TW201709910A - 用於治療翼狀胬肉之組合物及方法 - Google Patents
用於治療翼狀胬肉之組合物及方法 Download PDFInfo
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- TW201709910A TW201709910A TW105117765A TW105117765A TW201709910A TW 201709910 A TW201709910 A TW 201709910A TW 105117765 A TW105117765 A TW 105117765A TW 105117765 A TW105117765 A TW 105117765A TW 201709910 A TW201709910 A TW 201709910A
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- pterygium
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Abstract
本發明揭示用於誘導翼狀胬肉自視軸/中央角膜消退、穩定翼狀胬肉、治療翼狀胬肉患者中之充血及症狀及治療翼狀胬肉切除術後之翼狀胬肉復發之組合物及方法。該等方法包括向有需要之患者投與多激酶抑制劑、抗代謝物或其組合。
Description
本申請案主張於2015年6月6日提出申請之美國臨時專利申請案第62/172,063號及於2015年6月30日提出申請之美國臨時專利申請案第62/186,660號之優先權,每一申請案之全部內容皆以引用方式併入本文中。
本揭示內容係關於用於治療原發及復發翼狀胬肉之眼組合物及方法,且更具體而言係關於用於在翼狀胬肉手術之前、與翼狀胬肉手術同時或在翼狀胬肉手術之後誘導翼狀胬肉自視軸/中央角膜消退、穩定翼狀胬肉、減少眼充血及翼狀胬肉復發之組合物及方法。
翼狀胬肉係眼表疾病,其中異常上皮及纖維母細胞生長自鼻側結膜或顳側結膜跨越邊緣延伸至角膜上。翼狀胬肉患者通常經歷眼不適、充血之症狀且若病灶於視軸上侵佔則處於視覺損傷之風險中。
在某些態樣中,本揭示內容提供用於治療原發及復發翼狀胬肉之方法,該方法藉由向需要此治療之個體之眼投與(1)多激酶抑制劑、(2)抗代謝物或(3)多激酶抑制劑及抗代謝物之組合來實施。在某一態樣中,所揭示之方法穩定翼狀胬肉且防止患病組織之進一步生長。在另一態樣中,所揭示之方法誘導翼狀胬肉自視軸/中央角膜消
退。在某一態樣中,所揭示之多激酶抑制劑靶向VEGFR(1、2、3)及PDGFR(α、β)之激酶受體。在某一態樣中,多激酶抑制劑係於局部投與患眼之局部眼調配物中。在某一態樣中,局部眼調配物係溶液、懸浮液或乳液。在另一態樣中,多激酶抑制劑係於注射至患眼中之植入物或半固體持續釋放調配物中。在某一態樣中,抗代謝物係絲裂黴素C、5-氟尿嘧啶及噻替派(Thiotepa)。在某一態樣中,抗代謝物係於局部投與患眼之局部眼調配物中。在某一態樣中,局部眼調配物係溶液、懸浮液或乳液。在另一態樣中,抗代謝物係於注射至患眼中之植入物或半固體持續釋放調配物中。在某一態樣中,所揭示之方法係藉由多激酶抑制劑及抗代謝物之組合來實施。在某一態樣中,多激酶抑制劑及抗代謝物之組合係於局部投與患眼之局部眼調配物中。在某一態樣中,局部眼調配物係溶液、懸浮液或乳液。在另一態樣中,多激酶抑制劑及抗代謝物之組合係於注射至患眼中之植入物或半固體持續釋放調配物中。在某一態樣中,所揭示之方法減少充血、異常新血管形成及翼狀胬肉患者中之其他症狀。在另一態樣中,所揭示之方法防止在翼狀胬肉手術後翼狀胬肉復發。在某一態樣中,所揭示之方法係在翼狀胬肉之手術移除之前、與翼狀胬肉移除手術同時或在翼狀胬肉之手術移除之後實施以減少或防止翼狀胬肉復發。在某一態樣中,所揭示之多激酶抑制劑靶向VEGFR(1、2、3);PDGFR(α、β);FGFR(1、2、3、4)之最少激酶受體及另外FLT3、Lck、Lyn及Src之最佳激酶受體。在某一態樣中,所揭示之多激酶抑制劑係尼達尼布(nintedanib)。在某一態樣中,所揭示之方法使用局部眼調配物。在某一態樣中,調配物係水溶液、懸浮液或乳液。在某一態樣中,調配物中之尼達尼布濃度係0.001%至10%。在某一態樣中,調配物係注射至患眼中之植入物或半固體持續釋放調配物。在某一態樣中,植入物中尼達尼布之量係1μg至100mg。
在一態樣中,本揭示內容提供用於誘導翼狀胬肉自視軸/中央角膜消退之方法,其包括向需要此治療之個體之患眼投與治療有效量之(1)多激酶抑制劑;(2)阻斷上皮及纖維母細胞增殖之抗代謝物;或(3)其組合。在所有態樣之一些實施例中,多激酶抑制劑、抗代謝物或其組合之投與使得患眼中之翼狀胬肉大小減小。在一些情形中,多激酶抑制劑、抗代謝物或其組合之投與導致患眼中之翼狀胬肉生長速率為負。
在另一態樣中,本揭示內容提供用於穩定翼狀胬肉之方法,其包括向需要此治療之個體之患眼投與治療有效量之(1)多激酶抑制劑;(2)阻斷上皮及纖維母細胞增殖之抗代謝物;或(3)其組合。在一些情形中,多激酶抑制劑、抗代謝物或其組合之投與使得患眼中之翼狀胬肉大小穩定。在一些情形中,多激酶抑制劑、抗代謝物或其組合之投與導致患眼中之翼狀胬肉生長速率為約零。
在所有態樣之一些實施例中,多激酶抑制劑降低翼狀胬肉中之一或多種選自以下之細胞內及/或細胞表面蛋白激酶之活性:EGFR、ErbB2、ErbB3、FGFR1、FGFR2、FGFR3、FGFR4、TrkA、NGFR、VEGFR(1、2、3)、PDGFR(α、β)、TGF-βR(I、II、III)、FLT3、Lck、Lyn、Src、c-Kit、c-Fms、Raf-1、B-Raf、RET、CSF-1R。在一些情形中,多激酶抑制劑針對VEGFR(1、2、3)之IC50<200nM,針對PDGFR(α、β)之IC50<200nM,且/或針對FGFR(1、2、3)之IC50<1000nM。
在所有態樣之一些實施例中,多激酶抑制劑選自由以下組成之群:阿法替尼(Afatinib)、阿姆替尼(Amuvatinib)、阿西替尼(Axitinib)、卡博替尼(Cabozantinib)、卡奈替尼(Canertinib)、西地尼布(Cediranib)、色瑞替尼(Ceritinib)、克萊拉尼(Crenolanib)、克唑替尼(Crizotinib)、達拉菲尼(Dabrafenib)、達克替尼(Dacomitinib)、達沙
