缓释微丸片剂具有给药次数少、患者依从性好和生物利用度高等优点,因而受到广泛关注。但受压后功能性衣膜容易破损,导致药物的释放速率变快,这限制了缓释微丸片剂的应用。因此减少衣膜受损成为开发缓释微丸片剂的技术难点。本文总结了缓释微丸片剂的最新研究进展,介绍了影响功能性衣膜完整性的关键因素,同时汇总了减少受压时缓释微丸衣膜受损的最新方法。本文可供研究人员开发缓释微丸片剂参考。
表 1 已上市的 ERPT
图 1 影响 ERPT 功能性衣膜完整性的关键因素
Part1 丸芯
丸芯的粒径、孔隙率、组成、堆密度及流动性等都会影响微丸缓释包衣和压片结果[19],而这些关键属性受其制备方法的影响。不同方法制备的丸芯,孔隙率、粒径、圆整度不同。常见的丸芯制备方法如下: 利用流化床对空白丸芯上药或将药物和辅料混合后通过冻干制粒等方法制备丸芯[20]。
1.1
丸芯的粒径
丸芯的粒径影响物料的可压性和受压时 ERP 功能性衣膜的完整性。当包衣增重相同时,丸芯的粒径过小导致衣膜较薄,压片时衣膜容易受损,最终导致药物的溶出速率变快; 而丸芯的粒径过大,压片时容易出现物料分层,且大粒度微丸衣膜彼此间的接触面积大,也会影响药物的溶出。Johansson 等[21]考察了 425 ~ 500 μm 和 1 250 ~ 1 400μm 两种微晶纤维素微丸的形变能力,发现后者形变程度更明显,这是因为该微丸彼此间空隙大。有研究表明当微丸的平均粒径相同时,粒度分布宽的微丸受压后药物的溶出速率变化更小,因为小粒径微丸可嵌入到辅料空隙中,减少传递到衣膜的应力[15]。
1.2
丸芯的材料
1.3
丸芯的孔隙率
为丸芯的孔隙率影响 ERP 的形变能力和压缩机制。组成辅料不同,丸芯的孔隙率不同。含氯化钠的 MCC 丸芯,其孔隙率较无氯化钠的 MCC 丸芯高[29]。干燥方法不同,丸芯的孔隙率也不相同。冷冻干燥的丸芯孔隙率最高,烘箱干燥的丸芯孔隙率最低[29]。
有研究报道,在 100 Mpa 压力下,高孔隙率微丸不会破碎,而是发生轻度的致密化和变形,且压实后微丸的抗性变能力增强[30]。有研究表明,高孔隙率丸芯制备的 ERP 受压后形变程度更大,但药物的释放速率没有发生明显变化; 而低孔隙率丸芯制备的ERP 受压后形变程度小,但药物的释放速率明显变快[31]。综上所述,丸芯的孔隙率影响着 ERP 的形变行为及压片前后药物的溶出行为,需在开发ERPT 时加以控制。
Part2 缓释包衣
2.1
缓释包衣材料
表 2 常见的缓释包衣材料
2.1.1
乙基纤维素
图 2 缓冲层[33]和热压片技术[16]
2.1.2
丙烯酸树脂类聚合物
2.1.3
聚乙烯醋酸酯共聚物
2.2
包衣增重
2.3
增塑剂
理想的缓释衣膜应具备良好的延展性和较高的断裂应力,才能保证受压时不破损。虽然增塑剂可以改善包衣材料的延展性,但其用量并不是越多越好,因为增塑剂过多会导致衣膜的拉伸强度过低。Abbaspour 等[35]发现柠檬酸三乙酯用量为 10%时,衣膜的延长率小; 而当枸橼酸三乙酯用量为 30%时,衣膜的断裂应力明显降低,最终选择枸橼酸三乙酯的用量为 20%。水也是一种增塑剂。Rujivipat等[40]将对乙酰氨基酚微丸放置在 84%RH 老化 15 h后压片,对乙酰氨基酚的溶出速率没有发生变化。这是因为水发挥了增塑剂作用,使衣膜的致密性和抗压能力。
Part3 压片
3.1
压力大小
3.2
外加辅料的类型
3.3
外加辅料的粒径
3.4
外加辅料的占比
综上所述,筛选外加辅料占比对于 ERPT 至关重要。除了影响功能性衣膜的完整性之外,外加辅料占比还影响片剂的硬度、脆碎度、崩解性能以及含量均匀度等。因此,可根据所面临的问题和缓释包衣材料来筛选外加辅料的占比。
Part4 新型缓冲辅料和微丸压片技术
4.1
新型缓冲辅料
4.2
缓冲层
4.3
缓冲颗粒
图 3 高孔隙率缓冲颗粒降低 ERPT 功能性衣膜的受损程度[50]
4.4
润滑剂
润滑剂可降低微丸彼此间的相互作用力,改善缓释衣膜受损情况。有文献报道,在外加辅料或隔离层中加入润滑剂,有助于减少受压缓释微丸衣膜的受损程度。Li 等[51]将 MCC 与硬脂酸的物理混合物、喷雾干燥混合物分别与缓释微丸压片,在扫描电镜观察到前者缓释衣膜出现了裂缝,而后者缓释衣膜完整,这是因为喷雾干燥混合物具有更好塑性变形和缓冲能力,且含硬脂酸的喷雾干燥混合物的缓冲作用优于无硬脂酸的喷雾干燥混合物。有人发现缓释微丸( 含 3%硬脂酸镁缓冲层) 压片前后药物的溶出速率一致,而缓冲层中无硬脂酸镁的缓释微丸压片后药物的溶出速率明显变快,这是因为硬脂酸镁可以降低缓释衣膜与缓冲层间的相互作用力[33]。
Part5 结语
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作者:王志刚、刘依宽、刘佳鑫
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