CN103269690A - 含有水难溶性药物的缓释聚合物微粒及其制备方法 - Google Patents
含有水难溶性药物的缓释聚合物微粒及其制备方法 Download PDFInfo
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- CN103269690A CN103269690A CN2011800622076A CN201180062207A CN103269690A CN 103269690 A CN103269690 A CN 103269690A CN 2011800622076 A CN2011800622076 A CN 2011800622076A CN 201180062207 A CN201180062207 A CN 201180062207A CN 103269690 A CN103269690 A CN 103269690A
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- poorly water
- water soluble
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- acid
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Abstract
本发明公开了含有水难溶性药物的缓释聚合物微粒及其制备方法。
Description
技术领域
本发明涉及含有水难溶性药物的缓释聚合物微粒及其制备方法。更具体的，本发明涉及聚合物微粒，其包含具有至少一个端羧基的聚乳酸或者其衍生物的多价金属阳离子盐，其中水难溶性药物包埋于聚乳酸或者其衍生物的多价金属阳离子盐中，通过其能够持续地保持药物的恒定释放速率和有效的血液浓度，而没有药物的突释或者迟释。因此，本发明的微粒及其制备方法能够有效用于水难溶性药物的长期缓释制剂。
背景技术
在治疗慢性疾病的药物的情况中，为了降低给药频率，它们被制成缓释制剂，通过其能够长时间保持治疗有效的药物浓度，甚至仅仅单次给药也是如此，并且能改善患者对于药物治疗的适应性。在这样的持续释放制剂中，聚合物微球受到了许多药物公司的大量关注。目前市售聚合物微球产品的实例包括利培酮(Risperdal Consta)，其是一种用于治疗精神***的利培酮的两周释放制剂，以及纳曲酮（Vivitrol），其是一种用于药物成瘾的环丙甲羟二羟***酮的四周释放制剂。这些制剂通常是聚(丙交酯-共聚-乙交酯)(PLGA)微球制剂。但是，它们在药物给药后的初始阶段不能充分释放药物，并且该释放延迟了1-4周。因此，它们必须与口服制剂一起不方便地给药，以获得在初始阶段的快速疗效。
用于制备微球的生物可降解聚合物的实例包括聚丙交酯、聚乙交酯、聚(丙交酯-共聚-乙交酯)(PLGA)等。这些生物可降解聚合物通常的分子量是100,000-200,000道尔顿。该聚合物具有至少一个端羧酸，因此在水溶液中是酸性的，并且水解时释放有机酸如乳酸或乙醇酸，因此导致相邻的环境变成酸性。为此原因，这些聚合物不适用于对酸不稳定的药物。另外，因为分子量相当大，因此不易于将它们合成为具有均匀理化性能的常规聚合物。为此原因，当所用的合成聚合物的批次变化时，药物从它们所制备的微球的释放方式也会变化，因此不易于恒定地保持药物释放方式。此外，为了合成高分子量的生物可降解聚合物，必需使用开环聚合，该聚合使用了环状二聚体如丙交酯或者乙交酯，该方法要求合成在无水状态下进行。因此，通过这种方法进行大规模生产是相当困难的。另外，当施用疏水性药物时，微球的聚合物在预定时间后开始降解，因此它的缺点在于药物效力不能在给药后立即表现出来。例如利培酮（Risperdal Consta）在给药后大约两周开始释放药物，因此有时候需要在此期间使用口服药物(M.Eerdekens et al./Schizophrenia Research70(2004)91-100；S.Keith/Progress in Neuro-Psychopharmacology&Biological Psychiatry30(2006)996-1008)。
