CN105963257B - 一种缓释微粒的制备方法 - Google Patents
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Abstract
本发明提供了一种缓释微粒。本发明中缓释微粒的制备全程常温或低温,对于高温敏感的药物,特别是蛋白、核酸及肽类药物制备聚合物基质的组合物非常有利,相比已公开的技术,能够最大程度上在整个工艺过程中保持活性物质的生物活性;同时,所制备的缓释微粒具有接近零级的优异缓释效果,药物浓度在缓释期间稳定,解决了传统的要预先制备药物微小颗粒的S/O/W工艺得到的微粒前期没有药物释放,而后期药物快速释放的缺点;再者,缓释微粒具有较高的载药率和药物包封率。
Description
技术领域
本发明涉及一种将水溶性药物,特别是蛋白质、核酸、肽类药物包封在可生物降解、生物相容的聚合物中,从而得到能够持续释放药物的缓释微粒的方法。
背景技术
近年来,大量的生物活性物质如寡肽、多肽和蛋白作为候选药物获得了大量关注,其在治疗严重的病状(癌症、贫血症、多发性硬化、肝炎等)中发挥重要的作用。但是,这些大分子活性成分比较脆弱,因为它们在胃肠道中的稳定性差(容易在低pH或蛋白酶解下降解),循环半衰期较短,以及它们穿过肠壁的通透性差,从而导致生物利用度非常低,因此难以口服给药。注射或胃肠外途径给药仍是多肽和蛋白等活性成分的优选给药途径。可通过静脉、肌肉或皮下途径注射的肽和蛋白的很多制剂已经上市或在研发当中,如亮丙瑞林缓释微粒、戈舍瑞林缓释植入剂、曲普瑞林缓释微粒等。
对于许多肽试剂,特别是激素,需要以受控的速率长期连续给药,这些活性成分在靶组织或器官上产生期望的效果所需的全身浓度很高,因而需要通过频繁地注射高剂量获得治疗效用窗中所需的浓度,这常常造成对患者有损害的全身毒性。同时,注射给药是疼痛的,因此,患者的依从低,疗效差,副作用大。这些问题可以通过基于聚合物的活性成分的长效传递系统(Drug Delivery System,DDS)得以解决,该系统通过将活性成分包封入生物可降解和生物相容的聚合物基质中,制成微胶囊、微颗粒或可移植杆的形式,使活性成分长期稳定地释放出来,从而达到緩释控释的目的。
已经报道的微粒制备方法有多种,比如溶剂挥发法(solvent evaporation)、凝聚法(coacervation)、喷雾干燥法以及喷雾冷冻干燥法等。其中使用最多的是水相中溶剂挥发法,它又可细分为单乳化法(Oil/Water,O/W;Water/Oil,W/O)和复乳化法(Water/Oil/Water,W/O/W;Water/Oil/Oil,W/O/O)。
一种改进的复乳化方法(如CN102245210A、CN1826170B),直接将多肽粉末悬浮在有机相中,形成油包固(S/O)的悬浊液,然后将此悬浊液分散到水相中,形成S/O/W的复乳液。由于多肽粉末一般不溶于中间有机相溶剂,此方法可避免Wl/O/W2复乳化方法中内水相向外水相的扩散,进而提高包封率。
在S/O/W方法中,预制备的活性物质颗粒的大小十分重要,当固体蛋白质颗粒的直径从5微米增大到20微米时,不仅初期的释放速率翻倍,其微囊包封率从80%下降到20%。通常得到的蛋白质、多肽冻干粉末平均粒径在10-1000μm,比如,典型的蛋白质、多肽冷冻干燥粉末平均粒径约在10-500μm。如果直接用如此大粒径的粉末悬浮在有机溶剂中形成S/O悬浊液,然后应用S/O/W复乳化方法制备微粒,药物将得不到很好的包封,导致包封率低,或者緩释结果不令人满意(前期药物突释较大,而后期药物释放量不足),或者制备的微粒粒径太大,难以给药;同时,药物粉末的形状也影响微粒的形状。因此,一般要采用某种方法预先将药物粉末平均粒径减小到1-10μm,然后将此粉末用于S/O/W复乳化法制备緩释微粒(USP 6270700;Takada S,et al.Journal of Controlled Release.2003,88(2):229-42)。
然而,制备小粒径的药物往往要通过研磨、喷雾干燥、超声粉碎、气流粉碎、结晶法等方法(如CN1494900B),工艺复杂,并且容易导致活性成分失活。研磨法受限于造成粉尘、重金属污染以及研磨热引起的蛋白质变性;喷雾干燥法或许可以提供足够小的蛋白颗粒,但是喷嘴附近的高剪切力和液体与空气间的界面张力会使蛋白变性;此外,喷雾干燥或喷雾式冷冻干燥中须使用表面活性剂,而表面活性剂又造成蛋白质在下一步制剂程序中与溶剂互相作用。同时,如果降低制备颗粒工艺的复杂性,牺牲粒径大小以保证药物的活性,制备的颗粒粒径相对微粒略小(即颗粒半径比聚合物层厚度大得多),则会出现每个微粒只包裹一个或很少几个活性物质颗粒的情况,从而导致前期极少药物释放,而后期药物释快速释放,达不到缓释效果。
另一种改进的复乳化法(如CN102233129 B、CN102871969 A、CN101721375 B、CN102885785 B等),将活性物质与一种或几种添加剂(如葡聚糖、聚乙二醇、海藻酸钠等)制备小颗粒,然后用有机溶剂洗去部分或全部的添加剂,获得多孔、半镂空或镂空的活性物质小颗粒,然后再以常规的S/O/W工艺制备微粒。这种方法增加了制备小颗粒这一步较复杂的步骤,而且需要用有机溶剂除去其中的添加剂。并且,这些添加剂大多为水溶性物质,如果没有完全去除,容易影响释放效果,加快活性物质释放,或者形成凝胶(如高分子量的葡聚糖、海藻酸钠),可能导致微粒涨破、药物释放延迟或者释放不完全。
更进一步优化的制备方法(US5556642),将水溶性活性物质和聚合物溶于共溶剂,然后通过蒸发去除有机溶剂得到固体混合物,然后将固体混合物溶于有机溶剂中,通过O/W法制备微粒。这种方法克服了传统的S/O/W法前期没有药物释放,而后期药物释急剧释放的缺点。然而,挥发有机溶剂制备固体的工艺不利于对温度敏感的活性物质,容易致使其变性;如果于较低温度下挥发有机溶剂,由于溶剂挥发较慢则会造成活性物质在固化时聚集析出,干燥后的固体分散体中活性物质也会以较大的体积存在,如块状、带状、丝状,对后续的制备微粒工艺造成困难或造成浪费,也会导致释放不稳定。
发明内容
本发明的目的在于克服现有技术存在的不足之处而提供了一种无需预先制备小粒径药物粉末、通过乳化-溶剂挥发法制备缓释微粒的方法,工艺比较简单而且又能保持活性物质的生物活性、包封率高和缓释效果优异。
为实现上述目的,所采取的技术方案:一种缓释微粒的制备方法,包括以下步骤:
1)制备水溶性药物与可生物降解和生物相容的水难溶性聚合物的固体分散体;
2)将步骤1)制备的固体分散体溶于有机溶剂C中,形成固体分散体乳液(内油相),所述有机溶剂C为不能溶解所述水溶性药物但可以溶解所述水难溶性聚合物、沸点低于水且不溶于或难溶于水的有机溶剂;
3)将步骤2)得到的固体分散体乳液注入含有表面活性剂的水溶液(外水相)中形成均匀的乳液;
4)通过溶剂挥发或溶剂提取使乳液中的微粒固化,收集微粒,用超纯水洗涤数次,以除去附着于微粒表面的表面活性剂,然后进行干燥,获得所述缓释微粒。
优选地,所述步骤1)中水溶性药物为碱性物质、含有碱性基团的物质(如多肽、蛋白、核酸、抗体、抗原、抗生素等)以及它们的盐中的至少一种。优选地,所述水溶性药物为蛋白类药物、肽类药物和核酸类药物中的至少一种。优选的,所述水溶性药物的分子量大于约3350Da。
所述蛋白包括天然的、合成的、半合成的或重组的化合物或蛋白质,或含有通过肽键共价连接的α氨基酸的基本组成结构,或功能上相关。具体的包括但不限于球状蛋白(如白蛋白、球蛋白、组蛋白),纤维蛋白(如胶原,弹性蛋白,角蛋白),化合物蛋白(可含有一个或多个非肽组分,如糖蛋白、核蛋白、粘蛋白、脂蛋白、金属蛋白),治疗性蛋白,融合蛋白,受体,抗原(如合成的或重组的抗原),病毒表面蛋白,激素和激素类似物,抗体(如单克隆或多克隆抗体),酶,Fab片段,白介素及其衍生物,干扰素及其衍生物中的至少一种。
所述核酸是指天然的、合成的、半合成的,或由两个或更多个相同或不同的核苷酸形成的至少部分重组的化合物,并且可以是单链或双链。核酸的非限制性例子包括寡核苷酸,反义寡核苷酸,适体,多核苷酸,脱氧核糖核酸,siRNA,核苷酸的构建体、单链或双链区段物以及前体及其衍生物(如糖基化、超糖基化、PEG化、FITC标记、核苷,以及它们的盐)。具体的,所述核酸包括但不限于Mipomersen、Alicaforsen、Nusinersen、Volanesorsen、Custirsen、Apatorsen、Plazomicin、RG-012、RG-101、ATL1102、ATL1103、IONIS-HBVRx、IONIS-HBV-LRx、IONIS-GCGRRx、IONIS-GCCRRx、IONIS-HTTRx、IONIS-TTRRx、IONIS-PKKRx、IONIS-FXIRx、IONIS-APO(a)-LRx、IONIS-ANGPTL3-LRx、IONIS-AR-2.5Rx、IONIS-DMPK-2.5Rx、IONIS-STAT3-2.5Rx、IONIS-SOD1Rx、IONIS-GSK4-LRx、IONIS-PTP1BRx、IONIS-FGFR4Rx、IONIS-DGAT2Rx中的至少一种。上述名词为核酸药物的名称或代号。
