TWI515008B - 含有磷脂質及膽固醇的眼睛藥物傳輸系統 - Google Patents
含有磷脂質及膽固醇的眼睛藥物傳輸系統 Download PDFInfo
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- TWI515008B TWI515008B TW099102626A TW99102626A TWI515008B TW I515008 B TWI515008 B TW I515008B TW 099102626 A TW099102626 A TW 099102626A TW 99102626 A TW99102626 A TW 99102626A TW I515008 B TWI515008 B TW I515008B
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- drug delivery
- phospholipid
- delivery system
- eye
- cholesterol
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Description
本申請案主張美國專利申請案第12/538,435號(2009年8月10日申請)之優先權。該申請案之內容全部以參考資料方式納入本說明書中。
本發明係關於一種含有磷脂質及膽固醇的眼睛藥物傳輸系統,其可用於延長藥物在眼睛停留的時間。
由於眼睛是具有緩慢血液循環之封閉器官,大部分的治療劑再由全身性之方式投與時並無法以有效量到達其中。
為解決此一問題,已採用玻璃體內注射進行眼睛的治療劑傳輸,特別是傳輸至眼之後端(如,視網膜及脈絡膜)。因治療劑一般而言僅會在眼中停留有限之時間,因此需要進行重複之玻璃體內注射以達成所欲之治療效應。然而,使用此種侵入性之方法所進行的頻繁投與並非想要的治療方式。
本領域需要一種可延長治療劑在眼中之壽命的藥物傳輸系統,以減少治療中所需之玻璃體內注射次數。
本發明係根據非可預期的發現,即含有磷脂質及膽固醇的藥物傳輸系統可顯著延長癌思停(Avastin)(一種對於血管內皮生長因子具有專一性之抗體)在眼中停留的期間。
因此,在一方面,本發明係關於一種藥物傳輸系統,其含有治療劑(如,蛋白、核酸、或小分子),以及包括磷脂質及膽固醇之傳輸載劑。膽固醇在該傳輸載劑中之莫耳百分比(如,在凍乾形式中)可為5-40%(如,10-33%或20-25%)。該傳輸載劑及該治療劑可為混合或分離。
在本發明之藥物傳輸系統中,該治療劑之50-90%係為非結合形式,而該磷脂質與膽固醇之組合對該治療劑的重量比為5-80比1。在一實例中,該治療劑係對抗血管內皮生長因子(VEGF)之抗體,且60-90%之該抗體皆為非結合形式,而該磷脂質與膽固醇之組合對該抗體的重量比為5-40比1。在另一實例中,該治療劑係抗發炎分子(如,皮質類固醇)。
本文所述傳輸載劑中之磷脂質可為兩種磷脂質之混合物。例如,該磷脂質可為與聚乙二醇-二硬脂醯磷脂醯乙醇胺(PEG-DSPE)或二油醯磷脂醯甘油(DOPG)混合的1,2-二油醯基-sn-丙三醇-3-磷脂醯膽鹼(DOPC)、1-棕櫚醯基-2-油醯基-sn-丙三醇-3-磷脂醯膽鹼(POPC)、大豆磷脂醯膽鹼(SPC)、或卵磷脂醯膽鹼(EPC)中之一者。當該磷脂質為DOPC與DOPG之混合物,該前者之莫耳百分比可為29.5-90%(如,50-80%),而該後者之莫耳百分比可為3-37.5%(如,3-18.75%)。在一實例中,該傳輸載劑含有莫耳百分比之比例為56.25-72.5:7.5-18.75:20-25的DOPC、DOPG、及膽固醇。
