CN103142491B - 一种单磷酸阿糖腺苷微球给药系统及其制备方法 - Google Patents
一种单磷酸阿糖腺苷微球给药系统及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种阿糖腺苷的壳聚糖微球给药系统及制备方法。其特征在于获得一种完整球状、粒径均匀、包埋率高及分散性良好的具有缓释性能的药物微球给药系统。具体技术方案为：以壳聚糖为膜材、聚乙二醇为致孔剂、戊二醛为交联剂，采用反相乳化-交联法制备载药微球。制备方法为：将药物溶解于的壳聚糖酸性水溶液中，加入聚乙二醇搅拌均匀作为水相；将上述水相缓慢加入到含有表面活性剂和分散剂的油相中，搅拌乳化至均匀，加入交联剂进行交联固化；将所得产物洗涤、干燥。本发明提供了具有缓释性能的阿糖腺苷壳聚糖微球的给药系统。
Description
技术领域
本发明属于医药领域，涉及一种微球给药系统的制备方法，具体涉及一种单磷酸阿糖腺苷微球给药系统及制备方法。
背景技术
本发明涉及一种微球给药系统的制备方法，具体涉及一种阿糖腺苷及其磷酸盐(单磷酸阿糖腺苷)壳聚糖微球给药系统及制备方法。
背景技术
阿糖腺苷具有广谱抗病毒活性。对疱疹病毒及带状疱疹病毒作用最强，对水痘带状疱疹病毒、牛痘病毒、乙肝病毒次之，对腺病毒、伪狂犬病毒和一些RNA肿瘤病毒有效。对大多数RNA病毒无效。经细胞酶磷酸化生成三磷酸阿糖腺苷，可与三磷酸脱氧腺苷竞争性抑制病毒的DNA多聚酶，并结合进病毒的DNA链，三磷酸阿糖腺苷也抑制核糖核苷酸还原酶，从而抑制病毒DNA的合成。
当前阿糖腺苷主要为冻干粉针和注射液，其半衰期短，需要多次给药给病人带来极大痛苦，病人顺从性低。因此有必要研究一种给药次数少，能够维持长时间药效的阿糖腺苷给药系统。
壳聚糖又名甲壳胺，它主要用来源于甲壳质的脱乙酰反应。甲壳质是一种天然有机高分子多糖，蕴藏量十分丰富，再加之其具有良好的生物学性质，如可降解性、低毒、抗菌性的特点而应用于医药领域，特别是载体材料。因此壳聚糖都有着广泛的应用空间。尤其在医药领域，壳聚糖因其成膜性、可吸收性和杀菌性，可被用于制备人造皮肤、人造血管、手术缝合线、用作止血剂和伤口愈合剂、抗肿瘤剂、免疫促进剂和抗胆固醇剂，又可作为人工肾的吸附解毒剂，脱内毒素超滤膜。壳聚糖作为药用辅料，其粘性、可压性、流动性和崩解性均非常优秀，也可广泛用于缓释剂及胃漂浮片上。壳聚糖作为药物载体可以控制药物释放，延长药物疗效、降低药物毒副作用，提高疏水性药物对细胞膜的通透性和药物的稳定性及改变给药途径，还可大大加强制剂的靶向给药能力。壳聚糖作为药物制剂的优点是，良好的生物降解性能和生物相容性，无免疫原性，在体内可被溶菌酶等酶解离成低聚壳聚糖，生成天然无毒的代谢物，且能被生物体完全吸收。因此，壳聚糖作为药物载体材料有明显的优越性。
发明内容
本发明的目的在于提供了一种单磷酸阿糖腺苷壳聚糖微球给药系统，获得完整圆球形的微球，以实现缓释给药的目的。壳聚糖作为膜材生物相容性好，安全、无毒等特点有利于单磷酸阿糖腺苷壳聚糖微球给药系统的临床应用。
本发明另一目的在于提供上述单磷酸阿糖腺苷壳聚糖微球的制备方法。
本发明还有一个目的在于提供上述单磷酸阿糖腺苷壳聚糖微球的临床应用。
本发明上述目的通过以下技术方案予以实现：
一种单磷酸阿糖腺苷壳聚糖微球，以壳聚糖为膜材、聚乙二醇为致孔剂、戊二醛为交联剂，采用反相乳化-交联法制备载药微球。
具体步骤包括：
(1)取壳聚糖溶于醋酸水溶液中，静置，去除气泡；
(2)将聚乙二醇和单磷酸阿糖腺苷加入到上述溶液中，混合均匀作为水相；
(3)将水相缓慢滴入含有3％-10％(v/v)表面活性剂和质量浓度0.1％-1％分散剂的油相，快速搅拌，乳化完全，形成W/O体系；
(4)向W/O体系中，缓慢滴入交联剂，快速搅拌，交联固化形成珠状颗粒；
(5)收集沉淀，抽滤，有机溶剂脱水洗涤，干燥。
步骤(5)所述的有机溶剂为异丙醇、乙醇、石油醚一种或几种，以洗去表面油相为宜，实验结果显示，有机溶剂优选异丙醇和石油醚的任意比混合物。
所述油相为液体石蜡、环己烷、正庚烷、真空泵油、植物油或其与石油醚的混合物；表面活性剂为磷脂、OP-10、司盘80或司盘80与吐温80混合物；分散剂为硬脂酸镁。
本发明制备的单磷酸阿糖腺苷壳聚糖微球的包封率范围为10％-80％，获得微球粒径为1-50微米，微球之间无明显粘连现象，分散性良好。
本发明使用反相乳化-交联法制备单磷酸阿糖腺苷壳聚糖微球，其特点是在乳化中所形成的W/O乳滴，可以保证形成完整球形并且均匀分散的微球，化学交联法相对于离子聚合法形成的微球更为稳定，更能获得具有良好缓释效果的微球。