所述水溶性药物优选含有至少一个碱性胺基团的水溶性物质(如肽类药物),包括且不限于促肾上腺皮质激素(ACTH)及其衍生物、表皮生长因子(EGF)、血小板衍生生长因子(TOGF)、促性腺素释放激素(LHRH)及其衍生物或类似物、降钙素、胰岛素样生长因子(IGF-I、IGF-II)、细胞生长因子(例如EGF、TGF-α、TGF-β、PDGF、盐酸FGF、碱性FGF等)、胰高血糖素样肽(如GLP-1、GLP-2)及其衍生物或类似物、神经营养因子(例如NT-3、NT-4、CNTF、GDNF、BDNF等)、集落刺激因子(例如CSF、GCSF、GMCSF、MCSF等),以及它们的合成类似物、修饰物和药物活性片段中的至少一种。所述GLP-1的衍生物或类似物包括但不限于exendin-3和exendin-4。
所述含有至少一个碱性胺基团的水溶性药物优选肽类物质及其衍生物、类似物中的至少一种,所述肽类物质包括且不限于胰高血糖素(29肽)、舍莫瑞林(29肽)、阿肽地尔(28肽)、胰泌素(27肽)、齐考诺肽(25肽)、替可克肽(24肽)、比伐芦定(20肽)、生长抑素(14肽)、特利加压素(12肽)、戈舍瑞林(10肽)、曲普瑞林(10肽)、那法瑞林(10肽)、戈那瑞林(10肽)、西曲瑞克(10肽)、地加瑞克(10肽)、安替肽(10肽)、血管紧张素(6-10肽)、亮丙瑞林(9肽)、阿拉瑞林(9肽)、布舍瑞林(9肽)、德舍瑞林(9肽)、奥曲肽(8肽)、兰瑞肽(8肽)、布雷默浪丹(7肽)、埃替非巴肽(7肽)、海沙瑞林(6肽)、脾脏五肽(5肽)、胸腺五肽(5肽)、依降钙素(31肽)、胰高血糖素样肽-1(31肽)、索玛鲁肽(31肽)、利拉鲁肽(34肽)、特立帕肽(34肽)、普兰林肽(37肽)、恩夫韦地(38肽)、艾塞那肽(39肽)、促肾上腺皮质激素(39肽)、促肾上腺皮质激素释放激素(41肽)、替莫瑞林(44肽)、利西拉来(44肽)、促卵泡生成素(118肽)、杜拉鲁肽(274肽)和阿必鲁肽(645肽)中的至少一种。
所述肽类物质优选具有不少于30个氨基酸残基的多肽。所述肽类物质的衍生物、类似物是指具有不少于30个氨基酸残基的多肽及其变体、类似物中的至少一种经水溶性或水难溶性的基团或物质修饰的产物,其具有更高的生物及药理活性、稳定性,或具有新的功能或属性。
所述肽类药物的衍生物、类似物包括胰高血糖素样肽(如GLP-1、GLP-2)及其衍生物、类似物中的至少一种,包括但不限于exendin-3、exendin-4及它们的变体、衍生物中的至少一种。
所述变体、类似物是指氨基酸序列的一个或多个氨基酸残基被取代(或替换)、缺失、插入、融合、截短或其任意组合而不同的肽,变体多肽可以是完全功能性的或者可缺乏一种或多种功能。如胰高血糖素肽-1(GLP-1)的类似物exendin-4的第2位为甘氨酸,而GLP-1的第2位为丙氨酸,而且exendin-4能与GLP-1受体结合、并产生细胞信号级联传导。
所述水溶性或水难溶性的基团或物质选自聚乙二醇及其衍生物、环糊精、透明质酸、短肽、白蛋白、氨基酸序列、核酸、基因、抗体、磷酸、磺酸、荧光染料、KLH、OVA、PVP、PEO、PVA、烷烃、芳烃、生物素、免疫球蛋白、清蛋白、聚氨基酸、明胶、琥珀酰明胶、丙烯酰胺衍生物、脂肪酸、多糖、脂质氨基酸、壳聚糖和葡聚糖中的至少一种。优选聚乙二醇和/或其衍生物,所述聚乙二醇及其衍生物的结构可以是支链的、直链的、分叉的或哑铃状的。所述聚乙二醇的衍生物包括但不限于单甲氧基聚乙二醇、丙酸甲氧基聚乙二醇。所述聚乙二醇及其衍生物为市售的,或通过本领域技术人员熟知的技术自行制备的。
所述水溶性或水难溶性物质经修饰为带有活化基团的修饰剂后与所述肽类物质衍生物相偶联,所述活化基团选自马来酰亚胺、卤素、乙烯基砜、二硫键、巯基、醛基、羰基、O-取代羟氨、活性酯、烯基、炔基、叠氮基及其他具有高化学反应活性的基团中的至少一种;优选地,所述活化基团选自马来酰亚胺、卤素、乙烯基砜和二硫键中的至少一种;更优选为马来酰亚胺和/或二硫键。聚合物上所带有的活化基团个数为一个或多个,且当活化基团个数大于一个时,所述活化基团可为相同或不同。
一个或多个所述水溶性或水难溶性物质的分子量为1-60kDa,优选2-50kDa,更优选5-40kDa。
带有活化基团的修饰剂可以通过氨基酸序列上的氨基、羧基、羟基和/或巯基等与肽或其变体、类似物相偶联。这样的基团通常位于氨基酸残基如Lys(赖氨酸)、Asp(天冬氨酸)、Glu(谷氨酸)、Cys(半胱氨酸)、His(组氨酸)、4-巯基脯氨酸、Trp(色氨酸)、Arg(精氨酸)、Ala(丙氨酸)、Gly(甘氨酸)、Ser(丝氨酸)或Thr(苏氨酸)中的任何一个氨基酸或它们的衍生物的N端、C端、侧链或任意位点,优选为含有巯基的位点。如Exendin-4及其类似物中,位于2、14、21、25、28、35、38或任意位的任一个半胱氨酸残基位点或其他氨基酸残基被替换为半胱氨酸残基的位点。
所述肽及其变体、类似物的修饰为随机修饰、定位修饰物(特异性修饰)、单点修饰或多点修饰,优选单点定位修饰。
所述肽及其变体、类似物釆用常规的多肽合成方法制备,包括固相多肽合成方法、液相多肽合成方法、固相-液相多肽合成方法以及重组方法;肽及其变体、类似物与修饰剂的反应在水溶液或缓冲盐溶液中进行,适当控制反应体系的pH值,以HPLC、GPC等对修饰产物进行监测,并通过离子交换、凝胶色谱等分离纯化,浓缩并冷冻干燥获得目标产物。
优选地,所述步骤1)中水溶性药物为游离形式和药学可接受的盐的形式中的至少一种。其成盐的酸可选用无机酸或有机酸。所述无机酸包括盐酸、硫酸、磷酸,有机酸包括醋酸、甲酸、丙酸、乳酸、三氟乙酸、枸橼酸、富马酸、丙二酸、马来酸、酒石酸、门冬氨酸、苯甲酸、甲磺酸、苯磺酸、柠檬酸、苹果酸、草酸、琥珀酸、碳酸;优选盐酸、醋酸、富马酸、马来酸;更优选醋酸。
优选地,所述步骤1)中水难溶性聚合物包括聚酯、聚碳酸酯、聚缩醛、聚酐、聚羟基脂肪酸以及它们的共聚物、共混物中的至少一种。详细的,所述可生物降解和生物相容的聚合物为聚丙交酯(PLA)、聚乙交酯(PGA)、丙交酯-乙交酯共聚物(PLGA)及它们与聚己内酯(PCL)或聚乙二醇(PEG)的共聚物(如PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA、PEG-PCL、PCL-PLA-PCL、PCL-PLGA-PCL、PEG-PLA-PEG、PEG-PLGA-PEG)、聚己内酯及其与聚乙二醇的共聚物、聚羟基丁酸、聚羟基戊酸、聚对二氧环己酮(PPDO)、胶原蛋白、壳聚糖、海藻酸及其盐、聚氰基丙烯酸酯、纤维蛋白、聚酸酐、聚原酸酯、聚酰胺、聚磷腈、聚磷酸酯,以及它们的共聚物和/或混合物;优选PLA、PLGA以及它们与聚己内酯或聚乙二醇的共聚物,以及它们混合物;更优选PLA、PLGA或它们的混合物。
所述的PLA、PLGA及它们与PCL或PEG的共聚物的重均分子量为20000-130000Da,优选分子量为25000-110000Da,更优选分子量为30000-100000Da。本说明中所使用的重均分子量是通过凝胶渗透色谱(GPC)测量所获得的值。
或所述的PLA、PLGA及它们与PCL或PEG的共聚物的粘度(测试条件为~0.5%(w/v),CHCl3,25℃)为0.18-1.1dL/g,优选0.22-0.9dL/g,更优选0.27-0.85dL/g。
所述水难溶性聚合物的分子链都可以携带阴离子或阳离子基团,或者不携带这些基团。优选的,聚合物具有端羟基、端羧基或端酯基,更优选的具有端羧基的聚合物。
所述PLA、PLGA及它们与PCL或PEG的共聚物,其中丙交脂与乙交脂的比率从100:0到50:50,优选从大约90:10到50:50,更优选为85:15到50:50。
本发明中,制备缓释微粒的水难溶性聚合物可以为单一的聚合物,也可以为多种聚合物的混合物,如丙交脂与乙交脂的比率及分子量相同但携带基团不同的PLGA的组合、丙交脂与乙交脂的比率及携带基团相同但分子量不同的PLGA的组合、分子量及携带基团相同但丙交脂与乙交脂的比率不同的PLGA的组合、分子量、携带基团及丙交脂与乙交脂的比率均不同的PLGA的组合、PLGA与PLA的组合等。
优选地,所述步骤1)通过以下步骤实施:
11)将可生物降解和生物相容的水难溶性聚合物与水溶性药物完全溶解于有机溶剂A中,形成药物和聚合物的混合溶液;
12)将所述混合溶液注入有机溶剂B中或将有机溶液B注入所述混合溶液中,产生均匀、细微的沉淀物,收集沉淀物,并用有机溶剂B洗涤数次,去除有机溶剂B,获得水溶性药物和水难溶性聚合物的固体分散体;其中,有机溶剂B不能溶解所述水难溶性聚合物和所述水溶性药物。
所述步骤11)中有机溶剂A,能同时溶解水溶性药物和可生物降解、生物相容的水难溶性聚合物。优选地,所述有机溶剂A选自冰醋酸、乙腈、三氟乙酸、二甲基亚砜中的至少一种。更优选为冰醋酸或乙腈,最优选为冰醋酸。所述聚合物溶液中有机溶剂A的种类和比例根据不同药物有所不同,可根据实际情况调配。
所述步骤12)中有机溶剂B,同时不能溶解水溶性药物和可生物降解、生物相容的水难溶性聚合物。优选地,所述有机溶剂B选自无水乙醚、己烷、正庚烷中的至少一种。更优选为无水乙醚或己烷(包括环己烷、正己烷),最优选为无水乙醚。所述混合溶液中有机溶剂B的种类和比例根据不同药物和聚合物有所不同,可根据实际情况调配。
所述有机溶剂A控制为常温以下或低温,所述常温通常可以理解为20℃,优选10-15℃;所述低温通常可以理解为10℃以下,优选为4-6℃或以下;所述有机溶剂B控制为低温,所述低温通常可以理解为15℃以下,优选为10℃或以下,更优选为6℃以下;有机溶剂A比有机溶剂B的温度高0-10℃,优选3-8℃。
