CN1921880A - 蛋白质类药物的注射用缓释微粒制剂及其制造方法 - Google Patents
蛋白质类药物的注射用缓释微粒制剂及其制造方法 Download PDFInfo
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Abstract
提供蛋白质类药物的注射用缓释微粒制剂及其制造方法,其特点是在制造时,尽量避免使用有机溶剂,避免同时使用与水不互溶的有机溶剂和水溶液,所得制剂兼有生物体内的消失性和缓释性,在3天以上时间内,以基本一定的速度缓慢释放所含蛋白质类药物,而且其药物含量在5%以上,分散性,通针性良好。使生物体内消失性高分子覆盖或附着含有蛋白质类药物的多孔性磷灰石或其衍生物而制成该制剂。
Description
技术领域
本发明涉及以生物体内缓慢消失的多孔性磷灰石或其衍生物的微粒为基质的蛋白质类药物的注射用缓释性微粒制剂及其制造方法。
背景技术
关于蛋白质类药物的长时间缓释注射用制剂,目前为止大部分对聚乳酸·乙醇酸(PLGA)作为基质的方法进行了研究(例如,参照专利文献1,2,非专利文献1,2,3)。另外,含有人生长激素(hGH)并以PLGA作为基质的缓释微囊在美国已用于实际的治疗(例如,参照非专利文献4)。PLGA是在生物体内可以通过水解而缓慢消失的生物体内消失性基质,作为注射剂的基质具有优选的性质。一般情况下,制造使用PLGA的缓释制剂时,使用溶解其的有机溶剂。另外,大多数蛋白质类药物为水溶性,制造使用PLGA的缓释微粒制剂时,要同时使用有机溶剂溶液与水溶液。
如果同时使用这两种溶剂,蛋白质类药物的一部分会变性,失活。这样的活性下降,不仅会使有效性受损,还有可能对生物体造成不良影响。另外,对于水溶性蛋白质类药物的缓释微粒制剂,不能避免给药初期(刚给药后)一过性的过量释放。另外,已有关于使用羟基磷灰石的人类生长激素(蛋白质类药物)的缓释微粒制剂的报道(例如,参照非专利文献5,6)。但是,所有制剂都是2成分***,磷灰石的粒径为40到80μm或200μm,很难用细针进行注射给药。另外,其体内缓释效果不明。另外,磷灰石中含有的人生长激素量在1%以下,药量很小。
专利文献1:特开平10-231252
专利文献2:美国专利5656297
非专利文献1:O.L.Johnson et al:Nature Medicine,2:795-799,(1996)
非专利文献2:M.Takenaga et al:J.Pharmacy Pharmacology,54:1189-1194,(2002)
非专利文献3:S.Takada et al:J.Controlled Release,88:229-242,(2003)
非专利文献4:NDA 21-075
非专利文献5:J.Guicheux et al:J.Biomedical MaterialsResearch,34:165-170,(1997)
非专利文献6:H.Gautier et al:J.Biomedical MaterialsResearch,40:606-613,(1998)
发明内容
对于蛋白质类药物的注射用缓释制剂,必须选择给药后、在药物释放结束后,具有从生物体内消失的生物体内消失性功能的材料。另外,关于其制造,应避免同时使用与水不互溶的有机溶剂和水溶液,必须避免蛋白质类药物的变性。另外,还存在以下问题,微粒制剂中的药物含量如不能达到5%以上,制剂的给药量会过大,用较细的注射针给药时会产生困难,而且,多数情况要反复给药,优选能够通过细针的制剂,另外,缓释时间至少在3天以上,优选1周以上,同时必须尽力减少作为引起副作用的原因的初期过量释放。
因此,本发明的目的是提供在制造时,极力回避有机溶剂的使用,避免同时使用非水混合性的有机溶剂和水溶液,所得的制剂,兼有生物体内消失性及缓释性机能,在3天以上时间中,以基本一定速度缓慢释放所含蛋白质类药物,而且其药物含量在5%以上,分散性,通针性良好的蛋白质类药物的注射用缓释性微粒制剂及其制造方法。