在另一方面,本發明係關於一種將治療劑傳輸至個體之眼睛的方法。此種方法包括(i)提供上述之藥物傳輸系統,其可為水性懸浮液之形式,及(ii)使用,例如,玻璃體內注射將其投與至需要之個體的眼。該傳輸系統可藉著以下步驟製備:將磷脂質、膽固醇、以及一或多種治療劑混合以形成混合物;凍乾該混合物;以及,在投與之前,使該混合物懸浮於水性溶液中以形成該水性懸浮液。或者,其可藉著以下步驟製備:將磷脂質及膽固醇混合以形成混合物;凍乾該混合物;以及,在投與之前,使該混合物與一或多種治療劑共同懸浮於水性溶液中以形成該水性懸浮液。
本發明之範圍亦包括使用上述之傳輸載劑以對眼傳輸治療劑以及製造用於治療眼睛疾病之藥物的用途。
本發明一或多個具體實例之細節示於下文之敘述。本發明之其他特徵或優點將可由下文之圖式及數個具體實例之詳細敘述以及附呈之申請專利範圍而得悉。
本文所述係一種用於對眼睛投與至少一種治療劑之較佳藥物傳輸系統,該治療劑在傳遞時具有眼中之延長壽命,特別是玻璃體中。
本文所述之此種藥物傳輸系統包括含有磷脂質及膽固醇之傳輸載劑。該磷脂質可為同種群之磷脂質,較佳為中性磷脂質,或者可為不同類型磷脂質之混合物。用於製造該傳輸載劑之磷脂質實例包括,但不限於,磷脂醯膽鹼(PC)、磷脂醯甘油(PG)、磷脂醯乙醇胺(PE)、磷脂醯絲胺酸(PS)、磷脂酸(PA)、磷脂醯肌醇(PI)、卵磷脂醯膽鹼(EPC)、卵磷脂醯甘油(EPG)、卵磷脂醯乙醇胺(EPE)、卵磷脂醯絲胺酸(EPS)、卵磷脂酸(EPA)、卵磷脂醯肌醇(EPI)、大豆磷脂醯膽鹼(SPC)、大豆磷脂醯甘油(SPG)、大豆磷脂醯乙醇胺(SPE)、大豆磷脂醯絲胺酸(SPS)、大豆磷脂酸(SPA)、大豆磷脂醯肌醇(SPI)、二棕櫚醯磷脂醯膽鹼(DPPC)、1,2-二油醯基-sn-丙三醇-3-磷脂醯膽鹼(DOPC)、二肉豆蔻醯磷脂醯膽鹼(DMPC)、二棕櫚醯磷脂醯甘油(DPPG)、二油醯磷脂醯甘油(DOPG)、二肉豆蔻醯磷脂醯甘油(DMPG)、十六烷基磷酸膽鹼(HEPC)、氫化大豆磷脂醯膽鹼(HSPC)、二硬脂醯磷脂醯膽鹼(DSPC)、二硬脂醯磷脂醯甘油(DSPG)、二油醯磷脂醯乙醇胺(DOPE)、棕櫚醯硬脂醯磷脂醯膽鹼(PSPC)、棕櫚醯硬脂醯磷脂醯甘油(PSPG)、單油醯磷脂醯乙醇胺(MOPE)、1-棕櫚醯基-2-油醯基-sn-丙三醇-3-磷脂醯膽鹼(POPC)、聚乙二醇-二硬脂醯磷脂醯乙醇胺(PEG-DSPE)、二棕櫚醯磷脂醯絲胺酸(DPPS)、1,2-二油醯基-sn-丙三醇-3-
磷脂醯絲胺酸(DOPS)、二肉豆蔻醯磷脂醯絲胺酸(DMPS)、二硬脂醯磷脂醯絲胺酸(DSPS)、二棕櫚醯磷脂酸(DPPA)、1,2-二油醯基-sn-丙三醇-3-磷脂酸(DOPA)、二肉豆蔻醯磷脂酸(DMPA)、二硬脂醯磷脂酸(DSPA)、二棕櫚醯磷脂醯肌醇(DPPI)、1,2-二油醯基-sn-丙三醇-3-磷脂醯肌醇(DOPI)、二肉豆蔻醯磷脂醯肌醇(DMPI)、二硬脂醯磷脂醯肌醇(DSPI)、及其混合物。
在一實例中,該傳輸載劑不含脂肪酸(亦即,具有長非支鏈脂族尾之羧酸)、陽離子脂質(亦即,在生理pH下帶有淨正電荷之脂質)、及黏膜黏附性聚合物(如,Carbopol 934 P、泊洛沙姆(polyaxomer)、卡波姆(carbomer)、及植物凝集素)。