所述水不溶性聚合物于有机溶剂A中的浓度依据聚合物的类型、重均分子量以及有机溶剂的类型而变化。通常,其质量浓度(聚合物质量/有机溶剂质量*100%)为1-18%(w/w),优选为2-15%(w/w),更优选为3-12%(w/w)。
优选地,所述固体分散体中,水溶性药物与水难溶性聚合物的质量比为1:1~1:99。更优选地,所述固体分散体中,水溶性药物与水难溶性聚合物的质量比为2:3~3:97,更优选地,所述固体分散体中,水溶性药物与水难溶性聚合物的质量比为7:13~1:19。
优选地,所述去除有机溶剂B的步骤不含升温程序,该步骤在常温以下或低温下进行,所述常温通常可以理解为20-30℃,优选20-25℃;所述低温通常可以理解为15℃以下,优选为10℃及以下。去除有机溶剂B的方法包括但不限于真空干燥、冷冻干燥和流化干燥。
所述有机溶剂C,不能溶解水溶性药物,但可以溶解可生物降解和生物相容的水难溶性聚合物,沸点低于水且不溶于或难溶于水。所述有机溶剂C可为单一的有机溶剂,也可以为混溶的两种及以上的有机溶剂。所述有机溶剂C选自脂肪烃(分子结构为直链、支链或环状,例如正己烷、正庚烷、正戊烷、环己烷、石油醚等)、卤代烃(如二氯甲烷、氯仿、氯乙烷、四氯乙烯、三氯乙烯、二氯乙烷、三氯乙烷、四氯化碳、氟烃、氯代苯(单、双、三取代)、三氯氟甲烷等)、脂肪酸酯(如乙酸乙酯、乙酸丁酯等)、芳香烃(如苯、甲苯、二甲苯等)和醚(如二乙基醚、二异丙基醚、甲基异丁基醚、甲基叔丁基醚、甲氧基化醚、烷基醚、二卤代醚、三卤代醚、环醚、冠醚等)中的至少一种,优选卤代脂肪烃类溶剂,更优选二氯甲烷、氯仿。所述内油相中有机溶剂C的种类和比例根据不同药物和聚合物有所不同,根据实际情况调配。
所述沸点低于水且不溶于或难溶于水的有机溶剂是指只能够与水以<5%体积比混溶的有机溶剂,而且具有较低沸点(小于或远小于100℃),以便容易地通过例如冻干、蒸发或鼓风来除去。
水难溶性聚合物于有机溶剂C中的浓度依据聚合物的类型、重均分子量以及有机溶剂的类型而变化;通常,其质量浓度(聚合物质量/有机溶剂质量*100%)为约1-18%(w/w),优选为约2-15%(w/w),更优选为约3-12%(w/w)。
所述内油相为较低温度,所述较低温度可以理解为20℃或以下,优选15℃或以下,更优选10℃或以下。
所述步骤3)中含有表面活性剂(或稳定剂)的水溶液(外水相)为低温,所述低温可以理解为12℃或以下,优选9℃或以下,更优选6℃或以下。
优选地,所述步骤3)中表面活性剂(或稳定剂)为阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子性表面活性剂和表面活性生物分子中的至少一种;优选地,所述步骤3)中表面活性剂为阴离子表面活性剂、非离子性表面活性剂和表面活性生物分子中的至少一种;更优选地,所述步骤3)中表面活性剂为非离子性表面活性剂和表面活性生物分子中的至少一种。所述表面活性剂可以增加有机相的湿润性质、提高乳化过程中小液珠的稳定性及形状,避免小液珠重新聚合、减少未包封的或部分包封的小球颗粒的数量,从而避免微粒在释放过程中的初始突释。
所述阳离子表面活性剂包括但不限于季铵化合物如苯扎氯铵、溴化十六烷基三甲基铵、月桂酸基二甲基苯甲基氯铵、酰基肉毒碱盐酸盐或烷基吡啶卤化物。
所述阴离子表面活性剂包括但不限于十二烷基硫酸钠、十二烷基硫酸铵、十八烷基硫酸钠等烷基硫酸盐、月桂酸钾、藻酸钠、聚丙烯酸钠及其衍生物、烷基聚环氧乙烯硫酸酯、丁二酸二辛基磺酸钠、羧甲基纤维素钠、油酸钠、硬脂酸钠、胆酸和其它胆汁酸(如胆酸、脱氧胆酸、甘氨胆酸、牛磺胆酸、甘氨脱氧胆酸)的钠盐。
所述非离子性表面活性剂包括但不限于聚氧乙烯脂肪醇醚(苄泽)、聚山梨酸酯(如吐温80、吐温60)、聚氧乙烯脂肪酸酯(OEO)、聚氧乙烯蓖麻油衍生物、聚氧乙烯聚丙二醇共聚物、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯、聚氧乙烯山梨糖醇酐单脂肪酸酯、聚氧乙烯山梨糖醇酐二脂肪酸酯、聚氧乙烯甘油单脂肪酸酯、聚氧乙烯甘油二脂肪酸酯、聚甘油脂肪酸酯、聚丙二醇单酯、芳基烧基聚醚醇、聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆)、聚乙烯醇(PVA)及其衍生物、聚乙烯比咯烷酮(PVP)和多糖,优选泊洛沙姆、聚乙烯醇、聚山梨酸酯、聚乙烯比咯烷酮和多糖,更优选聚乙烯醇、多糖。
所述多糖包括但不限于淀粉和淀粉衍生物、甲基纤维素、乙基纤维素、羟基纤维素、羟丙基纤维素、羟丙甲基纤维素、阿拉伯胶、壳聚糖衍生物、结冷胶、藻酸衍生物、葡聚糖衍生物和非晶态纤维素,优选羟丙甲纤维素、壳聚糖及其衍生物、支链淀粉或葡聚糖及其衍生物。
表面活性生物分子包括但不限于聚氨基酸(如聚天冬氨酸或聚谷氨酸或它们的类似物)、肽(如碱性肽)、蛋白质(如明胶、酪蛋白、白蛋白、水蛭素、淀粉羟乙基酶等,优选的蛋白是白蛋白)。
所述表面活性剂(或稳定剂)在外水相中的质量百分比浓度一般在0.1-20%,优选为0.5-15%,更优选1-10%。
进一步的,所述含有表面活性剂的水溶液中还可含有无机盐,以降低微粒固化过程中水溶性活性物质溶渗至外水相中,其机理为提高外相的渗透压或降低活性物质在外相中的溶解度。对于多肽、蛋白、核酸、抗体、抗原、抗生素等活性物质,含锌离子的化合物是比较理想的选择,包括且不限于醋酸锌、氯化锌、硫酸锌、硫酸氢锌、硝酸锌、葡萄糖酸锌、碳酸锌或它们的任意混合物,其于水溶液中的重量百分比浓度为:0-5%,优选0.05-4%,更优选0.05-3%
外水相的盐度也可以被用来降低两相的溶混性,主要是降低内油相中的有机溶剂在外水相中的溶解度。适合的盐包括但不限于水溶性的磷酸、硫酸、乙酸、碳酸的钾盐或钠盐、Tris、MES、HEPES。在使用盐的实施方案中,所述盐的浓度为0.01-10M,更优选从0.01M-5M,更优选从0.05-2M。pH范围为3-9,优选4-8,更优选5.5-7.5。
外水相的使用量,通常为内油相的约50倍体积以上,优选为约70倍体积以上,且特别优选为约100倍体积以上。
所述形成均匀的乳液的方法与众所周知的乳化方法相同,采用产生高剪切力的装置(如磁力搅拌器、机械搅拌器、高速均质机、超声仪、膜乳化器、转子-定子混合器、静态混合器、高压均质机等)将内油相与外水相混合,以形成均匀乳液。
所述步骤4)中溶剂除去可以应用下述方法:
(A)通过加热、减压(或联合加热)除去有机溶剂;
(B)气流鼓吹液体表面,并控制液相与气相的接触面积、乳液搅拌和循环的速率(如JP-A-9-221418)加速有机溶剂的挥发,所述气流优选干燥的氮气;
(C)用空心纤维薄膜快速除去有机溶剂(如W00183594),空心纤维薄膜优选硅橡胶全蒸发薄膜,特别是由聚二甲基硅氧烷制备的全蒸发薄膜。
所述步骤4)中通过离心、过筛或过滤的方式收集微粒。
所述步骤4)中洗涤微粒所用的超纯水温度为低温,所述低温可以理解为12℃或以下,优选9℃或以下,更优选6℃或以下。
所述步骤4)中洗涤所用的超纯水中还可含有外水相中所述的无机盐(如锌盐),以减少洗涤过程中水溶性活性物质溶渗至水相,提高药物包封率。超纯水中无机盐的质量浓度为0.01-3%,优选0.01-1.5%,更优选0.01-1%。
进一步地,所述方法还包括加入助剂的步骤,助剂在所述步骤1)制备固体分散体的过程中加入,或在所述步骤2)制备固体分散体乳液时加入。优选在所述步骤1)制备固体分散体的过程中加入。所述助剂溶解或混悬于内油相中。所述助剂加入时可为极细微的粉末,其粒径小于0.5μm,优选为粒径小于0.1μm,更优选粒径小于0.05μm。
所述助剂可以赋予活性药物或微粒其它的特征,例如增加微粒、活性药物或聚合物的稳定性,促进活性药物从微粒中的可控释放,或调节活性药物的生物学组织渗透性。所述助剂为所述水溶性药物与所述水难溶性聚合物的质量之和的0.01-10%,优选0.1-8%,更优选0.5-8%。
本发明所述助剂包括但不限于糖类、氨基酸、脂肪酸、醇类、抗氧化剂和缓冲剂中的至少一种。
所述缓冲剂包括但不限于无机酸或有机酸的盐,如碳酸、乙酸、草酸、柠檬酸、磷酸、盐酸的盐。具体的,包括但不限于碳酸钙、氢氧化钙、肉豆蘧酸钙、油酸钙、棕榈酸钙、硬脂酸钙、磷酸钙、醋酸钙、醋酸镁、碳酸镁、氢氧化镁、磷酸镁、肉豆蔻酸镁、油酸镁、棕榈酸镁、硬脂酸镁、碳酸锌、氢氧化锌、氧化锌、肉豆蘧酸锌、油酸锌、醋酸锌、氯化锌、硫酸锌、硫酸氢锌、硝酸锌、葡萄糖酸锌、棕榈酸锌、硬脂酸锌、磷酸锌、碳酸钠、碳酸氢钠、亚硫酸氢钠、硫代硫酸钠、醋酸-醋酸钠缓冲盐,及它们的任意组合。优选无机酸或有机酸的锌盐,更优选氯化锌。所述缓冲剂为所述水溶性药物与所述水难溶性聚合物的质量之和的0-5%,优选0.01-3%,更优选0.01-2%。
所述抗氧化剂包括但不限于叔丁基对羟基茴香醚、二丁基苯酚、生育酚、肉豆蘧酸异丙酯、d-a乙酸生育酚、抗坏血酸、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、丁基化羟基醌、羟基香豆素、丁基化羟基甲苯、掊酸脂肪酸酯(如乙酯、丙酯、辛酯、月桂酯)、丙羟基苯甲酸酯、三羟基苯丁酮、维生素E、维生素E-TPGS、ρ-羟基苯甲酸酯(如甲酯、乙酯、丙酯、丁酯),或它们的任意组合。抗氧化剂可以有效地去除缓释微粒中的自由基或过氧化物。所述抗氧化剂为所述水溶性药物与所述水难溶性聚合物的质量之和的0-1%,优选0-0.05%,更优选0-0.01%。