本发明人为解决这些课题,通过利用多孔性磷灰石或其衍生物的微粒,发现不用同时使用水和有机溶剂,即可得到兼有生物体内消失性及缓释性机能的制剂。另外,发现在蛋白质类药物中并用水溶性2价金属化合物可以抑制蛋白质类药物的初期过剩释放。而且,发现用蛋白质类药物充分浸润多孔性磷灰石中后,使生物体内消失性高分子化合物覆盖或附着,可以有更长时间的缓慢释放,同时初期的过剩释放更少。
这里记载的构成蛋白质类药物的注射用缓释性微粒制剂的多孔性磷灰石及其衍生物,可以是羟基磷灰石,也可以是将其构成成分钙的一部分置换为锌的化合物。此时锌的置换率优选1~20%。多孔性磷灰石及其衍生物的微粒可以通过已知方法获得。例如,可以列举出“山口乔、柳田博明编,牧岛亮南、青木秀希著:陶瓷科学丛书7:生物陶瓷,技报堂出版(株),7-9页,1984”中记载的方法等。根据构成羟基磷灰石的钙(Ca)和磷(P)的比例不同,在生物体内的消失速度也不同,如果(Ca+Zn)/P的值小于1.67则易溶于水而在生物体内的消失速度变快。(Ca+Zn)/P的值优选1.67~1.51范围。另外,制造磷灰石时的处理温度较低时,易溶于水,消失速度也变快。采用室温~800℃的处理温度,优选150~600℃。进而更优选150~400℃。如果在800℃以上烧制则不能在生物体内消失。另外,如在100℃以下处理,粒子之间易于凝集,会引起难以进行通常的注射给药。对于粒径优选使用平均值50μm以下的粒子。但是,如果粒径过小,蛋白质类药物的封入率有可能降低,优选使用0.1~50μm,更优选0.5~30μm,进一步优选0.5~10μm。
覆盖该多孔性磷灰石的生物体内消失性高分子化合物,包括聚乳酸(PLA)或聚乳酸·乙醇酸(PLGA),在聚乙二醇(PEG)中结合了PLA及/或PLGA的嵌段共聚物,胶原,聚氰基丙烯酸,聚氨基酸衍生物等,但是使用高浓度的PLA或PLGA,覆盖了生物体内消失性高分子的磷灰石之间会发生凝集。另外,由于此时使用不与水混合的有机溶剂,如不完全除去,在最终工艺中的冷冻干燥时,由于加水,蛋白质类药物有可能发生变性。因此,经过各种研究,结果确定在PEG中结合PLA或PLGA的嵌段共聚物是优选的。这一结合样式中,可以是PEG的两个末端的羟基与PLA或PLGA形成酯键结合的化合物,也可以是PEG的单末端形成酯键结合的化合物。单末端酯的情况,优选用OCH3,烷氧基等保护其他末端,但也可以结合氨基,羧基等官能基。PEG和PLA或PLGA的比例,优选PEG以重量比为20~90%,特别优选25~65%。嵌段共聚物的分子量优选全部为3,000~20,000,特别优选5,000~12,000。生物体内消失性高分子的用量,在磷灰石衍生物的3~100重量%的范围使用,优选在5~30%的范围使用。
作为水溶性2价金属化合物,可以列举出氯化锌,醋酸锌,碳酸锌,氯化钙,氢氧化钙,氯化铁,氢氧化铁,氯化钴等。其中优选使用氯化锌。除了氯化锌也可以并用碳酸钠或碳酸氢钠等。其用量根据内封的蛋白质类药物的不同而不同,一般来说,优选使用多孔性磷灰石的2~100重量%的范围。进一步的优选范围为2~30%。
作为蛋白质类药物,适用分子量5,000以上的化合物。例如,可以列举出人类生长激素,肝细胞生长因子(HGF),成纤维细胞生长因子(FGF),IGF-1,EGF,NK4,VEGF,NGF,BDNF,BMP,脂联素(adiponectin),干扰素(INF-α),白介素(IL-2,IL-4,IL-5等),EPO,G-CSF,胰岛素,ANP,TNF-α,抗体等。其用量根据蛋白质类药物及缓释时间而异,向多孔性磷灰石内的封入量优选尽可能多。向多孔性磷灰石内稳定地封入的量一般为磷灰石的5~50%。
