TWI620578B - 用以減少眼用類固醇的倂發症之藥學組成物 - Google Patents
用以減少眼用類固醇的倂發症之藥學組成物 Download PDFInfo
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- TWI620578B TWI620578B TW102105245A TW102105245A TWI620578B TW I620578 B TWI620578 B TW I620578B TW 102105245 A TW102105245 A TW 102105245A TW 102105245 A TW102105245 A TW 102105245A TW I620578 B TWI620578 B TW I620578B
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- phospholipids
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Abstract
本發明是關於包含下列組合的藥學組成物：此組成物包含一或多種磷脂質及帶有或不帶有膽固醇的脂質混合物，以及包含眼用類固醇、其藥用的鹽類或其前驅藥的類固醇溶液，該藥學組成物中磷脂質的總量是每50μL的藥學組成物含有大約0.1μmol至低於大約2.5μmol，並且該組成物會減少眼用類固醇的副作用。該藥學組成物較適用藉由眼睛投藥途徑來治療眼科疾病。
Description
本發明是關於包含脂質混合物以及類固醇所組成的藥學組合物，該藥學組合物會減少眼用類固醇的副作用以及用於治療眼科疾病(ophthalmic diseases)的方法。
黃斑水腫(macular edema)會引起中心視覺(central vision)的喪失並且是糖尿病視網膜病變(diabetic retinopathy)的一種臨床表現。它是由視網膜微血管病變(retinal microvascular changes)所導致，而致病機制不僅與VEGF有關，也與可被皮質類固醇(corticosteroids)所抑制的其它發炎性以及血管新生(angiogenic)的細胞激素濃度有關(Sohn HJ et al.Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema.Am J Ophthalmol.Oct 2011；152(4)：686-94.)。
針對一些對典型治療[諸如雷射光凝固(laser
photocoagulation)、眼睛周圍局部施打類固醇與全身性使用
類固醇或碳酸酐酶抑制劑(carbonic anhydrase inhibitors)]沒有反應的慢性黃斑水腫的案例而言，玻璃體內的皮質類固醇注射(intravitreal corticosteroid injection)是一種治療選擇。
玻璃體內的皮質類固醇注射亦被用來治療眼色素層炎(uveitis)以及用來改善視網膜分支靜脈阻塞(branch retinal vein occlusion)或視網膜中央靜脈阻塞(central retina vein occlusion)病患的視覺敏銳度(visual acuity)。然而，眼內最佳且有效的皮質類固醇濃度之維持需要重覆性的玻璃體內注射，而重覆性的玻璃體內注射會造成許多併發症[諸如傳染性眼內炎(infectious endophthalmitis)、視網膜剝離(retinal detachment)、外傷性白內障(traumatic cataract)以及眼內壓(intra-ocular pressure,IOP)升高]。有研究顯示：在玻璃體內的類固醇注射後的第1個月，眼內壓升高的比例是57.69%，而在第3與第6個月時分別是75%與47.05%，且在22.72%的病患中發現有白內障的生成(García Fernández M et al.Intravitreal triamcinolone acetonide use in diffuse persistent diabetic macular edema.Arch Soc Esp Oftalmol 2011 Oct；86(10)：314-319.)。
鑑於以上所概述的缺陷，一個較低副作用的玻璃體內類固醇注射劑有其需求。
本發明是針對一個包含下列組合的藥學組成物：
此藥學組成物包含磷脂質或磷脂質的混合物及帶有或不帶有膽固醇；以及一個包含眼用類固醇(ocular steroid)、其藥用的鹽類或其前驅藥(prodrug)；其中每50μL的該藥學組成物中磷脂質的總量低於大約2.5μmol，並且相對於每50μL的藥學組成物之磷脂質總量至少大約5μmol的磷脂質來說，含有低於大約2.5μmol磷脂質的藥學組成物並且此藥學組成物含有眼用類固醇、其藥用的鹽類或其前驅藥的溶液會降低此類藥物的副作用。
該藥學組成物可藉由混合脂質混合物與一類固醇溶液而被製備，其中該類固醇溶液包含有眼用類固醇、其藥用的鹽類或其前驅藥。
本發明亦是針對需要眼科疾病治療的個體給予治療的方法。該方法包含下列的步驟：對該個體投予本案描述的藥學組成物，藉此減少在該個體中的症狀。本發明對於藉由眼睛遞送(ocular delivery)至眼睛後段的眼科疾病是特別有用的。
如上述以及在整個揭露內容中所使用的下列術語，除非另外有所指明，應被理解為具有下列意義。
除非本文另外有清楚地指明，此處所使用的單數的形式“一(a)”、“一(an)”以及“該(the)”包含複數的引述意
思。