所述糖类包括但不限于单糖、寡糖和多糖,以及它们的衍生物。具体的,包括但不限于海藻糖、葡萄糖、蔗糖、甘油、赤藓醇、阿糖醇、,木糖醇、山梨醇、甘露糖醇、葡萄糖醛酸、艾杜糖醛酸、神经氨糖酸、半乳糖醛酸、葡萄糖酮酸、甘露糖醛酸、透明质酸及其盐、硫酸软骨素及其盐、肝素、菊粉、几丁质及其衍生物、糊精、葡聚糖和海藻酸及其盐,或它们的任意组合。优选蔗糖、甘露糖醇、木糖醇,或它们的任意组合。所述糖类为所述水溶性药物与所述水难溶性聚合物的质量之和的0.1-10%,优选0.5-8%,更优选1-6%。
所述氨基酸包括但不限于甘氨酸、丙氨酸、丝氨酸、天冬氨酸、谷氨酸、苏氨酸、色氨酸、赖氨酸、羟赖氨酸、组氨酸、精氨酸、胱氨酸、半胱氨酸、甲硫氨酸、苯丙氨酸、亮氨酸、异亮氨酸以及它们的衍生物,优选碱性氨基酸,包括但不限于精氨酸、组氨酸、赖氨酸,或它们的任意组合。所述氨基酸类为所述水溶性药物与所述水难溶性聚合物的质量之和的0-4%,优选0-2%,更优选0.01-1%。
所述脂肪酸包括12~24烷酸及其衍生物,包括但不限于油酸、硬脂酸、月桂酸、肉豆蔻酸、棕榈酸、花生酸、山俞酸、木质素酸,优选硬脂酸、山俞酸、棕榈酸,或它们的任意组合。所述脂肪酸为所述水溶性药物与所述水难溶性聚合物的质量之和的0-5%,优选0.01-4%,更优选0.05-3%。
所述醇类包括但不限于聚乙二醇。所述聚乙二醇的分子量为400-6000Da,优选为400-4000Da,更优选为400-2000Da。所述醇类为所述水溶性药物与所述水难溶性聚合物的质量之和的0-5%,优选0.01-4%,更优选0.05-3%。
注射用的制剂要求无菌,具体的灭菌方法属于本领域技术人员的一般知识和技术,如采用无菌操作、热压、环氧乙烷或者伽马射线保证制剂无菌。本发明制备缓释微粒优选无菌操作,如用醋酸纤维素膜过滤外相水溶液、用聚醚砜膜过滤PLGA的乙酸溶液、用聚四氟乙烯膜过滤二氯甲烷,且全部设备是容易密闭的并配备有机溶剂回收装置,以防止细菌的污染以及有机溶剂扩散到空气中。
因为微粒用于注射给药时,粒径太大容易导致堵针,必须用更大号的注射针头,患者的疼痛感更强,而粒径太小将导致共聚物无法很好的包裹药物,达不到良好的缓释效果。本发明提供了一种缓释微粒,所述缓释微粒是采用上述所述的缓释微粒的制备方法制得的。本发明制备的缓释微粒优选具有小于200μm的粒径大小。所述缓释微粒的粒径为10-200μm,优选10-150μm,更优选20-150μm。缓释微粒粒径大小通过动态光散射方法(例如激光衍射法)、或显微技术(如扫描电镜法)来测量。
本发明的缓释微粒体可以包封大量的活性成分,剂量可依据活性成分的类型与含量、剂型、释放持续时间、给药受试者、给药途径、给药目的、靶标疾病及症状等而适当地选择。然而,只要活性成分可于活体内维持在药物有效浓度达预期的持续时间,则该剂量可认为是令人满意的。
本发明的缓释微粒中,活性剂质量含量百分比大约为1-40%,优选3-35%,更优选5-30%
在本文中当陈述范围时,意味着包含了其中的任何范围或范围的组合。
当缓释微粒以混悬剂形式给药时,其可与适当的分散介质制成混悬液制剂。
所述分散介质包括非离子表面活性剂、聚氧乙烯蓖麻油衍生物、纤维素增稠剂、海藻酸钠、透明质酸、糊精、淀粉中的至少一种。或可选择的,还可以与其他组分如等渗剂(如氯化钠、甘露醇、甘油、山梨醇、乳糖、木糖醇、麦芽糖、半乳糖、蔗糖、葡萄糖等)、pH调节剂(例如碳酸、醋酸、草酸、柠檬酸、磷酸、盐酸或这些酸的盐,例如碳酸钠、碳酸氢钠等)、防腐剂(例如对羟基苯甲酸酯、对羟基苯甲酸丙酯、苯甲醇、氯代丁醇、山梨酸、硼酸等)等结合制成水性溶液,或者后续通过冷冻干燥、减压干燥、喷雾干燥等方法固化,使用前再将固化物溶解于注射用水中获得分散缓释微粒的分散介质。
此外,缓释注射剂也可通过下述方法获得:将缓释微粒分散于植物油(诸如芝麻油及玉米油)或添加有磷脂(诸如卵磷脂)的植物油中,或者分散于中链甘油三酯中,以获得油性混悬液。
本发明制备的水溶性药物缓释组合物,特别是蛋白、核酸以及肽类药物的缓释组合物还可以为棒状物、片状物,其制备方法主要包括以下两个步骤:
I、制备水溶性药物与可生物降解和生物相容的聚合物的固体分散体;
II、将上述制备的固体混合物通过加热后采用模压成型、挤出成型等专业技术人员所熟知的方法成型,冷却制得棒状、片状的緩释组合物。
进一步地,本发明的制备水溶性药物,特别是蛋白、核酸以及肽类药物的缓释组合物为棒状、片状的植入剂,其制备方法主要为:按照上述制备缓释微粒的方法制备缓释微粒,然后将微粒通过专业技术人员所熟知的成型方法制得棒状物或片状物。
本发明获得的缓释微粒可用于颗粒剂形式、悬浮剂形式、埋植形式的制剂、注射剂形式、粘附制剂形式等等,并可以口服或非胃肠道给药(肌内注射、皮下注射、经皮给药、粘膜给药(颊内、阴道内、直肠内等))。
本发明的植入剂以可生物降解材料为基质,外观呈细棒状、圆棒状或片状(圆盘状),可通过注射或手术方式植入到体内,药物释放完全后无需手术取出。该植入剂的优点是容易获得高包封率和载药率,突释率低,并能够持续释放治疗所需剂量的活性药物达一个月至数月之久,大大降低医疗成本,提高病患的依从性。
本发明的有益效果:本发明中,缓释微粒的制备全程常温或低温,对于高温敏感的药物,特别是蛋白、核酸及肽类药物制备聚合物基质的组合物非常有利,相比已公开的技术,能够最大程度上在整个工艺过程中保持活性物质的生物活性;同时,所制备的缓释微粒具有接近零级的优异缓释效果,药物浓度在释放期间稳定,解决了传统的要预先制备药物微小颗粒的S/O/W工艺得到的缓释微粒前期没有药物释放,而后期药物释快速释放的缺点;再者,缓释微粒具有较高的载药率和药物包封率。
本发明的缓释微粒在给药后,蛋白、肽、核酸、生物碱等活性物质能够在体内持续输送一段时间,释放周期长达几周或几个月。
附图说明
图1为实施例6-11制备的艾塞那肽缓释微粒或利拉鲁肽缓释微粒给药的糖尿病模型小鼠的平均HbA1c值-时间曲线图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。
实施例1:阿必鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.90g PLGA(分子量25kDa,单体比例65/35,端羧基)溶于约6.00mL冰乙酸中,然后加入0.10g醋酸阿必鲁肽,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约6.00g二氯甲烷中获得内油相,接着将内油相注入230mL已预先恒温至约4℃的1%(w/w)聚乙烯醇水溶液中,并使用高速均质机制备S/O/W乳液(转子速度约3000rpm,5min)。将S/O/W乳液继续机械搅拌约3小时(400rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中阿必鲁肽的含量为9.19%,微粒粒径为16-53μm。
实施例2:杜拉鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.95g PLGA(分子量30kDa,单体比例50/50,端羧基)溶于约7.92mL冰乙酸中,然后加入0.05g醋酸杜拉鲁肽,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约7.92g二氯甲烷中获得内油相,接着将内油相注入420mL已预先恒温至约4℃的1.5%(w/w)聚乙烯醇水溶液中,并使用高速均质机制备S/O/W乳液(转子速度约3000rpm,5min)。将S/O/W乳液继续机械搅拌约3小时(400rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中杜拉鲁肽的含量为4.64%,微粒粒径为28-100μm。
实施例3:促卵泡生成素/PLA微粒的制备
(I)固体分散体的制备
将0.97g PLA(分子量20kDa,端酯基)溶于约5.39mL冰乙酸/乙腈混合液中,然后加入0.03g醋酸促卵泡生成素、0.05g木糖醇和0.03g氯化锌,涡旋下溶解,然后搅拌下慢慢注入环己烷(8℃),产生白色沉淀物,收集白色沉淀物并用环己烷取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约5.39g氯仿中获得内油相,接着将内油相注入400mL已预先恒温至约6℃的0.5%(w/w)羟丙甲纤维素水溶液中,并使用润轮式均匀混合器乳化制备S/O/W乳液(润转速度约5500rpm,5min)。将S/O/W乳液转移至密封玻璃烧瓶中继续机械搅拌约3小时(400rpm)固化微粒,然后使用离心机通过离心(约2500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中促卵泡生成素的含量为2.77%,微粒粒径为35-94μm。
实施例4:利西拉来/PLGA微粒的制备
(I)固体分散体的制备