本发明的蛋白质类药物的注射用缓释性微粒制剂的制造方法,一般按下面操作进行。将多孔性磷灰石或其衍生物的微粒分散于蛋白质类药物水溶液中,搅拌使水溶液充分浸润到该磷灰石中。然后,通过离心分离等操作除去未浸润的水溶液,如有必要,加入水溶性2价金属化合物水溶液,搅拌,使水溶液浸润。然后,过滤,真空干燥或冷冻干燥,得到含有蛋白质类药物的粉末。将该粉末分散于生物体内消失性高分子的水溶液或混悬液,或含有水混合性溶剂(如丙酮,乙醇等)的生物体内消失性高分子水溶液中或混悬液中,搅拌后,按需要加入稳定剂等,通过冷冻干燥或真空干燥制造粉末。实际给药时,将该粉末分散到适当的分散溶剂中,皮下或肌肉内等注射给药。最终得到的缓释性微粒制剂的粒径,能通过通常给药时所用的注射针就可以。实际上,注射针的直径越小给患者造成的恐慌越小。更优选能通过已有的表示注射针的粗度的国际标准为25G以下的注射针。满足这一要求的缓释性微粒制剂的粒径为0.5~50μm。另外,蛋白质类药物的缓释时间根据药物的活性各异,一般优选一周以上的缓释时间。
本发明得到的微粒制剂,蛋白质类药物至少可以持续缓慢释放3天以上时间,初期的过剩释放非常小,蛋白质类药物的含量最大可达30%。另外,所得制剂可以通过25G注射针。另外,最终通过冷冻干燥可以调制粉末化微粒制剂,使内封的蛋白质类药物非常稳定。
实施例
以下通过实施例说明其缓释性及生物体内消失性,但不仅限于以下实施例。
(实施例1)
使用不同烧成温度的2种锌置换羟基磷灰石(平均粒径8μm)进行生物体内消失的确认试验。使用SD系雄性大鼠(6周)每组5只。将180℃处理品和400℃处理品分别分散于混悬液(0.1%吐温80,0.5%CMC-Na,5%甘露糖醇水溶液),每种羟基磷灰石5mg以1只0.2ml的容量在背部中央皮下的左右部给药。给药后(3小时,1,5,10,15,20天)经时地摘出给药部位的残存物,测定其湿重量和钙量(表-1,2)。给药后1到5天由于膨润等使湿重量增加近2倍,而钙量仅有一些增加。其后,湿重量、钙量都迅速消失,180℃处理品约15天,400℃处理品约20天后基本消失。
表-1摘出羟基磷灰石湿重量(mg)
3hr | 1天 | 5天 | 10天 | 15天 | 20天 | |
180℃处理品(n=5) | 14.2 | 27.1 | 28.0 | 17.0 | 2.3 | 0.0 |
400℃处理品(n=5) | 14.0 | 23.9 | 29.1 | 23.2 | 10.8 | 0.0 |
表-2摘出羟基磷灰石残存钙量(mg)
3hr | 1天 | 5天 | 10天 | 15天 | 20天 | |
180℃处理品(n=5) | 1.27 | 1.53 | 1.45 | 0.26 | 0.01 | 0.00 |
400℃处理品(n=5) | 1.33 | 1.62 | 1.91 | 0.48 | 0.20 | 0.00 |
(实施例2)
向将400℃处理的羟基磷灰石(HAp)中的钙的5%置换为锌的衍生物(HAp-Zn-0.5;相对于钙9.5mol,锌0.5mol)100mg中添加700μl用PD-10柱(amersham pharmacia)进行脱盐处理的hGH溶液(50mg/ml),然后加水使最终体积为5ml。搅拌3分钟后,进行3,000rpm、3分钟的离心处理。向所得沉淀中添加10ml水,搅拌1分钟。再次进行3,000rpm、3分钟的离心处理,向所得沉淀中加入20.4mg/ml氯化锌(和光纯药,大阪)水溶液2.0ml(氯化锌300μmol),用接触混合器搅拌后,进行冷冻干燥。将PLA-PEG-PLA-Y004(PEG比例32%,分子量8,200)溶于丙酮使其浓度达到20%,将丙酮溶液与水按1∶4的比例混合,制成含聚合物的丙酮、水混合液。向所得冷冻干燥粉末中,添加这一含聚合物的丙酮、水混合液500μl,用接触混合器充分搅拌后,进行冷冻干燥。还制成不对聚合物溶液进行处理的制剂作为对照。所得制剂中的hGH含量通过微BCA蛋白分析试剂盒(microBCA protein assay kit(Pierce))进行定量。
比较所得hGH微粒制剂样品的体外释放性。精确称量hGH微粒制剂样品2.5mg,向其中添加PBS(生理食盐磷酸缓冲液)0.250ml,在37℃搅拌。3,000rpm离心处理3分钟,经时回收上清液,通过凝胶过滤HPLC分析(TOSO G2000SW-x1)定量上清液中释放的hGH量。结果如表3所示。与作为对照制成的未进行聚合物溶液处理的制剂相对比,进行聚合物溶液处理的制剂,其向PBS中的hGH释放受到抑制。
