β受體阻斷藥之組合。
然而,任一文獻中對於具有高EP2受體選擇性及強效之EP2促效劑作用之(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥的組合並未具體地揭示報告,當然,對於該等之組合針對眼壓可顯示何等效果仍是一切未知的。
專利文獻1 國際公開第2010/113957號
專利文獻2 日本專利第2726672號公報
專利文獻3 國際公開第2002/38158號
專利文獻4 國際公開第2004/019951號
專利文獻5 國際公開第2004/045644號
發現作為青光眼或高眼壓症之預防或治療劑有用的青光眼或高眼壓症之預防或治療藥之組合為非常有興趣的課題。
本發明人等潛心研究由青光眼或高眼壓症之預防或治療劑之組合所帶來的效果,結果發現相較於各藥劑單獨使用時,組合(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥增強了降眼壓作用,進而完成本發明。即,本發明係關於以下。
(1)一種青光眼或高眼壓症之預防或治療劑,其係組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與1或多種其它之青光眼或高眼壓症之預防或治療藥(其中,他氟前列腺素(tafluprost)除外)。
(2)一種降眼壓劑,其係組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與1或多種其它之青光眼或高眼壓症之預防或治療藥(其中,他氟前列腺素除外)。
(3)如上述(1)或(2)之預防或治療劑或降眼壓劑,其中其它之青光眼或高眼壓症之預防或治療藥(其中,他氟前列腺素除外)係選自由非選擇性交感神經促效藥、α2受體促效藥、α1受體阻斷藥、β受體阻斷藥、副交感神經促效藥、碳酸酐酶抑制劑、前列腺素類及Rho激酶抑制劑所構成之群中之1或多種之預防或治療劑。
(4)如上述(3)之預防或治療劑或降眼壓劑,其中非選擇性交感神經促效藥為地匹福林。
(5)如上述(3)之預防或治療劑或降眼壓劑,其中α2受體促效藥為溴莫尼定或阿可樂定(apraclonidine)。
(6)如上述(3)之預防或治療劑或降眼壓劑,其中α1受體阻斷藥為布那唑嗪。
(7)如上述(3)之預防或治療劑或降眼壓劑,其中β受體阻斷藥為噻嗎洛爾、苯呋洛爾、卡替洛爾、尼普地洛、倍他洛爾、左布諾洛爾或美替洛爾。
(8)如上述(3)之預防或治療劑或降眼壓劑,其中副交感神經促效藥為毛果芸香鹼。
(9)如上述(3)之預防或治療劑或降眼壓劑,其中碳酸酐酶抑制劑為多佐胺(dorzolamide)、布林唑胺(brinzolamide)或乙醯唑胺(acetazolamide)。
(10)如上述(3)之預防或治療劑或降眼壓劑,其中前列腺素類為異丙基烏諾前列酮、拉坦前列腺素、曲伏前列腺素或比馬前列腺素。
(11)如上述(3)之預防或治療劑或降眼壓劑,其中Rho激酶抑制劑為(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺、1-(5-異喹啉磺醯基)高哌嗪(1-(5-isoquinolinesulfonyl)homopiperazine)或1-(5-異喹啉磺醯基)-2-甲基哌嗪。
再者,上述(1)至(11)之各構成係可任意地選擇1以上而組合。
又,在說明書之後述中,「其它之青光眼或高眼壓症之預防或治療藥」之記載係意指除了他氟前列腺素以外之「其它之青光眼或高眼壓症之預防或治療藥」。
藉由組合(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯與其它之青光眼或高眼壓症之預防或治療藥且將其投予眼,而增強降眼壓作用。因此,本發明係作為青光眼或高眼壓症之預防或治療劑、降眼壓劑為有用。
本發明係組合有下述式(1)所示之(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯(以下,稱為本化合物)與1或多種其它之青光眼或高眼壓症之預防或治療藥的青光眼或高眼壓症之預防或治療劑、降眼壓劑,而相互地輔助及/或增強其作用者
本發明中之本化合物係可藉由國際公開第2009/113600號或國際公開第2010/113957號所記載之方法來合成。
本發明之特徵在於組合本化合物與其它之青光眼或高眼壓症之預防或治療藥,來預防或治療青光眼或高眼壓症。本發明中之青光眼,例示有原發性開角型青光眼、正常眼壓青光眼、房水分泌過多性青光眼、高眼壓症、急性閉角型青光眼、慢性閉角型青光眼、混合型青光眼、類固醇性青光眼(steroid glaucoma)、類澱粉蛋白青光眼(amyloid glaucoma)、新生血管青光眼、惡性青光眼、晶狀體之囊膜性青光眼、高原型虹膜症候群(plateau iris syndrome)等。
本發明中,本化合物與1或多種其它之青光眼或高眼壓症之預防或治療藥的組合,較佳為組合本化合物與1至3種其它之青光眼或高眼壓症之預防或治療藥,更佳為組合本化合物與1或2種其它之青光眼或高眼壓症之預防或治療藥。
