TWI400080B - 藥物於治療患有青光眼和其他退化性眼疾之人的視力喪失上之用途 - Google Patents
藥物於治療患有青光眼和其他退化性眼疾之人的視力喪失上之用途 Download PDFInfo
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- TWI400080B TWI400080B TW097131444A TW97131444A TWI400080B TW I400080 B TWI400080 B TW I400080B TW 097131444 A TW097131444 A TW 097131444A TW 97131444 A TW97131444 A TW 97131444A TW I400080 B TWI400080 B TW I400080B
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- glaucoma
- peptide
- eye
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Description
本發明關於透過阻斷β
-澱粉樣蛋白(Aβ
)衍生物之毒性作用以預防及治療眼疾(尤其是青光眼)的方法及使該預防和治療有效之醫藥組成物。
研究顯示青光眼為美國引起失明的第二個主要原因[Leske MC.The epidemiology of open-angle glaucoma:a review.Am J Epidemiology 1983;118:166-191]。青光眼之病理相關性為形成視神經之視網膜神經節細胞及其軸突的進行性退化。
青光眼之分類包括下列不同類型:原發性閉角型青光眼、繼發性開角型青光眼、由類固醇引起之青光眼、外傷性青光眼、色素性播散綜合徵、假性剝脫綜合徵、繼發性閉角型青光眼、新生血管性青光眼、葡萄膜炎和青光眼以及其他未進一步具體指明之眼部病變。另外,老年性黃斑部變性為一種反映青光眼之特性且造成視力逐漸喪失而最終導致失明之病況。
過去,青光眼之定義包括眼內壓(IOP)升高超過正常範圍。然而,許多IOP明顯提高之個體並未發展出青光眼且至多50%之罹患青光眼的患者其IOP並未增加。
目前可用於治療青光眼的藥劑屬於數種藥理學類別,包括β
-腎上腺素能阻斷劑、膽鹼能激動劑、碳酸酐酶抑
制劑、α激動劑。其作用機制均為降低IOP。這些現存療法通常係以眼滴液形式投服。用於緊急治療之高張溶液可經由靜脈內途徑投服。另外,在特殊病例中可應用雷射治療及外科手術法。
不論何種療法,在追踪青光眼患者20年後,在至少一隻眼睛中出現與青光眼相關之失明者達27%,二隻眼睛中出現與青光眼相關之失明者達9%[Hattenhaure MG,Johnson DH,Ing HH,et al.The probability of blindness from open-angle glaucoma.Ophthalmology 1998;105:2099-2104]。因此,對替換之治療策略的醫療需求仍明顯未達到滿足。尤其是,聚焦在挽救退化性視網膜神經節細胞之療法對於那些IOP正常但患有進行性青光眼性損傷的患者而言是有需要的。
關於視網膜神經節細胞退化之原因有不同的理論,包括機械性、血管性及興奮毒性機制。就在最近,β
-澱粉樣蛋白(Aβ
)被發現與死亡之視網膜神經節細胞共同定位[Mckinnon SJ.Glaucoma:Ocular Alzheimer’ disease?Front Biosci.2003;8:1140-1156;Yoneda S,Hara H,Hirata A,Fukushima M,Inomata Y,Tanihara H.Vitreous fluid levels of beta-amyloid((1-42))and tau in patients with retinal diseases.Jpn J Ophthalmpl.2005;49(2):106-108]。尤其是,動物研究證明可溶性Aβ 1-42
肽寡聚物對視網膜神經節細胞而言為非常強之毒素[Dahlgren KN,Manelli AM,Stine WB Jr,Baker LK,Krafft GA,LaDu
MJ.Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability.J Biol Chem.2002;277(35):32046-32053;Guo L,Salt TE,Luong V,Wood N,Cheung W,Maass A,Ferrari G,Russo-Marie F,Sillito AM,Cheetham ME,Moss SE,Fitzke FW,Cordeiro F.Targeting amyloid-β in glaucoma treatment.PNAS 2007;104(33):13444-13449]。
Guo等人最近發表之研究(2007)證明抑制Aβ
聚集可減少視網膜神經節細胞之青光眼變性。在這些動物實驗中所使用之抑制劑為剛果紅及Aβ
抗體。這些作用劑僅為藥學研究工具,不適合為了各種不同理由用來治療人類。
剛果紅(聯苯胺重氮基-雙-1-萘胺-4-磺酸之鈉鹽)為一種重氮基染料。由於其毒性,其於紡織工業中之原始用途已被廢棄多年。剛果紅以中度特異性與澱粉樣蛋白纖維結合並用於組織病理學染色。由於其毒性,該物質不能在人體中經由系統性途徑投服。在動物實驗方面,該染色係直接注射入眼睛。除了繁冗之程序外,該溶液之強烈顏色阻止其經由眼內途徑施用於人體。因此,剛果紅製劑無法作為治療人類青光眼之藥劑。
已知Aβ
抗體可相當特異地阻斷Aβ
之聚集[Bard F,Cannon C,Barbour R,Burke RL,Games D,Grajeda H,Guido T,Hu K,Huang J,Johnson-Wood K,Khan K,Kholodenko D,Lee M,Lieberburg I,Motter R,Nguyen M,Soriano F,Vasquez N,Weiss K,Welch B,Seubert P,
Schenk D,Yednock T.Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’s disease.Nat Med.2000;6(8):916-919]。然而,抗-Aβ