将0.99g PLGA(分子量22kDa,单体比例90/10,端羧基)溶于约5.50mL三氟乙酸中,然后加入0.01g醋酸利西拉来、0.05g木糖醇和0.05g氯化锌,涡旋下溶解,然后慢慢注入搅拌下的正己烷(6℃)中,产生白色沉淀物,收集白色沉淀物并用正己烷萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约5.50g二氯甲烷中获得内油相,接着将内油相注入330mL已预先恒温至约4℃的0.1%(w/w)白蛋白水溶液中,并使用SPG膜乳化器制备S/O/W乳液(膜孔径20-50μm,循环3次)。将S/O/W乳液继续机械搅拌约3.5小时(500rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中利西拉来的含量为0.93%,微粒粒径为32-95μm。
实施例5:促肾上腺皮质激素释放激素/PLGA微粒的制备
(I)固体分散体的制备
将0.85g PLGA(分子量25kDa,单体比例85/15,端羧基)溶于约8.50mL二甲基亚砜中,然后加入0.15g醋酸促肾上腺皮质激素释放激素,涡旋下溶解,然后慢慢注入搅拌下的正庚烷(6℃)中,产生白色沉淀物,收集白色沉淀物并用正庚烷萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约8.50g苯中获得内油相,接着将内油相注入580mL已预先恒温至约4℃的1.5%(w/w)泊洛沙姆水溶液中,并使用静态混合器制备S/O/W乳液(转速5000rpm,循环3次)。将S/O/W乳液转移至密封玻璃烧瓶中继续机械搅拌约3.5小时(500rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中生长抑素的含量为13.81%,微粒粒径为39-107μm。
实施例6:艾塞那肽/PLGA微粒的制备
(I)固体分散体的制备
将0.95g PLGA(分子量35kDa,单体比例75/25,端羧基)溶于约6.33mL冰乙酸中,然后加入0.05g醋酸艾塞那肽和0.08g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约6.33g二氯甲烷中获得内油相,接着将内油相注入430mL已预先恒温至约4℃的2%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(500rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(350rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中艾塞那肽的含量为4.64%,微粒粒径为30-105μm。
实施例7:利拉鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.93g PLGA(分子量40kDa,单体比例65/35,端羧基)溶于约7.75mL冰乙酸中,然后加入0.07g醋酸利拉鲁肽和0.06g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约7.75g甲苯中获得内油相,接着将内油相注入470mL已预先恒温至约4℃的3%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(600rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(400rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中利拉鲁肽的含量为6.43%,微粒粒径为32-117μm。
实施例8:艾塞那肽/PLGA微粒的制备
(I)固体分散体的制备
将0.90g PLGA(分子量45kDa,单体比例50/50,端羧基)溶于约9.00mL冰乙酸中,然后加入0.10g醋酸艾塞那肽和0.04g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约9.00g二氯甲烷中获得内油相,接着将内油相注入680mL已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1000rpm,7min)。将S/O/W乳液继续机械搅拌约4小时(500rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中艾塞那肽的含量为9.15%,微粒粒径为24-99μm。
实施例9:利拉鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.86g PLGA(分子量50kDa,单体比例50/50,端羧基)溶于约10.75mL冰乙酸中,然后加入0.14g醋酸利拉鲁肽和0.02g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约10.75g二氯甲烷中获得内油相,接着将内油相注入970mL已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1500rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中利拉鲁肽的含量为12.85%,微粒粒径为30-108μm。
实施例10:艾塞那肽/PLGA微粒的制备
(I)固体分散体的制备
将0.82g PLGA(分子量55kDa,单体比例50/50,端羧基)溶于约11.71mL冰乙酸中,然后加入0.18g醋酸艾塞那肽和0.01g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约11.71g二氯甲烷中获得内油相,接着将内油相注入700mL已预先恒温至约4℃的5%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1000rpm,5min)。将S/O/W乳液继续机械搅拌约5小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中艾塞那肽的含量为16.97%,微粒粒径为19-86μm。
实施例11:利拉鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.80g PLGA(分子量60kDa,单体比例50/50,端羧基)溶于约13.33mL冰乙酸中,然后加入0.20g醋酸利拉鲁肽,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约13.33g二氯甲烷中获得内油相,接着将内油相注入900mL已预先恒温至约4℃的6%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1600rpm,5min)。将S/O/W乳液继续机械搅拌约5小时(700rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中利拉鲁肽的含量为18.79%,微粒粒径为17-92μm。
实施例12:恩夫韦地/PLGA微粒的制备
(I)固体分散体的制备
将0.75g PLGA(分子量65kDa,单体比例65/35,端羧基)溶于约15.00mL冰乙酸中,然后加入0.25g醋酸恩夫韦地、0.03g蔗糖和0.01g硬脂酸,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约15.00g二氯甲烷中获得内油相,接着将内油相注入1.1L已预先恒温至约4℃的5%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1500rpm,5min)。将S/O/W乳液继续机械搅拌约5小时(450rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中恩夫韦地的含量为23.24%,微粒粒径为19-89μm。
实施例13:普兰林肽/PLGA微粒的制备
(I)固体分散体的制备
将0.70g PLGA(分子量70kDa,单体比例50/50,端羧基)溶于约17.50mL冰乙酸中,然后加入0.30g醋酸普兰林肽和0.02g甘露醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约17.50g二氯甲烷中获得内油相,接着将内油相注入1.3L已预先恒温至约4℃的6%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1600rpm,5min)。将S/O/W乳液继续机械搅拌约5小时(600rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中普兰林肽的含量为27.75%,微粒粒径为15-88μm。
实施例14:特立帕肽/PLGA微粒的制备
(I)固体分散体的制备
将0.65g PLGA(分子量85kDa,单体比例50/50,端羧基)溶于约21.6702mL冰乙酸中,然后加入0.35g醋酸特立帕肽、0.03g甘露醇和0.03gPEG-400,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约21.67g二氯甲烷中获得内油相,接着将内油相注入1.6L已预先恒温至约4℃的8%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1800rpm,5min)。将S/O/W乳液继续机械搅拌约5小时(700rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中特立帕肽的含量为31.73%,微粒粒径为26-104μm。