本發明中之其它之青光眼或高眼壓症之預防或治療藥係具有降眼壓作用且對青光眼治療有用者即可,可舉出:非選擇性交感神經促效藥、α2受體促效藥、α1受體阻斷藥、β受體阻斷藥、副交感神經促效藥、碳酸酐酶抑制劑、前列腺素類、Rho激酶抑制劑等。組合本化合物與2種其它之青光眼或高眼壓症之預防或治療藥時,2種其它之青光眼或高眼壓症之預防或治療藥較佳為選自由β受體阻斷藥、碳酸酐酶抑制劑及前列腺素類所構成之群中之2種預防或治療藥,更佳為β受體阻斷藥及碳酸酐酶抑制劑,或β受體阻斷藥及前列腺素類。
作為非選擇性交感神經促效藥之具體例,可舉出地匹福林;作為α2受體促效藥之具體例,可舉出溴莫尼定、阿可樂定;作為α1受體阻斷藥之具體例,可舉出布那唑嗪;作為β受體阻斷藥之具體例,可舉出噻嗎洛爾、苯呋洛爾、卡替洛爾、尼普地洛、倍他洛爾、左布諾洛爾、美替洛爾;作為副交感神經促效藥之具體例,可舉出毛果芸香鹼;作為碳酸酐酶抑制劑之具體例,可舉出多佐胺、布林唑胺或乙醯唑胺。
作為前列腺素類之具體例,可舉出:揭示於日本特開昭59-1418號公報之前列腺素類(特別是如前列
腺素F2α之天然前列腺素)、揭示於日本特表平3-501025號公報之拉坦前列腺素等前列腺素類、揭示於日本特開平2-108號公報之異丙基烏諾前列酮等前列腺素類、揭示於日本特表平8-501310號公報之比馬前列腺素等前列腺素類、揭示於日本特開平10-182465號公報之曲伏前列腺素等前列腺素類、揭示於Surv Ophthalmol 47(Suppl 1):S13-S33,2002之AL-6598等前列腺素類,揭示於Exp Eye Res.89:608-17,2009之PF-04475270等前列腺素類,其中較佳為PGF2α或PGF2α衍生物,更佳為異丙基烏諾前列酮、拉坦前列腺素、曲伏前列腺素或比馬前列腺素。
本發明中之Rho激酶抑制劑,其係意指抑制伴隨著Rho之活性化而被活化之絲胺酸/蘇胺酸激酶的化合物。可舉出例如:抑制ROKα(ROCK-II)、p160ROCK(ROKβ、ROCK-I)及其它之具有絲胺酸/蘇胺酸活性之蛋白質的化合物。作為Rho激酶抑制劑之具體例,可舉例:於國際公開第98/06433號、國際公開第00/09162號揭示之(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺等Rho激酶抑制劑,或於國際公開第97/23222號、Nature,389,990-994(1997)所揭示之1-(5-異喹啉磺醯基)高哌嗪(1-(5-isoquinolinesulfonyl)homopiperazine)、1-(5-異喹啉磺醯基)-2-甲基哌嗪等Rho激酶抑制劑,國際公開第01/56988號所揭示之(1-苄基吡咯啶-3-基)-(1H-吲唑-5-基)胺等Rho激酶抑制劑,國際公開第
02/100833號所揭示之(1-苄基哌啶-4-基)-(1H-吲唑-5-基)胺等Rho激酶抑制劑,國際公開第02/076976號所揭示之N-[2-(4-氟苯基)-6,7-二甲氧基-4-喹唑啉基]-N-(1H-吲唑-5-基)胺等Rho激酶抑制劑,國際公開第02/076977號所揭示之N-4-(1H-吲唑-5-基)-6,7-二甲氧基-N-2-吡啶-4基-喹唑啉基-2,4-二胺等Rho激酶抑制劑,國際公開第99/64011號所揭示之4-甲基-5-(2-甲基-[1,4]苯甲二氮焯-1-磺醯基)異喹啉(4-methyl-5-(2-methyl-[1,4]-diazepane-1-sulfonyl)isoquinoline)等Rho激酶抑制劑。其中特佳為(R)-反-N-(吡啶-4-基)-4-(1-胺乙基)環己烷甲醯胺、(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-胺乙基)苯甲醯胺、1-(5-異喹啉磺醯基)高哌嗪或1-(5-異喹啉磺醯基)-2-甲基哌嗪。
作為組合本化合物與2種其它之青光眼或高眼壓症之預防或治療藥時之2種其它之青光眼或高眼壓症之預防或治療藥的具體例,可舉出:噻嗎洛爾及多佐胺,噻嗎洛爾及拉坦前列腺素,噻嗎洛爾及曲伏前列腺素。
本發明中之本化合物及其它之青光眼或高眼壓症之預防或治療藥亦包含鹽之形態。該等若為醫藥許可之鹽,則無特別限制,作為鹽可舉出:與無機酸之鹽、與有機酸之鹽、四級銨鹽、與鹵素離子之鹽、與鹼金屬之鹽、與鹼土金屬之鹽、金屬鹽、與氨之鹽、與有機胺之鹽等。作為與無機酸之鹽,可舉出:與鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等之鹽。作為與有機酸之鹽,
可舉出:與乙酸、草酸、反丁烯二酸、順丁烯二酸、琥珀酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡萄糖甲酸(glucoheptonic acid)、葡萄醣醛酸、對酞酸、甲磺酸、乳酸、馬尿酸、1,2-乙二磺酸、2-羥乙磺酸、乳糖醛酸、油酸、撲酸(pamoate)、聚半乳糖醛酸、硬脂酸、單寧酸、三氟甲磺酸、苯磺酸、對甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺柳酸等之鹽。作為四級銨鹽,可舉出:與溴甲烷、碘甲烷等之鹽。作為與鹵素離子之鹽,可舉出:與氯離子、溴離子、碘離子等之鹽;作為與鹼金屬之鹽,可舉出:與鋰、鈉、鉀等之鹽。作為與鹼土金屬之鹽,可舉出:與鈣、鎂等之鹽;作為金屬之鹽,可舉出:與鐵、鋅等之鹽。作為與有機胺之鹽,可舉出:與三乙二胺、2-胺乙醇、2.2-亞胺基雙(乙醇)、1-去氧-1-(甲胺基)-2-D-山梨醇、2-胺基-2-(羥甲基)-1,3-丙二醇、普羅卡因、N,N-雙(苯基甲基)-1,2-乙二胺等之鹽。