抗體於治療人類青光眼之用途受限於這些生物製品誘導中和抗體之副作用,此副作用造成重複投服後效力喪失。其他副作用為激發免疫性發炎反應且在靶的器官中出現由抗體引起之微量出血[Vasilevko V,Cribbs DH.Novel approaches for immunotherapeutic intervention in Alzheimer’s disease.Neurochem Int.2006;49(2):113-126]。再者,抗體並非用於口服,而需(重複)注射(經常導致皮膚應答)。最後,以工業規模製造抗體相當複雜且昂貴。
理論上,β
-分泌酶抑制劑對於與Aβ
相關之神經毒性亦可能有所助益。然而,在老鼠視網膜神經節細胞中所觀察到之效果並不明顯且此方法似乎並不能保證青光眼的進一步進展[Guo等人,2007]。
本發明的目標之一係提供用於預防及治療眼疾(尤其是青光眼)之新穎方法及使該預防及治療有效之醫藥組成物。而本發明之其他目標將可從下述內容中變得顯明,熟習本技藝之人士也將可察明還有之其他目標。
因此,吾人相信本發明所包含之內容尤其可摘要於下列文字中:一種用於預防及治療活動物(包括人類)的與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾的治療方法,其包含給予該活動物治療上有效量之肽(其包含胺基酸序列X-Y或Y-X,其中X為芳香族胺基酸且Y為一或多種除了甘胺酸外之其他胺基酸,該肽具有至少2個胺基酸殘基且具有少於15個胺基酸殘基)的步驟,以藉此抑制Aβ
形成及/或Aβ
出現,如此可有效緩和該病況。
這類方法中,該病況係選自下列:原發性閉角型青光眼、繼發性開角型青光眼、寬角型青光眼、由類固醇引起之青光眼、外傷性青光眼、色素性播散綜合徵、假性剝脫綜合徵、繼發性閉角型青光眼、新生血管性青光眼、葡萄膜炎及青光眼、老年性黃斑部變性、糖尿病性視網膜病變、退化性視神經病變及特徵為視力逐漸喪失而最終導致失明之眼部病變。
這類方法包含共同給予存活動物治療上有效量之如上述的肽與至少一種可有效治療眼疾之其他藥學製劑,其中該肽與至少一種其他藥學製劑的組合可有效治療該病況。
這類方法中該至少一種其他藥學製劑係選自包含下列之用來治療眼疾的投服藥劑:抗青光眼藥物、抗生素、抗發炎藥物、類固醇、抗過敏藥物及人工淚水。
這類方法中該至少一種其他藥學製劑係選自乙醯偶氮
胺(acetazolamide)、雙氯非那胺(diclofenamide)、卡替洛爾(carteolol)、塞瑪洛爾(timolol)、美替洛爾(metipranolol)、貝他洛爾(betaxolol)、平朵洛爾(pindolol)、左布諾洛爾(levobunolol)、溴莫尼定(brimonidine)、克洛尼定(clonidine)、皮洛卡賓(pilocarpine)、胺甲醯膽鹼(carbachol)、地匹福林(dipivefrine)、阿可樂定(apraclonidine)、布林佐胺(brinzolamide)、杜塞醯胺(dorzolaminde)、盧美根(bimatoprost)、蘇為坦(travaprost)、拉坦前列素(latanoprost)、氯四環素(chlortetracycline)、環丙沙星(ciprofloxacine)、氧氟沙星(ofloxacine)、夫西地酸(fusidinic acid)、正大黴素(gentamicine)、卡那黴素(kanamycine)、左氧氟沙星(levofloxacine)、洛美沙星(lomefloxacine)、土黴素(oxytetracycline)、納他黴素(natamycine)、阿利丹芬尼可(azidamfenicole)、氯黴素(chloramphenicole)、妥布黴素(tobramycine)、紅黴素(erythromycine)、多黏菌素-B(polymyxin-B)、阿卡克洛維(acaclovir)、三氟尿甘(trifluridine)、倍他米松(betamethasone)、地塞米松(dexamethasone)、氟米龍(fluorometholone)、氫化可的松(hydrocortisone)、潑的松龍(prednisolone)、利美索龍(rimexolone)、色甘酸(cromoglicate)、氮卓斯汀(azelastine)、洛度沙胺(lodoxamide)、伊美斯汀(emedastine)、奈多羅米(nedocromile)、左卡斯汀(
levocabastine)、歐洛巴塔廸尼(olopatadinea)、克多芬(ketotifene)、羥丙基甲基纖維素(hypromellose)、卡波姆(carbomere)、玻尿酸(hyaluronate)、羧甲基纖維素(carmellose)、羥丙基甲基纖維素(hypromellose)、共聚維酮(povidone)、海提纖維素(hyetellose)、聚乙烯醇(polivinylalcohole)、戴潘思諾(dexpanthenole)、四氫唑林(tetryzoline)、曲克蘆丁(troxerutine)、曲馬唑林(tramazoline)、萘甲唑林(naphazoline)、賽唑洛林(xylometazoline)、苯福林(phenylephrine)及安他啉(antazoline)。
這類方法中係每天投服一次、每天投服二次或每天投服三次該肽。
這類方法中係長期投服該肽。
這類方法中係將該肽以眼滴液、眼藥膏及眼內儲積(intraocular depot)調製劑之形式投服。
這類方法中係將該肽在立即釋出調製劑或改良釋出型調製劑中投服。
這類方法中係將該肽和該至少一種其他藥學製劑共同投服。
這類方法中係將該肽及該至少一種其他藥學製劑在單一調製劑中投服。
本發明之另一種觀點係關於一種醫藥組成物,其包含單獨之如上述的肽或其藥學上可接受之加成鹽或加上一或多種藥學上可接受之載體及/或賦形劑。
這類醫藥組成物進一步包含至少一種單獨之可有效治療眼疾之其他藥學製劑(其中該肽與該至少一種其他藥學製劑之組合可有效治療病況)、或其藥學上可接受之加成鹽、或加上一或多種藥學上可接受之載體及/或賦形劑。
本發明之另一種觀點係關於包含胺基酸序列X-Y或Y-X之肽於製造用於預防及治療與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾(其中係抑制Aβ
之形成及/或該Aβ
之出現)的藥劑上之用途,其中X為一種芳香族胺基酸且Y為除了甘胺酸外之一或多種其他胺基酸,該肽具有至少2個胺基酸殘基且具有少於15個胺基酸殘基。
這類用途之特徵在於該病況係選自原發性閉角型青光眼、繼發性開角型青光眼、寬角型青光眼、由類固醇引起之青光眼、外傷性青光眼、色素性播散綜合徵、假性剝脫綜合徵、繼發性閉角型青光眼、新生血管性青光眼、葡萄膜炎及青光眼、老年性黃斑部變性、糖尿病性視網膜病變、退化性視神經病變及特徵為視力逐漸喪失而最終導致失明之眼部病變。
