CN105148278A - 包含磷脂和胆固醇的眼部药物递送系统 - Google Patents
包含磷脂和胆固醇的眼部药物递送系统 Download PDFInfo
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- CN105148278A CN105148278A CN201510461150.7A CN201510461150A CN105148278A CN 105148278 A CN105148278 A CN 105148278A CN 201510461150 A CN201510461150 A CN 201510461150A CN 105148278 A CN105148278 A CN 105148278A
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- phospholipid
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- drug delivery
- cholesterol
- therapeutic agent
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Abstract
本发明涉及用于延长药物在眼内的滞留时间的包含磷脂和胆固醇的眼部药物递送系统。
Description
本申请是2010年1月29日提交的发明名称为“包含磷脂和胆固醇的眼部药物递送系统”的中国专利申请201080035729.2的分案申请。
相关申请的交叉引用
本申请主张2009年8月10日提交的美国专利申请NO.12/538,435的优先权。该申请的内容以其整体通过援引加入本文。
背景技术
由于眼睛是血液循环缓慢的封闭器官,所以大多数治疗剂在全身给药时不能以有效量到达眼部。
为了解决这一问题,已采用玻璃体内注射用于向眼部特别是向眼的后部(例如,视网膜和脉络膜)递送治疗剂。由于治疗剂通常在眼内滞留有限的时间,所以需要重复玻璃体内注射来实现预期疗效。然而,使用这一介入性方法进行频繁给药是非常不利的。
因此需要这样一种药物递送系统,其延长治疗剂在眼内的滞留时间(lifetime)从而减少治疗中需要的玻璃体内注射的次数。
发明内容
本发明是基于以下出乎预料的发现:包含磷脂和胆固醇的药物递送系统显著延长Avastin(贝伐单抗)(对血管内皮生长因子具有特异性的抗体)在眼内的滞留时间。
因此,本发明的一个方面涉及包含治疗剂(例如,蛋白质、核酸或小分子)和含有磷脂和胆固醇的递送载体的药物递送系统。在所述递送载体(例如为冻干形式)中,胆固醇的摩尔百分数可为5-40%(例如,10-33%或20-25%)。所述递送载体和所述治疗剂可为混合的或分开的。
在本发明的药物递送系统中,50-90%的所述治疗剂是非缔合形式(non-associatedform)的并且所述磷脂和胆固醇一起与所述治疗剂的重量比是5-80:1。在一个实施方案中,所述治疗剂是抗血管内皮生长因子(VEGF)的抗体,并且60-90%的所述抗体是非缔合形式的并且所述磷脂和胆固醇一起与所述抗体的重量比是5-40:1。在另一个实施方案中,所述治疗剂是抗炎分子(例如皮质类固醇)。