又,本發明中之本化合物及其它之青光眼或高眼壓症之預防或治療藥亦包含酯、醯胺等之衍生物。作為酯之具體例,可舉例:將其它之青光眼或高眼壓症之預防或治療藥中之羥基與乙酸、丙酸、異丙酸、丁酸、異丁酸、三甲基乙酸等之羧酸縮合而成之酯,將其它之青光眼或高眼壓症之預防或治療藥中之羧基與甲醇、乙醇、丙醇、異丙醇等之醇縮合而成之酯。作為醯胺之具體例,可舉例:將本化合物及/或其它之青光眼或高眼壓症之預防或治療藥之胺基與乙酸、丙酸、異丙酸、丁酸、異丁酸、三甲基乙酸等之羧酸縮合而成之醯胺,將其它
之青光眼或高眼壓症之預防或治療藥中之羧基與甲胺、乙胺、丙胺、異丙胺等之胺縮合而成之醯胺。
進而,本發明中之本化合物及其它之青光眼或高眼壓症之預防或治療藥,亦可為水合物或溶劑合物之形態。
作為投予形態,可將本化合物與其它之青光眼或高眼壓症之預防或治療藥以各別處方之多種製劑的形態進行投予(併用投予),又,亦可將各別的成分調配成一種製劑的形態(合劑)進行投予。較佳為合劑的情形。進而,組合有本化合物與多種其它之青光眼或高眼壓症之預防或治療藥時,可併用投予各別的成分,亦可將本化合物與其它之青光眼或高眼壓症之預防或治療藥中任意成分調配成之合劑與殘餘成分併用投予亦可,另可將所有成分調配成合劑。
本發明之製劑可為經口、亦可為非經口投予,該等之製劑化不需特別之技術,可使用廣泛使用之技術來進行製劑化。作為投予劑型,可舉出:點眼劑、眼軟膏、注射劑、錠劑、膠囊、顆粒、粉劑等。較佳為點眼劑、眼軟膏。
將本化合物與其它之青光眼或高眼壓症之預防或治療藥各別地製劑化時,可分別根據周知的方法來製備製劑。例如:本化合物之製劑係可參考國際公開第2009/113600號或國際公開第2010/113957號所記載之製劑例來製備。作為其它之青光眼或高眼壓症之預防或治療藥的製劑,可使用已於市面販售之地匹福林、溴莫尼
定、阿可樂定、布那唑嗪、噻嗎洛爾、苯呋洛爾、卡替洛爾、尼普地洛、倍他洛爾、左布諾洛爾、美替洛爾、毛果芸香鹼、多佐胺、布林唑胺、乙醯唑胺、異丙基烏諾前列酮、拉坦前列腺素、曲伏前列腺素、比馬前列腺素、Cosopt(註冊商標)調配點眼液、Xalacom(註冊商標)調配點眼液、DuoTrav(註冊商標)調配點眼液等製劑或根據該等者。Rho激酶抑制劑之製劑係可參考上述之國際公開第00/09162號、國際公開第97/23222號等所記載之製劑例來製備。
又,製備將本化合物與其它之青光眼或高眼壓症之預防或治療藥任意組合調配成之一種製劑時,可根據周知的方法來製備。
作成點眼劑時,於蒸餾水、緩衝液等添加本化合物或其它之青光眼或高眼壓症之預防或治療藥且進行攪拌後,利用pH調整劑調整pH,藉此可製備所欲之點眼劑。又,視需要,可使用廣泛使用於點眼劑之添加劑,而作為添加劑,可舉出:等張劑、緩衝劑、界面活性劑、安定劑、防腐劑等。作為等張劑,可舉出氯化鈉、濃縮甘油等,作為緩衝劑,可舉出磷酸鈉、乙酸鈉、硼酸、硼砂、檸檬酸等,作為界面活性劑,可舉出聚氧乙烯去水山梨醇單油酯、聚氧乙烯硬脂酸酯、聚氧乙烯硬化蓖麻油酯等,作為安定劑,可舉出檸檬酸鈉、乙二胺四乙基二鈉等,作為防腐劑,可舉出氯化烷基二甲基苄基銨(benzalkonium chloride)、苯甲酸酯類(paraben)等之防腐劑。
點眼劑之pH值為眼科製劑之許可範圍內即可,較佳為pH4~8之範圍,更佳為pH5~7之範圍。
作成眼軟膏時,可使用廣泛使用之基劑來製備,作為基劑可舉出白色凡士林、液態石蠟等。
作成錠劑、膠囊、顆粒、粉劑等經口劑時,視需要可添加增量劑、潤澤劑、黏合劑、崩散劑、塗膜劑、被膜劑等而製備。作為增量劑,可舉出乳糖、結晶纖維素、澱粉、植物油等,作為潤澤劑,可舉出硬脂酸鎂、滑石等,作為黏合劑,可舉出羥丙基纖維素、聚乙烯氫吡咯酮等,作為崩散劑,可舉出羧甲基纖維素鈣、低取代羥丙基甲基纖維素等,作為塗膜劑,可舉出羥丙基甲基纖維素、聚乙二醇(macrogol)、矽樹脂等,作為被膜劑,可舉出明膠被膜等。
本化合物及其它之青光眼或高眼壓症之預防或治療藥的投予量係可視劑型、應投予之患者之症狀的輕重、年齡、體重、投予途徑、醫師的判斷等適當地改變。以點眼投予為主要例而進行以下說明。
本化合物之投予量,當為點眼劑時,通常1日的投予量在0.05~500μg之範圍,可1日1次或分成數次投予,根據患者的年齡、症狀等可適當地增減。點眼劑中本化合物的濃度並無特別限制,可將在0.00001~3w/v%之範圍內,較佳為0.0001~1w/v%之範圍內,更佳為0.001~0.1w/v%之範圍內,再更佳為0.003~0.03w/v%之範圍內之濃度的點眼劑,1日1次或數次點眼。再者,點眼劑之濃度係可將本化合物之自由體
及其之鹽之任一者的重量作為基準計算者(以下相同)又,為眼軟膏時,通常,通常1日的投予量可為在0.0001~30mg之範圍內,較佳為0.0003~10mg之範圍內,更佳為0.001~3mg之範圍內,再更佳為0.003~1mg之範圍內,1次或分為數次投予。