因此，虽然使用疏水药物，但是仍然需要开发具有如此释放曲线的缓释微粒，其中在给药后初始释放是平滑进行的，并且血液中的药物浓度能够有效地保持长的时间。
发明内容
技术问题
作为深入研究开发技术来有效控制药物从微粒释放速率的结果，本发明人发现药物的释放速率和量可以容易地通过用多价金属离子取代分子量为5000道尔顿或者更低的生物可降解聚合物的单价金属盐中的单价金属离子，其可以容易地标准化和大规模生产，并且调整聚合物分子量和药物与该聚合物的比率来控制，由此完成了本发明。
所以，本发明的一个目的是提供含有水难溶性药物的缓释聚合物微粒，其使用分子量500-5,000道尔顿的生物可降解聚合物，其能够容易地标准化和大规模生产，通过其能够防止药物过分延迟释放，并且药物在血液中的浓度会在短时间内升高到有效水平，并且能够获得长时间内保持血液中有效的药物浓度的释放曲线；以及其制备方法。
技术方案
根据本发明的一个方面，提供了一种含有水难溶性药物的缓释微粒，其包含水难溶性药物和具有至少一个端羧基的聚乳酸或者其衍生物的多价金属离子盐，其中该水难溶性药物包埋于聚乳酸或者其衍生物的多价金属离子盐中。
根据本发明的另一个方面，提供了一种制备含有水难溶性药物的缓释微粒的方法，其包含：i)制备聚合物-药物溶液，其含有在有机溶剂中的具有至少一个端羧基的聚乳酸或者其衍生物的单价金属盐和水难溶性药物；和ii)将该聚合物-药物溶液分散在含有多价金属离子和任选的表面活性剂的水溶液中，以形成微粒。
有益效果
本发明提供了微粒，其易于控制药物释放，在长时间内保持血液中有效的药物浓度，因此适用于需要频繁重复给药的持续释放的药物制剂中。
附图说明
图1是一个扫描电镜(SEM)图，其示出了本发明实施例2所制备的微粒。
图2是一个扫描电镜(SEM)图，其示出了本发明实施例5所制备的微粒。
图3是一个扫描电镜(SEM)图，其示出了本发明实施例6所制备的微粒。
图4示出了在测试实施例3(释放测试)中，根据药物与聚合物比例的变化，药物释放量的变化。
图5示出了在测试实施例3(释放测试)中，根据聚合物分子量的变化，同时恒定保持药物与聚合物的比例时，药物释放量的变化。
具体实施方式
下文中，将详细描述本发明。
在本发明中，具有至少一个端羧基的聚乳酸或者其衍生物的具体实例包括选自下组的一种或多种：聚乳酸、聚丙交酯、聚乙交酯、聚扁桃酸、聚己内酯、聚酸酐和其共聚物。
该聚乳酸或者其衍生物的除了端羧基的其余端基是选自下组的一种或多种端基：羟基、乙酰氧基、苯甲酰氧基、癸酰氧基、棕榈酰氧基、甲基和乙基。
用于本发明的微粒的聚乳酸或者其衍生物的数均分子量可以通过控制制备过程中的反应温度、时间等来调整，并且其优选是500-5,000道尔顿，更优选是2,000-5,000道尔顿。当分子量低于500道尔顿时，难以预期该持续的药物释放。当分子量高于5,000道尔顿时，不容易合成作为具有均匀物理和化学性能的标准化聚合物的聚合物。此外，在高分子量聚合物的情况中，该合成应当在无水条件下进行，因此大规模生产是困难的。但是，具有上面的分子量范围的生物可降解聚合物可以通过共缩聚、通过合成有机酸单体如乳酸或者乙醇酸来制备，并且在这种情况中，不必保持无水条件，因此大规模生产是相当容易的。
在本发明中，具有至少一个端羧基的聚乳酸或者其衍生物优选是选自下组的式1-6中的一种或多种：
[式1]
