TWI587857B - 用於治療眼部發炎病症之酯類(二) - Google Patents
用於治療眼部發炎病症之酯類(二) Download PDFInfo
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- TWI587857B TWI587857B TW101123366A TW101123366A TWI587857B TW I587857 B TWI587857 B TW I587857B TW 101123366 A TW101123366 A TW 101123366A TW 101123366 A TW101123366 A TW 101123366A TW I587857 B TWI587857 B TW I587857B
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- surfactant
- inflammatory
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Description
本申請案主張於2012年6月13日提出申請之美國專利申請第13/495,052號以及2011年6月30日所提申之美國專利臨時申請案第61/503,158號之優先權。
本發明關於含有酯化抗發炎脂質媒介物之眼用產品,該等媒介物用於乾眼之緩解或發炎性眼部病症的治療。本發明提供一種眼用組成物,其包含一酯化抗發炎脂質媒介物。本發明進一步提供投與於眼睛及/或隱形眼鏡之無菌製劑、溶液、凝膠、軟膏及/或貼條(strip),其包含一酯化抗發炎脂質媒介物者。
咸知充分潤滑是良好眼睛健康所必需的。淚液滋潤眼睛組織並保護眼睛表面不受外物傷害。由於淚液質或量上的變化(肇因於淚液生產減少或淚膜蒸散增加)而在眼睛表面上的變化可能導致乾眼症及其他發炎性眼部病症。乾眼之典型病症及其他發炎性眼部病症,包括乾燥、灼熱、發癢、搔癢感、刺痛、感覺有沙粒入眼、疲倦的眼睛及對光敏感度。這些病症通常會隨著時間發展而愈加嚴重。其他病症包括疼痛、發紅、拉扯感、眼睛後方壓力,以及感覺眼睛裡有異物。由於這些病症,罹患乾眼及其他發炎性眼部病症之苦的人往往也會抱
怨眼睛感到刺激和不適。
若放任乾眼及其他發炎性眼部病症不加治療,可能引起會傷害眼睛的併發症,甚或造成視力減弱或(罕見)視力的喪失。病症嚴重時,乾眼可能影響個人生活品質。
眼睛表面通常覆有淚膜,這是一層覆蓋眼睛外側組織的清澈液體。淚膜是由三層組成;淚膜最表層為脂質層,其覆蓋淚膜之水層,且然後第三層為一黏液性層。三層之任何一層中的任何異常,尤其是在脂質層中的失調,產生一不穩定淚膜,該不穩定淚膜導致乾眼病症及其他發炎性眼部病症。
目前緩解乾眼病症的方法,包括在眼睛表面投與人工淚液。然而,這些人工淚液每幾小時就必須投與一次,而且對乾眼病症只能提供暫時且不完全的緩解。因此,有用來治療各種眼睛疾患與病症的組成物及方法的需要,所述疾患與病症包括但不限於乾眼症及其他發炎性眼部病症。
已知食用含有飲食性ω-3脂肪酸的紅肉魚類與減少乾眼症發生有關聯。由於ω-3及ω-6脂肪酸對人體健康是必需的,其等為通稱「必需」脂肪酸的化合物。然而,這些脂肪酸非由人體所產生;而是這些脂肪酸可經由食品形式或作為營養補充品之飲食攝取而被引入人體。然而,經口食用ω-3脂肪酸的確產生潛在副作用,如對出血時間的影響、提高膽固醇(LDL)位準、高熱量攝取、口中殘留魚腥味,以及造成腸胃功能障礙。因其
具有改善乾眼病症及其他發炎性眼部病症的潛力,研究顯示將ω-3脂肪酸局部使用於眼睛表面可展現令人期待的結果。(Rashid,S.et al.,“Topical Omega-3 and Omega-6 Fatty Acids for Treatment of Dry Eye,”Arch Opthalmol.2008;126(2):219-225)。使用脂肪酸的局部配方以治療乾眼將對治療提供更大的彈性,包括減少病患可能因經口攝食脂肪酸而受到的副作用。
如植物油之含ω-3脂肪酸油類已經被使用以形成非刺激性眼用組成物(如美國專利申請公開案第2010/0305045號(Abbott Medical Optics,Inc.))。水凝膠隱形眼鏡可包含聚合基質與散佈於其中的疏水性舒適劑,其中所述疏水性舒適劑可包括單甘油酯、雙甘油酯、三酸甘油酯、醣脂、甘油醣脂質、神經脂質、抱合糖脂質、磷脂質、脂肪酸、脂肪醇、長度上具有C12-C28鏈之烴、礦油、聚矽氧油或其混合物。(美國專利申請公開案第第2010/0140114號(Ciba Vision Corporation))。目前已有含抗毒劑之眼用鏡片,所述抗毒劑為一多元脂肪醇及一脂肪酸單酯類及/或雙酯類,含有八至十八個碳原子,且其中該單酯具有至少一與其脂肪族醇殘留物連結之羥基(美國專利第5,472,703號)。緩解素(resolvin)與保護素(protectin)已用於協助治療與下列有關的之病狀:血管生成及眼睛新血管生成,特別是與早產兒視網膜病變者有關(如美國專利申請公開案第20100105773號(Children’s Medical Center
Corp.))。脂氧素(lipoxin)也已用於治療與眼睛新血管生成有關之病狀(如美國專利申請公開案第20100105772號(Serhan等人))。
據此,此技藝中仍需要能夠緩解/減輕乾眼病症及其他發炎性眼部病症之改良眼用產品。