該傳輸載劑可以醫藥產業中之已知方法製備。其中一個實例如下。使磷脂質、膽固醇、及其他組成份(如有)懸浮於蒸餾水或水溶液中形成懸浮液。接著以習知方法對該懸浮液進行均質化,如,超音波處理、震盪、或擠出。在滅菌後,可將該經均質化之載劑懸浮液無菌置於容器中,接著再凍乾以形成粉末。
任何用於治療眼部疾病之治療劑(如,小分子、蛋白、肽、或核酸)皆可與上述之傳輸載劑混合,並投與至個體之眼睛。在一實例中,該治療劑係抗發炎藥物,諸如,皮質類固醇化合物。名辭「皮質類固醇化合物」係指天然存在之類固醇激素(包括糖皮質激素)以及其衍生物,其較佳為水溶性者。皮質類固醇之實例包括,但不限於,可體松(cortisone)、氫化可體松(hydrocortisone)、醋酸氫化可體松(hydrocortisone acetate)、巰氫考的松(tixocortol pivalate)、氟輕松(flucinolone)、潑尼松龍(prednisolone)、甲潑尼松龍(methylprednisolone)、潑尼松(prednisone)、曲安奈德(triamcinolone acetonide)、去炎松(triamcinolone)、莫米松(mometasone)、安西奈德(amcinonide)、布地奈德(budesonide)、地索奈德(desonide)、
氟西奈德(fluocinonide)、醋酸氟輕松(fluocinolone acetonide)、氯氟輕松(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)、氟可龍(fluocortolone)、氢化可的松-17-丁酸(hydrocortisone-17-butyrate)、氢化可的松-17-戊酸(hydrocortisone-17-valerate)、阿氯米松及丙酸酯(aclometasone dipropionate)、倍他米松戊酸酯(betamethasone valerate)、倍他米松双丙酸酯(betamethasone dipropionate)、潑尼卡酯(prednicarbate)、氯倍他松-17-丁酸(clobetasone-17-butyrate)、氯倍他松-17-丙酸(clobetasol-17-propionate)、己酸氟可龍(fluocortolone caproate)、新戊酸氟可龍(fluocortolone pivalate)、及醋酸氟潑尼定(fluprednidene acetate)。在另一實例中,該試劑係VEGF之拮抗劑,其可為對VEGF具專一性之抗體、可溶性VEGF受體、結合VEGF之核酸、或可干擾VEGF與其同源受體之作用並阻斷VEGF信號傳導途徑的小分子。名辭「抗體」在本文中係指天然存在之免疫球蛋白、其功能性片段(諸如,Fab、Fab’、F(ab)2、或F(ab’)2)、或是經基因修飾之免疫球蛋白(諸如,人源化抗體、鑲嵌抗體、雙鏈抗體(diabody)、及單鏈抗體)。
本發明之藥物傳輸系統包括上述之傳輸載劑以及一或多種亦如上述之治療劑。其可含有凍乾形式之載劑-藥物混合物。在一實例中,該混合物係藉著使該載劑之所有組成份懸浮於水或水溶液中以形成懸浮液,對該懸浮液進行勻質化,在使該經均質化之懸浮液與一或多種治療劑混合以形成混合物,最後再凍乾該混合物而製備。在另一實例中,該混合物係藉著使該載劑與一或多種治療劑之所有組成份懸浮於水或水溶液中以形成懸浮液,接著再凍乾該懸浮液以形成凍乾混合物而製
備。可在凍乾過程中,於該載劑-藥物懸浮液中加入冷凍保護劑(如,甘露糖醇、蔗糖、海藻糖、及乳糖)。在使用甘露糖醇時,較佳之濃度範圍係0.5-5%(如,0.5-2%或1%)。在投與前,將該凍乾之載劑-藥物混合物再次懸浮於水溶液中,接著可將其傳輸至個體之眼睛。
