Scalable Manufacturing of Enteric Encapsulation Systems for Site Specific Oral Insulin Delivery
Scalable Manufacturing of Enteric Encapsulation Systems for Site Specific Oral Insulin Delivery
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用于特定部位口服胰岛素输送的肠溶胶囊系统的可扩展制造
DOI：
10.1021/acs.biomac.8b01530
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发表时间：
2019
影响因子：
6.2
通讯作者：
Chen Yongming
中科院分区：
文献类型：
--
作者：
Sun Lilong;Liu Zhijia;Tian Houkuan;Le Zhicheng;Liu Lixin;Leong Kam W;Mao Hai Quan;Chen Yongming
口服给药是一种更受欢迎的给药方式，因为它易于给药、患者依从性高、医疗费用低。然而，由于胃肠道（GI）屏障不利，导致大分子药物的口服生物利用度微不足道，目前尚无市售口服蛋白质制剂。在此，我们使用胰岛素作为模型蛋白药物；将负载胰岛素的N-（2-羟基）-丙基-3-三甲基氯化铵改性壳聚糖（HTCC）/三聚磷酸钠（TPP）纳米复合物（NC）作为纳米核心，通过两步快速纳米复合（FNC）工艺以可靠且可扩展的方式进一步封装到肠溶Eudragit L100-55材料中，形成我们的NC-in-Eudragit复合颗粒（NE）。我们优化的NE的粒径和表面特性经过定制，可保护装载的胰岛素在恶劣的胃环境中免受酸性降解，并实现肠道特定位点药物释放以及提高胰岛素的口服递送效率。此外，优化的NE给1型糖尿病大鼠口服可引起非常显着的降血糖作用，相对口服生物利用度为13.3%。我们的结果表明，使用 FNC 装置对纳米治疗药物进行肠溶包封可以使药物制剂具有更好的尺寸可控性、批量模式重现性和均匀的表面包衣，然后显着提高其胰岛素的口服生物利用度，表明其在口服蛋白质治疗药物临床转化方面的巨大潜力。
Oral drug delivery is a more favored mode of administration because of its ease of administration, high patient compliance, and low healthcare costs. However, no oral protein formulations are commercially available currently due to hostile gastrointestinal (GI) barriers resulting in insignificant oral bioavailability of macromolecular drugs. Herein, we used insulin as a model protein drug; insulin-loadedN-(2-hydroxy)-propyl-3-trimethylammonium chloride modified chitosan (HTCC)/sodium tripolyphosphate (TPP) nanocomplex (NC) as a nanocore was further encapsulated into enteric Eudragit L100-55 material, through a two-step flash nanocomplexation (FNC) process in a reliable and scalable manner, forming our NC-in-Eudragit composite particles (NE). Particle size and surface properties of our optimized NE were tailored to protect the loaded insulin from acidic degradation in the hostile stomach environment and to achieve intestinal site-specific drug release as well as the improvement of oral delivery efficiency of insulin. In addition, the oral administration of the optimized NE to type 1 diabetic rats could induce a very significant hypoglycemic effect with a relative oral bioavailability of 13.3%. Our results demonstrated that enteric encapsulation of nanotherapeutics using a FNC apparatus could cause drug formulations to possess better size controllability, batch-mode reproducibility, and homogeneous surface coating and then significantly enhance their oral bioavailability of insulin, indicating its great potential for clinical translation of oral protein therapeutics.