Palacios Joshua I, Wood-Yang Amy J, Klavohn Nicholas, Friesenhahn Nicholas, Raman Nisha, Baker Nusaiba, Ashby Grant, Prausnitz Mark R
Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, GA 30332, USA.
School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
J Control Release. 2025 Sep 10;385:113963. doi: 10.1016/j.jconrel.2025.113963. Epub 2025 Jun 18.
Biologic drugs have transformed medicine, but are limited by their need for administration by injection. To enable oral delivery of biologics, we propose convective force as a physical method to overcome the barriers of the gastrointestinal tract (GIT). We designed oral capsules that self-pressurize in the GIT, mechanically fail at a specific pressure (100-170 kPa), and eject lyophilized drug with sufficient velocity to penetrate the mucosal barrier. This oral, self-pressurized aerosol (OSPRAE) was produced by a coated gelatin capsule filled with pressure-generating effervescent excipients (sodium bicarbonate, citric acid) and drug in a biodegradable polymer chamber (poly(lactic acid)). After initial optimization in vitro, OSPRAE allowed for insulin delivery to surgically exposed intestinal mucosa in vivo with similar pharmacokinetics and pharmacodynamics to subcutaneous injection in rats, despite lower bioavailability. Histological analysis showed only superficial damage to the intestinal epithelium that was highly localized to the microscopic area of impact. Future studies should administer OSPRAE orally to larger animals and, ultimately, to humans. The OSPRAE capsule offers a novel method to increase delivery of biologics across the intestinal mucosa using convective force, which contrasts with prior approaches involving chemical penetration enhancers and electromechanical devices.
生物药物已经改变了医学，但因其需要注射给药而受到限制。为了实现生物制剂的口服给药，我们提出对流力作为一种克服胃肠道（GIT）屏障的物理方法。我们设计了一种口服胶囊，它能在胃肠道内自我加压，在特定压力（100 - 170kPa）下机械破裂，并以足够的速度喷射冻干药物以穿透粘膜屏障。这种口服自加压气雾剂（OSPRAE）由一个包衣明胶胶囊制成，胶囊内填充有产生压力的泡腾赋形剂（碳酸氢钠、柠檬酸）和置于可生物降解聚合物腔室（聚乳酸）中的药物。在体外初步优化后，尽管生物利用度较低，但OSPRAE在体内能将胰岛素递送至手术暴露的肠粘膜，其药代动力学和药效学与大鼠皮下注射相似。组织学分析表明，仅对肠上皮有浅表损伤，且高度局限于微观撞击区域。未来的研究应将OSPRAE口服给药于更大的动物，并最终应用于人类。OSPRAE胶囊提供了一种利用对流力增加生物制剂跨肠粘膜递送的新方法，这与先前涉及化学渗透促进剂和机电装置的方法形成对比。