在此藥物傳輸系統中,該治療劑之50-90%係為非結合形式。名辭「非結合形式之治療劑」係指可經由凝膠過濾而由該傳輸系統之磷脂質/膽固醇級份分離之治療劑分子。該非結合性治療劑之百分比係以下文實施例7所述之方法測定。
視情況言之,本發明之藥物傳輸系統可進一步包括醫藥可接受之載體,亦即,與該系統中之治療劑相容之載體,且較佳者,該載體可安定該治療劑並對該待治療個體無害。
上述之藥物傳輸系統可經由,如,玻璃體內注射而投與至個體之眼睛以治療眼部疾病。
在不須進一步詳盡闡述之情形下,咸信熟習技藝者根據上文之敘述已可將本發明使用至其最廣泛為。因此,下述之特定具體實例僅被視為說明,且不以任何方式限制本揭示內容之其他部分。所有本文所引述之刊物因此併入本文作為參考。
將磷脂質DOPC及DOPG與膽固醇以不同莫耳濃度比混合(如,67.5:7.5:25、72:8:20、及56.25:18.75:25)以形成液態混合物。使該混合物懸浮於氯仿中,再在旋轉蒸發器上於真空下乾燥。將各種乾燥之混合物再次懸浮於去離子H2O中,以杯狀探頭超音波破碎儀(Misonix Sonicator 3000)進行均質化,接著使用滅菌過濾器進行滅菌。將該等經滅菌之液態混合物無菌裝填至小瓶中,與1%之甘露糖醇混合,接著再進行凍乾。以磷量分析測定各個該等經凍乾混合物中之磷脂質總濃
度。在傳輸至眼之前,將適量之上述液態混合物與適量之癌思停(Avastin)混合,並懸浮於水溶液中,以形成水性懸浮液。
根據述於上文實施例1之方法,製備含有不同莫耳濃度比之DOPC、PEG-DSPE、及膽固醇的傳輸載劑。將各個此等傳輸載劑與適量之癌思停混合以形成水性懸浮液。
根據述於Bakri et al.,Ophthalmology,2007,114:5,855-859之方法,檢驗上述之傳輸載劑對於延長癌思停之壽命的效應。簡言之,藉由肌內注射含有舒泰(Zoletil,15mg/ml)及若朋(Rompun,7mg/ml)之混合物而麻醉紐西蘭白兔。針對每隻兔子的雙眼,使用30號針,進行50μl癌思停(25mg/ml)或是上述水性懸浮液的玻璃體內注射(癌思停之劑量為每眼1.25mg)。在注射後7天或21天犧牲兔子,並立刻摘除其眼睛。由各眼分離玻璃體液以及視網膜,並如下以ELISA測定癌思停之濃度。
在4℃下,以VEGF(10μg/ml於PBS中,pH 7,4;100μl/孔)隔夜塗覆F96 MaxiSorpTM NUNC-IMMUNO盤。以PBS清洗該經VEGF塗覆之盤,接著再在室溫下,以阻斷緩衝液(5%脫脂牛乳於PBS中)進行阻斷1小時。以該相同之阻斷緩衝液稀釋上述之玻璃體液/視網膜樣本,並以100μl/孔之量將該所得之稀釋液加至該經VEGF塗覆之盤。在室溫下共置1小時後,以0.1%Tween-20及PBS中之0.5%脫脂牛乳清洗該盤5次,再以PBS清洗5次。接著將以阻斷緩衝液稀釋之HRP標記性山羊抗人類IgG(Jackson ImmunoResearch Lab.Inc.)加入該盤。在室溫下共置30分鐘後,大量清洗該盤。接著將含有四甲基聯苯胺之反應試劑加入該盤中以進行呈色。在足夠之時間後,在各孔中加入50μl之2N HCl以終止反應。以ELISA視讀器測定各孔在450nm之吸收值(OD450)。使用各
種不同之預定癌思停濃度(3.125-25ng/ml)以建立標準癌思停/OD450濃度曲線。相對於該標準曲線,根據各樣本之OD450值而判定其癌思停濃度。
由此實驗取得之結果示於下文表1。
