CN1319593C - 胸腺素口服肠溶微球及制备方法 - Google Patents
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Abstract
本发明公开了一种水溶性多肽蛋白类药物胸腺素口服肠溶微球及制备方法。该方法采用油包油乳化溶剂挥发技术,采用内油相和外油相,并加入混合乳化剂。制备时将外油相置于搅拌容器中,中速搅拌下加入内油相,然后在室温下磁力搅拌挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,真空干燥。本发明可使胸腺素的包埋率提高到60-95%,在人工胃液中释放药物小于10%,在人工肠液中释放药物90%以上,可实现胸腺素的肠定向释放。
Description
技术领域
本发明属医药技术领域,涉及胸腺素口服肠溶微球及其制备方法。
背景技术
动物胸腺中有多种多肽类激素,总称为胸腺激素。已由小牛胸腺分离精制的胸腺激素有胸腺素(Thymosin)、胸腺体液因子(Thymus humoral factor)、胸腺增生素(Thymopoietin)和胸腺因子(Thymic factor)等多种。临床上研究最为广泛的是胸腺素,目前国外临床试用的主要是由小牛胸腺素纯化而得的胸腺素组分5(胸腺素F5,Thymosin fraction 5),它含12种主要的多肽和20余种次要的肽素,分子量1000~15000。我国生产的猪胸腺素(猪胸腺素F5)系由猪胸腺提取的含8~9种不同等电点的蛋白质组分的混合物,分子量为9000~68000不等,低分子量组分占70%~80%。
胸腺素可使由骨髓产生的干细胞转变成T细胞,因而有增强细胞免疫功能的作用,对体液免疫的影响甚微。动物试验表明,它能使去胸腺小鼠部分或接近全部地恢复免疫排异和移植物抗宿主反应,能使萎缩的淋巴组织复生,淋巴细胞增殖,使幼淋巴细胞成熟,变为有免疫功能的淋巴细胞。胸腺素无明显的种属特异性。胸腺素已试用于胸腺发育不全综合征、运动失调性毛细血管扩张症、慢性皮肤粘膜真菌病等免疫缺陷病。对胸腺发育不全症患儿可长期应用作替代性治疗。用于肿瘤病人,可见大部分患者T细胞数增多,也见有临床症状改善。对全身性红斑狼疮、类风湿性关节炎等自身免疫性疾病有一定疗效。
目前国内外临床使用的胸腺素制剂主要有注射及口服两种给药途径[1-4]。注射制剂包括注射液和冻干剂。口服制剂为肠溶片和肠溶胶囊。两者相比口服给药更具有用药方便、安全、患者易接受等优点,尤其适应长期频繁用药患者的需要。由于微球制剂可有效提高多肽蛋白质药物口服生物利用度,近年也有关于口服胸腺素肠溶微球制剂的研究报道[5]。其胸腺素微球以邻苯二甲酸醋酸纤维素(CAP)为成球材料,丙酮为溶剂,氯仿为非溶剂,采用溶剂-非溶剂法制备。我们采用改良的油包油乳化溶剂挥发法,以丙烯酸树脂II号或III号为成球材料制备得到胸腺素肠溶微球。
发明内容
本发明的目的是提供一种胸腺素口服肠溶微球,主要由主药胸腺素和肠溶基质组成,其特征是:每毫克微球中含主药胸腺素3~30微克(载药量3~30μg/mg),肠溶基质为丙烯酸树脂II号或丙烯酸树脂III号。
本发明的另一个目的是提供这种胸腺素口服肠溶微球的制备方法。为了得到具有高包埋率的胸腺素肠溶微球,本发明采取如下措施:内油相由胸腺素水溶液与丙烯酸树脂乙醇溶液通过机械搅拌获得,胸腺素水溶液浓度为1-50mg/ml,丙烯酸树脂乙醇溶液浓度为1.5%-7.5%,外油相采用液体石蜡,内加司盘80和卵磷脂作为复合乳化剂,其中卵磷脂的重量体积比为0.25-1.0%,司盘80的重量体积比为0.15-1.0%,制备时,将外油相置于搅拌容器中,在室温和每分钟500转中速搅拌下缓缓加入内油相,形成油包油乳液,该乳液在室温下磁力搅拌挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,真空干燥即得。
本发明的技术特点是:用一种独特的复合乳化剂通过油包油乳化溶剂挥发法制备了胸腺素口服肠溶微球,整个制备方法操作简便,重现性好,避免有毒有机溶剂的使用。采用本方法制得的微球形态圆整,大小均匀,粒径为15-70μm,控制微球制备条件(胸腺素水溶液浓度、丙烯酸树脂类型、丙烯酸树脂乙醇液浓度、复合乳化剂用量等),可使胸腺素微球包埋率达到90%以上,药物在人工胃液中释放小于10%,在pH7.2的缓冲液中释放大于90%,可实现胸腺素的肠定向释放。
具体实施方式
下面结合实施例作进一步详细说明。
实施例1
内油相用胸腺素水溶液与丙烯酸树脂II号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为6mg/ml,与3%丙烯酸树脂II号乙醇溶液以1∶20的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.25%卵磷脂和0.35%司盘80为乳化剂。将外油相置于烧瓶中,室温下以搅拌速度为500转/分钟缓缓加入内油相,形成油包油乳液。该乳液在室温下电磁搅拌挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,真空干燥。所得微球的胸腺素的包埋率为86.1%,载药量为10μg/mg。人工胃液中2h释药37.5%,pH7.2的缓冲液中4h释药达91.6%。
实施例2
内油相用胸腺素水溶液与丙烯酸树脂II号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为18mg/ml,与3%丙烯酸树脂II号乙醇溶液以1∶60的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.25%卵磷脂和0.35%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为83.4%,载药量为20μg/mg。人工胃液中2h释药36.8%,pH7.2的缓冲液中4h释药92%。
实施例3