在一實施例中,本發明提供一種用以治療眼部病症之眼用組成物,該組成物包含一抗發炎脂質媒介物之酯或醯胺,該酯或醯胺為該抗發炎脂質媒介物與一碳鏈長度為四至十個碳之多元醇的反應產物。一般而言,大部分之該抗發炎脂質媒介物係以一酯形式存在。此係和以酸形式存在之抗發炎脂質媒介物形成對照。在一或多個實施例中,該組成物係實質上不含脂肪酸。此種酯化抗發炎脂質媒介物可被分散及/或可溶解或可乳化於含水傳遞系統中。
在另一實施例中,本發明提供一投與於眼睛或隱形眼鏡之無菌製劑、溶液、凝膠,軟膏、乳膠或貼條,其包含一酯化抗發炎脂質媒介物。
在又一實施例中,本發明提供一種用以治療、預防或減輕個體發炎性眼部病症及/或乾眼的方法,其包含將一治療有效量之含抗發炎脂質媒介物組成物傳遞至該個體之眼睛表面。
本發明之上述及其他實施例將可藉由以下較佳實
施例之敘述而顯明。詳細說明僅為說明本發明之用,且不構成對於本發明範疇之限制,本發明之範疇係由本案申請專利範圍及其等之等同替換者所定義。本發明的變化與修改可能在不脫本揭露新穎內容之精神與範疇下被完成。
本發明提供製作與使用含酯化抗發炎脂質媒介物之眼用產品的程序,其中該抗發炎脂質媒介物之大部分係以酯形式存在。已經發現,當大部分之該抗發炎脂質媒介物以酯形式存在時,酯化抗發炎脂質媒介物的使用結果形成一眼用產品,該眼用產品可大幅改善接觸或投與於眼睛表面時之開始的舒適度。眼用產品包括但不限於製劑、溶液、凝膠、軟膏、乳膠、貼條、眼用裝置及類似物,任何可投與於眼睛表面,包括眼球者。
有關本說明書中使用術語,其定義分別如下所述。
提及「抗發炎脂質媒介物」包括能夠直接或間接發揮以下作用的分子:抑制上皮細胞或免疫細胞產生細胞介素、抑制上皮細胞或免疫細胞產生活性氧化物(ROS)、控制及/或抑制白血球募集回流(減少白血球浸潤),及/或發炎的消退(死細胞之攝取的促進作用)。適合之抗發炎脂質媒介物通常為其烴鏈之羧基可被酯化的酸基實體。大部分之該抗發炎脂質媒介物是以酯形式存在。抗發炎脂質媒介物可視需要與各種實體之羥基
反應。該羥基由多元醇提供,配合酯化抗發炎脂質媒介物,可對眼睛有治療之效益,包括滲透保護。
本文中所使用的術語「約」意指所修改數字正負5%之範圍。例如:詞組「約10」將包括9.5及10.5二者。
如在此所用,「一」及「該」包括單數及複數。
本文中所使用的術語「眼用組成物」意指適合投與至眼睛或眼睛表面之化合物或混合物。眼睛組成物包括製劑、溶液、凝膠、軟膏、乳膠、貼條及類似物。
本文中所使用的術語「無菌製劑」包括任何用以直接投與至哺乳動物身體任何部位之化合物或混合物,包括植入、注射、以滴劑、凝膠或洗劑及類似物投藥,其中該製劑在投與前實質上不含任何異物。用於確保無菌之方法包括無菌包裝以及滅菌,藉由曝露在輻射、其之熱組合及類似物。
本文中所使用的術語「個體」包括人類及脊椎動物。
本文中所使用的術語「劑」包括為在本文所揭示方法中的療效而被測定之任何化合物、組成物。
本文中所使用的術語「眼睛表面」包括角膜、結膜、淚腺、副淚腺、鼻淚管及瞼腺之表面濕潤與腺上皮,以及其等之頂部與底部基質、點及相鄰或相關結構,該等結構包括透過上皮之連續性、透過神經分佈二者所連結為機能系統之眼瞼以及內分泌和免疫系統。
本文中所使用的術語「隱形眼鏡」意指可被放置於個體之眼睛的角膜上之結構體。隱形眼鏡可提供矯正、美容及治療效益,包括創傷癒合、藥物或營養製劑的遞送、診斷評估或監控、或阻擋紫外線及減少可見光或眩光、或其等之組合。隱形眼鏡可以本技藝中已知之任何適當材料製成,且可為軟式鏡片、硬式鏡片或混合式鏡片。
本文中所使用的術語「聚矽氧水凝膠隱形眼鏡」意指自一聚合物所形成之隱形眼鏡,該聚合物包含含聚矽氧以及親水性重複單元。
本文中所使用的術語「水凝膠」或「水凝膠材料」意指在平衡狀態下含水的水合交聯聚合系統。水凝膠於平衡時通常含有至少約15 wt%的水且在一些實施例中,至少約20 wt%的水。
習知水凝膠是以主要含親水性單體之單體混合物製成,所述單體如甲基丙烯酸2-羥乙酯(HEMA)、N-乙烯基吡咯啶酮(NVP)或醋酸乙烯酯。美國專利第4,495,313號、第4,889,664號及第5,039459號揭露習知水凝膠之形成。
本文中所使用的術語「聚矽氧水凝膠」意指由含聚矽氧單體、巨分子單體及預聚合物中至少一者與至少一親水性成分共聚合所獲得之水凝膠。聚矽氧水凝膠之實例包括巴拉菲康(balafilcon)、acquafilcon、lotrafilcon、comfilcon、galyfilcon、senofilcon、narafilcon、falcon II
3、asmofilcon A以及如在U.S.5,998,498、WO 03/22321、U.S.6,087,415、U.S.5,760,100、U.S.5,776,999、U.S.5,789,461、U.S.5,849,811、U.S.5.965.631、U.S.7,553,880,WO 2008/061992和U.S.2010/048847中所製備之聚矽氧水凝膠。上述專利以及所有於本段中揭露之其他專利,其整體以引用方式併入本文。
由包括但不限於下列的聚合物所製成的硬式隱形眼鏡:聚(甲基)丙烯酸甲酯、矽丙烯酸酯、含氟丙烯酸酯、氟醚、聚乙炔及聚醯亞胺之聚合物,其中代表性實例之製備可見於JP 200010055、JP 6123860及美國專利第4,330,383號。本發明之人工水晶體可使用已知材料而被製成。例如:該鏡片可以一硬質材料製成,包括但不限於聚甲基丙烯酸甲酯、聚苯乙烯、聚碳酸酯或類似物及其組合。此外,可用之彈性材料包括但不限於水凝膠、聚矽氧材料、丙烯酸材料、碳氟化合物材料及類似物或其組合。標準的人工水晶體係被揭示於WO 0026698、WO 0022460、WO 9929750、WO 9927978、WO 0022459及JP 2000107277中。所有於本案中所提及之參考文獻其整體以引用方式併入本文。