如上文表1所示,相較於單獨傳輸之癌思停,與該等含有DOPC/PEG-DSPE/膽固醇之載劑共同傳輸之癌思停可在眼中停留較長之時間期。該等結果亦指出,膽固醇對於該傳輸載劑延長癌思停之眼中壽命的效應而言具必要性,而PEG-DSPE之莫耳百分比則不會影響此效應。
根據述於上文實施例1之方法,製備含有不同莫耳濃度比之各種不同磷脂質及膽固醇的傳輸載劑。將該等載劑與癌思停混合,再將該等所得之混合物經玻璃體內注射至紐西蘭兔之眼睛中。注射後7或21天,根據述於上文實施例2之方法,檢驗該等兔眼中之癌思停濃度。如此取得之結果示於下文表2及3。
根據述於上文實施例1之方法,製備含有DOPG(一種陰離子磷脂質)、PEG-DSPE、或DOPC,且有或無膽固醇的傳輸載劑。將此等載劑與癌思停混合,再將該等所得之混合物經玻璃體內注射至紐西蘭兔之眼中。注射後7或21天,根據述於上文實施例2之方法,檢驗該等兔眼中之癌思停濃度。
如下文表4所示,在注射後7天,相較於不含DOPG之傳輸載劑,含有該陰離子磷脂質DOPG之傳輸載劑會造成癌思停濃度之增加。
由此實驗取得之結果亦指出,在注射後21天,含有膽固醇及DOPG之傳輸載劑顯著增加癌思停之玻璃體濃度。參見下文表5。
根據述於上文實施例1之方法,製備含有不同莫耳百分比之膽固醇、DOPC、及DOPG的傳輸載劑。將此等載劑與癌思停混合,再將該等所得之混合物經玻璃體內注射至紐西蘭兔之眼中。注射後21天,根據述於上文實施例2之方法,檢驗該等兔眼中之癌思停濃度。由此實驗取得之結果示於下文表6。
將單獨之癌思停(控制組兔)或是與含有67.5/25/7.5比例之DOPC/膽固醇/DOPG的傳輸載劑混合之癌思停(試驗組兔)對兔進行玻璃體注射。注射後7、21、及28天,以ELISA檢驗控制組兔之癌思停玻璃體濃度,並在注射後7、21、28、35、41、及49天,檢驗試驗組兔之癌思停玻璃體濃度。
相較於與傳輸載劑共同注射之癌思停,單獨注射之癌思停的玻璃體濃度隨時間降低的速度較快。參見圖1。此種結果說明,該傳輸載既可延長癌思停之眼中壽命。
在一類似實驗中,其在玻璃體內注射後之7、28、49、70、91及112天監測癌思停之玻璃體濃度。就控制組兔而言,其在注射後28天的癌思停玻璃體濃度為13μg/ml,而就試驗組兔而言,其在該相同時間點的癌思停玻璃體濃度為265μg/ml,較控制組兔高20倍。參見圖2。控制組兔之癌思停玻璃體半生期為3.9天。不同的是,試驗組兔之癌思停玻璃體半
生期具有二室特徵(2-compartment characteristic),其初及終半生期分別為5.5(t1/2α)及40.5(t1/2β)天。試驗組兔由第7天至無限期之癌思停AUC(亦即,曲線下面積)(AUC(7-∞))較控制組兔高6.8倍,而試驗組兔之AUC(112-∞)則較控制組兔之AUC(7-∞)高1.1倍。參見下文表7。
綜言之,上文所論之結果說明,該傳輸載劑可顯著延長癌思停在眼中之壽命。
將8.8/1/1.6重量比之DOPC、DOPG、及膽固醇溶於氯仿中,再將其使用旋轉蒸發器上於真空下乾燥。使如此取得之乾燥磷脂質與膽固醇混合物懸浮於去離子水中,以形成水性懸浮液。接著使用杯狀探頭超音波破碎儀(Misonix Sonicator
3000),經由超音波處理而對該懸浮液進行均質化,過濾滅菌,無菌裝填至小瓶中,再進行凍乾,以形成含有磷脂質-膽固醇之傳輸載劑。以習知之磷量分析測定該載劑中之磷脂質濃度,以確保該載劑含有適當之磷脂質總量。