非選擇性交感神經促效藥之投予量係根據藥物之種類而有所不同,通常1日之投予量在1~5000μg之範圍,可1日1次或分為數次投予。更具體而言,當為地匹福林時係通常使用2~3000μg作為1日量,該等之用量,視患者之年齡、症狀等可適當地增減。又,對於其它之非選擇性交感神經促效藥亦可基於同樣的基準而決定其用量。點眼液中之非選擇性交感神經促效藥之濃度並無特別限制,當為地匹福林時,可將在0.001~3w/v%之範圍內,較佳為0.04~0.1w/v%之範圍內,更佳為0.04w/v%或0.1w/v%之濃度的點眼劑,1日1次或數次點眼。
α2受體促效藥之投予量係根據藥物之種類而有所不同,通常1日之投予量在2~3000μg之範圍,可1日1次或分為數次投予。更具體而言,當為溴莫尼定時係通常使用2~1000μg作為1日量,當為阿可樂定時係通常使用20~3000μg作為1日量,該等之用量,視患者之年齡、症狀等可適當地增減。又,對於其它之α2受體促效藥亦可基於同樣的基準而決定其用量。點眼液中之α2受體促效藥之濃度並無特別限制,當為溴莫尼定時,可將在0.01~5w/v%之範圍內,較佳為0.1~0.5w/v%之範圍
內,更佳為0.1w/v%、0.15w/v%、0.2w/v%或0.5w/v%之濃度的點眼劑,1日1次或數次點眼。又,當為阿可樂定時,可將在0.01~5w/v%之範圍內,較佳為0.5~1w/v%之範圍內,更佳為0.5w/v%或1w/v%之濃度的點眼劑,1日1次或數次進行點眼。
α1受體阻斷藥之投予量係根據藥物之種類而有所不同,通常1日之投予量在1~5000μg之範圍,可1日1次或分為數次投予。更具體而言,當為布那唑嗪時係通常使用2~3000μg作為1日量,該等之用量,視患者之年齡、症狀等可適當地增減。又,對於其它之α1受體阻斷藥亦可基於同樣的基準而決定其用量。點眼液中之α1受體阻斷藥之濃度並無特別限制,當為布那唑嗪時,可將在0.001~0.3w/v%之範圍內,較佳為0.003~0.03w/v%之範圍內,更佳為0.01w/v%之濃度的點眼劑,1日1次或數次點眼。
β受體阻斷藥之投予量係根據藥物之種類而有所不同,通常1日之投予量在5~5000μg之範圍,可1日1次或分為數次投予。更具體而言,當為噻嗎洛爾時係通常使用5~1500μg作為1日量,當為苯呋洛爾時係通常使用10~2000μg作為1日量,當為卡替洛爾時係通常使用10~5000μg作為1日量,當為尼普地洛時係通常使用10~1250μg作為1日量,當為倍他洛爾時通常使用50~1000μg作為1日量,當為左布諾洛爾時係通常使用5~5000μg作為1日量,當為美替洛爾時係通常使用5~5000μg作為1日量,該等之用量,視患者之年齡、症
狀等可適當地增減。又,對於其它之β受體阻斷藥亦可基於同樣的基準而決定其用量。點眼液中之β受體阻斷藥之濃度並無特別限制,當為噻嗎洛爾時,可將在0.01~5w/v%之範圍內,較佳為0.1~0.5w/v%之範圍內,更佳為0.1w/v%、0.25w/v%或0.5w/v%之濃度的點眼劑,1日1次或數次點眼。又,當為苯呋洛爾時,可將在0.01~5w/v%之範圍內,較佳為0.25~1w/v%之範圍內,更佳為0.25w/v%、0.5w/v%或1w/v%之濃度的點眼劑,1日1次或數次點眼。當為卡替洛爾時,可將在0.01~5w/v%之範圍內,較佳為1~2w/v%之範圍內,更佳為1w/v%或2w/v%之濃度的點眼劑,1日1次或數次點眼。當為尼普地洛時,可將在0.01~5w/v%之範圍內,較佳為0.25w/v%之濃度的點眼劑,1日1次或數次點眼。當為倍他洛爾時,可將在0.01~5w/v%之範圍內,較佳為0.25~0.5w/v%之範圍內,更佳為0.25w/v%或0.5w/v%之濃度的點眼劑,1日1次或數次點眼。當為左布諾洛爾時,將在0.01~5w/v%之範圍內,較佳為0.25~0.5w/v%之範圍內,更佳為0.25w/v%或0.5w/v%之濃度的點眼劑,1日1次或數次點眼。當為美替洛爾時,將在0.01~5w/v%之範圍內,較佳為0.3w/v%之濃度的點眼劑,1日1次或數次點眼。
副交感神經促效藥之投予量係根據藥物之種類而有所不同,通常1日之投予量在5~300000μg之範圍,可1日1次或分為數次投予。更具體而言,當為毛果芸香鹼時係通常使用5~200000μg作為1日量,該等之
用量,視患者之年齡、症狀等可適當地增減。又,對於其它之副交感神經促效藥亦可基於同樣的基準而決定其用量。點眼液中之副交感神經促效藥之濃度並無特別限制,當為毛果芸香鹼時,可將在0.01~20w/v%之範圍內,較佳為0.1~5w/v%之範圍內,更佳為0.5w/v%、1w/v%、2w/v%、3w/v%或4w/v%之濃度的點眼劑,1日1次或數次點眼。