一治療有效量之抗發炎脂質媒介物係指一量,其可有效在受治療之疾病或病症的病理學上產生臨床可辨認良性改變者。治療有效量包括能夠有效治療、減少、
緩和、改善、減輕、消除或預防一或多種待治療之眼部病症或欲避免或治療之病症者。
具此技藝技術人士應可輕易判定治療有效量或有效量為何。
本文中所使用的術語「發炎性眼部病症」包括乾眼症,亦稱為乾性角膜結膜炎(KCS)。乾眼為一種淚液及眼睛表面的多因子疾病,會導致不適、視覺干擾以及淚膜不穩定等病症,可能傷害眼睛表面。其伴隨有淚膜滲透壓升高及眼睛表面發炎。乾眼症(DES)定義為淚膜失調,其原因為淚液不足及/或淚液過度蒸散,造成對眼睛表面的傷害及造成眼睛不適的病症。乾眼症主要有兩種型態:淚液不足型(包括休格倫氏症候群及非休格倫氏淚液不足)以及蒸散形式。淚膜常態覆蓋眼睛前方部位,亦即角膜及結膜。淚膜持續暴露於可刺激或阻滯其蒸散的多重環境因素,包括變化的溫度、氣流及濕度。尤其,低濕度且氣流大的環境會增加淚液蒸散,此為乾燥環境中的受試者經常通報的問題。確實,即使具正常淚液分泌速率的人,當暴露於乾燥環境的時候,如在飛機中和乾燥工作場所中,可感受乾眼病症。
乾眼亦可定義為淚液減少或品質改變的狀況,不論角膜及結膜是否損傷。其包括具有以下情況個體所會遭遇的乾眼病症:少淚症、無淚症、乾眼病及糖尿病、HIV/AIDS等等;白內障手術後乾眼;過敏性結膜炎關聯性乾眼;長期配戴隱形眼鏡關聯性乾眼;以及與年齡
有關的乾眼症。乾眼亦可包括在因長時間操作視覺顯示終端機(VDT)、空調造成室內乾燥及類似因素所導致的少淚症個體中所發現之病症。「發炎性眼部病症」可指,但不限於:乾性角膜結膜炎(KCS)、與年齡有關的乾眼、史帝芬強生併發症、休格倫氏症候群、眼睛瘢痕性類天疱瘡、瞼炎、角膜受傷、感染、萊里德併發症、先天無淚症、營養失調或不足(包括維生素)、藥物副作用、眼睛壓力、腺及組織破壞、環境暴露(如煙霧、煙、過乾空氣、空浮微粒)、自體免疫及其他免疫不全失調,及個體因昏迷無法眨眼。
如在此所用,「隱形眼鏡相關的乾眼」(CLRDE)是以至少一客觀臨床病症及至少一主觀病症所標出之失調。臨床病症選自:(a)在至少一眼中,淚液層「瓦解」時間(TFBUT)為少於約10秒;(b)在至少一眼中,螢光黃染色評分在0-15的量表上大於等於3;(c)在至少一眼中,麗絲胺綠染色評分在0-18的量表上大於等於3;或(d)在至少一眼中,「異常」的涙三角等級。依據病患意見回饋之主觀病症包括(a)平均每日隱形眼鏡配戴時間與平均每日舒適隱形眼鏡配戴時間之差為約2小時,及(b)配戴鏡片期間頻繁或持續發生之乾燥、灼熱、刺痛或不適感。CLRDE徵兆包括過度淚液蒸散及非休格倫氏水性涙液不足。過度淚液蒸散為一種由以下所標出的失調:至少一眼產生約10秒或更短之TFBUT或至少一眼產生10秒或更短之TFBUT且結膜或角膜汙染在
NEI表中為約3或更高。非休格倫氏水性涙液不足涙三角為由以下所標出的失調:至少一眼為「異常」等級,或至少一眼為「異常」涙三角等級且結膜或角膜汙染在NEI表中為約3或更高。
本文中所使用的術語「附屬區域發炎」包括眼睛或眼部系統任何區域或部分的發炎,包括但不限於眼瞼、淚腺以及眼外肌肉。
本文中所使用的術語「滲透保護」意指維持眼睛滲透壓在一正常生理範圍內(較佳的是270-320 mOsm/kg,具一約290 mOsm/kg的平均值)及/或保護上皮組織不受高張情況影響,其中單位「mOsm/kg」表示每公斤毫滲透莫耳。滲透保護劑為提供滲透保護之試劑,通常不帶電,可留滯於眼睛細胞中,具有相對低的分子量,且另外相容於細胞代謝。滲透保護劑可保護不受眼睛表面下高滲透壓影響,並對上皮表面提供水合作用。滲透保護劑包括但不限於甘油、肌醇、山梨醇、木糖醇,以及赤藻糖醇。
本文中所使用的術語「不飽和脂肪酸」意指含有至少一個雙鍵或三鍵的脂肪酸。此類脂肪酸用希臘字母以指認雙鍵的位置。「α」碳是最靠近羧基的碳,且「ω」碳則是鏈上最後一個碳。例如:亞麻油酸及γ-次亞麻油酸(分別為LA及GLA)為ω-6脂肪酸,因為它們遠離ω碳六個碳處具有雙鍵。α-次亞麻油酸為ω-3脂肪酸,因為它的雙鍵離ω碳有三個碳原子的距離。
本文中所使用的術語「ω-3脂肪酸」意指脂肪酸,該等脂肪酸距其等之ω碳原子三個碳原子遠具有雙鍵。例如:ω-3脂肪酸包括但不限於α次亞麻油酸(ALA)。其他ω-3脂肪酸包括ALA的衍生物。ALA的「衍生物」是經化學改質所製成的脂肪酸,該化學改質係在α次亞麻油酸上藉由,例如:酵素,所進行,或是經有機合成所對待。為ALA的衍生物之ω-3脂肪酸的實例包括但不限於二十碳五烯酸(EPA)、二十二碳六烯酸(DHA),及類似物。一「ω-3脂肪酸」可包含一或多個ω-3脂肪酸。
本文中所使用的術語「ω-6脂肪酸」意指一或多個脂肪酸,該等脂肪酸距其等之ω碳原子6個碳原子遠具有一雙鍵。例如:ω-6脂肪酸包括但不限於亞麻油酸(LA)。其他ω-6脂肪酸包括次亞麻油酸的衍生物。亞麻油酸的「衍生物」是經化學改質所製成的脂肪酸,該化學改質係在亞麻油酸上所進行。為亞麻油酸的衍生物之ω-6脂肪酸的實例,包括但不限於γ次亞麻油酸(GLA)、二高γ亞麻酸(DGLA)及類似物。在某些實施例中,該組成物包含至少一非發炎性ω-6脂肪酸。非發炎性ω-6脂肪酸是不會促進或造成發炎的ω-6脂肪酸。在一些實施例中,發炎是在眼睛內或影響眼睛表面。具此技藝技術人士可判定脂肪酸是否會造成或促進發炎。若脂肪酸會造成或促進發炎,則該脂肪酸就應排除於本發明組成物之外。