替尼(Dasatinib)、厄洛替尼(Erlotinib)、弗雷替尼(Foretinib)、吉非替尼(Gefitinib)、格瓦替尼(Golvatinib)、依魯替尼(Ibrutinib)、埃克替尼(Icotinib)、艾代拉裡斯(Idelalisib)、伊馬替尼(Imatinib)、拉帕替尼(Lapatinib)、樂伐替尼(Lenvatinib)、來那替尼(Neratinib)、尼羅替尼(Nilotinib)、尼達尼布、帕博西尼(Palbociclib)、帕唑帕尼(Pazopanib)、普納替尼(Ponatinib)、奎紮替尼(Quizartinib)、瑞格菲尼(Regorafenib)、魯索替尼(Ruxolitinib)、索拉菲尼(Sorafenib)、舒尼替尼(Sunitinib)、坦度替尼(Tandutinib)、提瓦替尼(Tivantinib)、替肟紮尼(Tivozanib)、曲美替尼(Trametinib)、凡德他尼(Vandetanib)、瓦他拉尼(Vatalanib)及威羅菲尼(Vemurafenib)。在一些情形中,抗代謝物選自由以下組成之群:絲裂黴素C、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-氮尿嘧啶、硫唑嘌呤、胺甲喋呤、嗎替麥考酚酯(Mycophenolate Mofetil)及噻替派。
在所有態樣之一些實施例中,向患眼投與呈以下形式之多激酶抑制劑、抗代謝物或其組合:局部眼調配物、軟膏、凝膠、持續釋放半固體調配物、持續釋放固體調配物或眼植入物。在一些情形中,多激酶抑制劑、抗代謝物或其組合係以局部眼調配物形式投與患眼且局部投與患眼。
在一些情形中,局部眼調配物係溶液、懸浮液或乳液。在一些情形中,局部眼調配物亦包括一或多種選自以下之醫藥上可接受之賦形劑:穩定劑、表面活性劑、聚合物基載劑、膠凝劑、有機共溶劑、pH活性組分、滲透活性組分且具有或不具有防腐劑。在一些情形中,將持續釋放半固體調配物、持續釋放固體調配物或眼植入物注射至患眼中。在一些實施例中,持續釋放半固體調配物、持續釋放固體調配物或眼植入物進一步包含醫藥上可接受之賦形劑。在一些情形中,持續釋放半固體調配物、持續釋放固體調配物或眼植入物包括多
激酶抑制劑、抗代謝物或其組合;及選自聚乳酸(PLA)、聚乙醇酸(PLGA)及聚乳酸聚乙醇酸共聚物之生物可降解聚合物。
在所有態樣之一些實施例中,投與係針對翼狀胬肉患者實施。
在另一態樣中,本揭示內容提供用於減少需要此治療之患者之翼狀胬肉、瞼裂斑及假性翼狀胬肉中之充血及其症狀之方法,其包括向個體之患眼投與治療有效量之多激酶抑制劑。
在另一態樣中,本揭示內容提供用於減少或防止需要此治療之個體中之翼狀胬肉復發之方法,其包括向個體之患眼投與治療有效量之多激酶抑制劑。在所有態樣之一些實施例中,投與係在翼狀胬肉之手術移除之前實施。在一些情形中,投與係在翼狀胬肉移除之手術程序期間實施。在一些情形中,投與係在翼狀胬肉之手術移除之後實施。
在所有態樣之一些實施例中,多激酶抑制劑針對VEGFR(1、2、3)之IC50<50nM,針對PDGFR(α、β)之IC50<100nM,針對FGFR(1、2、3)之IC50<150nM,針對FGFR4之IC50<1000nM,針對FLT3之IC50<50nM,針對Lck之IC50<50nM,針對Lyn之IC50<200nM)且針對Src之IC50<200nM。在一些情形中,多激酶抑制劑選自由以下組成之群:尼達尼布{(3Z)-3-{[(4-{[(4-甲基六氫吡嗪-1-基)乙醯基]胺基}苯基)胺基](苯基)亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-6-甲酸甲酯}、其游離鹼、水合物、溶劑合物或醫藥上可接受之鹽。在一些情形中,多激酶抑制劑係尼達尼布游離鹼或乙磺酸尼達尼布(乙磺酸鹽)。
在所有態樣之一些實施例中,向患眼投與呈局部眼調配物、持續釋放半固體調配物、持續釋放固體調配物或眼植入物形式之多激酶抑制劑。在一些情形中,尼達尼布係以局部眼調配物形式投與患眼且係局部投與患眼。在一些情形中,局部眼調配物係溶液、懸浮液或乳
液。在所有態樣之一些實施例中,局部眼調配物中之尼達尼布濃度係調配物總量之0.001重量%至10重量%。
在所有態樣之一些實施例中,局部眼調配物亦包括一或多種選自以下之醫藥上可接受之賦形劑:穩定劑、表面活性劑、聚合物基載劑、膠凝劑、有機共溶劑、pH活性組分、滲透活性組分及防腐劑。在一些情形中,將持續釋放半固體調配物、持續釋放固體調配物或眼植入物注射至患眼中。在一些情形中,持續釋放半固體調配物、持續釋放固體調配物或眼植入物包括尼達尼布及醫藥上可接受之賦形劑。在一些情形中,持續釋放半固體調配物、持續釋放固體調配物或眼植入物中尼達尼布之量係1μg至100mg。在一些情形中,持續釋放半固體調配物、持續釋放固體調配物或眼植入物包含尼達尼布;及選自聚乳酸(PLA)、聚乙醇酸(PLGA)及聚乳酸聚乙醇酸共聚物之生物可降解聚合物。
如本文所用術語「一或多個」包括至少一個、更適宜地1個、2個、3個、4個、5個、10個、20個、50個、100個、500個等「一或多個」所指之物項。
術語「個體」係指動物或人類或衍生自動物或人類之一或多種細胞。較佳地,個體係人類。個體亦可包括非人類靈長類動物。人類個體可稱為患者。
除非另有說明,否則本文所用之所有技術及科學術語均具有與熟習本發明所屬技術者通常所理解之含義相同的含義。本文闡述用於本發明中之方法及材料;亦可使用業內已知之其他適宜方法及材料。該等材料、方法及實例僅係闡釋性的且不欲具有限制性。本文提及之所有公開案、專利申請案、專利、序列、數據庫條目及其他參考文獻均以引用方式全部併入。倘若出現衝突,則將以本說明書(包括定義)為準。
本發明之其他特徵及優點自以下詳細說明及圖及申請專利範圍將顯而易見。
本專利或申請案檔案含有至少一個有色圖式。在要求並支付必要費用之後專利事務局將提供本專利或專利申請公開案具有彩圖之副本。
圖1A及1B係展示兔角膜縫合模型中尼達尼布之抗血管形成功效之圖。圖1A提供第12天之結果且圖1B提供第14天之結果。顯示各治療組之角膜新血管形成之面積。組1:陽性對照0.05%舒尼替尼TID;組2:0.2%尼達尼布BID;組3:0.2%尼達尼布TID;組4:0.05%尼達尼布BID;組5:0.05%尼達尼布TID;組6:媒劑對照TID。藉由星號符號顯示比較各組對媒劑之T測試顯著水準。
圖2A及2B係展示人類翼狀胬肉小鼠模型中尼達尼布(CBT-001)之效應之圖。(2A)0.2%尼達尼布減少小鼠角膜上之翼狀胬肉病灶面積。第14天及第17天之翼狀胬肉病灶面積顯著小於第7天之基線水準。與此相比,鹽水對照眼中之翼狀胬肉面積經10天時期增加,且第14天及第17天顯著大於第7天。(2B)0.2%尼達尼布減少角膜上之新血管形成且比較第17天之水準與第7天之基線,減少係顯著的。在鹽水對照眼中,新血管形成略有增加,與基線無統計學顯著差異。
圖3A及3B係展示翼狀胬肉小鼠模型中舒尼替尼(CBT-003)之效應之圖。(3A)0.05%舒尼替尼顯示翼狀胬肉病灶面積減少之趨勢,但每一時間點處與第7天基線之差異在統計學上並不顯著。鹽水對照眼中之翼狀胬肉面積經10天時期增加,且第14天及第17天顯著大於第7天。(3B)0.05%舒尼替尼減少角膜上之新血管形成且比較第14天及第17天之水準與第7天之基線,減少係顯著的。在鹽水對照眼中,新血管形成未顯著改變。