本文所述递送载体内的磷脂可为两种磷脂的混合物。例如,所述磷脂可为与聚乙二醇二硬脂酰磷脂酰乙醇胺(PEG-DSPE)或二油酰磷脂酰甘油(DOPG)混合的2-二油酰基-sn-甘油-3-磷脂酰胆碱(DOPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷脂酰胆碱(POPC)、大豆磷脂酰胆碱(SPC)或蛋黄磷脂酰胆碱(EPC)中的一种。当所述磷脂是DOPC和DOPG的混合物时,前者的摩尔百分数可为29.5-90%(例如,50-80%)并且后者的摩尔百分数可为3-37.5%(例如,3-18.75%)。在一个实施方案中,所述递送载体包含摩尔百分比为56.25-72.5:7.5-18.75:20-25的DOPC、DOPG和胆固醇。
本发明的另一个方面涉及向个体的眼部递送治疗剂的方法。该方法包括:(i)提供上述药物递送系统,其可为水性悬浮液的形式,和(ii)通过例如玻璃体内注射将其给药于有需要的个体的眼部。可通过以下方式制备所述递送系统:将磷脂、胆固醇和一种或多种治疗剂混合形成混合物;将所述混合物冻干;并且在给药前将所述混合物悬浮在水溶液中形成所述水性悬浮液。或者通过以下方式制备所述递送系统:将磷脂和胆固醇混合形成混合物;将所述混合物冻干;并且在给药前将所述混合物与一种或多种治疗剂一起悬浮在水溶液中形成所述水性悬浮液。
本发明的范围还包括上述递送载体向眼部递送治疗剂的用途和制备用于治疗眼部疾病的药物的用途。
本发明的一个或多个实施方案的细节列于下文的说明中。从下文的附图和几个实施方案的详细描述以及所附权利要求可显而易见本发明的其它特征或优点。
附图简述
首先描述附图。
图1是显示在玻璃体内注射后7天、21天、28天、35天、41天和49天时的玻璃体内Avastin浓度的图。TLC递送载体指包含比例为67.5/25/7.5的DOPC/胆固醇/DOPG的递送载体。“*”和“**”分别指检测1号兔和2号兔的眼睛的时间点。在其它时间点检测4号兔的眼睛。
图2是显示在玻璃体内注射后7天、28天、49天、70天、91天和112天时的玻璃体内Avastin浓度的图。TLC递送载体指包含比例为67.5/25/7.5的DOPC/胆固醇/DOPG的递送载体。“**”和“***”分别指检测2号兔和3号兔的眼睛的时间点。在其它时间点检测4号兔的眼睛。
图3是显示在玻璃体内注射后2h、1d、4d、8d、15d和35d时的玻璃体内地塞米松磷酸钠(DSP)浓度的图。TLC递送载体指包含比例为67.5/25/7.5的DOPC/胆固醇/DOPG的递送载体。
发明详述
本文描述了用于眼部给药至少一种治疗剂的有利的药物递送系统,所述治疗剂在递送后在眼内特别是玻璃体内表现出延长的滞留时间。
递送载体
本文描述的该药物递送系统包含含有磷脂和胆固醇的递送载体。所述磷脂可为同系(homologouspopulation)的磷脂,优选中性磷脂,或者可为不同类型的磷脂的混合物。用于制备所述递送载体的磷脂的实例包括但不限于磷脂酰胆碱(PC)、磷脂酰甘油(PG)、磷脂酰乙醇胺(PE)、磷脂酰丝氨酸(PS)、磷脂酸(PA)、磷脂酰肌醇(PI)、蛋黄磷脂酰胆碱(EPC)、蛋黄磷脂酰甘油(EPG)、蛋黄磷脂酰乙醇胺(EPE)、蛋黄磷脂酰丝氨酸(EPS)、蛋黄磷脂酸(EPA)、蛋黄磷脂酰肌醇(EPI)、大豆磷脂酰胆碱(SPC)、大豆磷脂酰甘油(SPG)、大豆磷脂酰乙醇胺(SPE)、大豆磷脂酰丝氨酸(SPS)、大豆磷脂酸(SPA)、大豆磷脂酰肌醇(SPI)、二棕榈酰磷脂酰胆碱(DPPC)、1,2-二油酰基-sn-甘油-3-磷脂酰胆碱(DOPC)、二肉豆蔻酰磷脂酰胆碱(DMPC)、二棕榈酰磷脂酰甘油(DPPG)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰甘油(DMPG)、十六烷基磷酸胆碱(HEPC)、氢化大豆磷脂酰胆碱(HSPC)、二硬脂酰磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