实施例15:利拉鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.60g PLGA(分子量100kDa,单体比例50/50,端羧基)溶于约30.00mL冰乙酸中,然后加入0.40g醋酸利拉鲁肽和0.005g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约30.00g二氯甲烷中获得内油相,接着将内油相注入2L已预先恒温至约4℃的10%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1900rpm,5min)。将S/O/W乳液继续机械搅拌约5小时(700rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中利拉鲁肽的含量为36.43%,微粒粒径为21-103μm。
实施例16:索玛鲁肽/PLGA微粒的制备
(I)固体分散体的制备
将0.55g PLGA(分子量110kDa,单体比例50/50,端羧基)溶于约55.00mL冰乙酸中,然后加入0.45g醋酸索玛鲁肽和0.005g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约55.00g二氯甲烷中获得内油相,接着将内油相注入3L已预先恒温至约4℃的15%(w/w)聚乙烯醇水溶液中,并使用SPG膜乳化器制备S/O/W乳液(膜孔径20-50μm,循环3次)。将S/O/W乳液继续机械搅拌约5小时(600rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中索玛鲁肽的含量为44.84%,微粒粒径为36-92μm。
实施例17:胰高血糖素样肽-1/PLGA微粒的制备
(I)固体分散体的制备
将0.50g PLGA(分子量130kDa,单体比例50/50,端羧基)溶于约50.00mL冰乙酸中,然后加入0.48g醋酸胰高血糖素样肽-1和0.05g木糖醇粉末,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约50.00g二氯甲烷中获得内油相,接着将内油相注入3L已预先恒温至约4℃的20%(w/w)聚乙烯醇水溶液中,并使用润轮式均匀混合器乳化制备S/O/W乳液(润转速度约7000rpm,5min)。将S/O/W乳液转移至密封玻璃烧瓶中继续机械搅拌约5小时(800rpm)固化微粒,然后使用离心机通过离心(约4000rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中胰高血糖素样肽-1的含量为44.03%,微粒粒径为27-109μm。
实施例18:Exendin-4衍生物/PLGA微粒的制备
(I)固体分散体的制备
固体分散体含有以下质量百分含量的成分:水溶性药物:Exendin-4衍生物20%、水难溶性聚合物:PLGA79.5%、助剂:木糖醇0.5%;其中所述PLGA的分子量为50kDa,其中丙交酯和乙交酯的比例为50/50,且所述PLGA具有端羧基。
(1)制备Exendin-4衍生物:制备10kDa PEG-NHS酯,然后在PBS缓冲液中与Exendin-4中28位的天冬酰胺反应,通过离子交换、凝胶色谱分离纯化,浓缩并冷冻干燥获得Exendin-4衍生物。
(2)将水难溶性聚合物完全溶解于冰乙酸中,然后再加入水溶性药物和助剂至完全溶解;其中水难溶性聚合物为冰乙酸的质量的6.5%;然后注入无水乙醚(6℃)使得产生白色沉淀物,收集沉淀物,并用无水乙醚萃取5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约12倍的二氯甲烷中获得内油相,接着将内油相注入970mL已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1200rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中Exendin-4衍生物的含量为17.95%,微粒粒径为29-128μm。
实施例19:Exendin-4衍生物/PLGA微粒的制备
(I)固体分散体的制备
固体分散体含有以下质量百分含量的成分:水溶性药物:Exendin-4衍生物15%、水难溶性聚合物:PLGA84%、助剂:木糖醇1%;其中所述PLGA的分子量为50kDa,其中丙交酯和乙交酯的比例为50/50,且所述PLGA具有端羧基。
(1)制备Exendin-4衍生物:通过固相多肽合成方法制备Exendin-4中28位的天冬酰胺替换为半胱氨酸的Exendin-4变体,然后在PBS缓冲液中与10kDa Y型单甲氧基聚乙二醇-马来酰亚胺反应,通过离子交换、凝胶色谱分离纯化,浓缩并冷冻干燥获得Exendin-4衍生物。
(2)将水难溶性聚合物完全溶解于冰乙酸中,然后再加入水溶性药物和助剂至完全溶解;其中水难溶性聚合物为冰乙酸的质量的6.5%;然后注入无水乙醚(6℃)使得产生白色沉淀物,收集沉淀物,并用无水乙醚萃取5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约13倍的二氯甲烷中获得内油相,接着将内油相注入1L已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1200rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中Exendin-4衍生物的含量为12.25%,微粒粒径为31-114μm。
实施例20:Exendin-4衍生物/PLGA微粒的制备
(I)固体分散体的制备
固体分散体含有以下质量百分含量的成分:水溶性药物:Exendin-4衍生物20%、水难溶性聚合物:PLGA78%、助剂:山梨醇2%;其中所述PLGA的分子量为55kDa,其中丙交酯和乙交酯的比例为50/50,且所述PLGA具有端羧基。
(1)制备Exendin-4衍生物:通过固相多肽合成方法制备Exendin-4中20位的精氨酸替换为半胱氨酸的Exendin-4变体,然后在PBS缓冲液中与5kDa单甲氧基聚乙二醇-马来酰亚胺反应,通过离子交换、凝胶色谱分离纯化,浓缩并冷冻干燥获得Exendin-4衍生物。
(2)将水难溶性聚合物完全溶解于冰乙酸中,然后再加入水溶性药物和助剂至完全溶解;其中水难溶性聚合物为冰乙酸的质量的6%;然后注入无水乙醚(6℃)使得产生白色沉淀物,收集沉淀物,并用无水乙醚萃取5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约14倍的二氯甲烷中获得内油相,接着将内油相注入1L已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1300rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中Exendin-4衍生物的含量为18.10%,微粒粒径为28-116μm。
实施例21:Exendin-4衍生物/PLGA微粒的制备
(I)固体分散体的制备
固体分散体含有以下质量百分含量的成分:水溶性药物:Exendin-4衍生物16%、水难溶性聚合物:PLGA81%、助剂:木糖醇3%;其中所述PLGA的分子量为45kDa,其中丙交酯和乙交酯的比例为50/50,且所述PLGA具有端羧基。
(1)制备Exendin-4衍生物:通过固相多肽合成方法制备Exendin-4中14位的甲硫氨酸替换为半胱氨酸的Exendin-4变体,然后在PBS缓冲液中与20kDa单甲氧基聚乙二醇-马来酰亚胺反应,通过离子交换、凝胶色谱分离纯化,浓缩并冷冻干燥获得Exendin-4衍生物。
(2)将水难溶性聚合物完全溶解于冰乙酸中,然后再加入水溶性药物和助剂至完全溶解;其中水难溶性聚合物为冰乙酸的质量的7%;然后注入无水乙醚(6℃)使得产生白色沉淀物,收集沉淀物,并用无水乙醚萃取5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约11倍的二氯甲烷中获得内油相,接着将内油相注入800mL已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1500rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中Exendin-4衍生物的含量为13.78%,微粒粒径为35-133μm。
实施例22:Exendin-4衍生物/PLGA微粒的制备
(I)固体分散体的制备
固体分散体含有以下质量百分含量的成分:水溶性药物:Exendin-4衍生物12%、水难溶性聚合物:PLGA84%、助剂:木糖醇4%;其中所述PLGA的分子量为40kDa,其中丙交酯和乙交酯的比例为50/50,且所述PLGA具有端羧基。