接著將該傳輸載劑與各種不同之治療劑混合,亦即,色胺酸(10mg/ml)、酪胺酸(10.4mg/ml)、HFRRHLC肽(10mg/ml)、HWRGWVC肽(10mg/ml)、蛋白W(13mg/ml)、牛血清白蛋白(50mg/ml)、癌思停(25mg/ml)、及地塞米松磷酸鈉(6.7mg/ml),其皆溶於50mM之磷酸緩衝液(pH 6.2)中。以該相同之磷酸緩衝液,將該等如此形成之混合物稀釋18-100倍,並對一小份之各個混合物(50-200ml)進行凝膠過濾,以測定非結合形式治療劑之百分比。簡言之,其將一小份之混合物加樣至Sepharose 4B管柱上(直徑:1.8mm;長度:315mm)。接著以50mM之磷酸緩衝液(pH 6.2)溶析該混合物中之組成份。收集含有不同形式(亦即,非結合形式或與磷脂質結合之形式)治療劑之級份,在215nm及254nm測量其吸收值。根據OD215及OD254之值測定各級份中該治療劑之量。根據此等數值,計算非結合形式治療劑之百分比以及脂質對藥物之重量比,並示於下文表8。
將單獨之地塞米松磷酸鈉(DSP)(控制組兔)或是與含有67.5/25/7.5比例之DOPC/膽固醇/DOPG的傳輸載劑混合之DSP(試驗組兔)對兔進行玻璃體注射。由玻璃體內對各兔之兩眼注射0.2mg DSP劑量之50μl DSP或DSP-傳輸載劑混合物。以具有光電二極管陣列(PDA)偵測器之超效液相層析(ACQUITY UPLCTM),在注射後2h、1d、4d、8d、及15d檢驗控制組兔之DSP玻璃體濃度,並在注射後2h、1d、4d、8d、15d、及35d檢驗試驗組兔之DSP玻璃體濃度。在各時間點皆檢驗兩眼。
如圖3所示,單獨注射之DSP的玻璃體濃度在注射後非常迅速的降低;相反的,甚至在注射後35天,仍可觀察到顯著量之與傳輸載劑共同注射的DSP。此種結果說明,該傳輸載既可延長DSP之眼中壽命。
所有揭示於此說明書中之特徵可以任何方式組合。各個揭示於此說明書中之特徵可以另一提供相同、相當、或類似目的之替代手段取代。因此,除非另有明示,各例示之特徵僅係一總括系列之相當或類似特徵中之一例。
由上文之敘述,熟習技藝者可輕易確認本發明之必要特徵,且在不偏離本發明精神及範圍之情形下,熟習技藝者可實施本發明之各種不同變化及修飾,以使其適用於各種用途及條件。因此,其他具體實例亦涵括於申請專利範圍中。
接著描述圖式。
圖1係顯示玻璃體注射後7、21、28、35、41、及49天之癌思停玻璃體濃度的圖表。TLC傳輸載劑係指含有67.5/25/7.5比例之DOPC/膽固醇/DOPG的傳輸載劑。“*”及“**”分別係指檢驗1或2隻兔眼的時間點。在其他時間點則檢驗4隻兔眼。
圖2係顯示玻璃體注射後7、28、49、70、91及112天之癌思停玻璃體濃度的圖表。TLC傳輸載劑係指含有67.5/25/7.5比例之DOPC/膽固醇/DOPG的傳輸載劑。“**”及“***”分別係指檢驗2或3隻兔眼的時間點。在其他時間點則檢驗4隻兔眼。
圖3係顯示玻璃體注射後2h、1d、4d、8d、15d、及35d之地塞米松磷酸鈉(DSP)玻璃體濃度的圖表。TLC傳輸載劑係指含有67.5/25/7.5比例之DOPC/膽固醇/DOPG的傳輸載劑。
Claims (21)
- 一種藥物傳輸系統,其包含:傳輸載劑,其含有磷脂質或選自於由下列所構成的群組中的磷脂質的混合物:DOPC、POPC、SPC、EPC、PEG-DSPE以及DOPG,以及膽固醇,其中該膽固醇係以相對於該傳輸載劑的10-33的莫耳百分比的數量而存在;以及一或多種水溶性的用於眼睛的治療劑;其中該水溶性的用於眼睛的治療劑之50-90%係為非結合形式,而該磷脂質與膽固醇之組合對該用於眼睛的治療劑的重量比為5-80比1。