這類用途之特徵在於該藥劑包含如上述鑑定之肽與至少一種可有效治療這類眼疾之其他藥學製劑,其進一步之特徵在於該其他藥學製劑係選自抗青光眼藥物、抗生素、抗發炎藥物、類固醇、抗過敏藥物及人工淚水。
本發明克服習知之眼疾療法的限制並提供其藥學上可
接受之療法以有效治療罹患青光眼及其他退化性眼疾之人類的視力喪失。該潛在機制為透過阻斷Aβ
物種之毒性作用來防止或逆轉視網膜神經節細胞的損失。
用於本療法之代表性物質原先之設計係用於治療其中形成澱粉樣蛋白纖維之疾病(諸如第Ⅱ型糖尿病及病原性蛋白顆粒病)[Porat Y,Mazor Y,Efrat S,Gazit E.Inhibition of islet amyloid polypeptide fibril formation:A potential role for heteroaromatic interactions.Biochemistry 2004;43:14454-14462]以及腦部之退化性疾病(包括老人痴呆症)[GAZIT,E.,美國發表之申請案第US2006/0234947 A1號]。更具體地說,Gazit揭示可能包含改質之胺基酸(諸如胺基異丁酸)的短鏈肽可藉由與分子辨識過程及澱粉樣蛋白纖維自行組合之交互作用來瓦解毒性Aβ
物種形成[Gazit,2006]。藉由本發明吾人可確定這些藥物在另一與腦不同之器官系統中(即,眼睛)顯示出療效。該根據本發明使用之藥物在青光眼之動物模型中顯示出預防及治療視網膜神經節細胞損傷的療效。與已知之作用劑(剛果紅及Aβ
抗體)相較下,本發明之藥物具有下列優點:-其為可有效管理成本以大規模製造之小分子。
-其可經由口服(例如:為錠片或膠囊形式)或局部途徑(例如:眼滴液、眼藥膏、眼內儲積調製劑)很容易地給予患者。
-不需要注射。
-患者即使長期連續施用亦對其有良好之耐受性。
-其具有可容許每日攝入1-3次之攝生法的簡單之藥物動力學性質。
-其在視網膜中顯示出對Aβ
物種具高親和力及特異性。
-其可具有雙重作用機制,即,其可作為β
-摺板破碎劑及寡聚作用抑制劑而產生明顯療效。其可與其他治療劑組合,諸如目前為止所使用之任何降低IPO的青光眼藥物以及其他可能之針對Aβ
及保護性之治療劑。
包含投服這些物質之方法可應用於治療罹患所有類型之眼疾的患者,這些眼疾包括如上述之所有形式之青光眼及色素性播散綜合徵、假性剝脫綜合徵、繼發性閉角型青光眼、新生血管性青光眼、葡萄膜炎、老年性黃斑部變性、糖尿病性視網膜病變、退化性視神經病變及本技藝之技術熟習人士所已知之特徵為視力逐漸喪失而最終導致失明之眼部病變。這類病況的共通性為與視網膜或視神經變性過程有關之視力逐漸衰退。治療可在疾病進展之所有階段進行,包括在非常早期時作為預防劑。臨床效果可為雙重,首先在那些已罹患青光眼病變之患者中快速改良其視力,接著,減緩或停止其視力之惡化過程。即使是那些已有一隻或二隻眼睛已發生與青光眼有關之失明的患者其視力亦可回復至某種程度。
本方法選擇性地包含連續投服含有這些藥物之製劑,
以提供最佳治療結果。根據受治療之疾病的類型及階段,治療周期可能為數天至數個月。在某些情況下,亦可能需持續之長期治療。
本方法選擇性地包含投服至少一種本技藝中已知可有效治療眼疾之其他藥學製劑,其為。這些附加作用劑可選自一般類別之抗青光眼藥物,包括上述之藥物、抗生素、抑病毒藥、類固醇、抗過敏藥物、人工淚水及其他用於局部及系統性治療眼睛的藥物。代表性之抗青光眼藥物包括乙醯偶氮胺、雙氯非那胺、卡替洛爾、塞瑪洛爾、美替洛爾、貝他洛爾、平朵洛爾、左布諾洛爾、溴莫尼定、克洛尼定、皮洛卡賓、胺甲醯膽鹼、地匹福林、阿可樂定、布林佐胺、杜塞醯胺、盧美根、蘇為坦及拉坦前列素。用於眼睛感染之代表性抗生素為氯四環素、環丙沙星、氧氟沙星、夫西地酸、正大黴素、卡那黴素、左氧氟沙星、洛美沙星、土黴素、納他黴素、阿利丹芬尼可、氯黴素、妥布黴素、紅黴素及多黏菌素-B。代表性抑病毒藥包括阿卡克洛維及三氟尿甘。代表性類固醇包括倍他米松、地塞米松、氟米龍、氫化可的松、潑的松龍及利美索龍。代表性抗過敏藥包括色甘酸、氮卓斯汀、洛度沙胺、伊美斯汀、奈多羅米、左卡斯汀、歐洛巴塔廸尼及克多芬。代表性人工淚水包括羥丙基甲基纖維素、卡波姆、玻尿酸化物、羧甲基纖維素、羥丙基甲基纖維素、共聚維酮、海提纖維素、聚乙烯醇及戴潘思諾。其他常用之代表性眼睛治療劑為四氫唑林、曲克蘆丁、曲馬唑林、萘甲唑林、賽唑洛林、苯
福林及安他啉。
描述於美國發表之申請案第US2006/0234947 A1中之下列肽為那些在本發明方法中具有活性之藥物的代表。D-Phe-D-Phe-D-Pro(SEQ ID NO.1),Aib-D-Phe-D-Ash-Aib(SEQ ID NO.2),D-Phe-D-Asn-D-Pro(SEQ ID NO.3),Aib-Asn-Phe-Aib(SEQ ID NO.4),Gln-Lys-Leu-Val-Phe-Phe(SEQ ID NO.5),Tyr-Tyr(SEQ ID NO.6),D-Phe-D-Phe-D-Pro(SEQ ID NO.7),Aib-D-Phe-D-Asn-Aib(SEQ ID NO.8),Aib-Asn-Phe-Aib(SEQ ID NO.9),Tyr-Tyr(SEQ ID NO.10),Tyr-Tyr-NH2
(SEQ ID NO.11),Aib-Phe-Phe(SEQ ID NO.12),Asn-Tyr-Aib(SEQ ID NO.13),Asn-Tyr-Pro(SEQ ID NO.14),β-胺基丁酸(Aib)-D-Pro-D-Tyr-D-Asn(SEQ ID NO.15),D-Tyr-Aib(SEQ ID NO.16),D-Pro-D-Tyr(SEQ ID NO.17),D-Tyr-D-Pro(SEQ ID NO.18),Asn-Tyr-Tyr-Pro(SEQ ID NO.19),Tyr-Tyr-Aib(SEQ ID NO.20),Aib-Tyr-Tyr(SEQ ID NO.21),Aib-Tyr-Tyr-Aib(SEQ ID NO.22),D-Asn-Tyr-Tyr-D-Pro(SEQ ID NO.23),Pro-Tyr-Tyr(SEQ ID NO.24),Tyr-Tyr-Pro(SEQ ID NO.25),Pro-Tyr-Tyr-Pro(SEQ ID NO.26),D-Tyr-D-Tyr(SEQ ID NO.27),D-Pro-Aib(SEQ ID NO.28),D-Phe-D-Pro(SEQ ID NO.29),D-Trp-Aib(SEQ ID NO.30),D-Trp-D-Pro(SEQ ID NO.31),D-Phe-Pro(SEQ ID NO.32),及Pro-D-Phe(SEQ ID NO.33)。除非另外指出,殘質Aib意指α胺基丁酸。