RO-CHZ-[A]n-[B]m-COOM
其中A是-COO-CHZ-；B是-COO-CHY-，-COO-CH2CH2CH2CH2CH2-或-COO-CH2CH2OCH2；R是氢原子或乙酰基、苯甲酰基、癸酰基、棕榈酰基、甲基或乙基；Z和Y各自独立地为氢原子、甲基或苯基；M独立地为H、Na、K或Li；n是1-30的整数；且m是0-20的整数；
[式2]
RO-CHZ-[COO-CHX]p-[COO-CHY’]q-COO-CHZ-COOM
其中X是甲基；Y’是氢原子或苯基；p是0-25的整数，q是0-25的整数，条件为p+q是5-25的整数；R是氢原子、乙酰基、苯甲酰基、癸酰基、棕榈酰基、甲基或者乙基；Z是氢原子、甲基或苯基；和M独立地为H、Na、K或Li；
[式3]
RO-PAD-COO-W-M’
其中W-M’是
或
PAD选自D,L-聚乳酸、D-聚乳酸、聚扁桃酸、D,L-乳酸和乙醇酸的共聚物、D,L-乳酸和扁桃酸的共聚物、D,L-乳酸和己内酯的共聚物和D,L-乳酸和1,4-二氧六环-2-酮的共聚物；R是氢原子、乙酰基、苯甲酰基、癸酰基、棕榈酰基、甲基或者乙基；且M独立地为H、Na、K或Li；
[式4]
S-O-PAD-COO-Q
其中S是
L是-NR1-或者-O-，其中R1是氢原子或者C1-10烷基；Q是CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3或者CH2C6H5；a是0-4的整数；b是1-10的整数；M是H、Na、K或Li；PAD是选自下组的一种或多种：D,L-聚乳酸、D-聚乳酸、聚扁桃酸、D,L-乳酸和乙醇酸的共聚物、D,L-乳酸和扁桃酸的共聚物、D,L-乳酸和己内酯的共聚物以及D,L-乳酸和1,4-二氧六环-2-酮的共聚物；
[式5]
其中R’是-PAD-O-C(O)-CH2CH2-C(O)-OM，其中PAD选自D,L-聚乳酸、D-聚乳酸、聚扁桃酸、D,L-乳酸和乙醇酸的共聚物、D,L-乳酸和扁桃酸的共聚物、D,L-乳酸和己内酯的共聚物以及D,L-乳酸和1,4-二氧六环-2-酮的共聚物，且M是H、Na、K或Li；a是1-4的整数，例如a=1时为3-臂PLA-COONa，a=2时为4-臂PLA-COONa，a=3时为5-臂PLA-COONa和a=4时为6-臂PLA-COONa；
[式6]
YO-[-C(O)-(CHX)a-O-]m-C(O)-R-C(O)-[-O-(CHX’)b-C(O)-]n-OZ
其中X和X'各自独立地为氢、烷基(例如具有1-10个碳原子的烷基如甲基)或者芳基(例如具有6-20个碳原子的芳基如苯基)；Y和Z各自独立地为H、Na、K或Li；m和n各自独立地为0-95的整数，条件为5<m+n<100；a和b各自独立地为1-6的整数；R是取代的或者未取代的-(CH2)k-其中k是0-10的整数，具有2-10个碳原子的二价链烯基，具有6-20个碳原子的二价芳基，或者其组合。
在本发明的一种实施方案中，聚乳酸或者其衍生物的多价金属离子盐是水不溶性聚乳酸或者其衍生物的多价金属盐，其是通过聚乳酸或者其衍生物的端羧基离子键合到二价或三价金属离子上来形成的。
该二价或者三价金属离子优选是选自下组的一种或多种：Ca2+、Mg2+、Ba2+、Cr3+、Fe3+、Mn2+、Ni2+、Cu2+、Zn2+和Al3+。该二价或者三价金属离子可以作为硫酸盐、盐酸盐、碳酸盐、磷酸盐或氢氧化物的形式来提供，优选作为CaCl2、MgCl2、ZnCl2、AlCl3、FeCl3、CaCO3、MgCO3、Ca3(PO4)2、Mg3(PO4)2、AlPO4、MgSO4、Ca(OH)2、Mg(OH)2、Al(OH)3或Zn(OH)2的形式来提供。