碳酸酐酶抑制劑之投予量係根據藥物之種類而有所不同,通常1日之投予量在10~10000μg之範圍,可1日1次或分為數次投予。更具體而言,當為多佐胺時係通常使用10~10000μg作為1日量,當為布林唑胺時係通常使用20~5000μg作為1日量,該等之用量,視患者之年齡、症狀等可適當地增減。又,對於其它之碳酸酐酶抑制劑亦可基於同樣的基準而決定其用量。點眼劑中之碳酸酐酶抑制劑之濃度並無特別限制,當為多佐胺時,可將在0.01~5w/v%之範圍內,較佳為0.5~2w/v%之範圍內,更佳為0.5w/v%、1w/v%或2w/v%之濃度的點眼劑,1日1次或數次點眼。又,當為布林唑胺時,可將在0.01~5w/v%之範圍內,較佳為0.1~2w/v%之範圍內,更佳為1w/v%之濃度的點眼劑,1日1次或數次點眼。又,當為乙醯唑胺時,可使用在0.01~5w/v%之範圍內,較佳為1~5w/v%之範圍內之濃度的點眼劑。再者,乙醯唑胺經口投予時係可使用250~1000mg作為1日量。
前列腺素類之投予量係根據藥物之種類而有所不同,通常1日之投予量在0.1~1000μg之範圍,可1
日1次或分為數次投予。更具體而言,當為拉坦前列腺素時係通常使用1~5μg作為1日量,當為異丙基烏諾前列酮時係通常使用30~300μg作為1日量,當為比馬前列腺素素時係通常使用2~30μg作為1日量,當為曲伏前列腺素時係通常使用0.5~5μg作為1日量,該等之用量,視患者之年齡、症狀等可適當地增減。又,對於其它之前列腺素類亦可基於同樣的基準而決定其用量。點眼劑中之前列腺素類之濃度並無特別限制,當為拉坦前列腺素時,可將在0.0001~5w/v%之範圍內,較佳為0.0005~1w/v%之範圍內,更佳為0.001~0.1w/v%之範圍內,再更佳為0.005w/v%之濃度的點眼劑,1日1次或數次點眼。當為異丙基烏諾前列酮時,可將在0.001~5w/v%之範圍內,較佳為0.01~1w/v%之範圍內,更佳為0.12~0.15w/v%之範圍內,再更佳為0.12w/v%或0.15w/v%之濃度的點眼劑,1日1次或數次點眼。當為比馬前列腺素時,可將在0.0001~5w/v%之範圍內,較佳為0.001~1w/v%之範圍內,更佳為0.01~0.03w/v%之範圍內,再更佳為0.01w/v%或0.03w/v%之濃度的點眼劑,1日1次或數次點眼。當為曲伏前列腺素時,可將在0.0001~5w/v%之範圍內,較佳為0.001~1w/v%之範圍內,更佳為0.004w/v%之濃度的點眼劑,1日1次或數次點眼。
Rho激酶抑制劑之投予量係根據藥物之種類而有所不同,通常1日之投予量在0.025~10000μg之範圍,可1日1次或分為數次投予,該等之用量,視患者
之年齡、症狀等可適當地增減。點眼液中之Rho激酶抑制劑之濃度並無特別限制,可將在0.001~5w/v%之範圍內,較佳為0.001~1w/v%之範圍內之濃度的點眼劑,1日1次或數次點眼。
該等之投予量適用於將本化合物與其它之青光眼或高眼壓症之預防或治療藥併用投予時,當將本化合物與其它之青光眼或高眼壓症之預防或治療藥之任意組合的合劑進行投予時,以使1日之投予量成為上述之各成分之投予量的範圍內的方式,製備經適當地選擇調配比例之製劑,而其調配製劑可1日1次或分為數次投予。
以下表示製劑例及藥理測試,惟該等係用於更了解本發明者,本發明之範圍並不限定於此。
以下表示將本發明中之本化合物與其它之青光眼或高眼壓症之預防或治療藥所調配而成之點眼劑及眼軟膏的具體製劑例。
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
點眼劑(100mL中)
眼軟膏(100g中)
眼軟膏(100g中)
眼軟膏(100g中)
上述處方中,將本化合物之量變更為0.001g、0.003g、0.03g、0.1g等,又,變更其它之青光眼或高眼壓症之預防或治療藥,或添加劑之種類及量,而可製備所欲之組合及所欲之濃度的點演劑及眼軟膏。
為了調查本化合物與β受體阻斷藥之組合的有用性,而研究於實驗動物(正常眼壓兔)併用投予本化合物與噻嗎洛爾時之降眼壓效果。
於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
於0.8g聚氧乙烯(35)蓖麻油加入0.001g本化合物,且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
直接使用市售之生理食鹽液(商品名:大塚生食注、由大塚製藥工廠(股)取得)。
直接使用市售之噻嗎洛爾點眼液。
研究將本化合物與噻嗎洛爾併用投予時之降眼壓效果。作為比較對象,亦研究單獨投予本化合物或單獨投予噻嗎洛爾時之降眼壓效果。對照組係投予基劑及生理食鹽水。
本化合物溶液:0.001w/v%本化合物溶液(點眼量:50μL)
噻嗎洛爾溶液:噻嗎洛爾點眼液(商品名:Timoptol(註冊商標)點眼液0.5%,點眼量:50μL)
實驗動物:日本白色兔(系統:JW、性別:雄性、一群6隻)
(1)將0.4%鹽酸丁氧普鲁卡因(oxybuprocaine hydrochloride)點眼液(商品名:Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。
(2)於被驗化合物溶液投予前測定眼壓,設為初期眼壓。
(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將噻嗎洛爾溶液點眼於同一眼。