除非另外有所指明，此處所使用的，術語“大約”，當涉及一可測量的數值(諸如數量、短暫的期間，以及類似之物)時，被意指為包含由指定值之±10%的變化，較佳為指定值之±5%的變化，更佳為指定值之±1%的變化，以及甚至極佳為指定值之±0.1%的變化。對於評估減少類固醇的副作用而言，變化本身是適當的。除非另外有所指明，此處所使用的，術語“大約”，當涉及一範圍時，被意指為包含在範圍的差異內由指定值之±10%的變化，較佳為指定值之±5%的變化，更佳為指定值之±1%的變化，以及甚至極佳為指定值之±0.1%的變化，對於評估減少類固醇的副作用而言，變化本身是適當的。
此處所使用的術語-“脂質體(liposome)”意指以水相(aqueous phase)為中心包封排列雙層脂質(lipid bilayers)之囊泡，或者小的或大的單層囊泡(unilammellar vesicles)。
此處所使用的，“有效量(effective amount)”，意指一足以減少眼科疾病的症狀以及徵兆[諸如模糊、褪色的視覺(blurry,washed out vision)]之藥學組成物的劑量。
此處所使用的，術語“治療(treating)”、“被治療的(treated)”或“治療(treatment)”包括預防的(preventative)[例如預防性(prophylactic)]、緩解性(palliative)以及治癒性(curative)的用途或結果。
術語“個體(subject)”包括一具有眼科疾病的脊椎動物。該個體較適用於溫血動物(warm-blooded animal)，包括哺乳動物，更適用於人類。
此處所使用的，術語“前驅藥(prodrug)”意指前驅化合物(precursor compound)，該前驅化合物在投藥之後經由活體內的一些化學或生理過程而釋放出生物活性化合物(例如，一前驅藥在達到生理pH或經由酵素作用後被轉換為生物活性化合物)。前驅藥本身可能缺少或具有其所欲達到的生物活性。
本發明的眼用類固醇之“藥學上可接受的鹽類(pharmaceutically acceptable salts)”是一酸性類固醇與鹼所形成的鹽類，亦即鹼聚鹽類(base addition salts)，諸如鹼金屬以及鹼土金屬鹽類(alkali and alkaline earth metal salts)(諸如鈉、鋰、鉀、鈣、鎂)，以及4銨鹽(ammonium salts){諸如銨(ammonium)、三甲基-銨(trimethyl-ammonium)、二乙基銨(diethylammonium)以及三-(羥甲基)-甲基-銨鹽[tris-(hydroxymethyl)-methyl-ammonium salts]}。
同樣地，酸聚鹽類(acid addition salts){諸如礦酸(mineral acids)、有機羧酸與有機磺酸(organic carboxylic and organic sulfonic acids)[例如氫氯酸(hydrochloric acid)、甲磺酸(methanesulfonic acid)、馬來酸(maleic acid)]}亦可能與鹼性眼用類固醇形成鹽類。
在一個方面，本發明提供一包含下列組合的藥
學組成物：此組成物包含一或多種磷脂質及帶有或不帶有膽固醇的脂質混合物；以及一包含配於二次蒸餾水(double-distilled water)(ddH2O)或一適合的緩衝液中之眼用類固醇、其藥用的鹽類或其前驅藥的類固醇溶液；其中每50μL的該藥學組成物中磷脂質的總量低於大約2.5μmol，並且相對於每50μL的藥學組成物之磷脂質總量至少大約5μmol磷脂質來說，低於大約2.5μmol磷脂質的藥學組成物並且此藥學組成物含有眼用類固醇、其藥用的鹽類或其前驅藥的溶液會降低此類藥物的副作用。另一個方面，本發明是針對治療眼用疾病的方法，其包含對於需要治療的個體投予此處所描述的藥學組成物之有效量，藉此減少在該個體中的眼科疾病的症狀以及徵兆。
在本發明中的脂質混合物意指一塊狀、薄膜狀或粉末狀的一固體脂質混合物。
在一個具體實施例中，帶有或不帶有膽固醇的磷脂質或磷脂質混合物先製備成脂質體，之後，再進一步加工處理成為一脂質混合物。
在另一個具體實施例中，帶有或不帶有膽固醇的磷脂質或磷脂質的混合物不製備成脂質體，直接加工處理成為一脂質混合物。
脂質體的粒徑是奈米等級，並且包含有粒子形成部分(particle-forming component)以及藥劑攜帶部分
(agent-carrying component)。該粒子形成部分形成一封閉的脂質障壁。
脂質混合物可由各種不同的脂質所製備，該脂質必須具有能形成或被併入至單層或雙層結構中的脂質之能力。在本發明中所使用的脂質包括一種或多種的磷脂質，並可帶有或不帶有膽固醇。在本發明中所使用的磷脂質的實例包括，但不限於：磷脂醯膽鹼(phosphatidylcholine,PC)、磷脂醯甘油(phosphatidylglycerol,PG)、磷脂醯乙醇胺(phosphatidylethanolamine,PE)、磷脂醯絲胺酸(phosphatidylserine,PS)、磷脂酸(phosphatidic acid,PA)、磷脂醯肌醇(phosphatidylinositol,PI)、蛋黃磷脂醯膽鹼(egg phosphatidylcholine,EPC)、蛋黃磷脂醯甘油(egg phosphatidylglycerol,EPG)、蛋黃磷脂醯乙醇胺(egg phosphatidylethanolamine,EPE)、蛋黃磷脂醯絲胺酸(egg phosphatidylserine,EPS)、蛋黃磷脂酸(egg phosphatidic acid,EPA)、蛋黃磷脂醯肌醇(egg phosphatidylinositol,EPI)、大豆磷脂醯膽鹼(soy phosphatidylcholine,SPC)、大豆磷脂醯甘油(soy phosphatidylglycerol,SPG)、大豆磷脂醯乙醇胺(soy phosphatidylethanolamine,SPE)、大豆磷脂醯絲胺酸(soy phosphatidylserine,SPS)、大豆磷脂酸(soy phosphatidic acid,SPA)、大豆磷脂醯肌醇(soy phosphatidylinositol,SPI)、二棕櫚醯基磷脂醯膽鹼(dipalmitoylphosphatidylcholine,DPPC)、1,2-二油醯基-sn-