在本发明的微粒中，聚乳酸或者其衍生物的多价金属离子盐可以占微粒总重量的50-99wt%的量。当该聚合物的含量小于50wt%时，不能获得缓释效果，和当该含量大于99wt%时，它会不利地超过可以通过常规方法一次给药的剂量。
在本发明中，水难溶性药物表示水溶解度(25°C)是100mg/mL或者更低的疏水性药物。其具体的实例包括奥氮平、利培酮、齐拉西酮、利斯的明、纳洛酮、环丙甲羟二羟***酮、西罗莫司、他克莫司、卡莫司汀、***、***、***、左炔诺孕酮、炔诺酮等。在本发明的一种优选实施方案中使用利培酮。水难溶性药物在本发明微粒中的含量可以是微粒总重量的1-50wt%，但是不特别限于其中。当该含量小于1wt%时，不能获得预期的药物效果，而当该含量大于50wt%时，会出现药物突释的问题。
本发明微粒的粒径可以为例如1-400μm，特别是5-250μm，更特别是50-150μm。它具有无定形或者球形形状，其中水难溶性药物包埋于包含聚乳酸或者其衍生物的多价金属离子盐的微粒内核中。
如本文所用，术语“缓释”、“缓释递送”和“缓释药物递送”表示通过单次给药，药物在血液中的有效浓度保持了长的时间，例如72小时或更长。该给药途径可为皮下、肌肉或静脉注射。频繁给药造成的麻烦可以通过缓释递送来解决。
除了上面解释的成分之外，本发明的微粒可以进一步包含一种或多种药物添加剂如防腐剂、稳定剂、水合剂或者用于控制渗透压的盐和/或缓冲剂，或者其他治疗上有效的物质。本发明的微粒可以通过递送路线如注射和/或经皮下、肌肉、腹内或者皮肤植入和黏膜内给药来分散、递送或者施用到受测试者的目标位置上。例如本发明的微粒可以以在分散介质中的均匀悬浮液如注射溶液的形式来给药。分散介质的实例包括注射用蒸馏水、5%葡萄糖、生理盐水、矿物油以及单-、二-和三-甘油酯等。
在本发明的另一各方面，提供了一种制备含有水难溶性药物的缓释微粒的方法，其包含：i)制备聚合物-药物溶液，其含有在有机溶剂中的具有至少一个端羧基的聚乳酸或者其衍生物的单价金属盐和水难溶性药物；和ii)将该聚合物-药物溶液分散在含有多价金属离子和任选的表面活性剂的水溶液中，以形成微粒。
本发明的制备微粒的方法特征在于，将聚乳酸或者其衍生物的单价金属盐加入到多价金属离子的水溶液中，以将该聚乳酸或者其衍生物的单价金属盐转化成水不溶性聚乳酸或者其衍生物的多价金属盐，其然后沉淀和形成微粒。
制备本发明微粒的方法将逐步详细描述。
第一步：制备聚合物-药物溶液
制备含有在有机溶剂中的聚乳酸或者其衍生物的单价金属盐和水难溶性药物的聚合物-药物溶液，可以通过下面三种方式中任何一种来进行。
i-1)将聚乳酸或者其衍生物的单价金属盐溶解在有机溶剂中，以制备生物可降解聚合物溶液，并且将水难溶性药物加入该生物可降解聚合物溶液中，以制备含有聚合物和药物的溶液。
i-2)将水难溶性药物溶解在有机溶剂中，以制备药物溶液，并且将聚乳酸或者其衍生物的单金属盐加入该药物溶液中，以制备含有聚合物和药物的溶液。
i-3)将聚乳酸或者其衍生物的单价金属盐和水难溶性药物一起溶解在有机溶剂中，以制备含有聚合物和药物的溶液。
即，制备本发明的缓释组合物可以如下来进行：使用具有端羧酸基团的聚乳酸或者其衍生物作为起始材料(i-1)，或者用具有至少一个端羧酸基团的聚乳酸或者其衍生物开始，并且用碱金属盐中和它来将它转化成聚乳酸或者其衍生物的单价金属盐，然后使用该单价金属盐(i-2和i-3)。该碱金属盐可以由碳酸钠、碳酸氢钠、碳酸氢钾、碳酸钾等来提供。
聚乳酸或者其衍生物的单价金属盐可以如下来获得：将具有至少一种端羧酸基团的相应聚乳酸或者其衍生物如式1-6的化合物(其中M是H)用碱金属如钠、钾或者锂的盐进行中和，这里该碱金属盐可以由碳酸钠、碳酸氢钠、碳酸氢钾、碳酸钾等来提供。因此，用于本发明微粒的制备方法的聚乳酸或者其衍生物的单价金属盐可以是式1-6化合物中的任何一种，其中M是Na、K或Li。