)、二油酰磷脂酰乙醇胺(DOPE)、棕榈酰硬脂酰磷脂酰胆碱(PSPC)、棕榈酰硬脂酰磷脂酰甘油(PSPG)、单油酰磷脂酰乙醇胺(MOPE)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷脂酰胆碱(POPC)、聚乙二醇二硬酯酰磷脂酰乙醇胺(PEG-DSPE)、二棕榈酰磷脂酰丝氨酸(DPPS)、1,2-二油酰基-sn-甘油-3-磷脂酰丝氨酸(DOPS)、二肉豆蔻酰磷脂酰丝氨酸(DMPS)、二硬脂酰磷脂酰丝氨酸(DSPS)、二棕榈酰磷脂酸(DPPA)、1,2-二油酰基-sn-甘油-3-磷脂酸(DOPA)、二肉豆蔻酰磷脂酸(DMPA)、二硬脂酰磷脂酸(DSPA)、二棕榈酰磷脂酰肌醇(DPPI)、1,2-二油酰基-sn-甘油-3-磷脂酰肌醇(DOPI)、二肉豆蔻酰磷脂酰肌醇(DMPI)、二硬脂酰磷脂酰肌醇(DSPI)以及它们的混合物。
在一个实施方案中,所述递送载体不含脂肪酸(即具有长的、直链的脂族尾部的羧酸),阳离子脂质(即在生理pH下携带净正电荷的脂质);和粘膜附着剂聚合物(例如,Carbopol934P、泊洛沙姆(polyaxomer)、卡波姆和植物凝集素)。
可通过制药工业已知的方法制备所述递送载体。实例如下。将磷脂、胆固醇和其它组分(如果存在的话)悬浮在蒸馏水或水溶液中形成悬浮液。然后通过常规方法例如超声、振摇或挤压将所述悬浮液均质化。灭菌后,可在无菌操作下将所述均质化的载体悬浮液置于容器内,然后冻干形成粉末。
治疗剂
可将用于治疗眼部疾病的任何治疗剂(例如小分子、蛋白质、肽或核酸)与上述递送载体混合并给药于个体的眼部。在一个实施方案中,所述治疗剂是抗炎药,例如皮质类固醇化合物。术语“皮质类固醇化合物”指天然存在的类固醇激素(包括糖皮质激素)和它们的衍生物,优选是水溶性的。皮质类固醇的实例包括但不限于可的松、氢化可的松、醋酸氢化可的松、新戊酸替可的松、氟新诺龙(fluocinolone)、泼尼松龙、甲泼尼龙、泼尼松、曲安奈德、曲安西龙、莫米松、安西奈德、布地奈德、地奈德、氟轻松(fluocinonide)、氟氢松(fluocinoloneacetonide)、哈西奈德、倍他米松、倍他米松磷酸钠、地塞米松、地塞米松磷酸钠、氟可龙、氢化可的松-17-丁酸酯、氢化可的松-17-戊酸酯、二丙酸阿氯米松、戊酸倍他米松、二丙酸倍他米松、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍他索-17-丙酸酯、己酸氟可龙、匹伐酸氟可龙以及醋酸氟泼尼定。在另一个实施方案中,所述药剂是VEGF的拮抗剂,其可为对VEGF具有特异性的抗体、可溶性的VEGF受体、与VEGF结合的核酸或者干扰VEGF与其关联受体之间的相互作用并阻断VEGF信号转导途径的小分子。本文使用的术语“抗体”指天然存在的免疫球蛋白、其功能片段(例如Fab、Fab'、F(ab)2或F(ab')2)、或基因修饰的免疫球蛋白(例如人源化抗体、嵌合抗体、双抗体和单链抗体)。药物递送系统
本发明的药物递送系统包含上述递送载体和一种或多种上述治疗剂。其可包含为冻干形式的载体-药物混合物。在一个实施方式中,通过以下方式制备所述混合物:将所述载体的所有组分悬浮于水或水溶液中形成悬浮液,将所述悬浮液均质化,将均质化的悬浮液与一种或多种治疗剂混合形成混合物,并且最后将该混合物冻干。在另一个实施方案中,通过以下方式制备所述混合物:将所述载体的所有组分和一种或多种治疗剂悬浮于水或水溶液中形成悬浮液,然后将所述悬浮液冻干形成冻干的混合物。在冻干过程中,可向所述载体-药物悬浮液中加入冷冻保护剂(例如,甘露醇、蔗糖、海藻糖和乳糖)。当使用甘露醇时,优选的浓度是0.5-5%(例如,0.5-2%或1%)。在给药前,将冻干的载体-药物混合物重悬于水溶液中,然后可将其递送于个体的眼部。