甘油-3-磷脂醯膽鹼(1,2-dioleoyl-sn-glycero-3-phosphatidylcholine,DOPC)、二肉豆蔻醯基磷脂醯膽鹼(dimyristoylphosphatidylcholine,DMPC)、二棕櫚醯基磷脂醯甘油(dipalmitoylphosphatidylglycerol,DPPG)、二油醯基磷脂醯甘油(dioleoylphosphatidylglycerol,DOPG)、二肉豆蔻醯基磷脂醯甘油(dimyristoylphosphatidylglycerol,DMPG)、十六基磷膽鹼(hexadecylphosphocholine,HEPC)、氫化大豆磷脂醯膽鹼(hydrogenated soy phosphatidylcholine,HSPC)、二硬脂醯基磷脂醯膽鹼(distearoylphosphatidylcholine,DSPC)、二硬脂醯基磷脂醯甘油(distearoylphosphatidylglycerol,DSPG)、二油醯基磷脂醯乙醇胺(dioleoylphosphatidylethanolamine,DOPE)、棕櫚醯基硬脂醯基磷脂醯膽鹼(palmitoylstearoylphosphatidylcholine,PSPC)、棕櫚醯基硬脂醯基磷脂醯甘油(palmitoylstearoylphosphatidylcholine,PSPG)、單油醯基磷脂醯乙醇胺(monooleoylphosphatidylethanolamine,MOPE)、1-棕櫚醯基-2-油醯基-sn-甘油-3-磷脂醯膽鹼(1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine,POPC)、聚乙二醇二硬脂醯基磷脂醯乙醇胺(polyethyleneglycol distearoylphosphatidylethanolamine,PEG-DSPE)、二棕櫚醯基磷脂醯絲胺酸
(dipalmitoylphosphatidylserine,DPPS)、1,2-二油醯基-sn-甘油-3-磷脂醯絲胺酸(1,2-dioleoyl-sn-glycero-3-phosphatidylserine,DOPS)、二肉豆蔻醯基磷脂醯絲胺酸(dimyristoylphosphatidylserine,DMPS)、二硬脂醯基磷脂醯絲胺酸(distearoylphosphatidylserine,DSPS)、二棕櫚醯基磷脂酸(dipalmitoylphosphatidic acid,DPPA)、1,2-二油醯基-sn-甘油-3-磷脂酸(1,2-dioleoyl-sn-glycero-3-phosphatidic acid,DOPA)、二肉豆蔻醯基磷脂酸(dimyristoylphosphatidic acid,DMPA)、二硬脂醯基磷脂酸(distearoylphosphatidic acid,DSPA)、二棕櫚醯基磷脂醯肌醇(dipalmitoylphosphatidylinositol,DPPI)、1,2-二油醯基-sn-甘油-3-磷脂醯肌醇(1,2-dioleoyl-sn-glycero-3-phosphatidylinositol,DOPI)、二肉豆蔻醯基磷脂醯肌醇(dimyristoylphosphatidylinositol,DMPI)、二硬脂醯基磷脂醯肌醇(distearoylphosphatidylinositol,DSPI)，以及它們的混合物。特別建議的磷脂是選自於由DOPC以及DOPG所構成的群組。
在一個具體實施例中，脂質混合物包含29.5%至90%：3%至37.5%：10%至33%的莫耳比率(molar ratio)的DOPC、DOPG以及膽固醇。在另一個具體實施例中，脂質混合物包含大約15%至小於約30%莫耳比率的膽固醇。
在另一個具體實施例中，脂質混合物包含大約18至大約
28%莫耳比率的膽固醇。在又另一個具體實施例中，脂質混合物包含大約20至大約25%莫耳比率的膽固醇。
在一個具體實施例中，粒子形成組成份沒有脂肪酸(fatty acid)或陽離子脂質(cationic lipid)(亦即在生理pH值下，該脂質攜帶淨正電荷)。
