Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been re-ported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes,pH and other gastrointesti-nal barriers.In this study,we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration(insulin≥40μg/mL)-,ratio(SNAC/insulin≥20∶1)-and pH(≥6.8)-dependent manner,thus contributing to a significantly high efficacy of oral insulin delivery.Specifically,absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol.Furthermore,the complexes accelerated the exocytosis of insulin to the basolateral side,thereby enhancing its intestinal mucosal permeability.Eudragit? S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient(Papp)that was 6.6-fold higher than that of the insulin solution.In diabetic rats,hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into enteric-coated capsules.Further pharmacokinetic studies revealed an approximately 6.3％oral bioavailability in both the fasted and fed states,indicating a negligible food effect.Collectively,this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.

Huixian Weng;Lefei Hu;Lei Hu;Yihan Zhou;Aohua Wang;Ning Wang;Wenzhe Li;Chunliu Zhu;Shiyan Guo;Miaorong Yu;Yong Gan

School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210046,China;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China;Nano Science and Technology Institute,University of Science and Technology of China,Nanjing 215123,China;University of Chinese Academy of Sciences,Beijing 100049,China;NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients,National Institutes for Food and Drug Control,Beijing 100050,China

中国化学快报（英文版）

[1]Huixian Weng;Lefei Hu;Lei Hu;Yihan Zhou;Aohua Wang;Ning Wang;Wenzhe Li;Chunliu Zhu;Shiyan Guo;Miaorong Yu;Yong Gan-.The complexation of insulin with sodium N-[8-(2-hydroxybenzoyl)amino]-caprylate for enhanced oral delivery:Effects of concentration,ratio,and pH)[J].中国化学快报（英文版）,2022(04):1889-1894

caprylate,bioavailabilities

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