摘要
长效注射剂因可长时间控制药物释放,减少给药次数而显著改善了用药顺应性,在药物制剂研究领域中占据重要地位。本文以注射微球、原位凝胶植入剂两种类型的长效注射剂上市产品为切入点,剖析了此类长效制剂处方及工艺中为实现长时间释药所采用的策略与技术。同时就此类制剂普遍存在的突释现象,综述了现阶段研究中控制突释的相关策略,为此类长效制剂的设计、研发与优化提供理论参考。
长效注射剂(long-acting injectables,LAIs)属于复杂注射剂,一般包括微球、脂质体、纳米混悬剂、胶束、原位凝胶植入剂等,可通过常规注射器和针头注射给
微球(microspheres)是一种用高分子材料包载药物的微小球状聚合物,通常粒径范围为1 ~ 250 μ
aPLGA:聚乳酸-羟基乙酸共聚物
微球的制备材料主要分为天然高分子与合成高分子。天然高分子包括淀粉、明胶、凝集素、海藻酸盐、果胶和壳聚糖等,具有低毒性、生物相容性和可生物降解性,但其纯化困难,批次之间差异
微球制备方法主要分为溶剂挥发法、相分离法、喷雾干燥法等。溶剂挥发法中的双乳液溶剂挥发法(W/O/W法)因具有操作简便、包封率高的特点,多用于多肽、蛋白等亲水性药物微球的制备。
以武田与雅培联合推出的注射用醋酸亮丙瑞林微球(商品名:Lupron Depo
不同于Lupron Depo
中国的丽珠医药、博恩特药业与绿叶制药等企业在微球领域积极布局,目前已分别实现了醋酸亮丙瑞林微球(商品名:贝
原位凝胶植入剂(in situ forming gel implant,ISFGI)通过将药物与溶解在有机溶剂中的基质材料混合后注入体内,因注射部位的外界环境刺激而发生固态或半固态的相转变以形成局部药物储库的液体制
Artix实验室基于Atrige
相关长效注射剂产品的获批表明其总体收益大于潜在风险,但注射微球与原位凝胶植入剂普遍存在着不同程度的突释效
通过调整基质材料的性质,如采用与无机材料结合的复合材料或嵌段共聚物代替传统的高分子材料,可实现对注射微球与原位凝胶植入剂孔隙率及亲疏水性的控制,进而减少突释量。
Zhou
在原位凝胶植入剂方面,Kamali
微球制备过程中掺入添加剂可达到提高包封率与减少突释的效果,添加剂的加入增加了外水相的渗透压,阻止连续相进入分散相,减少水性通道的形成从而控制突释。常见的添加方法包括:内水相中加入吐温-20、葡聚糖,油相中加入疏水性阻滞剂、甘
Wang
W/O/W法包封亲水性药物可获得较高的包封率,但药物溶解在内部水相使内水相渗透压增加,对于小分子亲水性药物而言,易由内水相逃逸至外水相而导致包封率低且突释明显,故调整药物的亲水性可减少此类逃逸,有助于控制突释。
实现药物盐与游离碱形式的转化或形成疏水性复合物,可达到改变药物水溶性的效果。盐酸布比卡因易溶于水,将其通过碱沉淀法制得布比卡因游离碱,降低水溶性从而可采用O/W法制备微球以提高包封率并控制突

图1 传统W1/O/W2乳化法与改良疏水离子对(HIP)复合物-S/O/W乳化法示意图及制得微球的横截面形态对比
调整药物质子化也是诸多策略中的一种。Chitinart
阻止亲水性药物逃逸可通过上述方法在W/O/W技术的基础上进行优化,还可采用其他的改进制备技术以减少逃逸通道的形成从而控制药物突释。
Chen

图2 包裹艾塞那肽(Ex)的卵磷脂纳米颗粒的复合PLGA微球(Ex-NPs-PLGA-Ms)和常规W/O/W技术制备的艾塞那肽PLGA微球(Ex-PLGA-Ms)的制备和结构示意图
以上措施可进行组合以更大程度上实现对突释的控制,例如,近期研究较多的微球-凝胶给药系统与单独的微球或凝胶相比兼具了释药完全、释放行为易控制、突释少等优点。Zhang
长效注射剂可显著减少给药频率提高患者用药顺应性,具备较高的技术壁垒和可观的市场利润,是国内制药企业在“4+7”背景下寻求转型的热点领域。本文从微球与原位凝胶植入剂的已上市产品入手,剖析这些产品在长时间释药方面所采用的策略,为此类长效制剂的开发提供参考。因突释问题限制了此类制剂更好地发挥优势作用,掌握控制突释的方法将是开发和生产更具经济效益和临床意义的长效制剂的关键突破口。本文通过综述最新的相关解决措施与技术,为控制突释效应提供理论支持。全球已上市的长效注射剂通过延长原有品种的生命周期,大多获得了巨大的成功,目前国内仅实现了亮丙瑞林微球与利培酮微球的国产化,长效注射剂尚存在巨大的市场潜力和发展空间。
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