本文中所使用的術語「亞麻油酸」意指9,12-十八碳二烯酸,其具有18:2(n-6)的速記表示法,18:2(n-6)為碳數量:雙鍵數量(位置)。在本說明書中,亞麻油酸稱為亞麻油酸或「LA」。
本文中所使用的術語「花生油酸」意指5,8,11,14-二十碳四烯酸,其具有20:4(n-6)的速記表示法以及304.5的分子量。在本說明書中,花生油酸稱為花生油酸或「AA」。應注意花生油酸會產生發炎前列腺素。亦應注意花生油酸可與酵素製程有關,該等酵素製程結果形成有益抗發炎脂質媒介物,如脂氧素及一種內源性大麻素,該內源性大麻素為大麻素(花生四烯酸乙醇胺)。
本文中所使用的術語「α-次亞麻油酸」意指9,12,15-十八碳三烯酸,其具有18:3(n-3)的速記表示法以及278.4的分子量。在本說明書中,α-次亞麻油酸稱為α-次亞麻油酸或「ALA」。
本文中所使用的術語「γ-次亞麻油酸」意指9,6,12,-十八碳三烯酸,其具有18:3(n-6)的速記表示法以及278.4的分子量。在本說明書中,γ-次亞麻油酸稱為γ-次亞麻油酸或「GLA」。
本文中所使用的術語「二高γ-亞麻酸」意指8,11,14-二十碳三烯酸,其具有20:3(n-6)的速記表示法以及306.5的分子量。在本說明書中,二十碳三烯酸稱為二十碳三烯酸或「DGLA」。
本文中所使用的術語「二十碳五烯酸」意指5,8,11,14,17-二十碳五烯酸,其具有20:5(n-3)的速記表示法以及302.5的分子量。在本說明書中,二十碳五烯酸稱為二十碳五烯酸或「EPA」。
本文中所使用的術語「二十二碳六烯酸」意指4,7,10,13,16,19-二十二碳六烯酸,其具有22:6(n-3)的速記表示法以及328.6的分子量。在本說明書中,二十二碳六烯酸稱為二十二碳六烯酸或「DHA」。
本文中所使用的術語「酯」意指經含氧酸(一含有氧的有機酸)與羥基化合物反應所得到的任何化合物,如一醇。酯類通常從有機酸產生,其中至少一羥基(-OH)基團被一-O-烷基(烷氧基)基團所取代的。最常見的是,酯類是經由羧酸與醇縮合而形成。在一或多個實施例中,本發明之酯類可為天然產生或經脂肪酸與醇反應所形成者。
本文中所使用的術語「胺基酯」意指由含氧酸與胺反應所得到的任何化合物。一或多個實施例提供脂肪酸與胺之反應產生胺基酯。提及「酯形式」時,除指傳統酯之外,可包括胺基酯。提及「反應產物」時,意指由酸與醇或胺反應所產生之酯或胺基酯,不管該酯或胺基酯是天然產生或合成而來。若被合成,該酯或胺基酯可經本技藝中習知之各種酯化方法所製備。
本文中所使用的術語「蠟酯」意指脂肪酸與長鏈醇之酯。蠟酯類包括但不限於蜂蠟及棕櫚蠟。蜂蠟由C40
至C46分子物種組成。棕櫚蠟由C16至C20脂肪酸與C30至C34長鏈醇酯化而形成C46至C54分子物種構成。
本文中所使用的術語「醇」意指含有被鍵結至一碳原子之至少一羥基官能基團(-OH)的任何有機化合物,該碳原子通常係被鍵結至其他碳及氫原子;此包括但不限於非環醇類;環醇類;一級、二級和三級醇類;一元醇類及多元醇類。本發明之醇類包括多羥基醇類,又稱多元醇,其為包含至少兩個羥基功能基團及4至10碳原子之醇類;在某些實施例中碳原子之數量為4至8個,在其他實施例中碳原子之數量可為5至8個。在其他實施例中,醇類係為可提供滲透保護之多元醇,其包括但不限於聚乙二醇、聚乙烯醇、肌醇、山梨糖醇、木糖醇以及赤藻糖醇。
本文中所使用的術語「緩解素」係由ω-3多不飽和脂肪酸(如二十碳五烯酸(EPA)或二十二碳六烯酸(DHA))、環氧合酶-II(COX-2)與一止痛劑(如阿斯匹靈)相互作用所產生之試劑。E系列的緩解素從EPA產生,D系列的緩解素則從DHA產生。例示性緩解素包括緩解素E1(RvE1)、緩解素E2(RvE2)、緩解素D1(RvD1)、緩解素D2(RvD2)、緩解素D3(RvD3)、緩解素D4(RvD4),及其等之組合。
本文中所使用的術語「保護素」或「神經保護素」為一試劑,尤其,一類二十二烷酸(為藉由22-碳必需脂肪酸,特別是DHA,的加氧所產生之訊息分子),其
係從多不飽和脂肪酸二十二碳六烯酸(DHA)產生。「保護素」或「神經保護素」在多種大腦疾病及視網膜疾病實驗模型中,都能以奈米莫耳濃度發揮有效抗發炎及抗凋亡生物活性。例示性保護素包括保護素D1(PD1)。
本文中所使用的術語「脂氧素」意指以5-脂肪加氧酶路徑所合成的一系列抗發炎脂質媒介物。脂氧素為短期、內源性所產生、非傳統含四烯類廿烷酸,其在發炎時的出現成為發炎消退的預兆。脂氧素亦從花生油酸,一種ω-6脂肪酸,透過酵素作用方式取得。例示性脂氧素包括脂氧素A4(LXA)、脂氧素B4(LXB4),及其等之組合。
本文中所使用的術語「前列腺素」意指若干荷爾蒙類物質之一種,該等荷爾蒙類物質參與各種各樣的身體機能,如平滑肌的收縮與鬆弛、血管的擴張與收縮、血壓的控制及發炎的調節。前列腺素從ω-3及ω-6脂肪酸產生。前列腺素主要有三種:具有抗發炎性質的前列腺素E1(PGE1)和前列腺素E3(PGE3),以及促進發炎的前列腺素E2(PGE2)。PGE1,從二高-γ-亞麻酸產生,是有效的血管舒張劑,可增加末梢血流,抑制血小板凝集,且具有如支氣管擴張及發炎的調解之其他多種生物效應。PGE1對於淚腺及唾液腺分泌和對於T細胞功能十分重要。PGE2,從花生油酸產生,係應傳染或發炎而由血管壁所釋出,且作用於大腦而引起發燒;PGE2也廣泛作為催生劑使用。PGE3是經由二十碳五烯酸之
環氧合酶(COX)代謝而被形成。已知PGE3有助於降低眼內壓。