(4)本化合物溶液點眼後2小時、4小時及6小時,將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後,測定眼壓。又,眼壓係測定3次而以其平均值表示結果。
將噻嗎洛爾溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,噻嗎洛爾溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
各投予群之點眼後4小時之降眼壓幅度(對對照群平均值)表示於表1。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示基於各群之6隻的平均值。
由表1可以明白,本化合物與噻嗎洛爾之併用投予群之點眼後4小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群,即,大於本化合物投予群及噻嗎洛爾投予群之點眼後4小時的降眼壓幅度(對對照群平均值),且大於由各藥劑單獨投予所引起之點眼後4小時的降眼壓幅度(對對照群平均值)合併計算之和,本化合物與噻嗎洛爾之併用效果為加乘者。
由以上可知,藉由組合本化合物與β受體阻斷藥,可獲得加乘之降眼壓效果。
為了調查本化合物與前列腺素之組合的有用性,而研究於實驗動物(正常眼壓猴)併用投予本化合物與拉坦前列腺素時之降眼壓效果。
於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
於0.8g聚氧乙烯(35)蓖麻油加入0.0006g本化合物,且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
直接使用市售之生理食鹽液(商品名:大塚生食注、由大塚製藥工廠(股)取得)。
直接使用市售之拉坦前列腺素點眼液。
研究將本化合物與拉坦前列腺素併用投予時之降眼壓效果。作為比較對象,亦研究單獨投予本化合物或單獨投予拉坦前列腺素時之降眼壓效果。對照組係投予基劑及生理食鹽水。
本化合物溶液:0.0006w/v%本化合物溶液(點眼量:20μL)
拉坦前列腺素溶液:拉坦前列腺素點眼液(商品名:Xalatan(註冊商標)點眼液0.005%,點眼量:20μL)
實驗動物:食蟹獼猴(Macaca fascicularis)(性別:雄性、一群6頭)
(1)將0.4%鹽酸丁氧普鲁卡因點眼液(商品名:Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。
(2)於被驗化合物溶液投予前測定眼壓,設為初期眼壓。
(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將拉坦前列腺素溶液點眼於同一眼。
(4)本化合物溶液點眼後2小時、4小時、6小時及8小時,將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後,測定眼壓。又,眼壓係測定3次而以其平均值表示結果。
將拉坦前列腺素溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,拉坦前列腺素溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
各投予群之點眼後8小時之降眼壓幅度(對對照群平均值)表示於表2。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示各群6頭之平均值。
由表2可以明白,本化合物與拉坦前列腺素之併用投予群之點眼後8小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群,即,大於本化合物投予群及拉坦前列腺素投予群之點眼後8小時的降眼壓幅度(對對照群平均值),且大於由各藥劑單獨投予所引起之點眼
後8小時的降眼壓幅度(對對照群平均值)合併計算之和,本化合物與拉坦前列腺素之併用效果為加乘者。
由以上可知,藉由組合本化合物與前列腺素類,可獲得加乘之降眼壓效果。
為了調查本化合物與α2受體促效藥之組合的有用性,而研究於實驗動物(正常眼壓猴)併用投予本化合物與溴莫尼定時之降眼壓效果。
於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
於0.8g聚氧乙烯(35)蓖麻油加入0.0006g本化合物,且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
直接使用市售之生理食鹽液(商品名:大塚生食注、由大塚製藥工廠(股)取得)。
直接使用市售之溴莫尼定點眼液。
研究將本化合物與溴莫尼定併用投予時之降眼壓效果。作為比較對象,亦研究單獨投予本化合物或單獨投予溴莫尼定時之降眼壓效果。對照組係投予基劑及生理食鹽水。
本化合物溶液:0.0006w/v%本化合物溶液(點眼量:20μL)
溴莫尼定溶液:溴莫尼定點眼液(商品名:ALPHAGAN(註冊商標)P 0.15%,點眼量:20μL)
實驗動物:食蟹獼猴(性別:雄性、一群6頭)(投予方法及測定方法)