本技藝之技術熟習人士可察知所描述之藥物僅為代表性質且該替換之藥物為藥理學中之一般技術人士所已知。
此處所使用之“類似物”或“衍生物”一詞在習知之製藥學意義中係指構造上像本方法之活性物質(諸如D-Trp-Aib)的分子,但其以經瞄準及控制之方式修改過,以替換之取代基來取代該指示分子之一或多種特殊取代基而藉此產生構造上類似於參考分子之分子。合成並篩檢類似物(如:利用構造及/或生化分析)以鑑定可能具有改良或偏差之特點(諸如對特異瞄準之受體類型具較高之效力及/或選擇性、較佳之滲透入哺乳動物的血腦障壁的能力、較少之副作用,等)的經些微修改之已知物質變體為製藥化學中為人熟知之藥物設計方式。
另外,利用本技藝之技術熟習人士所已知之方法可創造在控制β
-澱粉樣蛋白(Aβ
)毒性上具有改良之療效的本發明藥物之類似物和衍生物,即,其對特異瞄準之受體類型具較高之效力及/或選擇性、較佳或較差之滲透入哺乳動物的血腦障壁的能力(如:較高或較低之血腦障壁滲透率)、較少之副作用,等。
由於其高度活性及低毒性(此二者加在一起代表最有利之治療指數),本發明之藥物可投給需要彼之個體(如活動物(包括人類)體)以治療、減輕、或緩和、減緩或排除對其具感受性之指徵或病況或那些本申請書中他處所列出之代表性指徵或病況,本發明之藥物宜與一或多種藥學上可接受之賦形劑、載體或稀釋劑同時、同步或一起投
服,尤其是,宜以其醫藥組成物之形式,以有效量經由口、直腸或腸胃道外途徑(包括靜脈內、眼內及皮下),或在某些病例中甚至是經由局部途徑(包括眼滴液、眼藥膏及眼內儲積調製劑)投服。通常,根據確實之投服模式、投服形式、投藥所針對之指徵、牽涉之個體和牽涉個體之體重,以及負責之醫師或獸醫師的偏好和經驗,合適之劑量範圍包括每日1-1000毫克,或每日10-500毫克及選擇性地每日50-500毫克。
應用於劑量或量之“治療上有效”一詞係指在投至有此需要之存活動物體(包括人體)時可足夠產生所需活性之藥物或醫藥組成物的量。此處所使用之“治療”一詞意指減輕或緩和至少一種個體疾病之症狀。本發明之意義中,“治療”一詞亦指遏制、延遲疾病開始(即臨床表現疾病前的期間)及/或降低疾病進展或惡化的風險。
與本發明之組成物有關之“藥學上可接受”一詞係指當投給哺乳動物(如:人類)時為生理學上可耐受且通常不會產生不適當之反應的這類組成物之分子實體和其他成分。“藥學上可接受”一詞亦可指被聯邦或州政府之管理機構核准或美國藥典或其他一般被認可之藥典中所列之用於哺乳動物(尤其是人類)者。
本發明之藥物可為藥學上可接受之鹽的形式。“藥學上可接受之鹽”係指那些擁有母化合物之生物效力及性質且非生物學上或其他方面不利之鹽類。該鹽或異構物之性質並無嚴格要求,只要其為非毒性且實質上不干擾所需之
藥學活性。
應用於本發明之醫藥組成物的“載體”一詞係指與活性物質(諸如D-Trp-Aib)一起投服之稀釋劑、賦形劑或載劑。這類藥學載體可為無菌液體,諸如水、生理食鹽水溶液、水性右旋糖溶液、水性甘油溶液及油,包括那些為石油、動物、蔬菜或合成來源者,諸如花生油、大豆油、礦物油、芝麻油,等。合適之藥學載體描述於“Remington’s Pharmaceutical Sciences”by A.R.Gennaro,20th
Edition中。
“約”或“大概”一詞通常係指在指定值或範圍之20%之內,或者在10%之內(包括在5%之內)。或者,尤其是在生物系統中,“約”一詞係指在約一對數(即一數量級)內,包括在指定值之二倍以內。
除本發明之方法外,本發明亦提供包含治療上有效量之活性物質的醫藥組成物。本發明之組成物可進一步包含載體或賦形劑(均為藥學上可接受的)。該組成物可調製成供每天投服一次、每天投服二次或每天投服三次。另外,儲積調製劑可供值入眼內以施藥3-12個月。
根據本發明,該活性物質之劑型可為如下述之固態、半固態、或液態調製劑。
本發明之活性物質可在含有習知之非毒性藥學上可接受之載體的劑量單位調製劑中經由口服、局部、腸胃道外或黏膜途徑(如:口腔、吸入或直腸途徑)投服。於另一用於投給兒科個體之較佳體系中,該活性物質可調製成經
調味之液體(如:薄荷口味)。該活性物質可以膠囊、錠片,等形式或以半固態或液態調製劑形式經口投服(see Remington’s Pharmaceutical Sciences,20th
Edition,by A.R.Gennaro)。
為了以錠片或膠囊形式經口投服,該活性物質可與非毒性之藥學上可接受之賦形劑組合,該藥學上可接受之賦形劑係諸如結合劑(如:預先凝膠化之玉米粉、聚乙烯吡咯烷酮或羥丙基甲基纖維素);充填劑(如:乳糖、蔗糖、葡萄糖、甘露醇、山梨糖醇及其他還原和非還原糖、微晶型纖維素、硫酸鈣或磷酸氫鈣);潤滑劑(如:硬脂酸鎂、滑石粉或矽石、硬脂酸、硬脂醯富馬酸鈉、山萮酸甘油酯、硬脂酸鈣,等);崩散劑(如:馬鈴薯澱粉、澱粉甘醇酸鈉);或濕潤劑(如:月桂基硫酸鈉)、染色劑及調味劑、凝膠、甜味劑、天然及合成膠(諸如金合歡膠、西黃蓍膠或藻酸化物)、奶油鹽、羧甲基纖維素鈉、聚乙二醇、蠟,等。
錠片可以濃縮之糖溶液塗覆,該糖溶液可含有,如:阿拉伯膠、凝膠、滑石粉、二氧化鈦,等。或者,可以溶解於容易揮發之有機溶劑或有機溶劑混合物中的聚合物來塗覆錠片。於特殊之較佳體系中,該活性物質係調製成立即釋出(IR)或經修改釋出(MR)之錠片。立即釋出之固態劑型容許大部分或全部活性成分在短時間內(諸如60分鐘或更少)釋出,且令藥物可能被快速吸收。經修改釋出之固態口服劑型容許該活性物質在延長之期間內持
續釋出,以在類似之延長期間內維持治療上有效量之血漿濃度及/或修改該活性物質之其他藥物動力學性質。
在軟膠囊之調製劑方面,該活性物質可與如:蔬菜油或聚乙二醇混合。硬膠囊可含有使用上述用於錠片之賦形劑(如:乳糖、蔗糖、山梨糖醇、甘露醇、澱粉(如:馬鈴薯澱粉、玉米粉或澱粉纖維素)、纖維素衍生物或凝膠)的活性物質之顆粒。亦可將藥物之液體或半固體填入硬膠囊中。
本發明之組成物亦可填入微球或微膠囊(如:自聚甘醇酸/乳酸(PGLA)製造)中(見,如:美國專利第5,814,344;5,100,669和4,849,222號;PCT刊物WO 95/11010及WO 93/07861號)。生物相容之聚合物可用來控制活性物質之釋出,這些生物相容之聚合物包括,如:聚乳酸、聚甘醇酸、聚乳酸與聚甘醇酸之共聚物、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚氫化吡喃、聚氰基丙烯酸酯及水凝膠之交聯或兩親性成塊共聚物。
亦可使用半固態或液態形式之活性物質的調製劑。此物質可構成調製劑之0.1至99重量%,更具體地說,在欲供注射用之調製劑方面為0.5至20重量%,在適合供口服之調製劑方面為0.2至50重量%。