圖4A及4B係展示翼狀胬肉小鼠模型中絲裂黴素(CBT-002)之效應之圖。(4A)0.002%絲裂黴素顯示翼狀胬肉病灶面積減少之趨勢,但每一時間點處與第7天基線之差異在統計學上並不顯著。鹽水對照眼中之翼狀胬肉面積增加,且第10、14及17天顯著大於第7天。(4B)0.002%絲裂黴素減少角膜上之新血管形成且比較第17天之水準與第7天之基線,減少係顯著的。在鹽水對照眼中,新血管形成未顯著改變。
圖5A及5B係展示翼狀胬肉小鼠模型中尼達尼布(CBT-001)及絲裂黴素(CBT-002)之組合之效應之圖。(5A)鹽水對照眼中之翼狀胬肉面積增加,且第14天及第17天顯著大於第7天,而組合治療組中面積未顯著增加。(5B)鹽水及組合治療組中新血管形成面積未顯著改變。
翼狀胬肉係眼表疾病,其中纖維小管生長自鼻側結膜或顳側結膜跨越邊緣延伸至角膜上。翼狀胬肉患者通常經歷眼不適、充血之症狀且若病灶於視軸上侵佔則處於視覺損傷之風險中。翼狀胬肉之發病率與終生日照及其他風險因素正相關,該等因素例如增加之年齡、男性性別及鄉村居住,同時已顯示佩戴眼鏡或帽子具有保護性效應。另外,在某些職業團體中翼狀胬肉更常見,例如銲工、體力勞動者及在戶外工作之彼等,此反映紫外線(UV)暴露在此疾病之發病機制中之主要作用。
翼狀胬肉通常視為良性腫瘤,此乃因其侵略性生長習性及復發但不轉移之傾向。目前對翼狀胬肉發病機制之理解係涉及多種過程且該等過程可分為遺傳因素、環境觸發因素(UV光、病毒感染)及保持其生長之因素(細胞介素、生長因子及基質金屬蛋白酶)。在其之間,長期UV暴露係翼狀胬肉發病機制中之單一最重要因素。UV暴露與翼狀胬肉之間之關係係由流行病學研究及翼狀胬肉與其他UV相關病況之
聯繫充分支持,該等病況例如光老化皮膚、白內障、氣候性滴狀角膜病變以及鱗狀細胞癌及基底細胞癌。諸如氧化壓力及生長因子受體(GFR)信號傳導等UV活化之分子機制導致保持翼狀胬肉生長之效應物分子(例如細胞介素、生長因子及基質金屬蛋白酶)之合成及分泌。UV係眾所周知的氧化壓力之誘導物及皮膚光老化之促進劑。由UV觸發之氧化壓力經由促分裂原活化之蛋白激酶路徑介導表皮生長因子受體(EGFR)及隨後之下游信號傳導之活化。
目前,尚未核準治療翼狀胬肉之藥理學療法。翼狀胬肉切除聯合結膜自體移植物移植仍係原發及復發翼狀胬肉二者之所選確定性治療程序。儘管許多該等病灶可容易地移除以使外科醫師及患者二者皆初步滿意,但翼狀胬肉可發生復發。已與翼狀胬肉手術同時或在翼狀胬肉手術後使用諸如5-FU及MMC等抗代謝物以減小翼狀胬肉之復發率(Almond等人,Pterygium:Techniques and Technologies for Surgical Success.Hovanesian JA.編輯,SLACK Incorporated.2012;第55-63頁)。
翼狀胬肉係多因子疾病且若干生長因子(例如VEGF及PDGF)係潛在病理學因素。然而,尚未研發出針對該等生長因子之藥物以治療該疾病。抗VEGF抗體貝伐珠單抗(bevacizumab)及蘭尼單抗(ranibizumab)已在世界各地的診療所中在翼狀胬肉患者中測試,但結果係高度可變的且不清楚使用抗體之此治療是否有效。幾個研究報導貝伐珠單抗可停止翼狀胬肉生長,但大多研究報導陰性結果。迄今為止,尚未報導在診療所針對翼狀胬肉測試小分子抗血管生成藥物。最近,研發出人類翼狀胬肉小鼠模型,僅由兩篇出版物(Lee等人,Graefes Arch Clin Exp Ophthalmol.2014;252(4):609-18;Cox等人,Ophthalmology.2010;117(9):1782-91)。先前未曾在此模型中測試抗血管生成藥物。下文中,本發明者首次展示在小鼠模型中,具有抗血管生成活性之多激酶抑制劑有效抑制且/或穩定翼狀胬肉生長且減小
翼狀胬肉組織病灶大小。另外,本發明者展示抗代謝物提供類似結果。本揭示內容部分基於該等新發現。因此,本揭示內容提供投與多激酶抑制劑、抗代謝物或多激酶抑制劑與抗代謝物之組合以藉由穩定疾病及誘導消退來治療翼狀胬肉之組合物及方法。
如本文所用術語「翼狀胬肉消退」意指患眼中翼狀胬肉大小之減小或降低。舉例而言,術語「翼狀胬肉消退」意指患眼中翼狀胬肉大小減小或降低至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%。
如本文所用術語「眼充血」或「充血」係指眼中由於眼白(鞏膜)中血液過量而發紅。術語「減少充血」意指患眼中紅色減少及\或白色增加。可藉由熟習此項技術者熟知之方法(包括專業人士目測評價)來確定或量測紅色減少及\或白色增加。
如本文所用術語「穩定翼狀胬肉」或「翼狀胬肉大小之穩定」係指意味著維持患眼中翼狀胬肉大小。
如本文所用術語「翼狀胬肉復發」意指在原發翼狀胬肉之移除(例如,手術移除)之後,翼狀胬肉在眼中再出現。
如本文所用,術語「治療有效」及「有效量」係指試劑有效產生期望藥理學、治療或預防結果之量。藥理學有效量使得病症之一或多種症狀之改善,或防止病症之進展,或引起病症消退,或預防病症。舉例而言,關於誘導翼狀胬肉消退,治療有效量係指治療劑使翼狀胬肉大小減少以下程度之量:至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%。
本文所述方法中之治療有效劑量可由治療醫師來確定。舉例而言,醫師可使用多激酶抑制劑或抗代謝物之製造商推薦之劑量來開始治療,且基於醫師對治療效應之觀察來進行調整。本文及實例中提供進一步指導。另外,可實施臨床試驗以確定在治療患者群體時有效產生統計學上顯著的治療效應之劑量。
片語「或其組合」或「與…組合」欲指提供第一試劑連同第二試劑(例如第二抑制性核酸分子或化學治療劑)之投與之所有形式,其中該兩種試劑係同時或以任何順序相繼投與。對於欲與彼此組合投與之兩種或更多種試劑,該等試劑不需要同時或於相同調配物中投與。與彼此組合投與之試劑在向其遞送該等試劑之個體中同時存在或具有生物活性。個體中試劑之存在之測定可藉由憑經驗監測或藉由使用試劑之已知藥物動力學性質計算容易地測定。
本文使用術語「治療(treatment、treating、treat)」及諸如此類大體上係指獲得期望藥理及/或生理效應。該效應就完全或部分防止疾病或其症狀而言可係預防性的;且/或就部分或完全穩定或治癒疾病及/或歸因於該疾病之不良效應而言可係治療性的。術語「治療」涵蓋哺乳動物、具體而言人類中疾病之任何治療,且包括:(a)在可易患疾病或症狀但尚未診斷為患有該疾病或症狀之個體中防止疾病及/或症狀出現;(b)抑制疾病及/或症狀,即阻止其發展;或(c)減輕疾病症狀,即引起疾病及/或症狀消退。需要治療之彼等包括已患病之彼等(例如,患有癌症之彼等、患有感染之彼等,等)以及期望預防之彼等(例如,癌症易感性增加之彼等、感染可能性增加之彼等、懷疑患有癌症之彼等、懷疑患有感染之彼等,等)。