(1)將0.4%鹽酸丁氧普鲁卡因點眼液(商品名:Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。
(2)於被驗化合物溶液投予前測定眼壓,設為初期眼壓。
(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將溴莫尼定溶液點眼於同一眼。
(4)本化合物溶液點眼後2小時、4小時、6小時及8小時,將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後,測定眼壓。又,眼壓係測定3次而以其平均值表示結果。
將溴莫尼定溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,溴莫尼定溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
各投予群之點眼後2小時之降眼壓幅度(對對照組平均值)表示於表3。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示各群6頭之平均值。
由表3可以明白,本化合物與溴莫尼定之併用投予群之點眼後2小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群,即,大於本化合物投予群及溴莫尼定投予群之點眼後2小時的降眼壓幅度(對對照群平均值),且大於由各藥劑單獨投予所引起之點眼後2小時的降眼壓幅度(對對照群平均值)合併計算之和,本化合物與溴莫尼定之併用效果為加乘者。
由以上可知,藉由組合本化合物與α2受體促效藥,可獲得加乘之降眼壓效果。
為了調查本化合物與碳酸酐酶抑制劑之組合的有用性,而研究於實驗動物(正常眼壓猴)併用投予本化合物與布林唑胺時之降眼壓效果。
於1.7g聚氧乙烯(35)蓖麻油加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
於0.8g聚氧乙烯(35)蓖麻油加入0.0006g本化合物,且加入10mL 0.5%乙二胺四乙基二鈉/10%甘油溶液、1mL 1%氯化烷基二甲基苄基銨溶液、30mL蒸餾
水、50mL 2%硼酸/0.2%山梨酸溶液且溶解。確認溶液後,於其加入適量氫氧化鈉溶液或稀鹽酸,而製劑之pH成為6.5前後之後,加入適量蒸餾水而使總量成為100mL。
直接使用市售之生理食鹽液(商品名:大塚生食注、由大塚製藥工廠(股)取得)。
直接使用市售之布林唑胺點眼液。
研究將本化合物與布林唑胺併用投予時之降眼壓效果。作為比較對象,亦研究單獨投予本化合物或單獨投予布林唑胺時之降眼壓效果。對照組係投予基劑及生理食鹽水。
本化合物溶液:0.0006w/v%本化合物溶液(點眼量:20μL)
布林唑胺懸浮液:布林唑胺懸浮性點眼液(商品名:Azopt(註冊商標)懸浮性點眼液1%,點眼量:20μL)
實驗動物:食蟹獼猴(Macaca fascicularis)(性別:雄性、一群5或6頭)
(1)將0.4%鹽酸丁氧普鲁卡因點眼液(商品名:Benoxil(註冊商標)點眼液0.4%)一滴點眼於實驗動物之雙眼而進行局部麻醉。
(2)於被驗化合物溶液投予前測定眼壓,設為初期眼壓。
(3)本化合物溶液點眼於實驗動物之單眼(對側眼無處理)。停留些許時間再將布林唑胺懸浮液點眼於同一眼。
(4)本化合物溶液點眼後2小時、4小時、6小時及8小時,將0.4%鹽酸丁氧普鲁卡因點眼液一滴一滴點眼於眼壓測定眼而進行局部麻醉後,測定眼壓。又,眼壓係測定3次而以其平均值表示結果。
將布林唑胺懸浮液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試
將本化合物以基劑代替,其它與上述併用投予測試同樣之方法進行測試。
將本化合物以基劑代替,布林唑胺溶液以生理食鹽水代替,其它與上述併用投予測試同樣之方法進行測試。
各投予群之點眼後4小時之降眼壓幅度(對對照群平均值)表示於表4。降眼壓幅度(對對照群平均值)係由對照群之初期眼壓值的眼壓值變動幅度(△IOP)之平均值與各個體之△IOP的差來表示各群5或6頭之平均值。
由表4可以明白,本化合物與布林唑胺之併用投予群之點眼後4小時的降眼壓幅度(對對照群平均值)係大於藥劑單獨投予群,即,大於本化合物投予群及布林唑胺投予群之點眼後4小時的降眼壓幅度(對對照群平均值)。
由以上可知,藉由組合本化合物與碳酸酐酶抑制劑,可獲得強力之降眼壓效果。
Claims (8)
- 一種醫藥組合物,其組合有(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯、與選自由溴莫尼定(brimonidine)、溴莫尼定酒石酸鹽、噻嗎洛爾(timolol)、噻嗎洛爾馬來酸鹽及拉坦前列腺素(latanoprost)所組成之群組中的1種之青光眼或高眼壓症之預防或治療藥。
- 如請求項1之醫藥組合物,其中(6-{[4-(吡唑-1-基)苄基](吡啶-3-基磺醯基)胺甲基}吡啶-2-基胺基)乙酸異丙酯的濃度為0.0001~1w/v%之範圍內。
- 如請求項2之醫藥組合物,其包含溴莫尼定或溴莫尼定酒石酸鹽,且溴莫尼定或溴莫尼定酒石酸鹽的濃度為0.01~5w/v%之範圍內。