於本發明之一種較佳體系中該活性物質係在改良釋出型調製劑中投服。改良之釋出劑型提供用於改良患者之適應性及經由減少不良藥物反應之發生率來確保有效及安全之療法的工具。與立即釋出之劑型相較下,改良之釋出劑
型可用於在投藥後延長藥物作用及降低整個給藥期內藥物之血漿濃度的變動性,以藉此排除或降低濃度尖峰。
改良之釋出劑型可包含以活性物質塗覆或含有活性物質之核心。然後,以釋出改良聚合物(該活性物質係分散於此聚合物中)塗覆核心。釋出改良聚合物逐漸崩散,而隨著時間釋出活性物質。因此,當組成物暴露於水性環境(即,胃腸道)時,該組成物之最外層可有效減緩及藉此調節活性物質穿過塗覆層擴散。活性物質之淨擴散率主要係取決於胃液滲透塗覆層或母質的能力及活性物質本身的溶解力。
於本發明之另一較佳體系中,該活性物質係調製在口服液態調製劑中。用於口服之液態製劑可為,如:溶液、糖漿、乳劑或懸浮液之形式,或者其可為在使用前以水或其他合適載劑重構成之乾燥產物形式。口服製劑可經過適當調製以控制或延遲活性化合物之釋出。
為了以液態形式口服,活性物質可與非毒性之藥學上可接受的惰性載體(如:乙醇、甘油、水)、懸浮劑(如:山梨糖醇糖漿、纖維素衍生物或氫化之可食性脂肪)、乳化劑(如:卵磷脂或金合歡膠)、非水性載劑(如:杏仁油、油酯類、乙醇或分餾之蔬菜油)、防腐劑(如:對一羥基苯甲酸甲酯或丙酯或山梨酸),等組合。亦可加入諸如抗氧化劑(BHA、BHT、沒食子酸丙酯、抗壞血酸鈉、檸檬酸)之類的安定劑以穩定劑型。例如:溶液可含有約0.2至約20重量%之活性物質,剩餘部分為糖及乙醇、
水、甘油和丙二醇之混合物。選擇性地,這類液態調製劑可含有染色劑、調味劑、糖精和作為增稠劑之羧甲基纖維素或其他賦形劑。
於另一較佳體系中係將治療上有效量之活性物質在含有防腐劑、甜味劑、安定劑及溶劑之口服溶液中投服。該口服溶液可包含一或多種緩衝劑、香料或其他賦形劑。於另一較佳體系中係在活性物質之口服液態調製劑中加入薄荷或其他香料。
為了經由吸入投服,較方便地,可將該活性物質自使用合適之推進劑(如:二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合適氣體)的加壓包裝或噴霧器中以霧狀滴噴霧形式遞送出。在加壓之霧狀滴的情況中,該劑量單位可經由提供活門來遞送計算過之量來決定。用於吸入器或吹藥器之,如:凝膠膠囊和藥筒可調製成含有化合物及合適之粉末基質(諸如乳糖或澱粉)的粉末混合物。
用於經由注射以供腸胃道外途徑施藥之溶液可製備成活性物質之水溶性藥學上可接受之鹽的水溶液,該活性物質之濃度宜為約0.5重量%至約10重量%。這些溶液亦可含有安定劑及/或緩衝劑,且較方便地,可將其提供在不同劑量單位安瓿中。
本發明之調製劑可經由腸胃道外途徑遞送,即,經由眼內、靜脈內(i.v.)、腦室內(i.c.v.)、皮下(s.c.)、腹膜內(i.p.)、肌肉內(i.m.)、皮下(s.d.)或皮內
(i.d.)投服,藉由直接注射,如:經由大丸藥注射或連續注入。用於注射之調製劑可存於單位劑型中,如:在加有添加之防腐劑的安瓿中或在複數劑量容器中。或者,該活性成分可為在使用前以合適之載劑(如:不含病原之無菌水)重建的粉末形式。
本發明亦提供包含一或多個含有活性物質之容器及選擇性地,多種該調製劑之成分的藥學包裝或套組。於一特殊之較佳體系中,該活性物質係以利用2茶匙容量之注射筒(劑量KORC)投服的口服液(例如:2毫克/毫升)形式提供。各口服注射筒具有用於測量之影線記號,注射筒(針頭朝下)右邊的線代表茶匙單位而左邊的線代表毫升單位。
理想之治療上有效量可藉由實驗及考量確實之投服模式、藥物自何種物質中投服、投藥所針對之指徵、牽涉之個體(如:體重、健康、年齡、性別,等)以及負責之醫師或獸醫師的偏好和經驗來決定。
用於直腸投服之劑量單位可為溶液或懸浮液或可製備成包含本發明藥物與中性脂質基質之混合物的栓劑或保留灌腸形式,或為包含活性物質與蔬菜油或石蠟油之混合物的明膠直腸膠囊。
本發明之組成物的毒性和療效可藉由標準之製藥程序在實驗動物中測定,如:經由測定LD50(造成50%之族群死亡之劑量)及ED50(對50%之族群為治療上有效之劑量)。治療與毒性效果間之劑量比為治療指數,其可以
LD50/ED50比來表示。顯示出較高治療指數之組成物較佳。
在人類之治療性治療中,本發明之活性物質的合適日劑量在經口投服時為約0.01-10毫克/公斤體重,在經由腸胃道外途徑投服時為約0.001-10毫克/公斤體重。
治療期間可為短期(如:數週(如:8-14週))或長期,直到主治醫師認為不需再進一步投藥。
本發明之活性物質可以單一藥物治療之形式投服或可與另一開立之用於治療與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾(更具體地說,青光眼)的藥物組合。
用於活性物質之“組合”一詞在此文中係用來定義包含二種活性物質之單一醫藥組成物(調製劑)(如:包含如此處所描述之活性物質與另一開立之用於治療與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾(更具體地說,青光眼)的藥物之醫藥組成物)或欲共同投服之各包含一種活性物質的二種分開之醫藥組成物(如:包含本發明之活性物質或另一開立用於治療與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾(更具體地說,青光眼)的藥物之醫藥組成物)。
在本發明之含義內,“共同投服”一詞係指同時在一種組成物中或同時在不同組成物中,或依投服如此處所描述之活性物質及第二種活性物質(如:另一開立之用於治療與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾(更具體地說,青光眼)的藥物)。然而,在被認為是“共同投服”之
依序投藥方面,投服如此處所描述之活性物質及第二種活性物質時必須分隔一段時間,但其仍可產生對治療哺乳動物中與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾有利的效果。
使用本發明之活性物質的方法及其醫藥組成物之獨特有利且出人預料的性質使得此文中所主張之“標的之整體”不明顯。因此,本方法及醫藥組成物在標準之可接受的可靠測試程序中展現出下列珍貴性質及特徵。