(1)制备Exendin-4衍生物:通过固相多肽合成方法制备Exendin-4中2位的甘氨酸替换为半胱氨酸的Exendin-4变体,然后在PBS缓冲液中与40kDa单甲氧基聚乙二醇-马来酰亚胺反应,通过离子交换、凝胶色谱分离纯化,浓缩并冷冻干燥获得Exendin-4衍生物。
(2)将水难溶性聚合物完全溶解于冰乙酸中,然后再加入水溶性药物和助剂至完全溶解;其中水难溶性聚合物为冰乙酸的质量的6%;然后注入无水乙醚(6℃)使得产生白色沉淀物,收集沉淀物,并用无水乙醚萃取5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约10倍质量的二氯甲烷中获得内油相,接着将内油相注入850mL已预先恒温至约4℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1500rpm,5min)。将S/O/W乳液继续机械搅拌约4小时(600rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。将微粒再次分散于超纯水(5℃)中洗涤2min,然后离心收集,重复洗涤步骤约5次,然后以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中Exendin-4衍生物的含量为10.82%,微粒粒径为33-126μm。
实施例23:Mipomersen/PLGA微粒的制备
(I)固体分散体的制备
将0.80g PLGA(分子量30kDa,单体比例50/50,端羧基)溶于约6.53mL冰乙酸和乙腈的混合液中,然后加入0.20g Mipomersen sodium和0.01g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用正己烷萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约6.53g四氯乙烯中获得内油相,接着将内油相注500mL已预先恒温至约6℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1000rpm,5min)。将S/O/W乳液继续机械搅拌约3.5小时(500rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。用环己烷将微粒洗涤约5次后,再次分散于超纯水(5℃)中洗涤约2次,然后离心收集,以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中Mipomersen的含量为18.00%,微粒粒径为30-114μm。
实施例24:白介素/PLGA微粒的制备
(I)固体分散体的制备
将0.82g PLGA(分子量35kDa,单体比例50/50,端羧基)溶于约6.12mL冰乙酸中,然后加入0.18g白介素和0.02g木糖醇,涡旋下溶解,然后慢慢注入搅拌下的无水乙醚(6℃)中,产生白色沉淀物,收集白色沉淀物并用无水乙醚萃取约5次,将沉淀物收集后于真空干燥箱中干燥24h(10℃),得固体分散体。
(II)微粒的制备
将步骤I所得的固体分散体分均匀散于约6.12g二氯甲烷与氯仿的混合液中获得内油相,接着将内油相注入500mL已预先恒温至约5℃的4%(w/w)聚乙烯醇水溶液中,并通过机械搅拌制备S/O/W乳液(1000rpm,5min)。将S/O/W乳液转移至密封玻璃烧瓶中继续机械搅拌约4小时(500rpm)固化微粒,然后使用离心机通过离心(约3500rpm,5min)收集微粒。用正庚烷和正己烷的混合液将微粒洗涤约5次后,再次分散于超纯水(5℃)中洗涤约2次,然后离心收集,以冷冻干燥机冷冻干燥,获得微粒。测得所得微粒中白介素的含量为16.02%,微粒粒径为29-117μm。
实施例25:利拉鲁肽/PLGA缓释植入剂的制备
将实施例11的步骤I制备的干燥的固体分散体进料到热熔挤出机中,热熔挤出成直径约1mm的条状物,冷却后切割得到长度约为5mm的柱状利拉鲁肽缓释植入剂。测得所得植入剂中利拉鲁肽的含量为18.84%。
实施例26:利拉鲁肽/PLGA缓释植入剂的制备
将实施例11的步骤II中所得微粒填入1mm*10mm的模具(内腔为圆柱状,圆底直径为1mm,深度约为10mm)中,升温至约43℃后,模压成型,得到柱状(1mm*5.01mm)利拉鲁肽缓释植入剂。测得所得植入剂中利拉鲁肽的含量为18.76%。
实施例27
上述实施例中微粒或植入剂的载药率和药物包封率分析方法为:取5mg微粒或植入剂,溶于50mL乙腈(ACN)中,再加入0.1%TFA 500μL,充分混合后,离心取上清液,用高效液相色谱分析其中的药物浓度。微粒(或植入剂)中包封的药物质量与投药量的比值即为药物的包封率,微粒(或植入剂)包封的药物质量与微粒(或植入剂)质量的比值即为药物的载药率。所有的实验均重复3次以上。
上述实施例1-24中微粒的粒径分析方法为:将约10mg微粒分散在液体石蜡中,超声约30s分散,使用Beckman Coulter的激光粒度分析仪进行测量。
实施例28:微粒及植入剂的突释和体外释放曲线的测定
将上述实施例1-26制备的缓释微粒及植入剂进行突释和体外释放曲线的测定,测定方法是:精密称取含药微粒或植入剂20mg置于15mL离心管中,以pH为7.4的磷酸缓冲液(含0.02%叠氮化钠作为抑菌剂)为释放介质,置于恒温气浴摇床中,在振荡速度100rpm、温度37℃±0.5℃条件下进行微粒及植入剂的体外释放度测定。分别在l天、2天、7天、14天、21天、28天、40天、50天和60天取出全部释放介质并补充等量的新释放介质,高效液相色谱法测定药物释放量,测定方法为:
液相色谱仪:安捷伦1260;
色谱柱:Proteonavi 4.6×250mm;
流动相:水-乙腈(含0.1%三氟乙酸),梯度洗脱;
流速:1mL/min;
检测波长:280nm。
测试结果如表1所示。
表1缓释微粒及植入剂体外释放累计释放度结果
由表1的体外释放结果可以看出,采用本发明所述固体分散体制备得到的缓释微粒及所制得的植入剂,没有突释现象或明显的迟释现象,整个释放趋势接近零级释放。其中,有的样品体外释放周期长达40-50天,有的样品体外释放周期长达50-60天,有的样品体外释放周期超过60天,具有优异的缓释效果。
实施例29:微粒通针性实验
将约20mg微粒样品混悬于2mL稀释剂(3%羧甲基纤维素、0.9%NaCl)中,然后吸入注射器,分别通过24-30G的注射针头注入市售的1kg重的猪后腿(肌肉)中。每次注射进行20秒或以下,观察通针性,结果如表2所示。
表2微粒通针性实验结果
注:++推针顺畅性很好,+推针顺畅性一般,-推针有阻滞感,--堵针。
表2的通针性结果表明,本发明制备的不同粒径的微粒悬浮液均可以通过30号针头吸入注射器内并将注射器中的内含物完全注射到猪肉中的能力,没有出现阻滞或堵针的现象,说明本发明的微粒可以通过皮下或肌肉注射的方式进行给药。
实施例30有机溶剂残留量测定试验
本发明实施例1-24制备的固体分散体中有机溶剂A、有机溶剂B,以及缓释微粒中有机溶剂A和有机溶剂C的残留量测定,测定方法为众所周知的测定方法。测定结果如表3所示。
表3有机溶剂残留量测定结果
注:-表示没有检测到或含量低于检测限。
由表3的有机溶剂残留量结果可以看出,本发明制备的固体分散体和缓释微粒中,有机溶剂的残留量很低,或者没有检测到,或残留量低于可检测范围,给药后对病人无因有机溶剂产生的副作用,也有利于保持微粒的稳定性,延长货架期。
实施例31:动物试验
选取糖尿病模型小鼠56只,体重20±5g,雌雄各半,随机每8只分成给药组(6组)和空白组(1组),给药组小鼠颈背部皮下注射实施例6-11的艾塞那肽微粒或利拉鲁肽微粒,微粒用含有3%羧甲基纤维素、0.9%NaCl的稀释剂混悬,给药组每只小鼠注射艾塞那肽2mg/kg或利拉鲁肽10mg/kg,空白组皮下注射同体积的生理盐水。在给药的第0d、0.5d、1d、3d、7d、14d、21d、28d、35d、42d、49d、56d、63d、70d的同一时间从尾静脉取血进行血糖测定,然后制作平均HbA1c值(糖化血红蛋白占总血红蛋白的百分比,%)和时间(d)的曲线图,结果如图1所示。
由图1曲线图可知,本发明的实施例6-11制备的艾塞那肽缓释微粒或利拉鲁肽缓释微粒在给药后的70天内能够很好地控制HbA1c值,且在给药后的第7-70天内是HbA1c值处于5-7之间,明显比空白组低,说明本发明的艾塞那肽缓释微粒或利拉鲁肽缓释微粒给药后能够长时间释放其中的活性药物,并达到理想的治疗效果,能够降低给药频率,有利于提高病人的依从性。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (7)
1.一种缓释微粒的制备方法,其特征在于:包括以下步骤:
1)制备水溶性药物与可生物降解和生物相容的水难溶性聚合物的固体分散体;
2)将步骤1)制备的固体分散体溶于有机溶剂C中,形成固体分散体乳液,所述有机溶剂C为不能溶解所述水溶性药物但可以溶解所述水难溶性聚合物、沸点低于水且不溶于或难溶于水的有机溶剂;
3)将步骤2)得到的固体分散体乳液注入含有表面活性剂的水溶液中形成均匀的乳液;
4)通过溶剂挥发或溶剂提取使乳液中的微粒固化,收集微粒,用超纯水洗涤数次,以除去附着于微粒表面的表面活性剂,然后进行干燥,获得所述缓释微粒;