如本文所用術語「多激酶抑制劑」(MKI)係指減少或抑制兩種或更多種激酶(包括(例如)細胞內及/或細胞表面蛋白激酶)之表現或活性的藥物化合物(例如,小分子)。
應理解,如本文所用之「小分子」係指分子量低於2,000道爾頓、更佳介於200道爾頓與1,000道爾頓之間且更佳介於300道爾頓與700道爾頓之間之化學化合物。較佳地,該等小分子係有機分子。在某些實施例中,「小分子」不包括肽或核酸分子。
用於本文所述方法中之實例性多激酶抑制劑展示某些激酶抑制譜。舉例而言,用於本文所述方法中之多激酶抑制劑可具有以下激酶抑制譜:針對VEGFR(1、2、3)之IC50為IC50<200nM,針對PDGFR(α、β)之IC50<200nM且針對FGFR(1、2、3)之IC50<1μM。
用於本文所述方法中之實例性多激酶抑制劑包括(例如)阿法替尼、阿姆替尼、阿西替尼、卡博替尼、卡奈替尼、西地尼布、色瑞替尼、克萊拉尼、克唑替尼、達拉菲尼、達克替尼、達沙替尼、厄洛替尼、弗雷替尼、吉非替尼、格瓦替尼、依魯替尼、埃克替尼、艾代拉裡斯、伊馬替尼、拉帕替尼、樂伐替尼、來那替尼、尼羅替尼、尼達尼布、帕博西尼、帕唑帕尼、普納替尼、奎紮替尼、瑞格菲尼、魯索替尼、索拉菲尼、舒尼替尼、坦度替尼、提瓦替尼、替肟紮尼、曲美替尼、凡德他尼、瓦他拉尼及威羅菲尼。
尼達尼布{(3Z)-3-{[(4-{甲基[(4-甲基六氫吡嗪-1-基)乙醯基]胺基}苯基)胺基](苯基)亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-6-甲酸甲酯}係如本文所述多激酶抑制劑之實例。尼達尼布主要抑制受體酪胺酸激酶,包括(例如)血管內皮生長因子受體(VEGFR 1-3)、血小板衍生之生長因子受體(PDGFR α及β)、纖維母細胞生長因子受體(FGFR 1-4)及其他(參見下表1),且尼達尼布顯示獨特激酶抑制譜。
如本文所用術語「抗代謝物」係指抑制代謝物之利用且從而減少、防止或抑制快速分裂細胞之生長之藥物化合物。舉例而言,本揭示內容之抗代謝物可經由不同機制來抑制DNA複製,從而導致減少、防止或抑制細胞分裂。用於本文所述方法中之實例性抗代謝物包括(例如)嘌呤及嘧啶類似物,例如5-氟尿嘧啶(5-FU);抗生素,例如絲裂黴素-C(MMC);及抗葉酸化合物,例如胺甲喋呤。用於本文所述方法中之實例性抗代謝物包括(例如)絲裂黴素C、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-氮尿嘧啶、硫唑嘌呤、胺甲喋呤、嗎替麥考酚酯及噻替派。
絲裂黴素-C(MMC)係如本文所述抗代謝物之實例。MMC係抗生素及抗瘤劑,其經歷還原活化變為強效烷基化劑。在缺氧條件下,其藉由通常在鳥嘌呤之N2位處交聯DNA來干擾DNA複製;因此其在活躍分裂之細胞中最有效。在好氧條件下,其產生能夠非特異性干擾RNA及蛋白質合成之有毒氧自由基。其已經靜脈內用作尤其針對胃腸道、胰臟、肺及乳房之腫瘤之抗瘤劑。其亦用於膀胱癌之血管內應用中。
5-FU係如本文所述抗代謝物之實例。5-FU係氟化嘧啶且據信其主要抗代謝效應係抑制胸苷酸合成酶,此導致缺少用於DNA產生之細胞內胸苷。5-FU之其他效應係歸因於抑制其他酶或將其代謝物納入RNA中。
多激酶抑制劑及抗代謝物為熟習此項技術者所熟知且通常用於治療癌症。
本文所述組合物及方法可用於治療處於翼狀胬肉或瞼裂斑或假性翼狀胬肉早期之患者,其中患者經歷眼不適、充血、刺激、視力模糊、異物感及疼痛,治療目標係減少充血及症狀。舉例而言,本揭示內容提供使用呈適宜眼劑型之多激酶抑制劑尼達尼布減少充血及其他症狀之治療組合物及方法。
本文所述組合物及方法亦可用於治療處於翼狀胬肉晚期之患者,其中纖維小管生長自結膜跨越邊緣延伸至中央角膜以侵佔視軸,裸露鞏膜翼狀胬肉切除聯合結膜自體移植物移植或聯合羊膜移植將係所選治療程序。儘管隨著手術技術及輔助療法之進步,復發之風險已顯著減小,但復發仍係外科醫師及患者之重大問題。為防止翼狀胬肉復發,本揭示內容提供使用呈適宜眼劑型之尼達尼布減少翼狀胬肉復發之治療組合物及方法。
本文所述組合物及方法亦可用於治療充血且減少與其相關之症
狀,如實例1中提供之兔縫合模型研究中所示。在此實例中,尼達尼布具有抑制角膜中縫線誘導之新血管形成之優良功效。下表2顯示與媒劑組相比,使用尼達尼布治療之眼中新血管面積之變化%顯著減少。尼達尼布之功效取決於劑量濃度及劑量頻率方案。有趣地,在減少新血管面積中尼達尼布顯示優於舒尼替尼之明顯趨勢。儘管兩種激酶抑制劑具有大量靶標重疊,但在此兔模型中記錄到不同功效。尼達尼布之另一優點係相較於舒尼替尼其抑制較小數目之靶標,此容許較佳安全性界限及較高劑量。實際上,如實例1中所示,在舒尼替尼組之給藥期間,在一隻兔中觀察到具有不完全晶狀體渾濁之異常晶狀體之潛在毒性,而在尼達尼布組中未觀察到。另外,在活體內角膜縫合兔模型研究(其中將縫線置於兔之角膜中且用舒尼替尼給藥7天)中,在第1天觀察到前房細胞反應(Perez-Santonja JJ等人,Am J Ophthalmol.2010;150(4):519-528)。在整個給藥期間觀察到虹膜表面黃色染色,此表示舒尼替尼沈積於虹膜表面上。舒尼替尼沈澱於虹膜之下象限上,在瞳孔邊緣處開始且在一定程度上擴展至瞳孔與前房角之間,此可潛在地導致長期毒性效應。此外,在>3.3μg/mL之濃度下在與人類角膜上皮細胞一起培育24小時之後觀察到舒尼替尼之顯著毒性(Bayyoud T等人,Current Eye Research,39(2):149-154,2014)。
尼達尼布及舒尼替尼二者皆抑制關鍵VEGFR及PDGFR家族,且有幾個靶標不重疊(參見表1)。但尼達尼布之獨特激酶靶標組似使其相較於舒尼替尼更有效且更安全,此指示尼達尼布可係用於減少角膜新血管形成之最有效多激酶抑制劑之一。在最大活體外IC50下抑制以下細胞內及/或細胞表面蛋白激酶之獨特譜指定為VEGFR(1、2、3)(IC50<50nM)、PDGFR(α、β)(IC50<100nM)、FGFR(1、2、3)(IC50<150nM)、FGFR4(IC50<1000nM)、FLT3(IC50<50nM)、Lck(IC50<50nM)、Lyn(IC50<200nM)及Src(IC50<200nM)。3個靶標FGFR4、Lyn及Src不受舒尼替尼或其他常用激酶抑制劑之抑制且該3個靶標可區分尼達尼布與舒尼替尼及其他激酶抑制劑。另外,尼達尼布對FGFR1-3之效力顯著高於舒尼替尼,此亦可有助於尼達尼布於角膜縫合兔模型中之較優功效。