在该药物递送系统中,50-90%的所述治疗剂是非缔合形式的。术语“非缔合形式的治疗剂”指可通过凝胶过滤与所述递送系统的磷脂/胆固醇组分分开的治疗性分子。根据下文实施例7中描述的方法测定非缔合的治疗剂的百分数。
任选地,本发明的药物递送系统还包含药学可接受的载体,即,与所述系统中的治疗剂相容并且优选能够稳定所述治疗剂且对待治疗的个体无害的载体。
可通过例如玻璃体内注射给药上述药物递送系统,以治疗眼部疾病。
无需进一步详细说明,我们认为本领域技术人员根据上文的描述能够充分地利用本发明。因此,应将下文的具体实施方案理解为仅为示例性的并且不以任何方式限制本公开的其余部分。本文引用的所有出版物均通过援引加入本文。
实施例1:制备用于眼部药物递送的含磷脂和胆固醇的组合物
以不同的摩尔比例(即67.5:7.5:25、72:8:20和56.25:18.75:25)将磷脂DOPC和DOPG与胆固醇混合形成脂质混合物。将混合物悬浮于氯仿中并且在旋转蒸发仪上真空干燥。将各干燥的混合物重悬于去离子水中,用杯-角型超声仪(cuphornsonicator)(MisonixSonicator3000)均质化,然后用无菌滤器灭菌。在无菌操作下将灭菌的脂质混合物装入小瓶内,与1%甘露醇混合,然后冻干。通过磷测定法测定各冻干混合物中的磷脂的总浓度。在递送于眼部之前,将适量的上述脂质混合物与适量的Avastin混合并且重悬于水溶液中形成水性悬浮液。
实施例2:使用包含DOPC/PEG-DSPE/胆固醇的递送载体将Avastin递送于眼部
按照上文实施例1中描述的方法制备包含不同摩尔比例的DOPC、PEG-DSPE和胆固醇的递送载体。将这些递送载体的每一种与适量的Avastin混合形成水性悬浮液。
按照Bakri等人,Ophthalmology,2007,114:5,855-859中描述的方法检测上述递送载体延长Avastin在眼内的滞留时间的作用。简而言之,通过肌肉内注射包含Zoletil(15mg/ml)和Rompun(7mg/ml)的混合物使新西兰白兔安静。使用30号针向每一只兔子的两只眼睛玻璃体内注射50μlAvastin(25mg/ml)或上述水性悬浮液之一(每只眼睛的Avastin剂量为1.25mg)。注射后第7天或第21天将兔子处死并立即摘除其眼。从每一只眼中分离玻璃体液和视网膜,并且通过ELISA如下测定Avastin的浓度。
用VEGF(PBS中10μg/ml,pH7,4;100μl/孔)将F96MaxiSorpTMNUNC-IMMUNO板于4℃包被过夜。用PBS洗涤VEGF包被的板子并且用封闭缓冲液(在PBS中的5%脱脂乳)于室温下封闭1小时。在相同的封闭缓冲液中稀释上所述玻璃体液/视网膜样品,并且以100μl/孔将所得稀释液加入VEGF包被的板子中。于室温下温育1小时后,用在PBS中的0.1%Tween-20和0.5%脱脂乳将板子洗涤5次并且用PBS另洗涤5次。然后向板子中加入稀释于所述封闭缓冲液内的HRP标记的羊抗人IgG(JacksonImmunoResearchLab.Inc.)。于室温下温育30分钟后,将板子充分洗涤。然后向板子中就加入含四甲基联苯胺的试剂用于显色。足够的时间后,通过向每一个孔内加入50μl2NHCl来终止反应。用ELISA读板仪测定每一个孔在450nm处的吸光度(OD450)。使用各种预先测定的Avastin浓度(3.125-25ng/ml)建立标准的Avastin浓度/OD450曲线。基于该标准曲线,根据每一个样品的OD450值测定其中的Avastin浓度。
