TW202344254A - 青光眼或高眼壓症之預防或治療用之醫藥 - Google Patents
青光眼或高眼壓症之預防或治療用之醫藥 Download PDFInfo
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- TW202344254A TW202344254A TW112103959A TW112103959A TW202344254A TW 202344254 A TW202344254 A TW 202344254A TW 112103959 A TW112103959 A TW 112103959A TW 112103959 A TW112103959 A TW 112103959A TW 202344254 A TW202344254 A TW 202344254A
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- glaucoma
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- methyl
- prostaglandins
- intraocular pressure
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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Abstract
本發明係提供眼壓下降作用強力且延長持續時間的青光眼或高眼壓症預防或治療之藥物療法。
本發明的組合藥劑,係青光眼預防或治療用,由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類組合而成。
Description
本發明係關於青光眼或高眼壓症的預防或治療之藥物療法。
所謂「青光眼」係因各種病因而導致眼壓上昇,造成視神經出現病變並萎縮,導致視野異常,致使視力降低的疾病。因為一經引發萎縮的視神經便無法復原,因而若放任青光眼不管,最終將至失明,即便治療成功,但僅止於維持現狀而已,屬於復原無望的難治性疾病。又,雖不會衍生視野異常,但經長期會演變成青光眼可能性極高的高眼壓症,亦潛藏著同樣的危險性。
青光眼可區分為「先天性青光眼」、「續發性青光眼」、及「原發性青光眼」等3種。先天性青光眼係與生俱來的隅角發育不全,因為妨礙房水的排出而引發的青光眼。續發性青光眼係因發炎或受傷等明確原因而引發的青光眼,除因葡萄膜炎、眼睛受傷等眼部原因之外,尚有因糖尿病而導致的出血、因其他疾病治療所使用之類固醇激素的長期使用等,亦會導致發病。原發性青光眼係原因未明者的統稱,多發現於中高年人,屬於青光眼中最多的病例。原發性青光眼與續發性青光眼係依照房水流動阻塞的方式,可更進一步區分為「隅角開放性青光眼」、與「隅角閉鎖性青光眼」等2種。又,亦多數存在有未發生眼壓上昇而出現正常眼壓青光眼的患者,但不管如何,青光眼治療的第一目標係使眼壓下降。
青光眼的治療方法係在無法利用藥物控制眼壓時、或隅角閉鎖性青光眼患者引發急性青光眼發作的情況,雖進行雷射治療法(雷射小梁網整形術)、手術療法(小梁切除術與小梁網切開術)等,但藥物療法仍是第一選擇。青光眼的藥物療法,有使用例如:交感神經刺激劑(腎上腺素等非選擇性刺激劑、阿可樂定(apraclonidine)等α2刺激劑)、交感神經阻斷劑(噻嗎心胺(timolol)、苯呋洛爾(befunolol)、卡替洛爾(carteolol)、尼普拉洛爾(nipradilol)、倍他洛爾(betaxolol)、左布諾洛爾(levobunolol)、美替洛爾(Metipranolol)等β阻斷劑;鹽酸布那唑嗪(bunazosin hydrochloride)等α1阻斷劑)、副交感神經興奮劑(毛果芸香(pilocarpine)等)、碳酸酐酶抑制劑(乙醯胺基硫唑嘧錠(acetazolamide)等)、前列腺素類(烏諾前列酮異丙酯(isopropyl unoprostone)、拉坦前列腺素(Latanoprost)、曲伏前列腺素(travoprost)、比馬前列腺素(bimatoprost)、塔伏前列腺素(tafluprost)等)等。
該等藥劑中,前列腺素類屬於促進來自葡萄膜鞏膜流出路徑的房水流出,而降低眼壓之形式的藥劑,在臨床上亦廣為通用(非專利文獻1)。
另一方面,作為以新穎之作用機制為基礎之青光眼候補治療藥,已發現有Rho激酶抑制劑(專利文獻1~2)。Rho激酶抑制劑係藉由促進來自小梁流出路徑的房水流出,而使眼壓下降(非專利文獻2),進一步教示此項作用係因小梁細胞(trabecular cells)的細胞骨架變化所造成(非專利文獻2、非專利文獻3)。
再者,青光眼與高眼壓症係在增強眼壓下降作用之目的下,亦有採行組合使用具有眼壓下降作用的藥劑。例如有報告指出:前列腺素類與交感神經阻斷劑的組合投藥(專利文獻3)、組合數種具眼壓下降作用的藥劑並投藥於眼部而進行的青光眼治療方法(專利文獻4)等。於Rho激酶抑制劑方面,亦有報告指出利用與前列腺素類組合而形成青光眼治療劑(專利文獻5~7)。