本文所述組合物及方法亦可用於治療處於翼狀胬肉中期之患者,其中纖維小管生長自結膜延伸至邊緣及角膜。在翼狀胬肉之中期,目標係穩定翼狀胬肉進展以延遲或避免移除翼狀胬肉之手術或甚至誘導翼狀胬肉自視軸/中央角膜消退。為達成此目標,本揭示內容
提供使用呈適宜眼劑型之多激酶抑制劑、抗代謝物或二者之組合之治療組合物及方法。
用於使用多激酶抑制劑以穩定翼狀胬肉且誘導翼狀胬肉消退來治療患眼之組合物及方法之實例提供於下文實例2中,其中顯示此等組合物對免疫缺陷小鼠之角膜上之人類翼狀胬肉細胞生長之效應。在此研究中,尼達尼布及舒尼替尼預防小鼠角膜上人類翼狀胬肉之生長且尼達尼布顯著減少翼狀胬肉之大小。如下文中提供之表3中所示,翼狀胬肉細胞在整個治療時期期間生長直至第17天,而在使用尼達尼布、舒尼替尼、MMC或尼達尼布及MMC之組合治療之組中,翼狀胬肉細胞不生長或在尼達尼布之情形下消退。因此,本發明者來自小鼠模型之新穎見解指示,可能使用諸如尼達尼布或舒尼替尼等多激酶抑制劑來停止翼狀胬肉生長或甚至誘導翼狀胬肉組織消退。作為實例,用於本文所述組合物及方法中之多激酶抑制劑之靶標激酶譜可在指定活體外IC50下靶向以下激酶:VEGFR(1、2、3)(IC50<200nM)、PDGFR(α、β)(IC50<200nM)、FGFR(1、2、3)(IC50<1μM)。
本文所述組合物及方法亦可用於使用上皮細胞及纖維母細胞增殖之抗代謝物抑制劑來治療患者以穩定翼狀胬肉且誘導翼狀胬肉消退
(參見實例2)。如上文表3中所示,絲裂黴素C(MMC)能夠阻止人類翼狀胬肉細胞之生長且顯示減小角膜上之翼狀胬肉組織大小之趨勢。
考慮到翼狀胬肉之多因子本質,可需要藉由藥物組合治療以達成最佳效應。如表3中所示,使用尼達尼布及MMC之組合治療之角膜上之翼狀胬肉細胞未顯示顯著生長,而鹽水對照顯著生長。
本文所述方法包括製造及使用醫藥組合物,其包括藉由本文所述方法鑑別為活性成份之化合物。亦包括醫藥組合物本身。
醫藥組合物通常包括醫藥上可接受之賦形劑。如本文所用,語言「醫藥上可接受之賦形劑」或「醫藥上可接受之載劑」包括與醫藥投與相容之鹽水、溶劑、分散介質、塗層、抗細菌及抗真菌劑、等滲劑及吸收延遲劑及諸如此類。
調配適宜醫藥組合物之方法為業內已知,參見(例如)Remington:The Science and Practice of Pharmacy,第21版,2005;及Drugs and the Pharmaceutical Sciences:a Series of Textbooks and Monographs(Dekker,NY)系列書籍。舉例而言,用於眼科應用之溶液、懸浮液或乳液可包括以下組份:無菌稀釋劑,例如注射用水、鹽水溶液、不揮發油、聚乙二醇、甘油、丙二醇或其他合成溶劑;抗細菌劑;抗氧化劑;螯合劑;緩衝劑,例如乙酸鹽、檸檬酸鹽或磷酸鹽;及張力調節劑,例如氯化鈉或右旋糖。可使用酸或鹼(例如鹽酸或氫氧化鈉)來調節pH。
適於注射使用之醫藥組合物可包括無菌水溶液(若可溶於水)或分散液及用於即時製備無菌可注射溶液或分散液之無菌粉末。其應在製造及儲存條件下穩定且必須抵抗諸如細菌及真菌等微生物之污染作用進行保存。載劑可係溶劑或分散介質,其含有(例如)水、乙醇、多元醇(例如甘油、丙二醇及液體聚乙二醇及諸如此類)及其適宜混合物。
可(例如)藉由使用塗層(例如卵磷脂)、藉由在分散液情形中維持所需粒徑及藉由使用表面活性劑來維持適當流動性。可藉由各種抗細菌及抗真菌劑來達成對微生物作用之預防,例如,對羥基苯甲酸酯、氯丁醇、酚、抗壞血酸、硫柳汞及諸如此類。在許多情形中,組合物中將較佳包括等滲劑,例如,糖、多元醇(例如,甘露醇、山梨醇)及氯化鈉。可藉由在組合物中包括延遲吸收之試劑(例如,單硬脂酸鋁及明膠)來實現可注射組合物之延長吸收。
無菌可注射溶液可藉由以下步驟來製備:將所需量之活性化合物納入具有一種上文所列舉成份或該等成份之組合(根據需要)之適當溶劑中,隨後過濾滅菌。通常,分散液係藉由將活性化合物納入無菌媒劑中來製備,該無菌媒劑含有基本分散介質及來自上文所列舉之彼等之所需其他成份。在用於製備無菌可注射溶液之無菌粉末之情形中,較佳製備方法係真空乾燥及冷凍乾燥,其自其先前無菌過濾溶液產生活性成份加上任何其他期望成份之粉末。
在一實施例中,使用將保護治療化合物抵抗身體快速消除之載劑來製備治療化合物,例如控制釋放調配物,包括植入物及微囊封之遞送系統。可使用生物可降解之生物相容聚合物,例如乙烯基乙酸乙烯酯、聚酸酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。可使用標準技術來製備或以商業方式獲得此等調配物。
醫藥組合物可連同投與說明書一起容納於容器、包裝或分配器中。
包括如本文所述多激酶抑制劑、抗代謝物或多激酶抑制劑及抗代謝物之組合之組合物及調配物可局部投與或以半固體調配物或固體植入物之注射劑形式投與,或藉由業內已知之任何其他適宜方法來投與。儘管可原樣使用本文所揭示之用於療法之試劑,但可較佳以醫藥調配物形式投與該試劑,例如,呈與關於期望投與途徑及標準醫藥實
踐來選擇之適宜醫藥賦形劑、稀釋劑或載劑之混合物。醫藥調配物包括至少一種與醫藥上可接受之賦形劑、稀釋劑及/或載劑聯合之活性化合物。
組合物或調配物之投與可係一天一次、一天兩次、一天三次、一天四次或更高頻率。在治療之治療維持期期間減少頻率,例如,每兩天或三天一次代替每天或一天兩次。劑量及投與頻率可基於治療醫師之判斷來調整,例如考慮使用本發明方法所治療病況之疾病之臨床跡象、病理學跡象及臨床及亞臨床症狀以及患者之病史。
應瞭解,用於治療中所需之本文所揭示之試劑之量將隨投與途徑、需要治療之病況之本質以及患者之年齡、體重及狀況而改變且最終將由主治醫師來決定。組合物通常將含有有效量之單獨或組合之活性試劑。初始劑量可根據動物測試來確定,且用於人類投與之劑量之縮放可根據業內公認之實踐來實施。
治療長度(即天數)將由治療個體之醫師容易地確定;然而,治療天數可在約1天至約365天之範圍內。如由本發明方法所提供,可在療程期間監測療效以確定治療是否已成功,或是否需要額外(或修改)治療。
治療化合物之劑量、毒性及治療功效可在細胞培養物或實驗動物中藉由標準醫藥程序來測定,例如用於測定LD50(對群體之50%致死之劑量)及ED50(在群體之50%中治療有效之劑量)之程序。多激酶抑制劑、抗代謝物之劑量及劑型及其在組合療法中之個別劑量強度可由熟習此項技術者容易地確定,且可(例如)在用於根據業內已知之標準方法確定劑量、安全性及功效之動物模型及文獻中所報導之臨床研究中獲得。確切配方、投與途徑及劑量可由個別醫師根據患者之狀況來選擇。
多激酶抑制劑之劑量強度包括(例如)約0.001mg至約100.0mg、