本文中所使用的術語「視黃酸」意指維生素A(視網醇)的代謝物,其調停成長和發展所需之維生素A的功能。視黃酸除了作為平衡皮脂抑制劑的功能之外,已經顯示具有強大的抗發炎性質。(見Plewig,G.等人,Archives of Dermatological Research,Vol.270,No.1,89-94)。視黃酸可包括但不限於13-順-視黃酸。
本文中所使用的術語「內源性大麻素」意指一類在體內產生,能夠啟動大麻物質受體的有機化合物。內源性大麻素(內源性大麻素),在組織中濃度升高時,提供抗發炎和止痛效果。內源性大麻素用作細胞間脂質傳訊者、訊息分子,其係從一細胞中所釋出並啟動其他鄰近細胞上的大麻受體;它們採用逆向訊息傳遞。內源性大麻素是親脂性分子,較不溶於水。內源性大麻素可包括但不限於大麻素(花生四烯酸乙醇胺)及2-花生四烯酸甘油。
本文中所使用的術語「磷脂質」意指任何主要由脂肪酸、磷酸基及如膽鹼之簡單有機分子組成之各種含磷脂質。較佳者,磷脂質含有一或多種脂肪酸之殘餘物,所述脂肪酸為ω-3脂肪酸,以及視需要,ω-6脂肪酸。磷脂質本質上為兩親媒性;也就是說,磷脂質之極性端可溶於水(親水性)及水溶液,而脂肪酸端則溶於油(疏水性)。在水性環境中,磷脂質結合以形成具疏水性端
在中間且被暴露於水性環境之親水性端的雙層構造(脂雙層)。此種脂雙層為細胞膜的結構基礎。
本文中所使用的術語「代謝物」意指為代謝之產物的化合物。代謝物係作為降解並消除化合物的天然生物化學程序部分而被形成。
本文中所使用的術語「代謝穩定類似物」意指一化合物為其母化合物之結構衍生物(有時與母化合物只有一個元素不同)者,或與其母化合物具有相似性質之化合物。類似物係不易被降解,且因此為代謝穩定。
本文中所使用的術語「CD11b+浸潤」係指乾眼發生後角膜中心和周邊之CD11b+細胞增加。
本文中所使用的術語「IL-1α或TNF-α表達」包括以定量即時聚合酶鏈鎖反應測量IL-1α與TNF-α之RNA轉錄本。
本文中所使用的術語「發炎性細胞介素」包括,但不限於,IL-1α及TNF-α。
以下進入本案細節說明,本發明提供製造及使用含酯化抗發炎脂質媒介物之眼用產品的程序,其中該抗發炎脂質媒介物中之大部分係以酯形式存在。一或多個實施例提供,實質上不含脂肪酸的組成物。亦即,在此等實施例中,該眼用產品含有10%以重量計或更少(或8%、或6%、或5%、或4%、或3%、或2%、或甚至1%)之該抗發炎脂質媒介物的酸形式。在一進一步實施例中,該眼用產品含有1%以重量計或更少(或0.8%、
或0.6%、或0.5%、或0.4%、或0.3%、或0.2%、或甚至0.1%、或0.05%、或0.025%、或0.01%)之該抗發炎脂質媒介物的酸形式。該酯化抗發炎脂質媒介物為酸性抗發炎脂質媒介物的酯類。該酯類可經使抗發炎脂質媒介物與至少一碳鏈長度為四至十個碳原子之多元醇反應而產生。理想的抗發炎脂質媒介物包括ω-3及/或ω-6脂肪酸、緩解素或一代謝穩定類似物、保護素或一代謝穩定類似物、脂氧素或一代謝穩定類似物、前列腺素或一代謝穩定類似物、視黃酸、內源性大麻素,以及磷脂質。發炎為乾眼的組成部分。因此需要提供能夠減輕發炎的活性成分,其形式應能在投與於眼睛時不會涉及初發不適(劇烈眼睛不適),同時對眼睛提供長時間效益。
在一或多個實施例中,該酯是以一治療有效量提供。亦即,該酯之存在量係足以對眼睛區域提供有益效果,包括但不限於眼睛表面、眼睛背面、淚液形成及穩定性。治療有效量之酯可傳遞適量之抗發炎脂質媒介物以改善眼睛環境。
在前案自由脂肪酸配方(例如:α-次亞麻油酸乳膠)中,在安裝於眼睛時引發的不適已被發現在前案,該前案如美國專利申請公開案20070265341(Dana等人)所揭示的那些組成物。改變界面活性劑濃度(多為Tween-80,從2.5%至0.25%)或外加界面活性劑(如兩性單原子界面活性劑)並無法改善安裝時的不適問題。
本發明用來避免或改善此種不適問題的方法是使必需脂肪酸為非離子性,亦即利用分子的酯化相應物。
抗發炎脂質媒介物,如多不飽和脂肪酸、緩解素或一代謝穩定類似物、保護素或一代謝穩定類似物、脂氧素或一代謝穩定類似物、前列腺素或一代謝穩定類似物、視黃酸、內源性大麻素及磷脂質為眼用產品的理想成分,有助於治療發炎、乾眼及/或乾燥病症及瞼板腺功能異常等眼部病症。已經發現,當大部分之該抗發炎脂質媒介物以酯形式存在時,酯化抗發炎脂質媒介物的使用結果形成一眼用產品,該眼用產品可大幅改善接觸或投與於眼睛表面時之開始的舒適度。一般而言,酯化抗發炎脂質媒介物為酸性抗發炎脂質媒介物與醇或胺之反應產物。
此種酯化抗發炎脂質媒介物在某些案例可用於濕潤滴劑中,或可與隱形眼鏡有闗聯,如聚矽氧水凝膠,藉此,鏡片可以酯化抗發炎脂質媒介物之混合物而被處理。該酯化抗發炎脂質媒介物可利用各種方法加入隱形眼鏡中,例如:結合可發生於鏡片取出時或水合程序或其組合期間。
先前使用脂肪酸及/或脂肪酸油無法提供此種特質。酯化抗發炎脂質媒介物可與含水傳遞系統結合,製成理想之眼用組成物。
酯化抗發炎脂質媒介物,當其大部分以酯形式存在時,具有標定乾眼疾病的發炎性部分(其干擾乾眼疾病)
之優勢,且在較大濃度範圍內皆較不易造成初發不適。不拘於理論,發明人認為與眼睛表面細胞接觸並為之吸收時,酯化抗發炎脂質媒介物,如酯化多不飽和脂肪酸、酯化緩解素或一代謝穩定類似物、酯化保護素或一代謝穩定類似物、酯化脂氧素或一代謝穩定類似物、酯化前列腺素或一代謝穩定類似物、酯化視黃酸、內源性大麻素及磷脂質,會產生水解且回復至其酸性抗發炎脂質媒介物狀態,並還原出用以形成該酯的醇。
轉向多不飽和脂肪酸(如ω-3及ω-6脂肪酸)之酯類,羧酸與醇或醋酸鹽之反應會產生酯類。一般而言,以下脂肪酸衍生物,如酯類(Ia),及其他官能基,如醯胺(Ib),具有較佳之穩定性及初發眼睛舒適度,因此較為理想:CH3-CH2-CH=CH-(CH2-CH=CH)n-(CH2)x-CO-O-R (Ia)