然而,如上述已知的青光眼與高眼壓症之治療劑及治療方法,就眼壓下降效果的作用強度與持續時間之方面,尚難謂已獲滿足。特別係正常眼壓青光眼的情況,使正常眼壓下降將較使已上昇的眼壓下降更困難,上述現有藥或該等的組合在正常眼壓青光眼的治療上存在有極限,醫療現況乃要求更加增強眼壓下降作用。
[先前技術文獻]
[專利文獻]
[專利文獻1]國際公開WO00/09162號公報
[專利文獻2]日本專利特開平11-349482號公報
[專利文獻3]日本專利第2726672號公報
[專利文獻4]國際公開WO02/38158號公報
[專利文獻5]日本專利特開2004-107335號公報
[專利文獻6]國際公開WO07/026664號公報
[專利文獻7]國際公開WO08/105058號公報
[非專利文獻]
[非專利文獻1]Journal of the Eye,15(4),475-480(1998)
[非專利文獻2]IOVS,42(1),137-144(2001)
[非專利文獻3]IOVS,42(5),1029-1037(2001)
(發明所欲解決之問題)
本發明係相關提供眼壓下降作用強力且延長持續時間的青光眼或高眼壓症預防或治療之藥物療法。
(解決問題之技術手段)
本發明者等為解決上述問題經深入鑽研,結果發現組合(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類進行投藥,便可發揮強力的眼壓下降作用且延長持續時間。
即,本發明係相關以下的發明。
1)一種組合藥劑,係青光眼預防或治療用,由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物與前列腺素類組合而成。
2)如上述1)之組合藥劑,其中,前列腺素類係拉坦前列腺素(Latanoprost)。
3)如上述1)或2)之組合藥劑,其係摻合劑。
4)如上述1)或2)之組合藥劑,係由含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤構成的藥劑、與含有前列腺素類構成的藥劑所構成之套組(kit)。
5)一種組合藥劑,係高眼壓症預防或治療用,由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類組合而成。
6)如上述5)之組合藥劑,其中,前列腺素類係拉坦前列腺素。
7)如上述5)或6)之組合藥劑,其係摻合劑。
8)如上述5)或6)之組合藥劑,係由含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤構成的藥劑、與含有前列腺素類構成的藥劑所形成之套組。
(對照先前技術之功效)
根據本發明,可提供眼壓下降作用強力、且延長持續時間的青光眼或高眼壓症之預防或治療手段。
本發明所使用的(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤,係具有物質P拮抗作用、白三烯D4拮抗作用、及Rho激酶抑制作用的化合物,利用公知方法(例如國際專利公開第99/20620號公報所記載方法)便可進行製造。
(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤的鹽係可舉例如:鹽酸、硫酸、硝酸、氫氟酸、氫溴酸等無機酸的鹽;或醋酸、酒石酸、乳酸、檸檬酸、反丁烯二酸、順丁烯二酸、琥珀酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸、樟腦磺酸(camphorsulfonic acid)等有機酸的鹽,特佳係鹽酸鹽。
(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽,不僅存在有未溶劑化型,亦存在有水合物或溶劑化物。較佳係水合物,但本發明係涵蓋所有的結晶型及水合或溶劑化物。
另一方面,前列腺素類係只要具有眼壓下降作用且對青光眼治療有效者便可。具有眼壓下降作用的前列腺素類之具體例,可例示如:日本專利特開昭59-1418所揭示的前列腺素類(特別係如前列腺素F2α般之天然前列腺素)、日本專利特表平3-501025所揭示的拉坦前列腺素等前列腺素類;日本專利特開平2-108所揭示的烏諾前列酮異丙酯等前列腺素類、日本專利特表平8-501310所揭示的比馬前列腺素等前列腺素類、日本專利特開平10-182465所揭示的曲伏前列腺素等前列腺素類、日本專利特開平11-071344所揭示的塔伏前列腺素等前列腺素類等等,特佳係使用當作青光眼治療藥販賣之例如:拉坦前列腺素((+)-異丙基(Z)-7-[(1R,2R,3R,5S)-3,5-二羥-2-[(3R)-3-羥-5-苯基苯基]環戊基]-5-庚烯酸酯)、烏諾前列酮異丙酯((+)-異丙基(Z)-7-[(1R,2R,3R,5S)-3,5-二羥-2-(3-側氧基癸基)環戊基]庚-5-烯酸酯)、比馬前列腺素((5Z)-7-[(1R,2R,3R,5S)-3,5-二羥-2-[(1E,3S)-3-羥-5-苯基戊-1-烯-1-基]環戊基]-N-乙基庚-5-烯醯胺)、曲伏前列腺素(異丙基(5Z)-7-((1R,2R,3R,5S)-3,5-二羥-2-[(1E,3R)-3-羥-4-[3-(三氟甲基) 苯氧基]丁-1-烯基]環戊基)庚-5-烯酸酯)、或塔伏前列腺素(1-甲基乙基(5Z)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-二氟-4-苯氧基-1-丁烯基]-3,5-二羥基環戊基]-5-庚烯酸酯)。