約0.01mg至約90mg、約0.1mg至約75mg、約0.25mg至約50mg、約0.5mg至約25mg、約0.75mg至約20mg、約1.0mg至約15mg、約1.25mg至約10mg、約1.5mg至約5.0mg、約1.75mg至約2.5mg,例如,0.001mg、0.01mg、0.1mg、0.25mg、0.5mg、0.75mg、1.0mg、1.25mg、1.5mg、1.75mg、2.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg、30.0mg、40.0mg、50.0mg、60.0mg、75.0mg或100.0mg之多激酶抑制劑。舉例而言,尼達尼布之劑量強度包括(例如)0.1mg、0.25mg、0.5mg、0.75mg、1.0mg、1.25mg、1.5mg、1.75mg、2.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg、30.0mg、40.0mg、50.0mg、60.0mg、75.0mg或100.0mg之尼達尼布。
用於本發明方法中之組合物可包括以組合物總量之重量或體積計0.001%至10%濃度的多激酶抑制劑。舉例而言,水性組合物包含0.001%、0.01%、0.1%、0.5%、1.0%、1.5%、2.0%、5.0%或至多10%尼達尼布。
抗代謝物之劑量強度包括(例如)約0.001mg至約100.0mg、約0.01mg至約90mg、約0.1mg至約75mg、約0.25mg至約50.0mg、約0.5mg至約25mg、約0.75mg至約20mg、約1.0mg至約15mg、約1.25mg至約10mg、約1.5mg至約5.0mg、約1.75mg至約2.5mg,例如0.001mg、0.01mg、0.1mg、0.25mg、0.5mg、0.75mg、1.0mg、1.25mg、1.5mg、1.75mg、2.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg、30.0mg、40.0mg、50.0mg、60.0mg、75.0mg、或100.0mg之抗代謝物。舉例而言,MMC之劑量強度包括(例如)0.1mg、0.25mg、0.5mg、0.75mg、1.0mg、1.25mg、1.5mg、1.75mg、2.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg、30.0mg、40.0mg、50.0mg、60.0mg、75.0mg、或100.0mg之MMC。
用於本發明方法中之組合物可包括以組合物總量之重量或體積計0.001%至10%濃度之抗代謝物。舉例而言,水性組合物包含0.001%、0.01%、0.1%、0.5%、1.0%、1.5%、2.0%、5.0%或至多10% MMC。
如熟習此項技術者將熟悉,投與眼之水溶液可呈來自滴管或吸量管或其他專用無菌裝置之「滴」或數滴(例如多激酶抑制劑溶液、抗代謝物溶液或其組合)之形式。此等滴通常將為以體積計至多50微升,但可能較少,例如少於10微升。
在以下實例中進一步闡述本發明,該等實例並不限制申請專利範圍中所述之本發明之範圍。
建立兔角膜縫合模型以評價藥物對角膜新血管形成之效應(Ko等人,Cornea.2013;32(5):689-695;Pérez-Santonja等人,Am J Ophthalmol.2010;150(4):519-528)。在此模型中研究尼達尼布之抗新血管形成活性。
製備包含於磷酸鹽緩衝溶液(pH7.4)中之10% 2-羥基丙基β環糊精中之0.2%或0.05%尼達尼布之局部組合物。另外,在相同媒劑中製備包含0.05%舒尼替尼之組合物以用作陽性對照。
使用36隻雌性紐西蘭白兔(Zealand White rabbits)實施研究。簡言之,第1天將5個縫線置於各動物右眼之上角膜中以誘導新血管形成。如表4中所述治療動物之兩隻眼。
BID:每天兩次(相隔約10小時至12小時)。TID:每天三次(相隔約6小時至8小時)。OD=右眼。OS=左眼。
對兩隻眼給藥,劑量體積係約40μL/眼。
注意:第1天鹽水之第一劑量係在縫線放置後4小時進行。
在研究期間,密切觀察動物之各種眼適應症以及一般身體狀況,包括體重。在第7、10、12、14、21、28天獲取眼影像用於分析。
使用NIH ImageJ®軟體分析眼影像。將各影像在ImageJ®中打開,使用照片中之尺來校準標尺且藉由選擇工具來選擇縫線附近角膜上之新血管形成面積。藉由軟體中之量測工具來計算面積(mm2),記錄於excel中且捕獲並保存影像。使用雙尾t測試測定成對之組是否顯著不同。為便於比較,將結果繪製為平均值及標凖偏差之直方圖。
將此研究之結果總結於下圖1A及1B及表5中。結果展示尼達尼布對兔角膜中縫線誘導之新血管形成具有顯著抑制效應。相較於0.05%尼達尼布,0.2%尼達尼布之較高劑量顯示改良之功效,同時相較於BID給藥,TID給藥之更頻繁給藥方案顯示改良之功效。令人驚訝地,在此模型中在減少新血管面積中尼達尼布顯示優於陽性對照舒尼替尼之明顯趨勢。
在兔縫合模型中,先前已顯示相較於貝伐珠單抗(抗VEGF抗體)舒尼替尼可更有效抑制血管形成(Ko等人,Cornea.2013;32(5):689-695;Pérez-Santonja等人Am J Ophthalmol.2010;150(4):519-528)。其觀察結果表明靶向多種受體-酪胺酸-激酶路徑之小分子激酶抑制劑可具有優於靶向選擇性極強的路徑之抗體藥物之優點。本發明結果顯示在縫合模型中尼達尼布亦極有效地抑制新血管形成。相當意外地,本發明者發現具有大量激酶靶標重疊之激酶抑制劑仍可具有不同功效。儘管尼達尼布及舒尼替尼二者皆抑制關鍵VEGFR家族,但其具有若干非重疊靶標。如表1中所示,尼達尼布之靶標譜不同於舒尼替尼以及若干種研究社群中認為極相似之其他MKI。尼達尼布之特殊激酶靶標組似提供至少兩個令人驚訝的優點:1)其使尼達尼布成為比舒尼替尼更有效之新血管形成之高效抑制劑,如兔縫合模型中所展示;2)相較於舒尼替尼其靶向較少激酶,容許較佳安全性界限及較高劑量。因此,應理解,相較於舒尼替尼,尼達尼布已展示改良之功效及較佳安全性概況。
先前癌症研究中之發現支持吾人之主張之原理,在癌症研究領域中廣泛使用MKI。對於癌症,一些具有大量重疊靶標之MKI仍可在患者中具有極為不同的功效。舉例而言,在非小細胞肺癌(NSCLC)患者中測試許多具有重疊靶標之小分子MKI,但有趣地,僅尼達尼布顯示出功效且經核準用於與其他藥物之組合療法中(Hall RD等人,Transl Lung Cancer Res.2015;4(5),515-23)。類似於此之觀察結果指示激酶抑制劑之靶標譜可顯著影響在某些適應症中之功效。
吾人之新穎見解總結如下:第一,通常,具有某些靶標譜之小
分子MKI對於治療異常角膜新血管形成優於抗體藥物。儘管先前研究暗示此結果,但其係基於貝伐珠單抗與舒尼替尼之間之單對比較。現在,吾人之尼達尼布研究更有力地支持此理論。第二,吾人之新穎想法係,各個MKI具有其獨特靶標譜且並非所有MKI皆將在治療翼狀胬肉症狀中同樣安全且有效。不受理論所束縛,據信尼達尼布提供獨特譜,其將提供用於翼狀胬肉之最有效且安全之治療之一。