所述水溶性药物为蛋白类药物、肽类药物和核酸类药物中的至少一种;
所述步骤1)通过以下步骤实施:
11)将可生物降解和生物相容的水难溶性聚合物与水溶性药物完全溶解于有机溶剂A中,形成药物和聚合物的混合溶液;
12)将所述混合溶液注入有机溶剂B中或将有机溶剂B注入所述混合溶液中,产生均匀、细微的沉淀物,收集沉淀物,并用有机溶剂B洗涤数次,去除有机溶剂B,获得水溶性药物和水难溶性聚合物的固体分散体;其中,有机溶剂B不能溶解所述水难溶性聚合物和所述水溶性药物;
所述有机溶剂A选自冰醋酸、乙腈、三氟乙酸和二甲基亚砜中的至少一种;
所述有机溶剂B选自无水乙醚、己烷、正庚烷中的至少一种;
所述固体分散体中,水溶性药物与水难溶性聚合物的质量比为1:1~1:99;
所述有机溶剂C选自脂肪烃、卤代烃、脂肪酸酯、芳香烃和醚中的至少一种。
2.根据权利要求1所述的缓释微粒的制备方法,其特征在于:所述水溶性药物为具有不少于30个氨基酸残基的多肽及其至少一种经水溶性或水难溶性的基团或物质修饰的产物。
3.根据权利要求2所述的缓释微粒的制备方法,其特征在于:所述水溶性或水难溶性的基团或物质为聚乙二醇。
4.根据权利要求1所述的缓释微粒的制备方法,其特征在于:所述步骤1)中水难溶性聚合物包括聚酯、聚碳酸酯、聚缩醛、聚酐、聚羟基脂肪酸以及它们的共聚物、共混物中的至少一种。
5.根据权利要求1所述的缓释微粒的制备方法,其特征在于:所述方法还包括加入助剂的步骤,所述助剂在所述步骤1)制备固体分散体的过程中加入,或在所述步骤2)制备固体分散体乳液时加入;所述助剂为所述水溶性药物与所述水难溶性聚合物的质量之和的0.01-10%。
6.根据权利要求5所述的缓释微粒的制备方法,其特征在于:所述助剂包括糖类、氨基酸类、脂肪酸、醇类、抗氧化剂和缓冲剂中的至少一种。
7.根据权利要求1~6中任一项所述的缓释微粒的制备方法制得的缓释微粒。
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CN105963257B (zh) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | 一种缓释微粒的制备方法 |
TWI795423B (zh) | 2017-07-17 | 2023-03-11 | 法商麥迪榭爾公司 | 用於調節至少一種活性成份之藥物釋放動力學的可生物降解之藥物傳遞之組合物混合物 |
JP2021529747A (ja) * | 2018-06-25 | 2021-11-04 | タイタン ファーマシューティカルズ インコーポレイテッド | 親油性又は両親媒性医薬物質の放出のためのインプラント |
CN115484935A (zh) * | 2020-02-14 | 2022-12-16 | G2G生物公司 | 包括含有glp-1类似物或其药学上可接受的盐的缓释微球的药物组合物 |
KR102583029B1 (ko) * | 2020-05-28 | 2023-09-26 | 주식회사 아울바이오 | 글루카곤 유사 펩타이드 1 작용제 함유 제어방출 미립구 및 이의 제조방법 |
CN112494456B (zh) * | 2020-12-16 | 2022-05-03 | 西南石油大学 | 一种乙基纤维素中空微囊 |
CN116003577B (zh) * | 2023-02-14 | 2023-10-31 | 广东丸美生物技术股份有限公司 | 一种用于皮肤舒缓修复的重组胶原蛋白及其应用 |
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US5556642A (en) * | 1992-07-16 | 1996-09-17 | Tanabe Seiyaku Co., Ltd. | Method for producing sustained release microsphere preparation |
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DE3738228A1 (de) * | 1987-11-11 | 1989-05-24 | Hoechst Ag | Verfahren zur herstellung von bioabbaubaren mikrokapseln wasserloeslicher peptide und proteine sowie nach diesem verfahren erhaltene mikrokapseln |
JP2670680B2 (ja) * | 1988-02-24 | 1997-10-29 | 株式会社ビーエムジー | 生理活性物質含有ポリ乳酸系微小球およびその製造法 |
YU48420B (sh) * | 1991-03-25 | 1998-07-10 | Hoechst Aktiengesellschaft | Postupak za dobijanje biološki razgradljivih mikročestica sa dugotrajnim delovanjem |
JP4287613B2 (ja) * | 2000-04-28 | 2009-07-01 | 田辺三菱製薬株式会社 | マイクロスフェアの製法 |
KR100994658B1 (ko) * | 2001-12-26 | 2010-11-16 | 다케다 야쿠힌 고교 가부시키가이샤 | 신규 마이크로스피어 및 이들의 제조 방법 |
JP5457680B2 (ja) * | 2006-01-24 | 2014-04-02 | アンサン バイオファーマ,インコーポレイテッド | 高分子マイクロスフェアの調製技術 |
CN102233129B (zh) * | 2010-04-29 | 2014-07-09 | 上海交通大学 | 一种预防或治疗视网膜损伤的长效缓释制剂及其制备方法 |
US20140128431A1 (en) * | 2012-04-03 | 2014-05-08 | Hoffmann-Laroche Inc. | Pharmaceutical composition with improved bioavailability, safety and tolerability |
CN105168137A (zh) * | 2014-06-23 | 2015-12-23 | 天津金耀集团有限公司 | 一种乳糖塞来昔布药物组合物 |
PT107846B (pt) * | 2014-08-01 | 2019-03-22 | Hovione Farm S A | Produção de nano- partículas de dispersões sólidas amorfas por co-precipitação controlada |
US20160083345A1 (en) * | 2014-09-19 | 2016-03-24 | Cadila Healthcare Limited | Polymorphic forms of lomitapide and its salts and processes for their preparation |
CN105963257B (zh) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | 一种缓释微粒的制备方法 |
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2017
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US5556642A (en) * | 1992-07-16 | 1996-09-17 | Tanabe Seiyaku Co., Ltd. | Method for producing sustained release microsphere preparation |
Non-Patent Citations (1)
Title |
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Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations;Yajun Liu等;《AAPS PharmSciTech》;20150218;第16卷(第5期);摘要部分和1092页第1-2段 * |
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EP3434262A4 (en) | 2019-03-27 |
US20190133951A1 (en) | 2019-05-09 |
EP3434262B1 (en) | 2020-08-26 |
WO2017186075A1 (zh) | 2017-11-02 |
CN105963257A (zh) | 2016-09-28 |
EP3434262A1 (en) | 2019-01-30 |
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