當組合使用(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類的情況,如後述實施例所示,即便正常眼壓仍可呈現強力且延長持續時間的眼壓下降作用。所以,該等的組合可有效使用作為青光眼與高眼壓症的預防或治療劑。又,若屬於該等的組合,便可使用於製造青光眼與高眼壓症的預防或治療劑。又,藉由組合該等並投藥給需要進行青光眼或高眼壓症預防或治療的人體(患者),便可預防或治療該青光眼與高眼壓症。此處,青光眼係可舉例如:原發性隅角開放性青光眼、正常眼壓青光眼、房水分泌過多性青光眼、高眼壓症、急性隅角閉鎖性青光眼、慢性隅角閉鎖性青光眼、高原型虹膜症候群(plateau iris syndrome)、混合性青光眼、類固醇性青光眼(steroid glaucoma)、水晶體的囊膜性青光眼(glaucoma capsulare)、色素性青光眼(pigmentary glaucoma)、澱粉樣變性青光眼(amyloid glaucoma)、新生血管性青光眼(neovascular glaucoma)、惡性青光眼等。又,高眼壓症(ocular hypertension)亦稱「眼性高血壓症」,係指不論視神經是否有出現明確的病變,只要呈現眼壓異常高的症狀即是,涵括手術後的高眼壓表現等多種高眼壓狀態。
本發明的青光眼或高眼壓症預防或治療用之(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類之組合,係屬於摻合劑,可將各自的有效量依適當摻合比予以製劑化形成單一劑型,亦可分別將各自含有效量的藥劑單獨形成製劑化物後,再同時或隔開間隔分別使用的套組。
當(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類,係分別進行製劑化的情況,分別可依照公知方法調製成製劑。例如(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物之製劑,可參考上述國際公開專利公報(WO00/09162、WO97/23222)所記載的製劑例進行調製。前列腺素類的製劑係可參考上述日本公開專利公報或日本公表專利公報(特開昭59-1418、特表平3-501025、特開平2-108、特表平8-501310、特開平10-182465、特開平11-071344)所記載的製劑例進行調製,特別係已被當作青光眼治療藥販賣的拉坦前列腺素、烏諾前列酮異丙酯、比馬前列腺素、曲伏前列腺素、塔伏前列腺素等,亦均係可使用的市售製劑。
調製由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類進行摻合的製劑時,亦可依照公知方法進行調製。例如點眼劑可視需要使用例如等滲壓化劑、緩衝劑、界面活性劑、防腐劑等進行調製。pH係在眼科製劑所容許範圍內便可,較佳係pH4~8範圍。
上述製劑可使用為眼科用製劑,特佳係使用為點眼用,該點眼劑可為水性點眼劑、非水性點眼劑、懸浮性點眼劑、乳化性點眼劑、眼軟膏等任一種。此種製劑係在適於投藥形態的組成物中,視需要經摻合入藥學上容許的載體(例如:等滲壓化劑、螯合劑、安定化劑、pH調節劑、防腐劑、抗氧化劑、溶解助劑、黏稠化劑等),並依照此技術領域的公知(製劑)方法便可製造。
於調製點眼劑的情況,例如使所需的上述成分溶解或懸浮於諸如:滅菌精製水、生理食鹽水等水性溶劑、或棉籽油、大豆油、麻油、花生油等植物油等等非水性溶劑中,經調整為既定滲透壓,並藉由施行過濾滅菌等滅菌處理而實施。
再者,調製眼軟膏劑的情況,除上述各種成分之外,尚可含有軟膏基劑。上述軟膏基劑並無特別的限定,較佳可舉例如:凡士林、流動石蠟、聚乙烯等油性基劑;使油相與水相利用界面活性劑等進行乳化的乳液性基劑;或由羥丙基甲基纖維素、羧甲基纖維素、聚乙二醇等構成的水溶性基劑等等。
當將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類的組合,使用為青光眼或高眼壓症的預防或治療用套組時,可設計為將經依如上述製劑化之含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物之藥劑、與含有前列腺素類的藥劑,分別各別包裝(package),並在投藥時才從各自的包裝中取出各個醫藥品製劑而使用。又,亦可預先將各個醫藥品製劑依適於每次併用投藥的形態進行包裝。