在青光眼之實驗模型中,澱粉樣蛋白先驅蛋白(APP)之表達增加且在視網膜神經節細胞(RGC)中出現可能相關之細胞凋亡[Mckinnon,S.J.;Lehman,D.M.;Kerrigan-Baumrind,L.A.;Merges,C.A.;Pease,M.E.;Kerrigan,D.F.;Ransom,N.L.;Tahzib,N.G.;Reitsamer,H.A.;Levkovitch-Verbin,H.;Quigley,H.A.,and Zack,D.J.Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension.Invest Ophthalmovl Vis Sci.2002 Apr;43(4):1077-87]。再者,注射Aβ 1-42
可造成RGC中細胞凋亡。干擾APP-Aβ
通路(諸如眼部施用抗體)、抑制β
-分泌酶之活性或抑制寡聚化作用可至少暫
時防止由眼壓增加所造成之青光眼中的RGC細胞凋亡(Guo等人,2007)。因此,顯示出雙重作用機制(即,β
-摺板破裂活性及寡聚化抑制作用)之本發明藥物可能更有效,尤其是若不僅在誘導眼壓增加時給藥且之後亦給藥時。
因此,在雄Dark Aguti大鼠模型中將高張食鹽水溶液注射入一隻眼睛之鞏膜外血管中以誘導眼壓增加(慢性高眼壓-OHT)來製造青光眼,而對側眼睛則作為對照組[Morrison J.C.;Moore C.G.,Deppmeier L.M.,Gold B.G.,Meshul C.K.,Johnson E.C.A rat model of chronic pressure-induced optic nerve damage.Exp Eye Res.1997;64(1):85-96]。在治療組(N=4-8/組)中,在誘導出青光眼時經由玻璃體內途徑注射不同劑量之本發明藥物(體積為5微升)且在一些群體中在接下去之7天連續給藥以檢查這類延長治療是否可增加效力。在誘導慢性高眼壓(OHT)後第3週和第6週藉動態共焦激光掃描檢眼鏡檢查法(ophthalmoscopy)和經螢光標記之Annexin V評估各動物中RGC細胞凋亡之程度。在第3週和第6週後殺死動物並摘除其眼睛並固定在4%三聚甲醛中一整夜。然後,將視網膜分開以評估與細胞凋亡相關之變化,例如:以FITC Annexin V套組(BD Biosciences,Franklin Lakes,美國)[Cordeiro,M.F.;Guo,L.,Luong,V.,Harding,G.,
Wang,W.,Jones,H.E.,Moss,S.E.,Sillito,A.M.,and Fitzke,F.W.2004 Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration.Proc Natl Acad Sci U S A,101,13352-6;Kietselaer,B.L.,Hofstra,L.,Dumont,E.A.,Reutelingsperger,C.P.,and Heidendal,G.A.2003 The role of labeled Annexin A5 in imaging of programmed cell death.From animal to clinical imaging.Q J Nucl Med,47,349-61]或TUNEL(dUTP缺口末端標記)[Roche,In situ cell death detection kit,fluorescein labelled][Szydlowska K.,Kaminska B.,Baude A.,Parsons C.G.,Danysz W.2007 Neuroprotective activity of selective mGlu1 and mGlu5 antagonists in vitro and in vivo.Eur,J.Pharmacol.554,18-29]目視檢查。在以本發明之實驗藥物治療的動物中,在至少一評估之時間點處的RGC細胞凋亡減少。
於另一實驗中,經由系統性途徑(p.o.或i.p.)治療大鼠並依上述重複實驗。本研究之目的係證明系統性投藥是否能在眼睛中產生足夠高之濃度。因此,另外分析眼睛玻璃體空間中之本發明藥物的濃度。在以實驗藥物進行系統性治療之動物中,在至少一評估之時間點處的RGC細胞凋亡減少且在眼睛玻璃體空間中可偵測到明顯之實驗藥物濃度。
另外,在玻管中證明實驗藥物對RGC細胞之毒性的效果。將β
-澱粉樣蛋白1-42
與實驗藥物(300、100、30
、10、3、1、0.3μM)或對照組預先聚集7天,然後,將此溶液之一部分加入初級RGC培養中48小時以產生最終濃度15μM。在此溫育期間係將細胞置於37℃、95%濕度及5%CO2
之保溫箱中。然後,利用FITC Annexin V套組(BD Biosciences,Franklin Lakes,美國)[Vermes,I.,Haanen,C.,Steffens-Nakken,H.,and Reutelingsperger,C.(1995)A novel assay for apoptosis.Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V.J Immunol Methods,184,39-51]及選擇性地,以碘化丙啶[Szydlowska等人.,2007]證明細胞凋亡/壞死。
利用單因子變數分析(One-Way ANOVA)及接下去之事後分析試驗(SigmaStat,Systat Software,Point Richmond,美國)來進行統計分析。
這些數據強烈暗示本發明之實驗藥物可用來治療青光眼和與年齡及/或阿玆海默氏症相關之RGC官能障礙,因Aβ
亦被認為涉入後項病況中[Guo,et al.,2007;Parisi,V.,Restuccia,R.,Fattapposta,F.,Mina,C.,Bucci,M.G.,and Pierelli,F.(2001)Morphological and functional retinal impairment in Alzheimer’s disease patients.Clin Neurophysiol,112,1860-7;Iseri,P.K.,Altinas,O.,Tokay,T.,and Yuksel,N.(2006)Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer’s disease.J
Neuroophthalmol,26,18-24]。再者,目前青光眼中所使用之降眼內壓劑與推薦之未來治療劑(諸如抗氧化劑、鈣道阻斷劑、NO合成酶抑制劑、神經營養素及抗細胞凋亡劑)的組合治療預期可取得看來合理之協同療效[Hartwick A.T.2001.Beyond intraocular pressure:neuroprotective strategies for future glaucoma therapy.Optom Vis Sci 78,85-94]。