内油相用胸腺素水溶液与丙烯酸树脂II号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为36mg/ml,与6%丙烯酸树脂II号以1∶20的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.5%卵磷脂和0.5%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为60.9%,载药量为17μg/mg。人工胃液中2h释药30.5%,pH7.2的缓冲液中4h释药达85%。
实施例4
内油相用胸腺素水溶液与丙烯酸树脂II号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为18mg/ml,与6%丙烯酸树脂II号以1∶60的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.25%卵磷脂和0.35%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为86.9%,载药量为13μg/mg。人工胃液中2h释药40.2%,pH7.2的缓冲液中4h释药达95%。
实施例5
内油相用胸腺素水溶液与丙烯酸树脂II号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为6mg/ml,与6%丙烯酸树脂II号以1∶20的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.5%卵磷脂和0.5%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为81.9%,载药量为4μg/mg。人工胃液中2h释药9.3%,pH7.2的缓冲液中4h释药达86.7%。
实施例6
内油相用胸腺素水溶液与丙烯酸树脂II号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为6mg/ml,与6%丙烯酸树脂II号乙醇溶液以1∶40的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.25%卵磷脂和0.35%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为90.2%,载药量为5μg/mg。人工胃液中2h释药6.5%,pH7.2的缓冲液中4h释药达88.4%。
实施例7
内油相用胸腺素水溶液与丙烯酸树脂III号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为6mg/ml,与6%丙烯酸树脂III号以1∶20的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.5%卵磷脂和0.5%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为91.9%,载药量为4.5μg/mg。人工胃液中2h释药8.5%,pH7.2的缓冲液中4h释药达87.2%。
实施例8
内油相用胸腺素水溶液与丙烯酸树脂III号乙醇溶液通过机械搅拌获得。胸腺素水溶液浓度为36mg/ml,与3%丙烯酸树脂III号以1∶20的比例通过机械搅拌混合均匀。外油相为50ml液体石蜡,内加0.5%卵磷脂和0.5%司盘80为乳化剂。其余同实施例1。所得微球的胸腺素的包埋率为56.9%,载药量为30μg/mg。人工胃液中2h释药42.1%,pH7.2的缓冲液中4h释药达92.5%。
无需进一步详细阐述,相信采用前面所公开的内容,本领域技术人员可最大限度地应用。因此,前面的优选具体实施方案应被理解为仅是举例说明,而非以任何方式限制本发明的范围。
本发明涉及的部分参考文献:
1.李惠雄.胸腺口服剂型和临床实验.中国药学杂志.1991.26(4):193
2.何树庄,郝晓敏,袁淑华,等.胸腺肽片剂与注射剂的免疫作用比较.哈尔滨医科大学学报.1994,28(4):295-297
3.钱林法,王伟祖,刘桦,等.口服胸腺肽结肠溶制剂的药效学研究I.对环孢素A免疫抑制BALB/C小鼠的免疫功能的影响.中国生化药物杂志.1999.20(2):79-81
4.钱林法,许德义,朱全芽,等.胸腺肽结肠控释胶囊制剂及胸腺肽提取分离方法发明专利申请公开说明书申请号00112353
5.张海松,陈阳述,胡军高,等.口服胸腺肽微球的研究.中国药房.1999.10(2):58-59
Claims (4)
1.胸腺素的口服肠溶微球的制备方法,其特征是通过以下步骤实现:
(1)内油相由药物胸腺素水溶液与丙烯酸树脂乙醇溶液通过机械搅拌获得,胸腺素水溶液浓度为1~50mg/ml,丙烯酸树脂乙醇溶液浓度为1.5%~7.5%;
(2)外油相选用液体石蜡,加入复合乳化剂;
(3)将外油相置于搅拌容器中,在室温和每分钟500转中速搅拌下缓缓加入内油相,形成油包油乳液,该乳液在室温下磁力搅拌挥发内油相溶剂,待微球硬化后,离心分离,用石油醚洗涤,真空干燥即得。
2.根据权利要求1所述的胸腺素口服肠溶微球的制备方法,其特征是:步骤(1)中丙烯酸树脂乙醇选自丙烯酸树脂II号乙醇溶液或丙烯酸树脂III号乙醇溶液中任一种。
3.根据权利要求1所述的胸腺素口服肠溶微球的制备方法,其特征是:步骤(2)中所说的复合乳化剂由司盘80和卵磷脂组成,其中卵磷脂的重量体积比为0.25~1.0%,司盘80的重量体积比为0.15~1.0%。
4.根据权利要求1所述的胸腺素口服肠溶微球的制备方法,其特征是:步骤(2)中所说的外油相选用液体石蜡。
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口服胸腺肽微球的研究 中国药房,第10卷第2期 1999;胸腺肽片肠溶衣处方的筛选 中国医院药学杂志,第18卷第12期 1998 * |
胸腺肽片肠溶衣处方的筛选 中国医院药学杂志,第18卷第12期 1998 * |
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