在另一個具體例中，粒子-形成組分包括一具有一附接於一磷脂質分子的長鏈的高度水合的可撓性中性聚合物的親水性聚合物(hydrophilic polymer)。沒有被任何理論限制，該親水性聚合物被認為會穩定脂質體並且在活體內導致一較長的循環時間。親水性聚合物的實例包括，但不限於：具有一為大約2,000至大約5,000道耳頓的分子量的聚乙二醇(polyethylene glycol,PEG)、甲氧基PEG(methoxy PEG,mPEG)、神經節苷脂GM1(ganglioside GM1)、聚唾液酸(polysialic acid)、聚乳酸(polylactic acid)[亦被稱為聚乳酸(polylactide)]、聚乙醇酸(polyglycolic acid)[亦被稱為聚乙醇酸(polyglycolide)]、聚乳酸聚乙醇酸(polylacticpolyglycolic acid)、聚乙烯醇(polyvinyl alcohol)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、聚甲噁唑啉(polymethoxazoline)、聚乙基噁唑啉(polyethyloxazoline)、聚羥乙基噁唑啉(polyhydroxyethyloxazoline)、聚羥丙基噁唑啉(polyhydroxypropyloxazoline)、聚天冬醯胺(polyaspartamide)、聚羥丙基甲基丙烯醯胺(polyhydroxypropyl methacrylamide)、聚甲基丙烯醯胺
(polymethacrylamide)、聚二甲基丙烯醯胺(polydimethylacrylamide)、聚乙烯甲基醚(polyvinylmethylether)、聚丙烯酸羥乙酯(polyhydroxyethyl acrylate)、衍生的纖維素(derivatized celluloses)[諸如羥甲基纖維素(hydroxymethylcellulose)或羥乙基纖維素(hydroxyethylcellulose)]以及合成聚合物(synthetic polymers)。
粒子形成的組成可進一步包含有抗體或胜肽(peptide)的脂質-結合物(lipid-conjugate)，該脂質-結合物作用如標靶部分(targeting moiety)而能夠使脂質體專一性地結合至具有標的分子的標的細胞。標的分子的實例包括，但不限於：表皮生長因子受體(epidermal growth factor receptor,EGFR)、血管內皮生長因子受體(vascular endothelial growth factor receptor,VEGF)、癌胚抗原(carcinoembryonic antigen,CEA)以及erbB-2/neu(HER2)。
在本發明中所製備的脂質體可藉由被用來製備脂質體囊泡的習知技術所產生。這些技術包括：醚注射法(ether injection method)(Deamer et al.,Acad.Sci.(1978)308：250)、介面活性劑法(surfactant method)(Brunner et al.,Biochim.Biophys.Acta(1976)455：322)、冷凍-解凍法(freeze-thaw method)(Pick et al.,Arch.Biochim.Biophys.(1981)212：186)、逆相蒸發法(reverse-phase evaporation method)(Szoka et al.,Biochim.Biophys.Acta.(1980)601：
559 71)、超音波處理法(ultrasonic treatment method)(Huang et al.,Biochemistry(1969)8：344)、乙醇注射法(ethanol injection method)(Kremer et al.,Biochemistry(1977)16：3932)、擠製法(extrusion method)(Hope et al.,Biochim.Biophys.Acta(1985)812：55 65)、法式壓碎機法(French press method)(Barenholz et al.,FEBS Lett.(1979)99：210)，以及在Szoka,F.,Jr.,et al.,Ann.Rev.Biophys.Bioeng.9：467(1980)中所詳述的方法。上面的所有方法是用於形成脂質體囊泡的基礎技術，以及這些方法在此處被併入本案以作為參考資料。在滅菌之後，製備完成的脂質體在無菌環境監控下充填至容器中，接著進行凍乾而形成粉末或塊狀物。因為在本發明中，包含製備完成的脂質體的脂質體混合物屬凍乾產品，因此需要至少添加一種抗凍劑(cryoprotectant)來製備脂質混合物。在一個具體實施例中，脂質混合物進一步包含有一或多種緩衝劑。
抗凍劑包括，但不限於：甘露糖醇(mannitol)、甘油(glycerol)、右旋糖(dextrose)、蔗糖(sucrose)和/或海藻糖(trehalose)。此脂質混合物較適用的抗凍劑是甘露糖醇。
緩衝劑包括，但不限於：磷酸二氫鈉(sodium phosphate monobasic dihydrate)以及無水磷酸氫二鈉(sodium phosphate dibasic anhydrous)。
脂質混合物包含不預先形成脂質體的脂質之具體實施例中，脂質混合物可藉由溶解於適合的有機溶劑[包
括，但不限於：乙醇、甲醇、t-丁醇(t-butyl alcohol)、醚以及氯仿(chloroform)]中而被製備，並且可藉由加熱(heating)、真空蒸發(vacuum evaporation)、氮氣蒸發(nitrogen evaporation)、冷凍乾燥(lyophilization)，或者其它溶劑移除的習知方法而被乾燥。
支持本發明的脂質混合物製備的特定實施例將描述如下。
在本發明中的類固醇溶液包含有眼用類固醇、其藥用的鹽類或其前驅藥。