當將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類的組合,使用於青光眼或高眼壓症的預防或治療之情況,投藥量係依照患者的體重、年齡、性別、症狀、投藥形態及投藥次數等而有所差異,通常對成人而言,就(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物係例如1日0.025~10000 μg、較佳0.025~2000 μg、更佳0.1~2000 μg的範圍,就前列腺素類係例如1日0.1~1000 μg、較佳1~300 μg範圍。相關前列腺素類的具體例,例如拉坦前列腺素的情況通常係1日使用1~5 μg,烏諾前列酮異丙酯的情況通常係1日使用30~300 μg。
又,由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類摻合進行製劑並投藥的情況,1日的投藥量係只要依上述各成分量或以下的方式,調製成經適當選擇摻合比例的製劑便可。
再者,投藥次數並無特別的限定,較佳係單次或分開數次投藥,當液體點眼劑的情況,只要1次施行1~數滴點眼便可。當作套組的情況,各自單獨的製劑可同時投藥,亦可相隔5分鐘~24小時的間隔投藥。
以下,針對本發明進行更詳細說明,惟本發明並不僅侷限於該等。
[實施例]
[實施例1]
為調查由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤、與前列腺素類的組合所產生的有用性,針對二藥物對實驗動物單獨或併用投藥時的眼壓下降效果,進行比較檢討。
1. 受驗化合物溶液之調製
A. (S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤溶液之調製
將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤一鹽酸鹽・二水合物溶解於生理食鹽水中之後,添加磷酸二氫鈉、氫氧化鈉而將溶液予以中和(pH6.0),調製得所需濃度的(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤溶液。
B. 前列腺素類之調製
直接使用市售的拉坦前列腺素(輝瑞公司、0.005%點眼液)。
2. 試驗方法
檢討(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤、與拉坦前列腺素併用投藥時的眼壓下降效果。比較對照係針對(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤單獨投藥時、或拉坦前列腺素單獨投藥時的眼壓下降效果進行檢討。
A. 試驗所使用的藥劑及動物
(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤溶液:0.4%溶液(點眼量:20 μl)
拉坦前列腺素:0.005%點眼液(點眼量:20 μl)
實驗動物:食蟹獼猴(性別:雄性、一組5隻)
B. 投藥方法及測定方法
(1) 二藥劑之併用投藥
1)將4%鹽酸奧布卡因(oxybuprocaine hydrochloride)點眼液(商品名:配樂視(Benoxil)0.4%液),一滴點眼於實驗動物的雙眼中而施行局部麻醉(數據僅為點眼側)。
2)測定受驗化合物溶液剛要投藥前的眼壓,並視為「初期眼壓」。
3)將(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤溶液,點眼於實驗動物的單眼,接著將拉坦前列腺素溶液點眼於同一眼中。
4)二藥劑點眼後經1小時、2小時、4小時、及6小時後,於雙眼中分別點眼一滴0.4%鹽酸奧布卡因點眼液,而施行局部麻醉後,測定眼壓。
(2) (S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤之單獨投藥
施行(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤的單獨點眼,並依照與上述併用投藥試驗相同的測定時間進行試驗。
(3) 拉坦前列腺素之單獨投藥
除了將上述(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤單獨投藥的受檢溶液,改為拉坦前列腺素之外,其餘均依照與上述單獨投藥試驗的相同方法進行試驗。
3. 結果及考察
試驗結果係如圖1所示。眼壓係表示距初期眼壓的變化值。另外,統計處理時係使用Microsoft Excel 2000 SP-3、Paired t-test。
由圖1中得知,(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤、與拉坦前列腺素的併用組,呈現較優於藥劑單獨投藥組(即(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤投藥組、或拉坦前列腺素投藥組)的眼壓下降作用,且亦呈現作用持續性提升。
由以上得知,藉由拉坦前列腺素、與(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤的組合,便可獲得更強的眼壓下降效果、以及持續效果提升。
(產業上之可利用性)