能够用于本发明的微粒的制备方法的水难溶性药物的实例可以是上面解释的那些。在本发明微粒制备方法的一个实施方案中，水难溶性药物的用量是0.01-0.5重量份，相对于1重量份的聚乳酸或者其衍生物的单价金属盐。
能够用于本发明的微粒的制备方法的有机溶剂的实例包括二氯甲烷、六氟异丙醇、乙酸乙酯、乙醇、甲醇、二甲基甲酰胺、丙酮、乙腈、四氢呋喃、乙酸、二甲基亚砜、氯仿、二氯乙酸甲酯、氯乙酸甲酯、氯乙酸乙酯、二氯乙酸乙酯、氟乙酸甲酯、二氟乙酸甲酯、氟乙酸乙酯、二氟乙酸乙酯、乙酸乙酯、乙酸甲酯、甲酸甲酯、甲酸乙酯、甲酸异丙酯、甲酸丙酯及其混合物。该有机溶剂可以考虑生物可降解聚合物、药物溶解度、生物相容性等来适当选择。具体的，可以使用二氯甲烷、丙酮和其混合物，其具有低的沸点，因此能够容易地除去。该有机溶剂的用量可以是0.5-100重量份，相对于1重量份的聚乳酸或者其衍生物的单价金属盐。
第二步：形成微粒
将第一步中所制备的聚合物-药物溶液分散在含有多价金属阳离子的水溶液中以形成微粒。
在这个步骤中，当聚合物-药物有机溶液分散在多价金属离子的水溶液中时，聚乳酸或者其衍生物的单价金属盐中的单价金属离子被二价或三价金属离子取代，以形成聚乳酸或者其衍生物的水不溶性多价金属盐，并且这样形成的聚合物水不溶性盐发生沉淀，因此获得了其中截留了疏水性药物的微粒。
能够用于本发明的微粒的制备方法的多价金属阳离子的实例可以是上面解释的那些。当使用二-或三价金属离子时，相对于聚乳酸或者其衍生物的端羧基，多价金属阳离子的用量是0.5-5当量，优选1-2当量，以使得聚乳酸或者其衍生物的全部端羧基被该二-或者三价金属离子所取代。
多价金属阳离子的水溶液可以任选的包含表面活性剂以提高微粒的形成产率和获得均匀的微粒。可以使用本领域常规使用的任何表面活性剂，而无特别的限制。具体的，可以使用聚合物表面活性剂如泊洛沙姆、聚乙烯醇、聚氧乙烯山梨聚糖脂肪酸酯，天然聚合物如凝胶，以及高级脂肪酸的碱性盐。这样的表面活性剂的用量，相对于一重量份水溶液中的水，可以例如是0.001-0.1重量份。
制备本发明的含有水难溶性药物的缓释微粒的方法可以进一步包含：iii)获得步骤ii)中形成的微粒，并且将它用水清洗。
此外，制备本发明的含有水难溶性药物的缓释微粒的方法可以进一步包含：iv)冻干在步骤iii)中清洗的微粒。在冻干过程中，可以加入冻干添加剂。该冻干添加剂的实例包括糖、糖醇或者其混合物。所述糖可以是选自下组的一种或多种：乳糖、麦芽糖、蔗糖和海藻糖，所述糖醇可以是选自下组的一种或多种：甘露醇、山梨糖醇、麦芽糖醇、木糖醇和乳糖醇。在本发明的一个实施方案中，基于冻干组合物的总干重，冻干添加剂的含量是1-50wt%，更优选1-30wt%。
下文中，将参考下面的实施例来更详细地描述本发明。但是，实施例仅用于说明本发明，而不应理解为对本发明保护范围的限制。
实施例1-6
制备含药物的微粒
实施例1-6的聚合物微粒是使用重均分子量为1860、3400或4220道尔顿的聚乳酸，根据下表1所述的组成来制备的。将均化器的叶片置于对应于圆柱反应器从底部开始的1/3高度的点上，该反应器的高度是150mm和直径是80mm。将2mL的二氯甲烷加入到有机相容器中的聚乳酸和利培酮中，随后密封该有机相容器，并且完全溶解所述成分。将500mL的1%(w/v)泊洛沙姆188水溶液(含有氯化钙)加入到反应器中用于制备微粒，在300rpm速率搅拌的同时，使用玻璃注射器将利培酮和聚合物在2mL二氯甲烷中的溶液缓慢加入其中，以凝固微粒。该凝固的微粒是使用38-200μm筛选柱筛选的，并且收集粒度处于这个范围内的那些微粒。将所收集的微粒用蒸馏水清洗3次，并且冻干24小时以完成制备。在使用前冷冻该微粒。全部上述程序是通过保持无菌工作台上的无菌条件来进行的。