表3聚合物溶液处理对hGH微粒制剂的体外释放性的影响
聚合物溶液处理 | 累计hGH释放量(μg) | ||||
2hr | 4hr | 24hr | 4天 | 7天 | |
无(n=2) | 0.8 | 2.3 | 6.3 | 7.8 | 9.6 |
有(n=2) | 1.5 | 2.6 | 2.6 | 2.6 | 2.9 |
(实施例3)
向100mg 400℃处理的HAp-Zn-0.5中添加700μl用PD-10柱(amersham pharmacia)进行脱盐处理的hGH溶液(50mg/ml),然后用接触混合器搅拌1分钟。然后,分别添加水,使最终液量达到5ml,再用接触混合器搅拌1分钟。静置3分钟后,3,000rpm离心处理3分钟,向所得沉淀中加水5ml,再次搅拌1分钟。再以3,000rpm离心处理3分钟,所得沉淀中加入20.4mg/ml氯化锌(和光纯药,大阪)水溶液2.7ml(氯化锌400μmol),用接触混合器搅拌后,进行冷冻干燥。
将PLA-PEG-PLA-Y001(PEG比例65.4%,分子量14,600)溶于丙酮以使其浓度达到20%。将丙酮溶液与水按1∶4的比例混合,制成含聚合物的丙酮、水混合液。向所得冷冻干燥粉末中,添加这一含聚合物的丙酮、水混合液500μl,用接触混合器充分搅拌后,进行冷冻干燥。再制成不对聚合物溶液进行处理的制剂作为对照。所得hGH微粒制剂中的hGH含量通过微BCA蛋白分析试剂盒进行定量。
制成的hGH微粒制剂用0.5%CMC-Na、5%甘露糖醇、0.1%吐温80混悬,在雄性SD系大鼠的背部皮下按10IU/kg(1IU∶0.35mg)给药。
给药后的1,2,4,8小时及以后每天进行尾静脉取血,用全自动EIA装置AIA-6000(东ソ-株式会社)及ETEST“TOSOH”II(HGH)测定血中hGH浓度。结果如表4所示。进行了聚合物溶液处理的制剂与未进行聚合物溶液处理的制剂相比长时间维持更高的血药浓度。
表4 hGH微粒制剂的体内缓释效果
聚合物溶液处理 | hGH含量(%) | hGH血液浓度(ng/ml) | |||||||
4hr | 8hr | 1天 | 2天 | 3天 | 4天 | 5天 | 6天 | ||
无(n=2) | 16.2 | 26.4 | 49.1 | 11.8 | 2.8 | 1.3 | 0.78 | 0.43 | 0.32 |
有(n=2) | 11.2 | 42.6 | 65.4 | 21.6 | 9.7 | 4.4 | 2.2 | 1.4 | 0.49 |
(实施例4)
向100mg在400℃处理的HAp-Zn-0.5中添加700μl用PD-10柱(amersham pharmacia)进行脱盐处理的hGH溶液(50mg/ml),然后加水使最终量为5ml。搅拌3分钟后3,000rpm离心处理3分钟。向所得沉淀中添加10ml水,搅拌1分钟。再以3,000rpm离心处理3分钟,所得沉淀中加入20.4mg/ml氯化锌(和光纯药,大阪)水溶液2.0ml(氯化锌300μmol),用接触混合器搅拌后,进行冷冻干燥。
将PLA-PEG-PLA-Y004(PEG比例32%,分子量8,200)溶于丙酮以使其浓度达到20%,将丙酮溶液与水按1∶4的比例混合,制成含聚合物的丙酮、水混合液。所得冷冻干燥粉末中,添加这一含聚合物的丙酮、水混合液500μl,用接触混合器充分搅拌后,进行冷冻干燥。所得hGH微粒制剂中的hGH含量用微BCA蛋白质分析试剂盒进行定量。
制成的hGH微粒制剂用0.5%CMC-Na、5%甘露糖醇、0.1%吐温80混悬,在用他克莫司(藤泽药品工业,大阪)进行了免疫抑制的雄性SD系大鼠的背部皮下按30IU/kg(1IU∶0.35mg)给药。应予说明,给予他克莫司(tacrolimus)应预先在给制剂前3天以0.4mg/只的量,而开始给予制剂后每隔3天以0.2mg/只的量在背部皮下给予。