總言之,從前述內容可明白本發明提供本發明方法中之藥物的新穎、有價值和令人驚異的應用和用途以及其新穎之醫藥組成物,這些均擁有前述具體列舉之特徵和優點。
由報告之試驗證明,該使用本發明之活性物質及其組成物的方法的高階活性為效用指示。然而,在人體中之臨床評估尚未完成。吾人需清楚了解,本發明範圍內之任何藥物或組成物的散佈及銷售當然必須先獲得負責及主管評審這類問題的政府機構(諸如美國聯邦食品藥物管理局)核准。
以本發明之藥物治療存活動物體來抑制其中選定之病痛的進展或緩和該病痛之方法係如前述般經由任何正常可接受之藥學途徑,使用可有效緩和欲緩和之特殊病痛的選定劑量。
本發明之藥物於製造供治療活動物以抑制所選定之病
痛或病況(尤其是諸如與β
-澱粉樣蛋白(Aβ
)毒性相關之眼疾類)的進展或緩和該病痛或病況之藥劑上的用途(其係以包含將有效量之本發明化合物與藥學上可接受之稀釋劑、賦形劑或載體混合之步驟的一般方式進行),及治療方法、醫藥組成物及本發明之化合物於製造藥劑上之用途。
經由將活性物質與合適之藥學上可接受的賦形劑、稀釋劑或載體混合來製備的代表性醫藥組成物包括錠片、膠囊、注射溶液、液態口服調製劑、霧狀滴調製劑、TDS調製劑及奈米粒調製劑,藉此,可根據前述內容來製造用於口服、注射、或局部使用的藥物。
本發明並不限於此處所描述之特殊較佳體系的範圍。確實,熟習本技藝之人士可從前述內容明白除了此處所描述者外之不同修改體。
所有此文中所列舉之專利、申請案、刊物、試驗方法、論文及其他此文中所列出之素材併為此文之參考資料。
<110> MERZ PHARMA <120> THE USE OF SUBSTANCES FOR THETREATMENT 0F LOSS OF EYESIGHT IN HUMANS WITH GLAUCOMA AND OTHER DEGENERATIVE EYE DISEASES <130> MERZ 72 PRO <160> 33 <170> PatentIn version 3.1 <210> 1 <211> 3 <212> PRT <213> 人工序列<220> <223> 合成肽<220> <221> 特性<222> (1)..(3) <223> 立體異構物D <400> 1<210> 2 <211> 4 <212> PRT <213> 人工序列<220> <223> 合成肽<220> <221> 特性<222> (1)..(1) <223>α
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<223>α
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Claims (12)
- 一種肽D-Trp-Aib(SEQ ID NO.30)於製造藥劑之用途,該藥劑係藉由抑制β-澱粉樣蛋白(A β)形成及/或該A β出現以治療與A β毒性相關之眼疾。
- 如申請專利範圍第1項之用途,其中該眼疾係選自:原發性閉角型青光眼、繼發性開角型青光眼、寬角型青光眼、由類固醇引起之青光眼、外傷性青光眼、色素性播散綜合徵、假性剝脫綜合徵、繼發性閉角型青光眼、新生血管性青光眼、葡萄膜炎及青光眼、老年性黃斑部變性、糖尿病性視網膜病變、退化性視神經病變及特徵為視力逐漸喪失而最終導致失明之眼部病變。
- 如申請專利範圍第1項之用途,其中該肽係與至少一種可有效治療該眼疾之其他藥學製劑併用,其中該肽與該至少一種其他藥學製劑之組合可有效治療該眼疾。
- 如申請專利範圍第3項之用途,其中該至少一種其他藥學製劑係選自下述經投服以治療眼疾的藥劑:抗青光眼藥物、抗生素、抗發炎藥物、類固醇、抗過敏藥物及人工淚水。
- 如申請專利範圍第3項之用途,其中該至少一種其他藥學製劑係選自乙醯偶氮胺(acetazolamide)、雙氯非那胺(diclofenamide)、卡替洛爾(carteolol)、塞瑪洛爾(timolol)、美替洛爾(metipranolol)、貝他洛爾(betaxolol)、平朵洛爾(pindolol)、左布諾洛爾(levobunolol)、溴莫尼定(brimonidine)、克洛尼定 (clonidine)、皮洛卡賓(pilocarpine)、胺甲醯膽鹼(carbachol)、地匹福林(dipivefrine)、阿可樂定(apraclonidine)、布林佐胺(brinzolamide)、杜塞醯胺(dorzolaminde)、盧美根(bimatoprost)、蘇為坦(travaprost)、拉坦前列素(latanoprost)、氯四環素(chlortetracycline)、環丙沙星(ciprofloxacine)、氧氟沙星(ofloxacine)、夫西地酸(fusidinic acid)、正大黴素(gentamicine)、卡那黴素(kanamycine)、左氧氟沙星(levofloxacine)、洛美沙星(lomefloxacine)、土黴素(oxytetracycline)、納他黴素(natamycine)、阿利丹芬尼可(azidamfenicole)、氯黴素(chloramphenicole)、妥布黴素(tobramycine)、紅黴素(erythromycine)、多黏菌素-B(polymyxin-B)、阿卡克洛維(acaclovir)、三氟尿甘(trifluridine)、倍他米松(betamethasone)、地塞米松(dexamethasone)、氟米龍(fluorometholone)、氫化可的松(hydrocortisone)、潑的松龍(prednisolone)、利美索龍(rimexolone)、色甘酸(cromoglicate)、氮卓斯汀(azelastine)、洛度沙胺(lodoxamide)、伊美斯汀(emedastine)、奈多羅米(nedocromile)、左卡斯汀(levocabastine)、歐洛巴塔廸尼(olopatadinea)、克多芬(ketotifene)、羥丙基甲基纖維素(hypromellose)、卡波姆(carbomere)、玻尿酸(hyaluronate)、羧甲基纖維素(carmellose)、羥丙基 甲基纖維素、共聚維酮(povidone)、海提纖維素(hyetellose)、聚乙烯醇(polivinylalcohole)、戴潘思諾(dexpanthenole)、四氫唑林(tetryzoline)、曲克蘆丁(troxerutine)、曲馬唑林(tramazoline)、萘甲唑林(naphazoline)、賽唑洛林(xylometazoline)、苯福林(phenylephrine)或安他啉(antazoline)。