[表1]
*0.1%(w/v)
对比例1-3
含药物的PLGA微球
将利培酮与下表2中所述的聚合物一起溶解在3mL二氯甲烷中，以制备药物溶液。分别地，使用0.02M碳酸盐缓冲剂(0.02M Na2CO3+0.02M NaHCO3)制备了5%的聚乙烯醇溶液(PVA)。在大约300rpm搅拌该5%PVA溶液的同时，使用玻璃注射器将所述药物溶液缓慢注射到该PVA溶液中。在药物溶液掺入完成后，使用搅拌器将所形成的溶液在300rpm搅拌1小时，以完全凝固微粒。该凝固的微粒是使用38-200μm筛选柱筛选的，并且收集粒度处于这个范围内的那些微粒。将所收集的微粒用蒸馏水清洗3次，并且冻干24小时以完成制备。在使用前冷冻该微粒。全部上述程序是通过保持无菌工作台上的无菌条件来进行的。
[表2]
LA：乳酸来源单元（unit）
GA：乙醇酸单元
测试实施例1：微粒的形状和表面状态的评价
在本发明的实施例2、5和6中所制备的微粒是使用扫描电镜来成图的。所形成的图分别表示在图1-3中。从图可见，这些实施例所制备的全部微粒为圆形且在它们的表面上具有微孔。随着分子量的提高，微孔的尺寸降低且表面变得更光滑。
测试实施例2：药物的含量和包封比
为了测量包封在微粒中的利培酮的量，根据下面的HPLC方法来进行定量分析。将实施例1-6和对比例1-3所制备的大约20mg的微粒加入到20mL烧瓶中，将乙腈加入其中以完成总体积20mL的溶液。将所形成的溶液用流动相溶液稀释10倍，并且通过0.45μm隔膜滤纸过滤，并且将50μL的过滤溶液注射到HPLC中。
HPLC条件
-色谱柱：Phenomenex Gemini-NX5u 
(150x4.6mm)
-流动相：乙酸缓冲液/甲醇=600/400(v/v)
-流速：1mL/min
-检测器：UV280nm
-乙酸缓冲液：6g乙酸铵和60mL乙酸在1.2L注射用蒸馏水中的溶液
为了计算微粒中所包含药物的量，根据下面的等式1和2计算药物在微粒中的含量及其包封比。结果表示在下表3中。
[等式1]
药物的含量(%)=药物在微粒中的量/微粒的量x100
[等式2]
药物的包封比(%)=实际包封的药物的量/理论包封的药物的量x100
[表3]
| 实施例 | 载药量% | 含量(%) | 包封比(%) |
| 实施例1 | 5 | 4.55 | 91.00 |
| 实施例2 | 10 | 8.20 | 82.00 |
| 实施例3 | 20 | 16.13 | 80.65 |
| 实施例4 | 30 | 22.86 | 76.20 |
| 实施例5 | 10 | 9.47 | 94.70 |
| 实施例6 | 10 | 9.66 | 96.60 |
| 对比例1 | 20 | 17.73 | 88.65 |
| 对比例2 | 30 | 25.97 | 86.57 |
| 对比例3 | 40 | 32.90 | 82.25 |
测试实施例3：释放测试
将实施例1-6和对比例1-3所制备的微粒，和市售产品RisperdalConsta进行体外药物释放测试。具体地，向含有500mL的pH7.4磷酸盐缓冲溶液的试管中，加入对应于20mg的药物量的微粒，将该试管封闭，并且在37°C的恒温室中以60转/min的转速搅拌使得药物连续释放30天或者更长时间。取样1mL的在释放测试下的溶液，通过上面的测试实施例2中解释的HPLC方法来定量分析，将该试管用1mL新的磷酸盐缓冲液补充。
结果如图4所示，初始释放量可以通过改变药物与聚合物的比例来控制，并且释放速率可以保持恒定。但是，市售产品利培酮实际上在14天内不释放药物，其后开始释放。
另外，如图5所示可知，当聚合物分子量增加的同时将药物与聚合物的比例恒定固定时，药物的释放速率降低。这意味着药物的释放速率可以通过调整聚合物的分子量来控制。同时，从对比例中可以证实，释放被延迟了几天到几周，虽然该时间根据分子量而变化。