- 如請求項2之醫藥組合物,其包含噻嗎洛爾或噻嗎洛爾馬來酸鹽,且噻嗎洛爾或噻嗎洛爾馬來酸鹽的濃度為0.01~5w/v%之範圍內。
- 如請求項3之醫藥組合物,其包含溴莫尼定酒石酸鹽。
- 如請求項4之醫藥組合物,其包含噻嗎洛爾馬來酸鹽。
- 如請求項1至6中任一項之醫藥組合物,其係用於青光眼或高眼壓症之預防或治療、或降低眼壓。
- 一種如請求項1至6中任一項之醫藥組合物之用途,其係用於製造青光眼或高眼壓症之預防或治療劑、或降眼壓劑。
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ATE546143T1 (de) * | 2002-08-29 | 2012-03-15 | Santen Pharmaceutical Co Ltd | Mittel zur behandlung von glaukom mit einem rho- kinase-hemmer und prostaglandinen |
CA2878370C (en) * | 2012-07-13 | 2021-01-19 | Santen Pharmaceutical Co., Ltd. | Combinations comprising a sulfonamide compound for the treatment of glaucoma or ocular hypertension |
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2013
- 2013-07-11 CA CA2878370A patent/CA2878370C/en active Active
- 2013-07-11 TW TW102124846A patent/TWI643619B/zh active
- 2013-07-11 KR KR1020157002710A patent/KR102074020B1/ko active IP Right Grant
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- 2013-07-11 WO PCT/JP2013/068927 patent/WO2014010654A2/ja active Application Filing
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2015
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2017
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11608319B2 (en) | 2019-12-31 | 2023-03-21 | Industrial Technology Research Institute | Beta-amino acid derivative, kinase inhibitor and pharmaceutical composition containing the same, and method for performing an in vivo related application that benefits from the inhibition of a kinase |
Also Published As
Publication number | Publication date |
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WO2014010654A2 (ja) | 2014-01-16 |
JP6383058B2 (ja) | 2018-08-29 |
PH12015500025A1 (en) | 2015-02-23 |
JP6193655B2 (ja) | 2017-09-06 |
KR102074020B1 (ko) | 2020-02-05 |
TW201408297A (zh) | 2014-03-01 |
PH12015500025B1 (en) | 2015-02-23 |
JP2017186375A (ja) | 2017-10-12 |
JP2018165285A (ja) | 2018-10-25 |
CA2878370A1 (en) | 2014-01-16 |
CA3099517A1 (en) | 2014-01-16 |
JP6667583B2 (ja) | 2020-03-18 |
WO2014010654A3 (ja) | 2014-03-06 |
JP2014031369A (ja) | 2014-02-20 |
KR20150036320A (ko) | 2015-04-07 |
CA3099517C (en) | 2022-04-26 |
CA2878370C (en) | 2021-01-19 |
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