给药后的1,2,4,8小时及以后每1天或2天进行尾静脉取血,用全自动EIA装置AIA-6000(东ソ-株式会社)及ETEST“TOSOH”II(HGH)测定血中hGH浓度。结果如表5所示。确认进行了聚合物溶液处理的hGH微粒制剂在约2周的时间内缓慢释放。
表5hGH微粒制剂(hGH含量14.3%)的体内缓释效果
给药后经过时间 | 4hr | 8hr | 12hr | 16hr | 1天 | 2天 | 3天 | 4天 | 5天 |
hGH血液浓度(ng/ml) | 4.6 | 31.6 | 99.9 | 101.3 | 95.7 | 29.9 | 11.4 | 8.5 | 5.8 |
6天 | 7天 | 8天 | 9天 | 10天 | 11天 | 12天 | 14天 |
4.2 | 3.4 | 2.6 | 2.0 | 1.8 | 1.6 | 1.9 | 1.3 |
(实施例5)
向将400℃烧成的HAp中的钙的一部分置换为锌的衍生物150mg(HAp-Zn-0.5;相对于钙的9.5mol,锌0.5mol)中添加525μl干扰素-α(INF-α)溶液(2.86mg/ml),然后加水使最终体积为2ml。搅拌5分钟后,以3,000rpm离心处理3分钟。向所得沉淀中添加15ml水,搅拌1分钟。再以3,000rpm离心处理3分钟,所得沉淀中加入20.4mg/ml氯化锌(和光纯药,大阪)水溶液2.0ml(氯化锌300μmol),用接触混合器搅拌后,进行冷冻干燥。将PLA-PEG-PLA(PEG比例32%,分子量8,200)溶于丙酮使其浓度达到20%,将丙酮溶液与水按1∶4的比例混合,制成含聚合物的丙酮、水混合液。向所得冷冻干燥粉末中,添加这一含聚合物的丙酮、水混合液750μl,用接触混合器充分搅拌后,进行冷冻干燥。另外制成不对聚合物溶液进行处理的制剂作为对照。所得HAp-IFN-α制剂中的IFN-α含量用人干扰素α(Hu IFN-α)ELISA Kit(PBL Biomedical Laboratories)进行定量。
对所得HAp-IFN-α样品的体外释放性进行比较。精确称量所得HAp-IFN-α样品2.5mg,向其中添加1/10稀释的PBS(生理食盐磷酸缓冲液)0.25ml,在37℃搅拌。经时以3,000rpm离心处理3分钟,回收上清液,用人干扰素α(Hu IFN-α)ELISA Kit(PBL BiomedicalLaboratories)对上清液中释放的IFN-α进行定量。结果如表6所示。与作为对照制成的未进行聚合物溶液处理的制剂比较,进行聚合物溶液处理的制剂向1/10稀释的PBS中释放IFN-α受到充分抑制。
表6聚合物溶液处理对HAp-IFN-α体外释放性的影响
累积释放干扰素α的量(pg) | |||||||
0 | 1hr | 2hr | 4hr | 24hr | 4天 | 7天 | |
无聚合物溶液处理 | 455 | 989 | 2601 | 3398 | 4017 | 4727 | 6338 |
有聚合物溶液处理 | 95 | 207 | 328 | 410 | 550 | 641 | 752 |
(实施例6)
向100mg在400℃处理的HAp-Zn-0.5中添加用0.01N HCl溶解成10mg/ml浓度的重组人胰岛素(和光纯药,大阪)溶液3.5ml,再加入0.01N HCl,使最终液体量为5ml。搅拌3分钟后,以3,000rpm离心处理3分钟。向所得沉淀中添加10ml水,搅拌1分钟。再以3,000rpm离心处理3分钟,将所得沉淀冷冻干燥。将PLA-PEG-PLA-Y004(PEG比例32%,分子量8,200)溶于丙酮以使其浓度达到20%,将丙酮溶液与水按1∶4的比例混合,制成含聚合物的丙酮、水混合液。所得冷冻干燥粉末中,添加这一含聚合物的丙酮、水混合液500μl,用接触混合器充分搅拌后,进行冷冻干燥。还制成不对聚合物溶液进行处理的制剂作为对照。所得制剂中的hGH含量用微BCA蛋白质分析试剂盒(Pierce)进行定量。