Claims (14)
1.一种含有水难溶性药物的缓释微粒，其包含水难溶性药物和具有至少一个端羧基的聚乳酸或其衍生物的多价金属离子盐，其中所述水难溶性药物包埋于聚乳酸或其衍生物的多价金属离子盐中。
2.根据权利要求1所述的含有水难溶性药物的缓释微粒，其中所述具有至少一个端羧基的聚乳酸或其衍生物选自下式1-6所示的化合物：
[式1]
RO-CHZ-[A]n-[B]m-COOM
其中A是-COO-CHZ-；B是-COO-CHY-、-COO-CH2CH2CH2CH2CH2-或者-COO-CH2CH2OCH2；R是氢原子、或者乙酰基、苯甲酰基、癸酰基、棕榈酰基、甲基或者乙基；Z和Y各自独立地为氢原子、甲基或苯基；M独立地为H、Na、K或Li；n是1-30的整数；和m是0-20的整数；
[式2]
RO-CHZ-[COO-CHX]p-[COO-CHY’]q-COO-CHZ-COOM
其中X是甲基；Y’是氢原子或苯基；p是0-25的整数，q是0-25的整数，条件为p+q是5-25的整数；R是氢原子、乙酰基、苯甲酰基、癸酰基、棕榈酰基、甲基或者乙基；Z是氢原子、甲基或者苯基；和M独立地为H、Na、K或Li；
[式3]
RO-PAD-COO-W-M’
其中W-M’是或
PAD选自下组：D,L-聚乳酸、D-聚乳酸、聚扁桃酸、D,L-乳酸和乙醇酸的共聚物、D,L-乳酸和扁桃酸的共聚物、D,L-乳酸和己内酯的共聚物以及D,L-乳酸和1,4-二氧六环-2-酮的共聚物；R是氢原子、乙酰基、苯甲酰基、癸酰基、棕榈酰基、甲基或者乙基；和M独立地为H、Na、K或Li；
[式4]
S-O-PAD-COO-Q
其中S是
L是-NR1-或者-O-，其中R1是氢原子或者C1-10烷基；Q是CH3、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3或者CH2C6H5；a是0-4的整数；b是1-10的整数；M是H、Na、K或Li；PAD是选自下组的一种或多种：D,L-聚乳酸、D-聚乳酸、聚扁桃酸、D,L-乳酸和乙醇酸的共聚物、D,L-乳酸和扁桃酸的共聚物、D,L-乳酸和己内酯的共聚物和D,L-乳酸和1,4-二氧六环-2-酮的共聚物；
[式5]
其中R’是-PAD-O-C(O)-CH2CH2-C(O)-OM，其中PAD选自下组：D,L-聚乳酸、D-聚乳酸、聚扁桃酸、D,L-乳酸和乙醇酸的共聚物、D,L-乳酸和扁桃酸的共聚物、D,L-乳酸和己内酯的共聚物以及D,L-乳酸和1,4-二氧六环-2-酮的共聚物，且M是H、Na、K或Li；a是1-4的整数；
[式6]
YO-[-C(O)-(CHX)a-O-]m-C(O)-R-C(O)-[-O-(CHX’)b-C(O)-]n-OZ
其中X和X'各自独立地为氢、烷基或者芳基；Y和Z各自独立地为H、Na、K或Li；m和n各自独立地为0-95的整数，条件为5<m+n<100；a和b各自独立地为1-6的整数；R是取代的或者未取代的-(CH2)k-，其中k是0-10的整数，具有2-10个碳原子的二价链烯基，具有6-20个碳原子的二价芳基或其组合。
3.根据权利要求1所述的含有水难溶性药物的缓释微粒，其中所述具有至少一个端羧基的聚乳酸或者其衍生物的数均分子量是500-5,000道尔顿。
4.根据权利要求1所述的含有水难溶性药物的缓释微粒，其中所述多价金属离子是选自下组的一种或多种：Ca2+、Mg2+、Ba2+、Cr3+、Fe3+、Mn2+、Ni2+、Cu2+、Zn2+和Al3+。
5.根据权利要求1所述的含有水难溶性药物的缓释微粒，其粒子直径是1-400μm。
6.根据权利要求1所述的含有水难溶性药物的缓释微粒，其中相对于微粒总重量，所述水难溶性药物的含量是1-50wt%。
