School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Control Release. 2020 May 10;321:641-653. doi: 10.1016/j.jconrel.2020.02.034. Epub 2020 Feb 22.
Macromolecular drugs, characterized by low stability and large molecular weight, still faced various difficulties by oral administration. And controlling drugs' release rate to reach the physiological concentration in the blood was recognized as one of the main challenges in this field but no studies are available so far. Thus, the objective of this study was to investigate the effect of insulin release rate on its in vitro and in vivo behavior when other obstacles (drug stability, mucus penetration and retention in gastrointestinal tract) was firstly overcome. Using n-butylcyanoacrylate (BCA) as the carrier, insulin-loaded Poly (n-butylcyanoacrylate) nanoparticles (Ins/PBCA NPs) were prepared by self-polymerization and the release rate of insulin was controlled by adjusting the mass ratio of Insulin/BCA. The NPs exhibited good stability in gastric fluid with controlled release in intestine and the release rate increased with the increase of Insulin/BCA mass ratio. All the Ins/PBCA NPs with different release rate showed excellent mucus penetration (>60%, 10 min) and strong gastrointestinal retention (~70%, 12 h). Especially, all the NPs showed promising hypoglycemic effect with the extent depending on drug release rate. Ins/BCA = 2/10 NPs exhibited fast hypoglycemic effect, while Ins/BCA = 2/15 NPs showed slow and outstanding performance. In conclusion, Ins/PBCA NPs could not only overcome the oral barriers of insulin delivery but also provide desired hypoglycemic effect by controlling insulin release rate.
高分子药物的特点是稳定性低、分子量较大，通过口服给药仍然面临各种困难。控制药物的释放速度，使其达到血液中的生理浓度，被认为是该领域的主要挑战之一，但迄今为止尚无相关研究。因此，本研究的目的是探讨胰岛素释放速度对其在体、体外行为的影响，同时首先克服其他障碍（药物稳定性、黏液穿透和在胃肠道中的滞留）。本研究采用正丁基氰基丙烯酸酯（BCA）作为载体，通过自聚合制备载胰岛素的聚正丁基氰基丙烯酸酯纳米粒（Ins/PBCA NPs），并通过调整胰岛素/BCA 的质量比来控制胰岛素的释放速度。纳米粒在胃液中表现出良好的稳定性，在肠道中具有控制释放的特性，且释放速度随胰岛素/BCA 质量比的增加而增加。所有具有不同释放速度的 Ins/PBCA NPs 均表现出良好的黏液穿透性（>60%，10 min）和较强的胃肠道滞留性（~70%，12 h）。特别是，所有纳米粒均表现出良好的降血糖效果，其程度取决于药物释放速度。Ins/BCA = 2/10 NPs 表现出快速降血糖作用，而 Ins/BCA = 2/15 NPs 则表现出缓慢而优异的性能。综上所述，Ins/PBCA NPs 不仅可以克服胰岛素递送的口服障碍，还可以通过控制胰岛素释放速度来提供理想的降血糖效果。