从该研究获得的结果显示于下表1中:
表1.玻璃体内注射后第7天通过包含不同摩尔比例的DOPC/PEG-DSPE/胆固醇的载体递送的Avastin的浓度
Avastin浓度(μg/ml) | |
Avastin | 247±27 |
Avastin+DOPC/PEG-DSPE(93/7)* | 234±21 |
Avastin+DOPC/CHOL/PEG-DSPE(70/25/5)* | 632±75 |
Avastin+DOPC/CHOL/PEG-DSPE(55/40/5)* | 354±91 |
Avastin+DOPC/CHOL/PEG-DSPE(74.5/25/0.5)* | 688±16 |
*括号内的数字表示磷脂和胆固醇的摩尔百分数。
如上表1所示,与单独递送的Avastin相比,当与包含DOPC/PEG-DSPE/胆固醇的载体一起递送时,Avastin在眼内滞留更长的时间。该结果还表明,胆固醇对于所述递送载体延长Avastin在眼内的滞留时间的作用是必要的,并且PEG-DSPE的摩尔百分数不影响这一作用。
实施例3:使用包含各种磷脂的递送载体延长Avastin在眼内的滞留时间
按照上文实施例1中描述的方法制备包含不同摩尔比的各种磷脂和胆固醇的递送载体。将所述载体与Avastin混合并且将所得混合物玻璃体内注射入新西兰白兔的眼内。在注射后第7天或21天,按照上文实施例2中描述的方法测定兔眼内的Avastin浓度。
由此获得的结果显示于以下表2和表3中。
表2.玻璃体内注射后第7天通过包含不同的磷脂和胆固醇的载体递送的Avastin的浓度
Avastin浓度(μg/ml) | |
Avastin | 247±27 |
Avastin+DOPC/CHOL/PEG-DSPE(74.5/25/0.5)* | 688±16 |
Avastin+POPC/CHOL/PEG-DSPE(74.5/25/0.5)* | 572±32 |
Avastin+SPC/CHOL/PEG-DSPE(74.5/25/0.5)* | 746 |
*括号内的数字表示磷脂和胆固醇的摩尔百分数。
表3.玻璃体内注射后第21天通过包含胆固醇和不同磷脂的载体递送的Avastin的浓度
Avastin浓度(μg/ml) | |
Avastin | 37±7 |
Avastin+DOPC/CHOL/PEG-DSPE(74.5/25/0.5)* | 41±6 |
Avastin+DOPC/CHOL/PEG-DSPE(55/40/5)* | 48±9 |
Avastin+蛋黄PC/CHOL/PEG-DSPE(74.5/25/0.5)* | 155±64 |
*括号内的数字表示磷脂和胆固醇的摩尔百分数。
实施例4:使用包含阴离子磷脂的递送载体延长Avastin在眼内的滞留时间
根据上文实施例1中描述的方法制备包含DOPG(阴离子磷脂)、PEG-DSPE或DOPC的递送载体,其包含或不包含胆固醇。将这些载体与Avastin混合并且将所得混合物玻璃体内注射入新西兰白兔的眼内。在注射后第7天或21天,按照上文实施例2中描述的方法测定兔眼内的Avastin浓度。
如下表4所示,与不包含DOPG的递送载体相比,包含阴离子磷脂DOPG的递送载体导致注射后第7天的Avastin浓度增加。
表4.注射后第7天通过包含阴离子磷脂的载体递送的Avastin的玻璃体内浓度
Avastin浓度(μg/ml) | |
Avastin | 247±27 |