7.根据权利要求1所述的含有水难溶性药物的缓释微粒，其中所述水难溶性药物是选自下组的一种或多种：奥氮平、利培酮、齐拉西酮、利斯的明、纳洛酮、环丙甲羟二羟***酮、西罗莫司、他克莫司、卡莫司汀、***、***、***、左炔诺孕酮和炔诺酮。
8.一种制备含有水难溶性药物的缓释微粒的方法，其包含：
i)制备聚合物-药物的溶液，其含有在有机溶剂中的具有至少一个端羧基的聚乳酸或其衍生物的单价金属盐和水难溶性药物；和
ii)将所述聚合物-药物溶液分散到含有多价金属离子和任选的表面活性剂的水溶液中，以形成微粒。
9.根据权利要求8所述的制备含有水难溶性药物的缓释微粒的方法，其中所述聚乳酸或其衍生物的单价金属盐选自权利要求1所定义的式1-6的化合物，其中M是Na、K或Li。
10.根据权利要求8所述的制备含有水难溶性药物的缓释微粒的方法，其中所述有机溶剂选自下组：二氯甲烷、六氟异丙醇、乙酸乙酯、乙醇、甲醇、二甲基甲酰胺、丙酮、乙腈、四氢呋喃、乙酸、二甲基亚砜、氯仿、二氯乙酸甲酯、氯乙酸甲酯、氯乙酸乙酯、二氯乙酸乙酯、氟乙酸甲酯、二氟乙酸甲酯、氟乙酸乙酯、二氟乙酸乙酯、乙酸乙酯、乙酸甲酯、甲酸甲酯、甲酸乙酯、甲酸异丙酯、甲酸丙酯及其混合物。
11.根据权利要求8所述的制备含有水难溶性药物的缓释微粒的方法，其中所述多价金属离子是选自下组的一种或多种：Ca2+、Mg2+、Ba2+、Cr3+、Fe3+、Mn2+、Ni2+、Cu2+、Zn2+和Al3+。
12.根据权利要求8所述的制备含有水难溶性药物的缓释微粒的方法，其中所述水难溶性药物是选自下组的一种或多种：奥氮平、利培酮、齐拉西酮、利斯的明、纳洛酮、环丙甲羟二羟***酮、西罗莫司、他克莫司、卡莫司汀、***、***、***、左炔诺孕酮和炔诺酮。
13.根据权利要求8所述的制备含有水难溶性药物的缓释微粒的方法，其进一步包含：
iii)获得步骤ii)中形成的微粒，并且用水清洗它。
14.根据权利要求13所述的制备含有水难溶性药物的缓释微粒的方法，其进一步包含：
iv)冻干在步骤iii)中清洗的微粒。
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| CN112791066B (zh) * | 2019-11-13 | 2024-04-02 | 鲁南制药集团股份有限公司 | 一种注射用西罗莫司缓释微球及其制备方法 |
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| EP2654724A4 (en) | 2014-11-19 |
| JP2016000744A (ja) | 2016-01-07 |
| WO2012087062A2 (en) | 2012-06-28 |
| US9011921B2 (en) | 2015-04-21 |
| KR101424163B1 (ko) | 2014-08-01 |
| JP2014501253A (ja) | 2014-01-20 |
| EP2654724B1 (en) | 2019-11-06 |
| CN107412168A (zh) | 2017-12-01 |
| KR20120072750A (ko) | 2012-07-04 |
| EP2654724A2 (en) | 2013-10-30 |
| US20130273167A1 (en) | 2013-10-17 |
| JP6002290B2 (ja) | 2016-10-05 |
| WO2012087062A3 (en) | 2012-08-23 |
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