Bertsch Pascal, Frøslev Patrick, Currie Jonathan, Carrière Frédéric, Müllertz Anette, Nielsen Hanne Mørck
Drug Delivery and Biophysics of Biopharmaceuticals, BioDelivery Center, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
Drug Delivery and Biophysics of Biopharmaceuticals, BioDelivery Center, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
J Colloid Interface Sci. 2025 Dec 15;700(Pt 1):138363. doi: 10.1016/j.jcis.2025.138363. Epub 2025 Jul 7.
Double emulsions are potential oral delivery systems for the simultaneous administration of hydrophilic drugs and hydrophobic permeation enhancers to enable effective intestinal absorption of macromolecular drugs. Emulsions stabilized by solid particles, i.e., Pickering stabilizers, have shown potential to form gastric-stable emulsions that can protect their cargo from release under gastric conditions. Here, we use acylated cellulose nanocrystals to facilitate the formation of stable double emulsions for intestinal drug delivery. Water-in-oil-in-water double emulsions were obtained by a two-step emulsification process and found to be colloidally stable over 6 months allowing permanent encapsulation of a high molecular weight compound (4 kDa fluorescein isothiocyanate-labelled dextran, FD4) in the inner water phase at >90 % encapsulation efficiency. Exposure to simulated gastric conditions and gastric lipase did not affect the emulsion structure or trigger FD4 release. Double emulsions underwent a pronounced restructuring under simulated intestinal conditions due to the presence of bile, yet without triggering excessive FD4 release (<10 %). Digested emulsions reduced the transepithelial electrical resistance of an intestinal in vitro Caco-2 cell culture model by hydrolysis of the emulsion oil phase into medium chain fatty acids that act as intrinsic permeation enhancers. The double emulsions facilitated permeation of FD4 across the intestinal in vitro model at similar levels as non-formulated FD4 and C10. Hence, double Pickering emulsions stabilized by acylated cellulose nanocrystals comprise a novel gastric stable oral delivery system that can co-deliver large hydrophilic macromolecules and permeation enhancers to the small intestine towards effective intestinal absorption.
双乳液是一种潜在的口服给药系统，可同时给予亲水性药物和疏水性渗透促进剂，以实现大分子药物的有效肠道吸收。由固体颗粒（即Pickering稳定剂）稳定的乳液已显示出形成胃稳定乳液的潜力，该乳液可以保护其所载物质在胃部条件下不释放。在此，我们使用酰化纤维素纳米晶体来促进用于肠道药物递送的稳定双乳液的形成。通过两步乳化过程获得了水包油包水型双乳液，发现其在6个月内具有胶体稳定性，能够以>90%的包封效率将高分子量化合物（4 kDa异硫氰酸荧光素标记的葡聚糖，FD4）永久包裹在内水相中。暴露于模拟胃部条件和胃脂肪酶下不会影响乳液结构或触发FD4释放。由于胆汁的存在，双乳液在模拟肠道条件下发生了明显的结构重组，但没有触发过多的FD4释放（<10%）。消化后的乳液通过将乳液油相水解为中链脂肪酸（作为内在渗透促进剂），降低了体外肠道Caco-2细胞培养模型的跨上皮电阻。双乳液促进了FD4在体外肠道模型中的渗透，其水平与未配制的FD4和C10相似。因此，由酰化纤维素纳米晶体稳定的双Pickering乳液构成了一种新型的胃稳定口服给药系统，该系统可以将大的亲水性大分子和渗透促进剂共同递送至小肠，以实现有效的肠道吸收。