Avastin+DOPC/PEG-DSPE(97/3)* | 234±21 |
Avastin+DOPC/DOPG(90/10)* | 371±16 |
*括号内的数字表示磷脂的摩尔百分数。
从该研究获得的结果还表明,包含胆固醇和DOPG的递送载体显著增加了注射后第21天的玻璃体内Avastin浓度。参见下表5。
表5.注射后第21天通过包含阴离子磷脂和胆固醇的载体递送的Avastin的玻璃体内浓度
Avastin浓度(μg/ml) | |
Avastin | 37±7 |
Avastin+DOPC/CHOL/PEG-DSPE(74.5/25/0.5) | 41±6 |
Avastin+DOPC/CHOL/DOPG(67.5/25/7.5)* | 225±21 |
●括号内的数字表示磷脂和胆固醇的摩尔百分数。
实施例5:使用包含不同摩尔百分数的胆固醇和阴离子磷脂的递送载体延长Avastin在眼内的滞留时间
按照上文实施例1中描述的方法制备包含不同摩尔百分数的胆固醇、DOPC和DOPG的递送载体。将这些载体与Avastin混合并且将所得混合物玻璃体内注射入新西兰白兔的眼内。在注射后第21天,按照上文实施例2中描述的方法测定兔眼内的Avastin浓度。从该研究获得的结果显示于下表6中:
表6.注射后第21天通过包含胆固醇的载体递送的Avastin的玻璃体内浓度
Avastin浓度(μg/ml) | |
Avastin | 37±7 |
Avastin+DOPC/CHOL/DOPG(81/10/9)* | 51±53 |
Avastin+DOPC/CHOL/DOPG(72/20/8)* | 198±131 |
Avastin+DOPC/CHOL/DOPG(67.5/25/7.5)* | 225±21 |
Avastin+DOPC/CHOL/DOPG(60/33/7)* | 58±6 |
Avastin+DOPC/CHOL/DOPG(56.25/25/18.75)* | 185±85 |
Avastin+DOPC/CHOL/DOPG(37.5/25/37.5)* | 65±39 |
Avastin+DOPC/CHOL/DOPG(18.75/25/56.25)* | 25 |
Avastin+DOPC/CHOL/DOPG(7.5/25/67.5)* | 68±22 |
Avastin+CHOL/DOPG(25/75)* | 130±45 |
*括号内的数字表示磷脂和胆固醇的摩尔百分数。
实施例6:通过包含磷脂和胆固醇的载体递送于玻璃体内的Avastin的药代动力学性质
向兔子玻璃体内注射单独的Avastin(对照兔)或者与包含比例为67.5/25/7.5的DOPC/胆固醇/DOPG的递送载体混合的Avastin(实验兔)。在注射后第7天、21天和28天通过ELISA测定对照兔的玻璃体内Avastin浓度,并且在注射后第7天、21天、28天、35天、41天和49天测定实验兔的玻璃体内Avastin浓度。
单独注射的Avastin的玻璃体内浓度随时间降低得比与递送载体一起注射的Avastin快得多。参见图1。该结果表明,递送载体延长了Avastin在眼内的滞留时间。
在相似的实验中,在玻璃体内注射后第7天、28天、49天、70天、91天和112天测定玻璃体内Avastin浓度。对照兔在注射后第28天的玻璃体内Avastin浓度为13μg/ml,而实验兔在相同时间点的玻璃体内Avastin浓度为265μg/ml,是对照兔的20倍。参见图2。对照兔的玻璃体内Avastin的半衰期为3.9天。不同的是,实验兔的玻璃体内Avastin的半衰期具有二房室特征,其初始半衰期和终末半衰期分别为5.5天(t1/2α)和40.5天(t1/2β)。实验兔从第7天到无穷大(AUC(7-∞))的AUC(即曲线下面积)是对照兔的6.8倍,并且实验兔的AvastinAUC(112-∞)是对照兔的AvastinAUC(7-∞)的1.1倍。参见下表7。