在本發明中適用的眼用類固醇包括任何天然存在的類固醇激素(steroid hormones)、合成類固醇(synthetic steroids)以及它們的衍生物。眼用類固醇的實施例包括，但不限於：可體松(cortisone)、氫化可體松(hydrocortisone)、乙酸氫化可體松(hydrocortisone acetate)、巰基氫化可的松特戌酸鹽(tixocortol pivalate)、氟欣諾隆(fluocinolone)、去氫皮質醇(prednisolone)、甲基去氫皮質醇(methylprednisolone)、強體松(prednisone)、丙酮特安皮質醇(triamcinolone acetonide)、特安皮質醇(triamcinolone)、莫米松(mometasone)、安西奈德(amcinonide)、布地奈德(budesonide)、地索奈德(desonide)、氟洛奈皮質醇(fluocinonide)、丙酮氟洛皮質醇(fluocinolone acetonide)、哈西奈德(halcinonide)、倍他米松(betamethasone)、倍他米
松磷酸鈉(betamethasone sodium phosphate)、地塞米松(dexamethasone)、地塞米松磷酸鈉(dexamethasone sodium phosphate,DSP)、氟可龍(fluocortolone)、17-氫化可體松丁酸酯(hydrocortisone-17-butyrate)、17-氫化可體松戊酸酯(hydrocortisone-17-valerate)、二丙酸安氯皮質醇(alclometasone dipropionate)、戊酸倍他米松(betamethasone valerate)、二丙酸倍他米松(betamethasone dipropionate)、潑尼卡酯(prednicarbate)、17-可洛貝他松丁酸酯(clobetasone-17-butyrate)、17-可洛貝他索丙酸酯(clobetasol-17-propionate)、己酸氟可龍(fluocortolone caproate)、三甲基乙酸氟可龍(fluocortolone pivalate)、醋酸氟潑尼定(fluprednidene acetate)、二氟潑尼松龍酯(difluprednate)、氯替潑諾(loteprednol)、氟美皮質醇(fluorometholone)、甲羥松(medrysone)、利美索龍(rimexolone)、貝可皮質醇(beclomethasone)、氯潑尼醇(cloprednol)、可的伐唑(cortivazol)、去氧皮質酮(deoxycortone)、二氟可龍(difluorocortolone)、氟克諾隆(fluclorolone)、氟化羥基可體酮(fluorocortisone)、氟皮質醇(flumethasone)、氟尼縮松(flunisolide)、氟可龍(fluorocortolone)、氟氫縮松(flurandrenolone)、甲潑尼松(meprednisone)、甲基培尼皮質醇(methylprednisolone)以及帕拉米松(paramethasone)。較適合用於本發明的眼用類固醇是水溶性類固醇。更適合用於本發明的眼用類固醇是
DSP。
眼用類固醇的藥學上可接受的鹽類包括從無毒性無機或有機鹼中所形成的無毒性鹽類。例如，無毒性鹽類可使用無機鹼[諸如鹼金屬或鹼土金屬氫氧化物(alkali or alkaline earth metal hydroxide)(例如鉀、鈉、鋰、鈣或鎂)]；以及使用有機鹼(諸如胺以及類似之物)而被形成。
眼用類固醇的藥學上可接受的鹽類亦包括從無毒性無機或有機酸中所形成的無毒性鹽類。有機以及無機酸的實例為：例如，氫氯酸、硫酸、磷酸、醋酸、琥珀酸、檸檬酸、乳酸、馬來酸、延胡索酸、棕櫚酸、膽酸、雙羥萘酸、黏液酸、D-麩胺酸、戊二酸、乙醇酸、酞酸、酒石酸、月桂酸、硬脂酸、水楊酸、山梨酸、苯甲酸，以及類似之物。
本發明的類固醇溶液可利用ddH2O或適合的緩衝液來製備。
本發明的藥學組成物是適合用於眼睛遞送類固醇並且包含有下列組合：此藥學組成物包含磷脂質或磷脂質的混合物及帶有或不帶有膽固醇；以及包含眼用類固醇或藥學上可接受的鹽類之類固醇溶液；其中磷脂質的總量在每50μL的藥學組成物是介於大約0.1μmol至低於大約2.5μmol之間，其中該組成物相對於每50μL的藥學組成物中含有至少大約5μmol的磷脂質組成物的副作用是較低
的。
在一個具體實施例中，磷脂質的總量是每50μL的藥學組成物大約0.5μmol至低於大約2.0μmol。在另一個具體實施例中，磷脂質的總量是每50μL的藥學組成物大約1μmol至低於大約1.5μmol。
在一個具體實施例中，藥學組成物進一步包含至少一種用於活性成分之藥學上可接受的賦形劑(excipient)、稀釋劑(diluent)、載劑(vehicle)、載劑(carrier)、介質(medium)、防腐劑(preservative)、抗凍劑，或者它們的一組合。
在一個具體實施例中，本發明的藥學組成物是藉由下列步驟而被製備：將一種或多種的磷脂質及帶有或不帶有膽固醇的脂質，以及一種或多種緩衝劑混合，以形成脂質體，將帶有一種或多種抗凍劑的脂質體凍乾，之後，形成呈粉末形式的脂質塊。該粉末狀的脂質塊可經由類固醇溶液重組而形成水性懸浮液。
在另一個具體實施例中，本發明的藥學組成物是藉由下列步驟而被製備：將一種或多種的磷脂質及帶有或不帶有膽固醇的脂質於溶劑中混合，接著將該溶劑移除以形成脂質塊。該脂質塊可經由類固醇溶液重組而形成水性懸浮液。
在一個較佳的具體實施例中，藥學組成物包含大約0.6至大約0.7mg的地塞米松。在另一個較佳的具體
實施例中，藥學組成物包含大約0.19至大約0.59mg的丙酮氟洛皮質醇。在又另一個較佳的具體實施例中，藥學組成物包含有大約4mg的丙酮特安皮質醇。