本发明壳聚糖醋酸水溶液中加入聚乙二醇(致孔剂)作为水相，本法制备的微球在维持牢固的球状结构同时又能在微球上形成足够的亲水通道，保证药物稳定释放。
本发明在油相中加入分散剂，在于可以获得均匀分散的乳滴，在交联后形成均匀分散的珠状颗粒，从而获得均匀分散的微球。
附图说明
图1：单磷酸阿糖腺苷壳聚糖微球电镜图。
图2：单磷酸阿糖腺苷壳聚糖微球在0.1mol/L HCl和pH＝7.4磷酸盐缓冲液的累积释放曲线。
图3：单磷酸阿糖腺苷壳聚糖微球在pH＝7.4磷酸盐缓冲液中的Higuchi释放模型的拟合曲线。拟合方程为Q％＝7.35+10.79t0.5，R2＝0.9569。
具体实施方式
以下结合实施例来进一步解释本发明，但实施例并不对本发明做任何形式的限定。
实施例1
称取0.4g壳聚糖(脱乙酰度96％)溶于20mL2％的醋酸水溶液中，静置，去除气泡。量取0.1g聚乙二醇400和0.1g单磷酸阿糖腺苷加入到上述溶液中组成水相。取100mL液体石蜡，加入5mL吐温80和0.5g的硬脂酸镁作为油相。将水相缓慢倒入油相，1000rpm机械搅拌，乳化完全后加入2mL戊二醛，继续搅拌交联固化4h，收集沉淀，异丙醇和石油醚洗涤后，干燥。
在电镜下可见微球呈圆整球形，结果见图1。
用0.25mol/L的盐酸破坏微球，HPLC法测得微球中单磷酸阿糖腺苷含量，根据下式计算包封率：
包封率＝微球中药物的含量/制备中加入药物量
由上式计算得实施例1的单磷酸阿糖腺苷壳聚糖微球的包封率为61％。
按2010版《中国药典》第二部溶出度测定方法测定单磷酸阿糖腺苷壳聚糖微球的释放曲线。具体操作如下：
取适量上述微球，37℃条件下，释放介质1000mL中，分别在0.1mol/L HCl、pH7.4的磷酸盐缓冲液中，定时取10mL释放介质并检测单磷酸阿糖腺苷浓度，同时补加释放介质，绘制时间-累积释放度曲线，结果见图2、图3。
实施例2
称取0.6g壳聚糖(脱乙酰度96％)溶于20mL2％的醋酸水溶液中，静置，去除气泡。量取0.2g聚乙二醇400和0.06g单磷酸阿糖腺苷加入到上述溶液中组成水相。取60mL液体石蜡，加入2mL吐温80和0.2g的硬脂酸镁作为油相。将水相缓慢倒入油相，1200rpm机械搅拌，乳化完全后加入1mL戊二醛，继续搅拌交联固化6h，收集沉淀，异丙醇和石油醚洗涤后，干燥。
经计算微球包封率为76％。
实施例3
称取0.1g壳聚糖(脱乙酰度96％)溶于20mL2％的醋酸水溶液中，静置，去除气泡。量取0.02g聚乙二醇4000和0.1g单磷酸阿糖腺苷加入到上述溶液中组成水相。取40mL液体石蜡，加入1mL吐温80和0.1g的硬脂酸镁作为油相。将水相缓慢倒入油相，1200rpm机械搅拌，乳化完全后加入0.2mL戊二醛，继续搅拌交联固化2h，收集沉淀，异丙醇和石油醚洗涤后，干燥。
经计算微球包封率为37％。
实施例4
称取0.5g壳聚糖(脱乙酰度96％)溶于20mL2％的醋酸水溶液中，静置，去除气泡。量取0.1g聚乙二醇600和0.1g单磷酸阿糖腺苷加入到上述溶液中组成水相。取150mL液体石蜡，加入5mL吐温80和0.5g的硬脂酸镁作为油相。将水相缓慢倒入油相，800rpm机械搅拌，乳化完全后加入2mL戊二醛，继续搅拌交联固化8h，收集沉淀，异丙醇和石油醚洗涤后，干燥。
经计算微球包封率为67％。
实施例5
称取0.4g壳聚糖(脱乙酰度96％)溶于20mL2％的醋酸水溶液中，静置，去除气泡。量取0.08g聚乙二醇6000和0.08g单磷酸阿糖腺苷加入到上述溶液中组成水相。取80mL液体石蜡，加入2mL吐温80和0.2g的硬脂酸镁作为油相。将水相缓慢倒入油相，1000rpm机械搅拌，乳化完全后加入0.5mL戊二醛，继续搅拌交联固化10h，收集沉淀，异丙醇和石油醚洗涤后，干燥。
经计算微球包封率为71％。
Claims (1)
1.一种单磷酸阿糖腺苷的壳聚糖微球给药系统，其特征在于制备方法为称取0.4g脱乙酰度为96％的壳聚糖，溶于20mL 2％的醋酸水溶液中，静置，去除气泡；称取0.1g聚乙二醇400和0.1g单磷酸阿糖腺苷加入到上述溶液中组成水相；取100mL液体石蜡，加入5mL吐温80和0.5g的硬脂酸镁作为油相；将水相缓慢倒入油相，1000rpm机械搅拌，乳化完全后加入2mL戊二醛，继续搅拌交联固化4h，收集沉淀，异丙醇和石油醚洗涤后，干燥。
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