CH3-CH2-CH=CH-(CH2-CH=CH)n-(CH2)x-CO-NH-R (Ib)
之後此種衍生物會轉換回其原始脂肪酸結構(II):CH3-CH2-CH=CH-(CH2-CH=CH)n-(CH2)x-酸{-CO-OH} (II)
一旦處於眼睛環境及/或溶入脂質層或細胞膜,脂雙層就會執行淚膜穩定效果及/或抗發炎效果。
n、x及R之範圍可落在以下範圍之內:n:2-5;x:2-7;R:眼科可相容的脫離基,包括但不限於:-(CH2)yCH3,其中y為0、1或以上。在一些實施例中,y是介於0與5之間,或甚至0與3之間,又以y=1為較佳。
尤其,但不限於此,酯化抗發炎脂質媒介物包含一酯化ω-3脂肪酸,其中該ω-3脂肪酸係選自於由下列所組成的群組:α-次亞麻油酸、十八碳四烯酸、二十碳四烯酸、二十碳五烯酸、二十二碳六烯酸、二十二碳五烯酸(DPA)、二十四碳五烯酸,及二十四碳六烯酸(鯡酸)、其衍生物、其代謝物,及其混合物。當酯化時,大部分之該酯化抗發炎脂質媒介物是以ω-3脂肪酸之酯形式存在。
特別,酯化ω-3脂肪酸可選自以下非限制性實例:乙基亞麻油酸酯(α-亞麻酸乙酯(ALA-EE));十八碳四烯酸乙基酯及十八碳四烯酸丙酯;二十碳四烯酸乙基酯及二十碳四烯酸丙酯;二十碳五烯酸乙基酯及二十碳五烯酸丙酯;以及二十二碳六烯酸乙基酯及二十二碳六烯酸丙酯。
將抗發炎脂質媒介物與碳鏈長度為四至十個碳之多元醇反應,以形成所需之抗發炎脂質媒介物型態。
抗發炎脂質媒介物與多元醇之反應係在酯形成條件下進行。適合之催化劑為此技藝中為已知,且包括酸類、鹼類、碳二亞胺及類似物。酯化及醯胺化反應可於
大氣壓力及室溫(通常為約19-25℃)下發生,不太需要加溫,但也可稍微加溫(約25℃至80℃)以加快反應完成時間。
或者,可用聚乙二醇或聚乙烯醇將脂肪酸酯化,以產生ω脂肪酸乙氧基化物及烷氧基化物。此外,也可加入同源分子之混合物以及醯胺類和其他官能性衍生物。例如:酯化抗發炎脂質媒介物可為一脂肪酸與一胺形成胺酯之反應產物。
ω-3脂肪酸亦可與以下分子/醇類反應:肌醇、山梨糖醇、木糖醇以及赤藻糖醇。使用這種酯型態/共軛材料之優點在於當ω-3脂肪酸材料水解釋放時,過程中釋出的小溶質/醇會提供滲透保護及其他優點,特別是對乾眼受試者及/或隱形眼鏡配戴者。這是因為肌醇、山梨糖醇、木糖醇以及赤藻糖醇為滲透保護劑,整體而言相當為組織所耐受。
若使用多元醇,如肌醇,若干羥基可被酯化為ω-3脂肪酸(如α-亞麻酸)以在每分子提供至組織的ω-3脂肪酸材料量之方面提高效率。每肌醇分子之脂肪酸分子數量會影響材料可溶性,或容許調整特定應用下之材料疏水性/從醫療裝置提供之控制率。
應知酯化抗發炎脂質媒介物並不會呈現如葵花油、芝麻油、蓖麻油、亞麻仁油及類似物之天然油的形式。亦應注意本發明酯化抗發炎脂質媒介物並非蠟酯類,因其是由短碳鏈(5至10個碳原子,在某些實施例
中為5至8個碳原子)醇所形成。
混合物可包括所需比例之ω-3及ω-6脂肪酸酯類。在一或多個實施例中,理想的是提供一組成物,該組成物在該酯水解時,在眼中,提供ω-3脂肪酸:ω-6脂肪酸至約1:1的平衡。在其他實施例中,理想的是提供眼用組成物,該等眼用組成物在水解時具有ω-3脂肪酸:ω-6脂肪酸在範圍約10:約1至不少於約1:約1中之比率及從約5:1至約1:1、從約4:1至約1:1、從約3:1至約1:1、從約2:1至約1:1、約1:1、約2:1、約3:1、約4:1、約5:1、約6:1、約7:1、約8:1、約9:1或約10:1。比率係基於各類ω脂肪酸之總量。
眼用組成物可在無菌條件混合或在環境條件下混合後被滅菌。溫度適用範圍可大,且反應可在環境溫度和壓力條件下被進行。
酯化抗發炎脂質媒介物除了是眼用組成物(包括再潤濕滴劑、多功能溶液、清潔及儲存溶液和用在隱形眼鏡本身之中)內的有用成分外,這種材質也可用於鏡片包裝溶液中。可用酯化抗發炎脂質媒介物之製劑及/或乳膠包裝鏡片,或將此種材料溶解於適當溶劑,用以水合鏡片,之後再將鏡片於包裝溶液中以平衡狀態儲存。
其他眼用組成物包括鏡片保養溶液,如多功能溶液、製劑、凝膠、軟膏、乳膠,及眼用產品,如貼條、嵌入物或淚管塞或任何接觸眼睛表面的產品。
在一實施例中,係將該酯化抗發炎脂質媒介物加入
於含水傳遞系統中。含水傳遞系統是以水為基礎的系統,其可直接安裝於眼睛中,或用以調整、存放或清潔待放入眼中的眼用裝置。含水傳遞系統之實例可包括以下一或多者:包裝溶液、儲存溶液、清潔和保養溶液、多功能溶液、調理溶液及眼用滴劑。含水傳遞系統亦可包含已知組份,如以下物質中之一或多種:乳化劑、螯合劑或穩定劑、界面活性劑、潤濕劑、抗氧化劑、官能調整劑、防腐劑、其組合物及類似物。
所述包裝溶液可為任何水性溶液,包括用於儲存隱形眼鏡者。該酯化抗發炎脂質媒介物係分散於包裝溶液中。其通常包含,但不限於,含鹽溶液、其他緩衝溶液與去離子水。較加水性溶液為鹽溶液,其包含鹽,包括但不限於,氯化鈉、硼酸鈉、磷酸鈉、磷酸氫鈉、磷酸二氫鈉,或其對應鉀鹽。此等成分通常混合形成包含一種酸與其共軛鹼之緩衝溶液,因此酸和鹼的加入僅僅造成相對較小的酸鹼值變化。緩衝溶液可另外包括2-(N-嗎福啉)乙磺酸(MES)、氫氧化鈉、2,2-雙(羥甲基)-2,2',2"-三乙醇胺、N-三(羥甲基)甲基-2-胺乙磺酸、檸檬酸、檸檬酸鈉、碳酸鈉、碳酸氫鈉、乙酸、醋酸鈉,及類似物及其組合。較佳的是,該溶液為一硼酸鹽緩衝或磷酸鹽緩衝的鹽溶液。
至少一界面活性劑或乳化劑以及任何附加成分係與水性溶液結合、攪拌且溶解或分散,以形成包裝溶液。該溶液之酸鹼值較佳的是被調整至約6.2至約7.5。