本發明的藥學組成物包含大約10%至50%與脂質相伴的DSP或大約50%至大約90%的無脂質相伴的DSP。
無脂質相伴的DSP在玻璃液(vitreous humor)中將輕易地被清除，其半衰期大約為3.5小時，然而脂質相伴的DSP在玻璃液中不會輕易地被清除，並且端視於藥學組成物成分而決定可被保留在玻璃液中達到數個月。
本發明的藥學組成物可被用來治療罹患眼科疾病的病患。在一個較佳的具體實施例中，眼科疾病是被限制於眼睛的後方。在更佳的具體實施例中，眼科疾病是下列的任一者：黃斑水腫、眼色素層炎、視網膜分支靜脈阻塞或視網膜中央靜脈阻塞，以及年齡相關的黃斑退化(age-related macular degeneration)。
另一方面，本發明是針對治療眼用疾病的方法，其包含對於需要治療的個體投予此處所描述的藥學組成物之有效量，藉此減少該個體中的眼科疾病的症狀以及徵兆。
藥學組成物可被組成為任何適合用於所選擇的投藥模式的形式。在一個具體實施例中，藥學組成物被配製以用於眼睛投藥。在另一個具體實施例中，藥學組成物
被配製以用於玻璃體內投藥。在另一個具體實施例中，藥學組成物被配製以用於局部投藥。
依據具體實施例，本發明的藥學組成物的劑量可被熟習此技藝的人士所決定。單一劑量或多重劑量的使用都可被考量，各個形式均可在特定的臨床情境(clinical settings)中提供優點。依據本發明，欲投藥的藥學組成物的實際量可依據年齡、重量與被治療個體的病況而做調整，並且端視於醫事人員的判斷力。
下面的實施例進一步例示說明本發明。這些實施例僅被意欲用以例示說明本發明，而不被解釋為限制。
實施例1. 製備脂質混合物
脂質混合物是藉由乙醇注射法而被製備。脂質，包括DOPC、DOPG[這兩者是商業上可購得的，且來自於NOF Corporation(日本)以及Lipoid LLC(USA)]以及膽固醇[商業上可購得的，且來自於MINAKEM(法國)]，是以67.5：7.5：25的莫耳比率而被組合並且在大約40℃下於一燒瓶中被溶解於99.9%乙醇中。桌上型超音波清洗槽(tabletop ultrasonic bath)可用來進行脂質溶解(lipid dissolution)。
利用蠕動泵(peristaltic pump)將溶解的脂質溶液加至磷酸鈉溶液中，此混合的速度是100mL/min。脂質
混合物接著通過0.2μm孔徑的聚碳酸酯膜(polycarbonate membrane)6-10次。脂質體(或大的單層囊泡)被形成並且平均囊泡直徑是大約120-140nm(由Malvern ZetaSizer Nano ZS-90所測量)。
脂質體混合物是藉由Millipore Pellicon 2 Mini Ultrafiltration Module Biomax-100C(0.1m2)的切向流過濾系統(tangential flow filtration system)透析並且濃縮，之後，甘露糖醇被添加而得到20mg/mL的最終甘露糖醇濃度。脂質體混合物接著使用0.2μm的無菌過濾器而達到滅菌的效果，而經滅菌的脂質體混合物再無菌環境監控下裝填至瓶(vials)中，接著被凍乾即形成脂質塊。脂質塊的主要組成物被概述於表1中。
藥學組成物的製備是藉由使用DSP溶液而將實施例1中經凍乾的脂質塊重組以形成多層囊泡(multilammellar vesicles)。
關於50μL之具有0.6mg的DSP以及5μmol磷脂質的藥學組成物，在實施例1中，經由一瓶的凍乾脂質塊加上0.3mL的DSP溶液而被重組，其中DSP的濃度是13.2mg/mL。
關於50μL之具有0.6mg的DSP以及2.5μmol磷脂質的藥學組成物，在實施例1中，經由一瓶的凍乾脂質塊加上0.6mL的DSP溶液而被重組，其中DSP的濃度是13.2mg/mL。
藥學組成物在減少眼用類固醇副作用的效用活體評估是使用紐西蘭大白兔(New Zealand albino rabbit)所執行。在此研究中25隻雄性兔子(介於10-12週大)被使用。
於實驗開始時兔子的平均體重是2.3kg。
兔子在此試驗期間均可以自由地獲得飲水以及
食物。
此研究設計分成5個研究組別，如下所述：
組別1：5隻兔子各接受50μL之包含有預先形成脂質體的脂質混合物以及0.05mg的地塞米松磷酸鈉(DSP)的藥學組成物，其中藥學組成物的總磷脂質是大約5μmol。
組別2：5隻兔子各個接受50μL之包含有預先形成脂質體的脂質混合物以及0.2mg的DSP的藥學組成物，其中藥學組成物的總磷脂質是大約5μmol。
組別3：5隻兔子各個接受50μL之包含有預先形成脂質體的脂質混合物以及0.6mg的DSP的藥學組成物，其中藥學組成物的總磷脂質是大約5μmol。
組別4：5隻兔子最初被分配至此組別，但1隻兔子在玻璃體內注射之前死於麻醉。因此，4隻兔子各接受50μL之包含有預先形成脂質體的脂質混合物以及0.6mg的DSP的藥學組成物，其中藥學組成物的總磷脂質是大約2.5μmol。
組別5：5隻兔子最初被分配至此組別，但1隻兔子在玻璃體內注射之前死於麻醉。因此，4隻兔子各接受50μL之包含有預先-形成脂質體的脂質混合物以及0.6mg的DSP的藥學組成物，其中藥學組成物的總磷脂質是大約1.25μmol。
藥學組成物是藉由玻璃體內注射而被投藥給兔
子。被投藥給各個眼睛的DSP的劑量與磷脂質的總量、被注射的眼睛的數目、藥學組成物的DSP強度與磷脂質濃度，以及被投藥給各個眼睛的藥學組成物的體積被概述於表2中。
在180天的試驗期間，兔子在固定的時間間隔中被檢測，其檢測結果如下：