本發明的(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類之組合,係具有優異的眼壓下降效果及持續效果,屬於有效的青光眼或高眼壓症預防或治療之醫藥。
圖1係表示各投藥組的眼壓經時變化的圖表。眼壓係依距初期眼壓的變化值(平均值±標準誤差)所表示。□:拉坦前列腺素(記載為「Latanoprost」)單獨投藥組,○:(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤(記載為「化合物1」)單獨投藥組,●:拉坦前列腺素(記載為「Latanoprost」)與(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤(記載為「化合物1」)的併用投藥組,統計分析:*p<0.05 vs. 「化合物1」組,#p<0.05,##p<0.01 vs. 「拉坦前列腺素」組。
Claims (8)
- 一種青光眼預防或治療用之醫藥,係由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類組合而成。
- 如請求項1之醫藥,其中,前列腺素類係拉坦前列腺素(Latanoprost)。
- 如請求項1或2之醫藥,其係摻合劑。
- 如請求項1或2之醫藥,其係由含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤而成的藥劑、與含有前列腺素類而成的藥劑所形成之套組(kit)。
- 一種高眼壓症預防或治療用之醫藥,係由(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤或其鹽或該等的溶劑化物、與前列腺素類組合而成。
- 如請求項5之醫藥,其中,前列腺素類係拉坦前列腺素。
- 如請求項5或6之醫藥,其係摻合劑。
- 如請求項5或6之醫藥,其係由含有(S)-(-)-1-(4-氟-5-異喹啉磺醯基)-2-甲基-1,4-高哌𠯤而成的藥劑、與含有前列腺素類而成的藥劑所形成之套組。
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CN101198354B (zh) * | 2005-06-21 | 2012-01-11 | 兴和株式会社 | 青光眼的预防或治疗剂 |
PT1905452E (pt) * | 2005-07-12 | 2013-07-16 | Kowa Co | Agente para a prevenção ou tratamento do glaucoma |
AU2006285915B2 (en) * | 2005-08-30 | 2011-02-24 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
JP4800720B2 (ja) * | 2005-09-21 | 2011-10-26 | 興和株式会社 | 点眼用組成物 |
US8415372B2 (en) * | 2007-02-27 | 2013-04-09 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
-
2012
- 2012-02-03 TW TW109132400A patent/TW202126308A/zh unknown
- 2012-02-03 TW TW112103959A patent/TW202344254A/zh unknown
- 2012-02-03 CN CN2012800077110A patent/CN103338772A/zh active Pending
- 2012-02-03 EP EP12742008.1A patent/EP2671586B1/en not_active Not-in-force
- 2012-02-03 TW TW107115062A patent/TW201906614A/zh unknown
- 2012-02-03 WO PCT/JP2012/052448 patent/WO2012105674A1/ja active Application Filing
- 2012-02-03 JP JP2012555967A patent/JPWO2012105674A1/ja active Pending
- 2012-02-03 TW TW110147315A patent/TW202239413A/zh unknown
- 2012-02-03 ES ES12742008.1T patent/ES2684351T3/es active Active
- 2012-02-03 TW TW101103472A patent/TW201235040A/zh unknown
- 2012-02-03 KR KR1020137020372A patent/KR20140010028A/ko not_active Application Discontinuation
- 2012-02-03 TW TW105135006A patent/TW201729813A/zh unknown