將鏡片存放於本發明包裝溶液時,係使鏡片浸沒於溶液中,並將溶液與鏡片放置於鏡片待被存放的包裝盒中。或者,可將溶液放入包裝盒,且之後將鏡片放入溶液中。通常,該包裝盒係以習之方式密封,如熱封,之後接受適合之滅菌程序。
適合在本發明中使用之界面活性劑具有任何適合之分子量,較佳者為約200至約1,000,000,更佳者約1000至約18,000。可效的界面活性劑具有一約10至約30的親水性-親油性均衡(HLB),較佳者為約15至約25,更佳者約15至約23。
任何符合上述標準之已知界面活性劑皆可使用,只要該界面活性劑在溶解度方面能與其所使用的溶液相容即可。因此,適合之界面活性劑包括但不限於陽離子性、離子性、非離子性界面活性劑,及其組合。然而,含陽離子性及離子性界面活性劑之鏡片包裝溶液的使用可能造成眼睛刺激。因此,該界面活性劑較佳的是一非離子性界面活性劑。
適合之非離子性界面活性劑,包括但不限於脂肪酸之聚乙二醇類,如聚山梨醇酯20、60或80(皆屬商業可購得之TWEEN®界面活性劑)、烷醇醯胺、胺氧化物、乙氧基化醇類及酸類,以及具有一或多個聚(氧化烯)鏈之界面活性劑,如泊洛沙胺(poloxamine)界面活性劑(一將脂質與環境殘渣自鏡片去除之表面活性劑);乙烯二胺之聚烷氧化嵌段聚合物或泊洛沙姆(poloxamer)
界面活性劑(聚氧丙烯-聚氧乙烯共聚物類型之非離子界面活性劑系列的任何一者,用作界面活性劑、乳化劑、穩定劑及食品添加物)及類似物,以及其組合。較佳者,該界面活性劑為聚山梨醇酯或泊洛沙姆界面活性劑。泊洛沙姆界面活性劑為市面上有售以PLURONIC200為名,其為聚氧乙烯--聚氧丙烯非離子界面活性劑,該等非離子界面活性劑具有佔分子之約10至約80重量百分比的聚氧乙基親水性端基。雖然任何PLURONIC®界面活性劑為較佳的,供本發明裡使用特別佳的為PLURONIC® 127,其為約70重量百分比環氧乙烷且具有約12,000至約15,0000的分子量。
該界面活性劑可結合任何已知可用於鏡片包裝溶液或再濕潤滴劑中之有效及載體成分。適合用於鏡片包裝溶液之有效成分,包括但不限於抗菌劑、抗乾燥劑,如聚乙烯醇、聚乙烯吡咯啶酮,以及葡聚糖、張力劑及類似物,以及其組合
適合之潤濕劑,連同黏度增強劑,包括但不限於:甲基葡糖醇聚醚-20(商品名為,例如Glucam E20)、羧甲基纖維素、葡聚糖70、明膠、羥甲基纖維素、羥丙基甲基纖維素、羥丙基乙基纖維素、羥丙基纖維素、甲基纖維素、PEG、丙二醇、聚乙烯醇(PVA)、聚乙烯吡咯啶酮(PVP)、卡波姆(Carbomer)、聚甲基乙烯基醚順丁烯二酸酐、玻尿酸、黃原膠,以及聚丙烯酸。
適合用於本發明之抗氧化劑,包括但不限於受阻酚類、兒茶酚類、生育醇、類胡蘿蔔素、玻尿酸、黃體素,或任何能夠捕捉自由基之種類。抗氧化劑是透過氧化還原化學反應抑制其他化學物質之氧化傷害的分子物種。這些反應通常用於將一分子種類電子轉移至氧化劑分子。這些可包括自由基,其可造成鏈鎖反應。簡言之,抗氧化劑即是還原劑。抗氧化劑之實例包括但不限於:維生素E、維生素C、β胡蘿蔔素(係被轉化為維生素A)及過氧化酶,以及可抑制自由基形成之其他試劑,如螯合劑、EDTA、二乙烯三胺五乙酸(DTPA)、N,N-雙[羧甲基]甘胺酸(NTA),及類似物。
在一些實施例中,係將維生素E係被加入包含酯化抗發炎脂質媒介物之溶液。
在另一實施例中,係將本發明組成物係被加入一眼用裝置中,該眼用裝置如隱形眼鏡,或尤其,一聚矽氧水凝膠隱形眼鏡。在此實施例中,該酯化抗發炎脂質媒介物,其中大部分以酯形式存在的酯化抗發炎脂質媒介物,可透過若干方式加入鏡片之中,此等方式包括但不限於:加入用以聚合成鏡片的反應混合物中;以及使鏡片在包裝前、包裝期間或包裝後接觸包含酯化抗發炎脂質媒介物之溶液。例如:該酯化抗發炎脂質媒介物可,在鏡片的製造期間,被包括於萃取、水合或儲存溶液中,或可被包括於與鏡片配戴者所接觸的隱形眼鏡之溶液中。在一實施例中,該溶液使鏡片膨脹,有助於加強
酯化抗發炎脂質媒介物的吸入。在酯化抗發炎脂質媒介物係被加入反應混合物之實施例中,酯化抗發炎脂質媒介物可作為單獨成分而被加入反應混合物中,或與至少一反應成分上的醇類官能基預反應。
在一些實施例中,本發明包含眼用組成物包含至少一酯化ω-3脂肪酸。在一些實施例中,本發明包含眼用組成物包含至少一酯化ω-6脂肪酸。在一些實施例中,本發明包含眼用組成物包含至少一酯化ω-6脂肪酸及至少一酯化ω-3脂肪酸。
本發明的優點之一,在於該酯化抗發炎脂質媒介物在中性酸鹼值下為水解上穩定,且於本發明之中性酸鹼值眼用組成物及無菌製劑儲存期間不會水解。這表示該眼用溶液及無菌製劑,當被安裝於眼睛中之時,不會造成刺痛。不拘於理論,本案發明人相信當接觸細胞膜及/或進入眼睛表面細胞時,酯化抗發炎脂質媒介物,如酯化多不飽和脂肪酸、酯化緩解素或一代謝穩定類似物、酯化保護素或一代謝穩定類似物、酯化脂氧素或一代謝穩定類似物、酯化前列腺素或一代謝穩定類似物、酯化視黃酸、內源性大麻素及磷脂質,會產生水解,並隨著醇回復至其酸性抗發炎脂質媒介物狀態,該醇用來形成該酯。
該酯化抗發炎脂質媒介物之用量可以總組成物之百分比表示,或以用於處理步驟,如鏡片水合作用步驟(可造成該材料加入裝置中之部分鏡片製造法),之溶
液的百分比表示。該酯化抗發炎脂質媒介物之百分比可經任何方法而被決定,但可經,例如:將該抗發炎脂質媒介物之重量除以該眼用組成物或裝置之總重量而被決定。該眼用組成物任何成分之百分比,可以相似方式決定。