總之,尼達尼布之獨特靶標譜可使其成為用於治療翼狀胬肉之更有效且更安全之藥物。尼達尼布比舒尼替尼更有效地抑制FGFR1-3。尼達尼布亦抑制並非係舒尼替尼靶標之FGFR4、Lyn、Src(參見背景部分中之表1)。另外,預期尼達尼布具有比舒尼替尼更佳的安全性概況,此乃因已知相較於相同類別中之化合物,舒尼替尼命中更多激酶(Kumar等人,Br J Cancer.2009;101(10):1717-23)且其抑制一些未列示於表1中之其他激酶。該等激酶中之一些(例如CaMK家族)對於正常細胞功能很重要且其抑制可具有安全性問題。
闡述人類翼狀胬肉小鼠模型以評價免疫缺陷小鼠角膜上之人類翼狀胬肉生長(Lee等人,Graefes Arch Clin Exp Ophthalmol.2014;252(4):609-18)。本發明研究調查若干藥物對翼狀胬肉生長之效應。該等藥物係尼達尼布、舒尼替尼及絲裂黴素C。
測試之物件製備於磷酸鹽緩衝溶液(pH 7.4)中之10% 2-羥基丙基β環糊精中。調配物之詳細資訊揭示於以下部分中。
將7週齡雄性無胸腺裸小鼠在無病原體條件下在頂部有過濾器之封閉籠中適應。
自手術切除後所收集之樣本分離人類翼狀胬肉上皮細胞(hPEC)並培養。所有參與者在已接受該研究之全面說明之後提供書面知情同意書。於補充有10%小牛血清、0.5%二甲亞碸及1%抗生素/抗黴劑之DMEM/F12培養基中將新鮮翼狀胬肉樣本在塗佈有膠原蛋白(大鼠尾I型膠原蛋白)之表面上培養3天,在此期間細胞自外植體遷移。然後,移除外植體且將培養基改變為具有5% BCS及1%抗生素/抗黴劑之角質細胞無血清培養基以進一步促進上皮細胞生長。
藉由i.p.注射用於結膜下注射之氯胺酮(30mg/kg)及隆朋(rumpun,2,5mg/kg)來麻醉小鼠。在第0天藉由在兩隻眼之鼻側結膜下空間中注射1×104個hPEC來誘導小鼠中之翼狀胬肉。在7天後,經hPEC誘導之小鼠經受測試。
如下治療動物:組1:媒劑右眼且鹽水左眼;組2:0.2%尼達尼布右眼且鹽水左眼;組3:0.002%絲裂黴素右眼且鹽水左眼;組4:0.05%舒尼替尼右眼且鹽水左眼;組5:0.2%尼達尼布及0.002%絲裂黴素混合物右眼且鹽水左眼。
藉由在第7、10及14天鼻側結膜下注射且藉由在第8、9、11、12、13、15及16天QID局部滴眼給藥來治療動物。在每次注射之前亦及在第17天,藉由使用立體顯微鏡觀察且對眼拍照。
在實驗期間每天觀察小鼠之毒性之臨床跡象。在注射之前且在第17天觀察且對眼拍照。記錄所有發現,包括疾病、診斷及療法。在
第0、7天、第11天、第15天及第17天量測小鼠之體重。
使用ImageJ®對照片實施影像分析以量測第0、7、10、14及17天之病灶大小。該等數據經計算為翼狀胬肉對整個角膜之比率。
評估所有小鼠之眼之臨床特徵。將角膜新血管形成(NV)之程度自0至3評分,其中0=無NV,1=NV限制在角膜外圍,2=NV延伸至瞳孔邊緣,且3=NV越過瞳孔邊緣延伸至中央角膜中。
藉由SPSS之Windows 18.0版(SPSS,Chicago,IL)分析數據且表示為平均值±標凖偏差。
結果顯示於圖2A-B、3A-B、4A-B及5A-B中,且亦總結於上表4中。在人類翼狀胬肉小鼠模型中,0.2%尼達尼布治療使得相較於第7天之基線水準,第14天及第17天之翼狀胬肉面積減小(圖2A及2B)。與此相比,對照鹽水治療之眼顯示第14天及第17天翼狀胬肉面積增加。尼達尼布亦在治療期間減少角膜上新血管形成分數,其中第17天之程度顯示與第7天基線之顯著差異(圖2A及2B),而對照眼顯示新血管形成之較小非統計學顯著的增加(圖2A及2B)。在此模型中,0.002%絲裂黴素及0.05%舒尼替尼亦顯示減小翼狀胬肉面積之趨勢,但在任何時間點均並未達到統計學顯著性(圖3A-3B、4A-4B)。與此相比,對照鹽水治療之眼在幾乎所有時間點顯示翼狀胬肉面積增加且增加幾乎相對於時間呈線性。絲裂黴素及舒尼替尼亦減少新血管形成分數,其中絲裂黴素在第17天顯著減少且舒尼替尼在第14天及第17天顯著減少(圖3A-3B、4A-4B)。同樣,對照眼在治療期間並未顯示新血管形成之顯著變化。在使用尼達尼布及絲裂黴素之組合治療之眼中,翼狀胬肉
面積未增加,而鹽水對照顯著增加(圖5A-5B)。在此動物組中新血管形成分數未顯示顯著變化。
藥物產物係於2-羥基丙基β環糊精或其他類似環糊精及緩衝溶液(pH在5.5至8.0範圍內)中製備之等滲眼科溶液。可添加其他增黏劑、潤滑劑、防腐劑以增強調配物功能。眼科溶液之組成揭示於表6中。
藥物產物係於羧甲基纖維素鈉及緩衝溶液(pH在5.5至8.0範圍內)中製備之等滲眼科懸浮液。藥物粒徑減少至小於40微米。可添加其他增黏劑、潤滑劑、增溶劑及防腐劑以增強調配物懸浮液之功能。組成揭示於表7中。
藥物產物係等滲眼科乳液。將藥物溶解於油相及乳化劑賦形劑之混合物中,然後將其乳化且與水相(pH在5.5至8.0範圍內)混合。可添加其他增黏劑、潤滑劑、增溶劑及防腐劑以增強乳液調配物之功能。組成揭示於表8中。
藥物產物係等滲持續釋放半固體調配物。將藥物溶解及/或懸浮於半固體介質(pH在5.5至8.0範圍內)中。可添加其他增黏劑、潤滑劑、增溶劑及防腐劑以增強持續釋放半固體調配物之功能。組成揭示於表9中。
藥物產物係固體植入物。將藥物與一或多種聚合物混合且摻和。將藥物及聚合物之混合物在預定之溫度下融化且擠製成具有預定直徑大小之絲。將調配物絲切割為可植入眼組織中之預定大小之節段。組成揭示於表10中。
不受限制,用於本發明方法中之實例組合物可自現有的眼科可接受之組合物修改。
應瞭解,儘管已結合其詳細說明來闡述本發明,但上文說明係意欲闡釋而非限制本發明範圍,本發明之範圍係由隨附申請專利範圍之範圍而界定。其他態樣、優點及修改形式係在以下申請專利範圍之範圍內。
Claims (35)
- 一種用於誘導翼狀胬肉自視軸/中央角膜消退之方法,其包含向需要此治療之個體之患眼投與治療有效量之(1)多激酶抑制劑;(2)抑制上皮及纖維母細胞增殖之抗代謝物;或(3)其組合。
- 如請求項1之方法,其中該多激酶抑制劑、該抗代謝物或其組合之投與使得該患眼中之該翼狀胬肉大小減小。
- 如請求項1之方法,其中該多激酶抑制劑、該抗代謝物或其組合之投與導致該患眼中之翼狀胬肉生長速率為負。
- 一種穩定翼狀胬肉之方法,其包含向需要此治療之個體之患眼投與治療有效量之(1)多激酶抑制劑;(2)阻斷上皮及纖維母細胞增殖之抗代謝物;或(3)其組合。
- 如請求項4之方法,其中該多激酶抑制劑、該抗代謝物或其組合之投與使得該患眼中之該翼狀胬肉大小穩定。
- 如請求項4之方法,其中該多激酶抑制劑、該抗代謝物或其組合之投與導致該患眼中之翼狀胬肉生長速率為約零。