- 根據申請專利範圍第1項之藥物傳輸系統,其中該用於眼睛的治療劑係對於血管內皮生長因子具有專一性之拮抗劑或抗發炎分子。
- 根據申請專利範圍第2項之藥物傳輸系統,其中該對於血管內皮生長因子具有專一性之拮抗劑係對於血管內皮生長因子具有專一性之抗體、血管內皮生長因子受體、核酸或小分子。
- 根據申請專利範圍第3項之藥物傳輸系統,其中該對於血管內皮生長因子具有專一性之抗體係天然存在之免疫球蛋白或其功能性片段、人源化抗體、鑲嵌抗體、雙鏈抗體或單鏈抗體。
- 根據申請專利範圍第4項之藥物傳輸系統,其中該對於血管內皮生長因子具有專一性之抗體係癌思停。
- 根據申請專利範圍第4項之藥物傳輸系統,其中該抗體係Fab、Fab’、F(ab)2或F(ab’)2片段。
- 根據申請專利範圍第2項之藥物傳輸系統,其中該抗發炎分子係皮質類固醇。
- 根據申請專利範圍第7項之藥物傳輸系統,其中該皮質類固醇係選自於由下列所構成之群組:可體松(cortisone)、氫化 可體松(hydrocortisone)、氟輕松(fluocinolone)、潑尼松龍(prednisolone)、潑尼松(prednisone)、去炎松(triamcinolone)、甲潑尼松龍(methylprednisolone)、地塞米松(dexamethasone)以及倍他米松(betamethasone)。
- 根據申請專利範圍第1項之藥物傳輸系統,其中該傳輸載劑以及該用於眼睛的治療劑係混合且為凍乾形式。
- 根據申請專利範圍第1項之藥物傳輸系統,其中該傳輸載劑以及該用於眼睛的治療劑係相互分離。
- 根據申請專利範圍第10項之藥物傳輸系統,其中該傳輸載劑係為凍乾形式。
- 根據申請專利範圍第1至8項中任一項之藥物傳輸系統,其中該磷脂質係第一磷脂質與第二磷脂質之混合物,該第一磷脂質為DOPC、POPC、SPC、或EPC,而該第二磷脂質為PEG-DSPE或DOPG。
- 根據申請專利範圍第12項之藥物傳輸系統,其中該第一磷脂質之莫耳百分比為29.5%至90%,該第二磷脂質之莫耳百分比為3%至37.5%。
- 根據申請專利範圍第12項之藥物傳輸系統,其中該第一磷脂質之莫耳百分比為56.25%至72%,該第二磷脂質之莫耳百分比為7.5%至18.75%。
- 根據申請專利範圍第12項之藥物傳輸系統,其中該膽固醇之莫耳百分比為10%至25%。
- 根據申請專利範圍第12項之藥物傳輸系統,其中該第一磷脂質為DOPC,而該第二磷脂質為DOPG。
- 根據申請專利範圍第16項之藥物傳輸系統,其中在該傳輸載劑中,DOPC之莫耳百分比為29.5%至90%,而DOPG之莫耳百分比為3%至37.5%。
- 根據申請專利範圍第16項之藥物傳輸系統,其中該 DOPC:DOPG:膽固醇之比例為以莫耳百分比計為56.25-72.5:7.5-18.75:20-25。
- 根據申請專利範圍第12項之藥物傳輸系統,其中60-90%之該水可溶性的用於眼睛的治療劑係非結合形式,而該磷脂質與膽固醇之組合對該水可溶性的用於眼睛的治療劑的重量比為5-40比1。
- 一種根據申請專利範圍第1至19項中任一項的藥物傳輸系統供應用於製備一用來治療眼睛疾病之醫藥品的用途。
- 根據申請專利範圍第20項之用途,其中該醫藥品係一水性懸浮液,其係藉著以下步驟製備:將該磷脂質、該膽固醇、以及該用於眼睛的治療劑混合以形成混合物;凍乾該混合物;以及,在投與之前,使該混合物懸浮於水性溶液中以形成該水性懸浮液。
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