比较所得胰岛素微粒制剂样品的体外释放性。精确称量胰岛素微粒制剂样品2.5mg,向其中添加PBS(生理食盐磷酸缓冲液)0.25ml,在37℃搅拌。经时地以3,000rpm离心处理3分钟,回收上清液,用微BCA蛋白质分析试剂盒(Pierce)对上清液中释放的胰岛素进行定量,算出相对于样品中所含胰岛素总量的比例。结果如表7所示。与作为对照制成的未进行聚合物溶液处理的制剂比较,进行了聚合物溶液处理的制剂向PBS中释放胰岛素受到抑制。
表7聚合物溶液处理对胰岛素微粒制剂体外释放性的影响
聚合物溶液处理 | 累积胰岛素释放量(%总胰岛素) | ||||
1hr | 2hr | 4hr | 24hr | 4天 | |
无(n=2) | 29.3 | 47.4 | 56.8 | 61.6 | 61.6 |
有(n=2) | 21.8 | 39.8 | 49.0 | 49.0 | 49.0 |
Claims (11)
1.一种蛋白质类药物的注射用缓释性微粒制剂,其特征是使生物体内消失性高分子覆盖或附着含有蛋白质类药物的多孔性磷灰石或其衍生物。
2.权利要求1中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述生物体内消失性高分子为由聚乙二醇和聚乳酸或聚乳酸·乙醇酸构成的嵌段共聚物。
3.权利要求2中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述由聚乙二醇和聚乳酸或聚乳酸·乙醇酸构成的嵌段共聚物为由聚乳酸或聚乳酸·乙醇酸-聚乙二醇-聚乳酸或聚乳酸·乙醇酸构成的嵌段共聚物。
4.权利要求2中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述由聚乙二醇和聚乳酸或聚乳酸·乙醇酸构成的嵌段共聚物的重均分子量为3,000到20,000。
5.权利要求2或3中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述由聚乙二醇和聚乳酸或聚乳酸·乙醇酸构成的嵌段共聚物中,聚乙二醇的重量比例为20%到90%。
6.权利要求1中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述多孔性磷灰石或其衍生物中含有蛋白质类药物及2价金属盐。
7.权利要求1中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述多孔性磷灰石或其衍生物中蛋白质类药物含量为5%到30%。
8.权利要求1中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述多孔性磷灰石或其衍生物的平均粒径为0.5~30μm。
9.权利要求1中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述多孔性磷灰石或其衍生物在100~600℃被处理。
10.权利要求1中记载的蛋白质类药物的注射用缓释性微粒制剂,其特征是前述多孔性磷灰石的一部分钙被锌置换的磷灰石衍生物。
11.一种蛋白质类药物的注射用缓释性微粒制剂的制造方法,其特征是将多孔性磷灰石或其衍生物的微粒分散于蛋白质类药物水溶液中,搅拌,将所得粉末分散于生物体内消失性高分子水溶液中或混悬液中,搅拌后,通过冷冻干燥或真空干燥得到粉末。
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US8652506B2 (en) * | 2008-06-05 | 2014-02-18 | Boston Scientific Scimed, Inc. | Bio-degradable block co-polymers for controlled release |
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