本發明眼用組成物或裝置中所含之酯化抗發炎脂質媒介物量可從約0.025重量百分比至5.0重量百分比,基於該眼用組成物之總成份。當該眼用組成物為再濕潤滴劑之時,則該酯化抗發炎脂質媒介物係以,基於該組成物中之總成分,從約0.025重量百分比至0.5重量百分比之量而存在且酸含量可為不多於0.1重量百分比(或0.075、或0.05、或0.025、或甚至0.01重量百分比)。當該眼用組成物係被加入到隱形眼鏡上之時,則該酯化抗發炎脂質媒介物係以,基於該組成物中之總成分,從0.025重量百分比至5.0重量百分比之量而存在且酸含量可為不多於1重量百分比(或0.75、或0.5、或0.25、或甚至0.1重量百分比)。
在一些實施例中,本發明目的在於一包含酯化抗發炎脂質媒介物(如酯化ALA)之組成物的局部塗抹,作為有效治療策略以減少眼睛表面發炎。如在此所述,眼睛表面發炎可見於,例如:乾眼症及其他發炎性眼部病症,包括但不限於眼睛前部與後部病症(例如:瞼板腺功能異常、瞼炎、異位性角膜結膜炎、隱形眼鏡相關的乾眼、休格倫氏症候群、葡萄膜炎、黃斑點退化,及
其他多種病症)。
在另一實施例中,本發明目的在於一包含酯化抗發炎脂質媒介物(如酯化ALA)之組成物的局部塗抹,作為一有效策略以改善淚膜功能或淚膜穩定性。不拘於理論,本案發明人相信該酯化抗發炎脂質媒介物改善鏡片與淚膜及/或眼瞼間之相互作用。
本發明亦可投與於已經被確認需要在此所描述之組成物的個體。若一個體經確認患有或具有乾眼症之病症或上述任一種其他發炎性眼部病症,其即可能為需要本發明組成物之個體。熟悉此技藝人士應知如何確認個體是否需要乾眼症治療。
本發明亦可投與於個體以減輕至少一乾眼徵兆及/或病症,或對有此需要的個體提供滲透保護。
不拘於理論,本案發明人相信,當該抗發炎脂質媒介物組成物係被裝載到隱形眼鏡上,用於隱形眼鏡配戴過程中傳遞至眼睛,借助於其抗發炎性質及對淚膜之益處,該抗發炎脂質媒介物經由隱形眼鏡留置於眼睛上之時間可長至足以使其有效傳遞至眼睛,以緩解個體之乾眼或其他發炎性眼部病症。
查閱遍及本說明書之「一實施例」、「特定實施例」、「一或多個實施例」、「進一步實施例」或「一種實施例」,意指所描述關於該實施例之一特定功能、結構、材料或特性係被包括於本發明之至少一實施例中。因此,遍及本說明書多處中,諸如「在一或多個實施例
中」、「在特定實施例中」、「在一實施例中」或「在一種實施例中」之詞組的出現未必指稱本發明之相同實施例。再者,在一或多個實施例中之特定功能、結構、材料或特性可以組合成任何適用之方式加。
雖然本發明在此是參照特定實施例加以描述,應知這些實施例僅為說明本發明之原理與應用。熟悉此技藝人士可依據發明之方法與裝置,在不脫離本發明精神與範疇之下進行多種修改與變化。因此,本發明意圖包括落在所附申請專利範圍及其等之等同替換之範疇內的修改與變化。
Claims (13)
- 一種用於治療眼部病症之眼用組成物,該眼用組成物包含一抗發炎脂質媒介物之酯,其包含0.025重量%至0.5重量%之α-次亞麻油酸肌醇酯;及一含水傳遞系統;其中該眼用組成物適於投與眼睛或眼部環境,且實質上不含抗發炎脂質媒介物之酸形式。
- 如申請專利範圍第1項之組成物,其中該組成物係實質上不含脂肪酸。
- 如申請專利範圍第1項之組成物,其中該組成物包含以重量1%或更少的α-次亞麻油酸肌醇酯之酸形式。
- 如申請專利範圍第1項之組成物,其進一步包含至少一種潤濕劑,其含量為0.025至5.0%之範圍;至少一種界面活性劑,其含量為0.025至5.0%之範圍;及至少一種抗氧化劑,其含量為0.01至0.1%之範圍。
- 如申請專利範圍第1項之組成物,其中該含水傳遞系統包含一或多種選自於由下列所組成的群組之成分:聚山梨醇酯80TM、泰洛沙泊(TyloxapolTM)、甲基葡糖醇聚醚 -20、維生素E、二伸乙基三胺五乙酸、硼酸鈉以及氯化鈉。
- 如申請專利範圍第4項之組成物,其中該潤濕劑為甲基葡糖醇聚醚-20;該界面活性劑為聚山梨醇酯80;該抗氧化劑為維生素E;且包含一種水性包裝溶液,其選擇地包含鹽類、防腐劑及緩衝液之一或多者。
- 如申請專利範圍第4項之組成物,其中該界面活性劑包含至少一種非離子性界面活性劑。
- 如申請專利範圍第4項之組成物,其中該界面活性劑選自下列所組成之群組:脂肪酸之聚乙二醇類、烷醇醯胺、胺氧化物、乙氧基化醇類及酸類,及具有一或多個聚(氧化烯)鏈之界面活性劑,及彼等之組合。
- 如申請專利範圍第4項之組成物,其中該界面活性劑選自下列所組成之群組:聚山梨醇酯或泊洛沙胺(poloxamine)界面活性劑。
- 如申請專利範圍第4項之組成物,其中該潤濕劑選自下列所組成之群組:甲基葡糖醇聚醚-20、羧甲基纖維素、 葡聚糖70、明膠、羥甲基纖維素、羥丙基甲基纖維素、羥丙基乙基纖維素、羥丙基纖維素、甲基纖維素、PEG、丙二醇、聚乙烯醇(PVA)、聚乙烯吡咯啶酮(PVP)、卡波姆(Carbomer)、聚甲基乙烯基醚順丁烯二酸酐、玻尿酸、黃原膠及聚丙烯酸,及彼等之組合。
- 如申請專利範圍第4項之組成物,其中該抗氧化劑選自下列所組成之群組:受阻酚類、兒茶酚類、生育醇、類胡蘿蔔素、玻尿酸、黃體素,及彼等之組合。
- 如申請專利範圍第4項之組成物,其中該抗氧化劑選自下列所組成之群組:維生素E、維生素C、β胡蘿蔔素、EDTA(乙二胺四乙酸(Ethylenediaminetetraacetic acid)」)、二乙烯三胺五乙酸(DTPA)、N,N-雙[羧甲基]甘胺酸(NTA),及彼等之組合。
- 一種投與至眼睛或隱形眼鏡的無菌製劑、溶液、凝膠、軟膏、乳膠或貼條(strip),其包含如申請專利範圍第1項之組成物。
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