- 2012-02-03 KR KR1020187005167A patent/KR102196825B1/ko active IP Right Grant
- 2012-02-03 CN CN201610262303.XA patent/CN105902551A/zh active Pending
- 2012-02-03 US US13/983,720 patent/US20130310370A1/en not_active Abandoned
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2016
- 2016-04-19 JP JP2016083647A patent/JP2016130268A/ja active Pending
- 2016-10-04 US US15/284,841 patent/US20170020889A1/en not_active Abandoned
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2017
- 2017-10-25 JP JP2017205995A patent/JP2018030878A/ja active Pending
-
2018
- 2018-02-27 US US15/905,902 patent/US20180185384A1/en not_active Abandoned
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2019
- 2019-06-05 JP JP2019105584A patent/JP2019142977A/ja active Pending
- 2019-09-04 US US16/559,858 patent/US20200030340A1/en not_active Abandoned
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2020
- 2020-11-10 US US17/094,492 patent/US20210052599A1/en not_active Abandoned
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2021
- 2021-02-10 JP JP2021019519A patent/JP2021073308A/ja active Pending
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2022
- 2022-12-27 JP JP2022209257A patent/JP2023026512A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2018030878A (ja) | 2018-03-01 |
TW202239413A (zh) | 2022-10-16 |
KR20180023041A (ko) | 2018-03-06 |
ES2684351T3 (es) | 2018-10-02 |
TW201906614A (zh) | 2019-02-16 |
TW201729813A (zh) | 2017-09-01 |
WO2012105674A1 (ja) | 2012-08-09 |
JP2021073308A (ja) | 2021-05-13 |
JP2023026512A (ja) | 2023-02-24 |
EP2671586A4 (en) | 2014-10-22 |
CN103338772A (zh) | 2013-10-02 |
KR20140010028A (ko) | 2014-01-23 |
JP2016130268A (ja) | 2016-07-21 |
JP2019142977A (ja) | 2019-08-29 |
US20180185384A1 (en) | 2018-07-05 |
US20210052599A1 (en) | 2021-02-25 |
EP2671586B1 (en) | 2018-05-30 |
JPWO2012105674A1 (ja) | 2014-07-03 |
EP2671586A1 (en) | 2013-12-11 |
US20130310370A1 (en) | 2013-11-21 |
US20200030340A1 (en) | 2020-01-30 |
US20170020889A1 (en) | 2017-01-26 |
CN105902551A (zh) | 2016-08-31 |
TW201235040A (en) | 2012-09-01 |
TW202126308A (zh) | 2021-07-16 |
KR102196825B1 (ko) | 2020-12-30 |
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