表7.玻璃体内Avastin的药代动力学性质
*t1/2:半衰期;
**t1/2α:初始半衰期;
t1/2β:终末半衰期
AUC(7-112):从第7天到第112天的曲线下面积
AUC(112-∞):从第112天到无穷大的曲线下面积
AUC(7-∞):从第7天到无穷大的曲线下面积
总而言之,以上讨论的结果表明,所述递送载体显著延长了Avastin在眼内的滞留时间。
实施例7:制备用于递送各种治疗剂的组合物
将重量比为8.8/1/1.6的DOPC、DOPG和胆固醇溶于氯仿,然后用旋转蒸发仪将其真空蒸发。将由此制备的磷脂和胆固醇的干燥混合物悬浮于去离子水中形成水性悬浮液。然后使用杯-角型超声仪(MisonixSonicator3000)将悬浮液均质化,过滤灭菌,在无菌操作下装入小瓶中,并且冻干从而形成包含磷脂和胆固醇的递送载体。通过常规的磷测定法测定载体中的磷脂浓度以确保载体包含适当总量的磷脂。
然后将递送载体与各种治疗剂混合,即色氨酸(10mg/ml)、酪氨酸(10.4mg/ml)、HFRRHLC肽(10mg/ml)、HWRGWVC肽(10mg/ml)、蛋白质W(13mg/ml)、牛血清白蛋白(50mg/ml)、Avastin(25mg/ml)和地塞米松磷酸钠(6.7mg/ml),其均溶于pH6.2的50mM磷酸盐缓冲液中。在相同的磷酸盐缓冲液中将如此形成的混合物稀释18-100倍,并且对各混合物的等分部分(50-200ml)进行凝胶过滤来测定为非缔合形式的治疗剂的百分数。简而言之,将混合物的等分部分上样于Sepharose4B柱(直径:1.8mm;长度:315mm)。然后用50mM磷酸盐缓冲液(pH6.2)洗脱混合物中的组分。收集包含不同形式的治疗剂(即非缔合形式或与磷脂缔合的形式)的流分,在215nm和254nm处测定它们的吸光度。基于OD215和OD254的数值测定各流分中治疗剂的量。基于这些值测定非缔合形式的治疗剂的百分数以及脂质与药物的重量比并显示于下表8中。
表8.非缔合药剂的百分数以及脂质与药物的重量比
实施例8:通过包含磷脂和胆固醇的载体递送于玻璃体内的地塞米松磷酸钠的药代动力学性质
向兔子玻璃体内注射单独的地塞米松磷酸钠(DSP)(对照兔)或与包含比例为67.5/25/7.5的DOPC/胆固醇/DOPG的递送载体混合的DSP(实验兔)。以0.2mg的DSP剂量向每一只兔子的两只眼睛玻璃体内注射50μlDSP或DSP-递送载体混合物。通过具有光电二极管阵列(PDA)检测器的超高效液相色谱仪(ACQUITYUPLCTM)测定注射后2h、1d、8d和15d对照兔的玻璃体内DSP浓度并且测定注射后2h、1d、4d、8d、15d和35d实验兔的玻璃体内DSP浓度。每一个时间点测定双眼。
如图3所示,单独注射的DSP的玻璃体内浓度在注射后非常迅速地降低;相反,即使在注射后35天仍观察到显著水平的与递送载体一起注射的DSP。该结果表明,递送载体延长了DSP在眼内的滞留时间。
其它实施方案
本说明书中公开的所有特征可以任何组合形式组合。本说明书中公开的每一个特征可被用于相同、等同或相似目的的其他特征代替。因此,除非另外指明,所公开的每一个特征仅是所有等同或相似特征的实例。
本领域的技术人员可从以上描述容易地确定本发明的必要特征,并且能够在不偏离本发明的精神和范围的前提下对本发明进行各种改变和修改从而使其适于各种用途和条件。因此,其它实施方案也在权利要求的范围内。