1.眼睛的有害徵兆，諸如中度角膜水腫(moderate corneal edema)、角膜混濁(corneal opacity)、軟化的角膜(softened cornea)[被定義為在角膜上使用眼壓計(tonometer)測量角膜彈性的缺失]以及結膜充血(conjunctiva hyperemia)。兔子的眼睛是在下列所規畫的天數中被檢測：0、4、7、11、14、21、25、28、32、35、39、42、46、49、53、56、60、63、67、70、74、77、82、85、89、92、96、99、103、106、
110、113、117、120、124、127、131、134、138、141、145、148、152、155、159、162、166、169、173、176以及180。
2.眼內壓(Intraocular pressure,IOP)升高。IOP是在藥學組成物的玻璃體內投藥之前以及在玻璃體內投藥之後的下列所規畫的天數中藉由Reichert Tono-Pen® XL眼壓計(Reichert,Inc.3362 Walden Avenue,Depew,NY 14034 USA)進行測量：0、4、7、11、14、18、21、25、28、32、35、39、42、46、49、53、56、60、63、67、70、74、77、82、85、89、92、96、99、103、106、110、113、117、120、124、127、131、134、138、141、145、148、152、155、159、162、166、169、173、176以及180。當IOP超過15mmHg，兔子被判定為具有眼內壓升高的情形。
3.玻璃體透明度(vitreous clarity)上的改變。已知脂質體會影響玻璃體透明度(B Short.Safety Evaluation of Ocular Drug Delivery Formulations：Techniques and Practical Considerations.Toxicol Pathol.Jan 2008；36(1)：49-62 at 52)。兔子中的玻璃體透明度是藉由直接式檢眼鏡(direct ophthalmoscope)被評估(PanOptic Ophthalmoscope 118 series；Model 11820：Type 71000A；Welch Allyn Inc.4341 State street road Skaneateles,NY 13153-0220)。玻璃體透明度被
分為0-4的計分值(0表示視野下可以清楚的看見視網膜血管；1表示視網膜血管仍可透過藥學組成物而被輕易地看見；2表示只能模糊的看到視網膜血管而血管不能被輕易地鑑別；3表示更模糊的視野，其中僅數個視網膜血管可被鑑別；4表示藥學組成物造成的玻璃體模糊)。
此外，在玻璃狀液(vitreous humor)中的藥學組成物的分佈是使用檢眼鏡來評估。眼底計分值(fundus score)被分為0-6的計分值，0表示眼底可被看見並且沒有被藥學組成物覆蓋，1表示六分之一的眼底是被藥學組成物覆蓋，2表示三分之一的眼底是被藥學組成物覆蓋，3表示二分之一的眼底是被藥學組成物覆蓋，4表示三分之二的眼底是被藥學組成物覆蓋，5表示六分之五的眼底是被藥學組成物覆蓋，6表示無法看見眼底並且完全地被藥學組成物覆蓋。
180天研究的結果被概述於表3中。這些結果顯示接受含有低於大約2.5μmol的磷脂質的藥學組成物的兔子(組別4以及組別5)相對於接受含有至少大約5μmol的磷脂質的藥學組成物的兔子(組別3)呈現較少的眼睛副作用。
此外，由於在玻璃狀液中較快速的清除，具有低於大約2.5μmol的磷脂質的藥學組成物(組別4以及組別5)相對於具有至少大約5μmol的磷脂質的藥學組成物(組別3)是較佳地分佈於玻璃狀液中。
表3之更詳細的結果摘要如下所示：
結果顯示：在組別1、組別2以及組別3兔子中(這些兔子接受含有一大於2.5μmol的磷脂質的藥學組成物)的中度角膜水腫的發病率分別是50%、80%以及40%。在組
別4兔子中沒有中度角膜水腫的發病率，而有50%的組別5兔子罹患中度角膜水腫。
50%的組別1兔子、80%的組別2兔子以及20%的組別3兔子罹患角膜混濁，而組別4以及組別5兔子中沒有一隻兔子具有角膜混濁。總而言之，接受低於大約2.5μmol的磷脂質的藥學組成物的兔子(組別4以及組別5)相對於接受至少大約5μmol的磷脂質的藥學組成物的兔子(組別3)展現較少的角膜混濁。
在組別1、組別2以及組別3兔子中的角膜軟化的發病率超過50%，而在組別4以及組別5兔子中的角膜軟化發病率是低於50%。總而言之，接受低於大約2.5μmol的磷脂質的藥學組成物的兔子(組別4以及組別5)相對於接受至少大約5μmol的磷脂質的藥學組成物的兔子(組別3)展現較少的角膜軟化。
在組別1以及組別2中60%的兔子，以及在組別3中30%的兔子罹患結膜充血。僅有12.5%的組別4兔子具有結膜充血，以及組別5兔子中沒有一隻兔子具有結膜充血。總而言之，接受低於大約2.5μmol的磷脂質的藥學組成物的兔子(組別4以及組別5)相對於接受至少大約5μmol的磷脂質的藥學組成物的兔子(組別3)展現較少的結
膜充血。
IOP升高是眼用類固醇注射的熟知副作用。組別1兔子有60%IOP升高、組別2兔子有80%IOP升高，以及組別3兔子有40%IOP升高，而IOP升高在組別4兔子中未被偵測到以及在組別5兔子中則有37.5%被偵測到。總而言之，接受低於大約2.5μmol的總磷脂質的藥學組成物的兔子(組別4以及組別5)相對於接受至少大約5μmol的磷脂質的藥學組成物的兔子(組別3)展現較少的IOP升高。