- 如請求項1至6中任一項之方法,其中該多激酶抑制劑降低翼狀胬肉中之一或多種選自以下之細胞內及/或細胞表面蛋白激酶之活性:EGFR、ErbB2、ErbB3、FGFR1、FGFR2、FGFR3、FGFR4、TrkA、NGFR、VEGFR(1、2、3)、PDGFR(α、β)、TGF-βR(I、II、III)、FLT3、Lck、Lyn、Src、c-Kit、c-Fms、Raf-1、B-Raf、RET、CSF-1R。
- 如請求項7之方法,其中該多激酶抑制劑具有針對VEGFR(1、2、3)之IC50<200nM,針對PDGFR(α、β)之IC50<200nM,及/或針對FGFR(1、2、3)之IC50<1000nM。
- 如請求項1至8中任一項之方法,其中該多激酶抑制劑選自由以下組成之群:阿法替尼(Afatinib)、阿姆替尼(Amuvatinib)、阿西替尼(Axitinib)、卡博替尼(Cabozantinib)、卡奈替尼(Canertinib)、西地尼布(Cediranib)、色瑞替尼(Ceritinib)、克萊拉尼(Crenolanib)、克唑替尼(Crizotinib)、達拉菲尼(Dabrafenib)、達克替尼(Dacomitinib)、達沙替尼(Dasatinib)、厄洛替尼(Erlotinib)、弗雷替尼(Foretinib)、吉非替尼(Gefitinib)、格瓦替尼(Golvatinib)、依魯替尼(Ibrutinib)、埃克替尼(Icotinib)、艾代拉裡斯(Idelalisib)、伊馬替尼(Imatinib)、拉帕替尼(Lapatinib)、樂伐替尼(Lenvatinib)、來那替尼(Neratinib)、尼羅替尼(Nilotinib)、尼達尼布(Nintedanib)、帕博西尼(Palbociclib)、帕唑帕尼(Pazopanib)、普納替尼(Ponatinib)、奎紮替尼(Quizartinib)、瑞格菲尼(Regorafenib)、魯索替尼(Ruxolitinib)、索拉菲尼(Sorafenib)、舒尼替尼(Sunitinib)、坦度替尼(Tandutinib)、提瓦替尼(Tivantinib)、替肟紮尼(Tivozanib)、曲美替尼(Trametinib)、凡德他尼(Vandetanib)、瓦他拉尼(Vatalanib)及威羅菲尼(Vemurafenib)。
- 如請求項1至6中任一項之方法,其中該抗代謝物選自由以下組成之群:絲裂黴素C、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-氮尿嘧啶、硫唑嘌呤、胺甲喋呤、嗎替麥考酚酯(Mycophenolate Mofetil)及噻替派(Thiotepa)。
- 如請求項1至10中任一項之方法,其中該多激酶抑制劑、該抗代謝物或其組合係以以下形式投與該患眼:局部眼調配物、軟膏、凝膠、持續釋放半固體調配物、持續釋放固體調配物或眼植入物。
- 如請求項11之方法,其中該多激酶抑制劑、該抗代謝物或其組 合係以局部眼調配物形式投與該患眼且係局部投與該患眼。
- 如請求項11之方法,其中該局部眼調配物係溶液、懸浮液或乳液。
- 如請求項13之方法,其中該局部眼調配物進一步包含一或多種選自以下之醫藥上可接受之賦形劑:穩定劑、表面活性劑、聚合物基載劑、膠凝劑、有機共溶劑、pH活性組分,滲透活性組分且具有或不具有防腐劑。
- 如請求項11之方法,其中將該持續釋放半固體調配物、持續釋放固體調配物或眼植入物注射至該患眼中。
- 如請求項15之方法,其中該持續釋放半固體調配物、持續釋放固體調配物或眼植入物進一步包含醫藥上可接受之賦形劑。
- 如請求項16之方法,其中持續釋放半固體調配物、持續釋放固體調配物或眼植入物包含多激酶抑制劑、該抗代謝物或其組合;及選自聚乳酸(PLA)、聚乙醇酸(PLGA)及聚乳酸聚乙醇酸共聚物之生物可降解聚合物。
- 如請求項1至17中任一項之方法,其中對翼狀胬肉患者實施投與。
- 一種用於減少需要此治療之患者之翼狀胬肉、瞼裂斑及假性翼狀胬肉中之充血及其症狀之方法,其包含向該個體之患眼投與治療有效量之多激酶抑制劑。
- 一種用於減少或防止需要此治療之個體之翼狀胬肉復發之方法,其包含向該個體之患眼投與治療有效量之多激酶抑制劑。
- 如請求項20之方法,其中在翼狀胬肉之手術移除之前實施投與。
- 如請求項20之方法,其中在翼狀胬肉之移除之手術程序期間實 施投與。
- 如請求項20之方法,其中在翼狀胬肉之手術移除後實施投與。
- 如請求項19至23中任一項之方法,其中該多激酶抑制劑具有針對VEGFR(1、2、3)之IC50<50nM,針對PDGFR(α、β)之IC50<100nM,針對FGFR(1、2、3)之IC50<150nM,針對FGFR4之IC50<1000nM,針對FLT3之IC50<50nM,針對Lck之IC50<50nM,針對Lyn之IC50<200nM及針對Src之IC50<200nM。
- 如請求項24之方法,其中該多激酶抑制劑選自由以下組成之群:尼達尼布{(3Z)-3-{[(4-{甲基[(4-甲基六氫吡嗪-1-基)乙醯基]胺基}苯基)胺基](苯基)亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-6-甲酸甲酯}、其游離鹼、水合物、溶劑合物或醫藥上可接受之鹽。
- 如請求項25之方法,其中該多激酶抑制劑係尼達尼布游離鹼或乙磺酸尼達尼布(乙磺酸鹽)。
- 如請求項19至26中任一項之方法,其中該多激酶抑制劑係以局部眼調配物、持續釋放半固體調配物、持續釋放固體調配物或眼植入物形式投與該患眼。
- 如請求項27之方法,其中尼達尼布係以局部眼調配物形式投與該患眼且係局部投與該患眼。
- 如請求項28之方法,其中該局部眼調配物係溶液、懸浮液或乳液。
- 如請求項28之方法,其中該局部眼調配物中尼達尼布之濃度係該調配物之總量之0.001重量%至10重量%。
- 如請求項27之方法,其中該局部眼調配物進一步包含一或多種選自以下之醫藥上可接受之賦形劑:穩定劑、表面活性劑、聚合物基載劑、膠凝劑、有機共溶劑、pH活性組分、滲透活性組分及防腐劑。
- 如請求項27之方法,其中將該持續釋放半固體調配物、持續釋放固體調配物或眼植入物注射至該患眼中。
- 如請求項32之方法,其中該持續釋放半固體調配物、持續釋放固體調配物或眼植入物包含尼達尼布及醫藥上可接受之賦形劑。
- 如請求項33之方法,其中該持續釋放半固體調配物、持續釋放固體調配物或眼植入物中尼達尼布之量係1μg至100mg。
- 如請求項27之方法,其中持續釋放半固體調配物、持續釋放固體調配物或眼植入物包含尼達尼布;及選自聚乳酸(PLA)、聚乙醇酸(PLGA)及聚乳酸聚乙醇酸共聚物之生物可降解聚合物。
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