Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada.
Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada.
Int J Pharm. 2020 Apr 15;579:119152. doi: 10.1016/j.ijpharm.2020.119152. Epub 2020 Feb 17.
Microparticles (MPs) with pH-responding macropores have recently proved their significance for the delivery of vulnerable biomolecules for oral drug administration. The previous MP systems were proven to provide enhanced protection against the gastric environment, however, their application is hindered due to insufficient loading efficiencies and deficient penetration capabilities of encapsulated drugs across the mucus barrier. Here, we report a new co-delivery approach based on amine-functionalized halloysite nanotube (HNT)-embedded MPs (amine-HNT-MPs) with pH-responding macropores specifically designed to deal with the mucus barrier at the absorption site. The mean diameter and polydispersity index of the pored MPs were measured by a particle size analyzer to be 37.6 ± 1.3 µm and 1.15, respectively. The drug loading capacity of the co-delivery system was shown to be 50-times higher than previously reported pored MPs. Fluorescence microscopy analysis of sulforhodamine B (into a hollow interior of HNTs)/ fluorescent nanoparticles (into a hollow interior of MPs)-encapsulated MPs confirmed biphasic release behavior due to pH-dependent pore closing/opening in the simulated gastrointestinal (GI) digestive conditions. To verify the protective effect of the co-delivery system, bromelain and lactase were loaded into HNTs and MPs, respectively, and found to exhibit 94.5 ± 3.3% (bromelain) and 70 ± 14.1% (lactase) functional activity in simulated GI tract conditions. The considerable improvement in the stability of the encapsulated enzymes against gastric conditions are attributed to the efficient pore sealing of the co-delivery system after the encapsulation of enzymes and maintenance of these closed pores in the gastric environment. Furthermore, the mucolytic enzyme (i.e. bromelain)-encapsulated co-delivery system was found to enhance mucopenetration of the encapsulated drug from histological analysis using ex vivo porcine intestine tissue. Therefore, the new microencapsulation design proposed in this study provides a promising solution to the major issues hampering the wide-spread application of MPs in the development of oral drug formulations for biopharmaceuticals and vaccines.
微粒（MPs）具有 pH 响应的大孔，最近已被证明对脆弱生物分子的口服药物给药具有重要意义。先前的 MPs 系统已被证明可提供增强的对胃环境的保护，然而，由于封装药物的负载效率不足和穿过黏液屏障的渗透能力不足，其应用受到限制。在这里，我们报告了一种新的基于胺功能化的埃洛石纳米管（HNT）嵌入 MPs（胺-HNT-MPs）的共递药方法，具有 pH 响应的大孔，专门设计用于处理吸收部位的黏液屏障。通过粒度分析仪测量多孔 MPs 的平均直径和多分散指数分别为 37.6±1.3μm 和 1.15。共递药系统的药物载药量被证明比以前报道的多孔 MPs 高 50 倍。荧光显微镜分析表明，罗丹明 B（进入 HNTs 的中空内部）/荧光纳米颗粒（进入 MPs 的中空内部）封装的 MPs 在模拟胃肠道（GI）消化条件下，由于 pH 依赖性孔的关闭/打开，呈现出两相释放行为。为了验证共递药系统的保护作用，将菠萝蛋白酶和乳糖酶分别装入 HNTs 和 MPs 中，发现其在模拟胃肠道条件下的功能活性分别为 94.5±3.3%（菠萝蛋白酶）和 70±14.1%（乳糖酶）。在胃条件下，封装酶后共递药系统有效地密封孔，并且在胃环境中保持这些封闭的孔，这归因于封装酶后封装酶的稳定性得到了显著提高。此外，发现粘液溶解酶（即菠萝蛋白酶）封装的共递药系统通过使用离体猪肠组织进行的组织学分析增强了包封药物的粘液穿透性。因此，本研究提出的新微封装设计为 MPs 在生物制药和疫苗的口服药物制剂开发中广泛应用所面临的主要问题提供了一种有前途的解决方案。
