Department of Chemical Engineering, Center for Bioengineering, University of California, Santa Barbara 93106, USA.
J Control Release. 2013 Dec 28;172(3):753-62. doi: 10.1016/j.jconrel.2013.09.004. Epub 2013 Sep 11.
One of the major challenges faced by therapeutic polypeptides remains their invasive route of delivery. Oral administration offers a potential alternative to injections; however, this route cannot be currently used for peptides due to their limited stability in the stomach and poor permeation across the intestine. Here, we report mucoadhesive devices for oral delivery that are inspired by the design of transdermal patches and demonstrate their capabilities in vivo for salmon calcitonin (sCT). The mucoadhesive devices were prepared by compressing a polymeric matrix containing carbopol, pectin and sodium carboxymethylcellulose (1:1:2), and were coated on all sides but one with an impermeable and flexible ethyl cellulose (EC) backing layer. Devices were tested for in vitro dissolution, mucoadhesion to intestinal mucosa, enhancement of drug absorption in vitro (Caco-2 monolayer transport) and in vivo in rats. Devices showed steady drug release with ≈75% cumulative drug released in 5h. Devices also demonstrated strong mucoadhesion to porcine small intestine to withstand forces up to 100 times their own weight. sCT-loaded mucoadhesive devices exhibited delivery of sCT across Caco-2 monolayers and across the intestinal epithelium in vivo in rats. A ≈52-fold (pharmacokinetic) and ≈44-fold (pharmacological) enhancement of oral bioavailability was observed with mucoadhesive devices when compared to direct intestinal injections. Oral delivery of devices in enteric coated capsules resulted in significant bioavailability enhancement.
治疗性多肽面临的主要挑战之一仍然是其侵入性的给药途径。口服给药提供了一种替代注射的潜在方法；然而，由于肽在胃中的稳定性有限且在肠道中的渗透性差，目前不能将这种途径用于肽类药物。在这里，我们报告了受透皮贴剂设计启发的用于口服递送的粘膜粘附装置，并在体内展示了它们在鲑鱼降钙素（sCT）中的应用。粘膜粘附装置通过压缩含有卡波姆、果胶和羧甲基纤维素钠（1:1:2）的聚合物基质制备而成，并在除一侧之外的所有侧面涂覆一层不可渗透和柔性的乙基纤维素（EC）背衬层。对装置进行了体外溶解、与肠道粘膜的粘膜粘附、体外（Caco-2 单层转运）和体内（大鼠）增强药物吸收的测试。装置显示出稳定的药物释放，约 75%的累积药物在 5 小时内释放。装置还表现出与猪小肠的强烈粘膜粘附力，能够承受自身重量 100 倍以上的力。负载 sCT 的粘膜粘附装置在体内展示了 sCT 在 Caco-2 单层和肠道上皮中的传递。与直接肠道注射相比，粘膜粘附装置使 sCT 的口服生物利用度提高了约 52 倍（药代动力学）和约 44 倍（药效学）。肠溶胶囊给药装置可显著提高生物利用度。