Claims (21)
1.药物递送系统,其包含:
递送载体,其含有磷脂和胆固醇,其中所述胆固醇以相对于所述递送载体的10-33的摩尔百分数的数量存在,其中所述磷脂是一种磷脂与另一种磷脂的混合物,所述一种磷脂是DOPC、POPC、SPC或EPC,并且所述另一种磷脂是PEG-DSPE或DOPG;和
一种或多种治疗剂,
其中50-90%的所述治疗剂是通过凝胶过滤与所述递送系统的磷脂和胆固醇分开的非缔合形式的,并且所述磷脂和胆固醇一起与所述治疗剂的重量比是5-80:1。
2.权利要求1的药物递送系统,其中所述治疗剂是用于治疗眼部疾病的治疗剂。
3.权利要求2的药物递送系统,其中所述用于治疗眼部疾病的治疗剂是抗炎分子或血管内皮生长因子的拮抗剂。
4.权利要求3的药物递送系统,其中所述血管内皮生长因子的拮抗剂是对血管内皮生长因子具有特异性的抗体、可溶性的血管内皮生长因子受体、与血管内皮生长因子结合的核酸或干扰血管内皮生长因子与其关联受体之间的相互作用并阻断血管内皮生长因子信号转导途径的小分子。
5.权利要求4的药物递送系统,其中所述对血管内皮生长因子具有特异性的抗体是天然存在的免疫球蛋白或其功能片段、人源化抗体、嵌合抗体、双价抗体或单链抗体。
6.权利要求4的药物递送系统,其中所述对血管内皮生长因子具有特异性的抗体是Avastin。
7.权利要求4的药物递送系统,其中所述抗体是Fab、Fab'、F(ab)2或F(ab')2片段。
8.权利要求3的药物递送系统,其中所述抗炎分子为水溶性。
9.权利要求8的药物递送系统,其中所述抗炎分子是皮质类固醇。
10.权利要求9的药物递送系统,其中所述皮质类固醇选自可的松、氢化可的松、氟新诺龙、泼尼松龙、泼尼松、曲安西龙、甲泼尼龙、地塞米松和倍他米松。
11.权利要求1至3中任一项的药物递送系统,其中所述递送载体和所述治疗剂是混合的且为冻干形式。
12.权利要求1至3中任一项的药物递送系统,其中所述递送载体和所述治疗剂是分开的。
13.权利要求12的药物递送系统,其中所述递送载体为冻干形式。
14.权利要求1至3中任一项的药物递送系统,其中所述一种磷脂是DOPC并且所述另一种磷脂是DOPG。
15.权利要求14的药物递送系统,其中在所述递送载体中,DOPC的摩尔百分数是29.5%-90%并且DOPG的摩尔百分数是3%-37.5%。
16.权利要求14的药物递送系统,其中DOPC:DOPG:胆固醇的摩尔百分数比是56.25-72.5:7.5-18.75:20-25。
17.权利要求1至3中任一项的药物递送系统,其中所述一种磷脂:所述另一种磷脂:胆固醇的摩尔百分数比是56.25-72.5:7.5-18.75:20-25。
18.权利要求1至3中任一项的药物递送系统,其中所述一种磷脂是DOPC、POPC、EPC或SPC并且所述另一种磷脂是PEG-DSPE。
19.权利要求1至3中任一项的药物递送系统,其中60-90%的所述治疗剂是通过凝胶过滤与所述递送系统的磷脂和胆固醇分开的非缔合形式的,并且所述磷脂和胆固醇一起与所述治疗剂的重量比是5-40:1。
20.权利要求1至19中任一项所述的药物递送系统在制备用来治疗眼部疾病的药物中的用途。
21.权利要求20的用途,其中所述药物是通过以下方式而被制备的水性悬浮液:将所述磷脂、所述胆固醇以及所述治疗剂混合形成混合物,将所述混合物冻干,并且在给药前将所述混合物悬浮在水溶液中形成所述水性悬浮液。
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