20%的組別1與組別2兔子以及10%的組別3兔子有玻璃體透明度降低情形(具有計分值3或更高)。在組別4以及組別5兔子中沒有發現到玻璃體透明度降低(具有計分值3或更高)。總而言之，低於大約2.5μmol的總磷脂質的藥學組成物(組別4以及組別5)相對於至少大約5μmol的磷脂質的藥學組成物(組別3)較不可能影響降低玻璃體透明度。
40%的組別1以及20%的組別2與組別3兔子具有高於4的眼底計分值，而組別4以及組別5兔子中沒有兔子具有高於4的眼底計分值。總而言之，低於大約2.5μmol的磷脂質的藥學組成物(組別4以及組別5)相對於至少大約5μmol的磷脂質的藥學組成物(組別3)是較均勻地分
佈於兔子的玻璃狀液中。
Claims (19)
- 一種適合用於眼睛遞送類固醇的藥學組成物，其包含有下列組合：(a)脂質混合物，其包含有磷脂質的混合物以及膽固醇，其中磷脂質的混合物包括二油醯基甘油磷脂醯膽鹼(dioleoyl-phosphatidylcholine,DOPC)、二油醯基磷脂醯甘油(dioleoylphosphatidylglycerol,DOPG)；以及(b)類固醇溶液，其包含有效量的眼用類固醇或其藥學上可接受的鹽類，其中該眼用類固醇或其藥學上可接受的鹽類係選自於由地塞米松(dexamethasone)、地塞米松磷酸鈉(dexamethasone sodium phosphate,DSP)、倍他米松(betamethasone)、倍他米松磷酸鈉(betamethasone sodium phosphate)以及氟可龍(fluocortolone)所組成的群組；其中磷脂質的混合物的總量在每50μL的藥學組成物是介於大約0.1μmol至低於大約2.5μmol之間，於每50μL的藥學組成物中介於大約0.1μmol至低於大約2.5μmol之間的磷脂質的混合物比含有至少大約5μmol的磷脂質的混合物有較低的副作用。
- 如請求項1的藥學組成物，其中該眼用類固醇藥學上可接受的鹽類是地塞米松磷酸鈉。
- 如請求項2的藥學組成物，其中地塞米松磷酸鈉的劑量是每50μL藥學組成物為大約0.6至大約0.7mg的地塞米松。
- 如請求項1至3中任一項的藥學組成物，其中該脂質混合物進一步包含有抗凍劑。
- 如請求項4的藥學組成物，其中該抗凍劑是甘露糖醇。
- 如請求項1至3中任一項的藥學組成物，其中該脂質混合物進一步包含有緩衝劑。
- 如請求項6的藥學組成物，其中該緩衝劑包含有二水合磷酸二氫鈉以及無水磷酸氫二鈉。
- 如請求項1至3中任一項的藥學組成物，其中該脂質混合物包含29.5%至90%：3%至37.5%：10%至33%的莫耳比率(molar ratio)的DOPC、DOPG以及膽固醇。
- 一種如請求項1之藥學組成物用以製造用於治療眼科疾病之醫藥品的用途，其中該醫藥品包含有效量之請求項1之藥學組成物。
- 如請求項9的用途，其中該眼科疾病是被限制於眼睛的後段。
- 如請求項10的用途，其中該眼科疾病是黃斑水腫。
- 如請求項10的用途，其中該眼科疾病是眼色素層炎。
- 如請求項10的用途，其中該眼科疾病是視網膜分支靜脈阻塞。
- 如請求項10的用途，其中該眼科疾病是視網膜中央靜脈阻塞。
- 如請求項10的用途，其中該眼科疾病是年齡-相關的黃斑退化。
- 如請求項9至15中任一項的用途，其中該藥學組成物是藉由玻璃體內注射投藥。
- 如請求項9至15中任一項的用途，其中該脂質混合物包含29.5%至90%：3%至37.5%：10%至33%的莫耳比率的DOPC、DOPG以及膽固醇。
- 如請求項9至15中任一項的用途，其中該眼用類固醇藥學上可接受的鹽類是地塞米松磷酸鈉。
- 如請求項9至15中任一項的用途，其中地塞米松磷酸鈉的劑量是每50μL藥學組成物為大約0.6至大約0.7mg的地塞米松。
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| EP3691654A4 (en) | 2017-09-25 | 2021-11-24 | Surface Pharmaceuticals, Inc. | OPHTHALMIC PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATMENT OF EYE SURFACE DISEASES |
| WO2020139525A1 (en) * | 2018-12-27 | 2020-07-02 | Surface Pharmaceuticals, Inc. | Ophthalmic pharmaceutical compositions and methods for treating ocular surface disease |
| US11759472B2 (en) | 2017-11-21 | 2023-09-19 | Cs Pharmaceuticals Limited | Compositions and methods of use for treating aberrant inflammation in peri-ocular secretory glands or at the ocular surface |
| BR112020008046A2 (pt) * | 2017-11-21 | 2020-10-27 | Axerovision, Inc. | composições e métodos de uso para tratamento de inflamação anormal em glândulas secretoras perioculares ou na superfície ocular |
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