- 如申請專利範圍第1項之用途,其中該肽係經適當包裝以供每天投服一次、每天投服二次或每天投服三次。
- 如申請專利範圍第1項之用途,其中該肽係經適當包裝以供長期投服。
- 如申請專利範圍第1項之用途,其中該藥劑係經製造以提供為眼滴液、眼藥膏及眼內儲積調製劑形式之肽。
- 如申請專利範圍第1項之用途,其中該藥劑係經製造以提供立即釋出型或改良釋出型調製劑中的肽。
- 如申請專利範圍第3項之用途,其中該肽及該至少一種其他藥學製劑係經適當包裝以供共同投服。
- 如申請專利範圍第10項之用途,其中該肽及該至少一種其他藥學製劑係在單一調製劑中。
- 一種藉由抑制β-澱粉樣蛋白(A β)形成及/或該A β出現以治療與A β毒性相關之眼疾的醫藥組成物,其包含單獨之如申請專利範圍第1項所述之肽或其藥學上可接受之加成鹽和至少一種可有效治療該眼疾之其他藥學製劑之組合,或彼與一或多種藥學上可接受之載體及/或賦形劑之組合。
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US20100168084A1 (en) * | 2008-05-08 | 2010-07-01 | Huber L Julie | Therapeutic compounds and related methods of use |
JP2012505162A (ja) | 2008-10-09 | 2012-03-01 | ワラタ ファーマシューティカルズ, インコーポレイテッド | 黄斑変性症関連障害を処置するためのscyllo−イノシトールの使用 |
US20110200531A1 (en) | 2009-09-14 | 2011-08-18 | The Regents Of The University Of California | Treatment and diagnosis of central nervous system disorders |
TWI486162B (zh) * | 2010-06-16 | 2015-06-01 | Sinphar Pharmaceutical Co Ltd | 異類葉升麻苷或其醫藥學上可接受之鹽於抑制澱粉樣β肽生成、累積或聚集、以及製備預防或治療澱粉樣β肽相關疾病或狀況的藥物之用途 |
CN103282349A (zh) | 2010-10-29 | 2013-09-04 | 德国麦氏大药厂 | 吲哚衍生物及其制备方法 |
CA2817830A1 (en) | 2010-11-15 | 2012-05-24 | Ramot At Tel Aviv University Ltd. | Dipeptide analogs for treating conditions associated with amyloid fibril formation |
TW201412325A (zh) * | 2012-06-20 | 2014-04-01 | 梅茲製藥有限兩合公司 | 用於治療患有青光眼及其他退化性眼疾之人類視力喪失的間隔醫療 |
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2007
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2008
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- 2008-08-21 RU RU2010110544/15A patent/RU2481120C2/ru not_active IP Right Cessation
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- 2008-08-21 JP JP2010519389A patent/JP2010535728A/ja active Pending
- 2008-08-21 CN CN200880021418A patent/CN101743015A/zh active Pending
- 2008-08-21 CA CA002688215A patent/CA2688215A1/en not_active Abandoned
- 2008-08-21 MX MX2009013604A patent/MX2009013604A/es unknown
- 2008-08-21 WO PCT/EP2008/006888 patent/WO2009024346A2/en active Application Filing
- 2008-08-21 AU AU2008290825A patent/AU2008290825B2/en not_active Ceased
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US20200085906A1 (en) | 2020-03-19 |
US20100204137A1 (en) | 2010-08-12 |
TW200916112A (en) | 2009-04-16 |
WO2009024346A3 (en) | 2009-06-04 |
JP2010535728A (ja) | 2010-11-25 |
US20170065664A1 (en) | 2017-03-09 |
EP2044951A1 (en) | 2009-04-08 |
AR069729A1 (es) | 2010-02-17 |
AU2008290825A1 (en) | 2009-02-26 |
CA2688215A1 (en) | 2009-02-26 |
US10987400B2 (en) | 2021-04-27 |
CN101743015A (zh) | 2010-06-16 |
RU2010110544A (ru) | 2011-09-27 |
RU2481120C2 (ru) | 2013-05-10 |
EP2180898A2 (en) | 2010-05-05 |
MX2009013604A (es) | 2010-01-26 |
US10525097B2 (en) | 2020-01-07 |
AU2008290825B2 (en) | 2012-07-12 |
WO2009024346A2 (en) | 2009-02-26 |
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