Exploring protein stabilized multiple emulsion with permeation enhancer for oral delivery of insulin

In present study, we have developed W/O/W microemulsion (ME) containing piperine (PiP) as a permeation enhancer and albumin (Alb) serving as a stabilizer for oral delivery of insulin (INS). The resultant formulation, ME(INS)-PiP-Alb exhibited droplet size of 3.35 +/- 0.25 mu m along with polydispersity index (PDI) of 0.30 +/- 0.10. The formulation process employed for developing ME(INS)-PiP-Alb showed no effect on INS's chemical and conformational stability. Further, ME(INS)-PiP-Alb was able to maintain desired attributes (size & PDI) along with INS stability in simulated gastrointestinal fluids. Also, ME(INS)-PiP-Alb rendered higher protection to INS in presence of pepsin and trypsin than ME(INS)-PiP. In qualitative Caco-2 cell uptake, INS loaded ME's showed higher uptake in comparison to free INS. Whereas, in permeability studies ME(INS)-PiP-Alb showed similar to 4 and similar to 1.5-fold enhanced permeation than free INS and ME(INS) without PiP groups respectively. Also, in ex vivo intestinal permeation studies similar fold increment in permeation were observed. Interestingly, the pharmacodynamic studies revealed similar to 3.2-fold higher hypoglycemic effect in animals treated with ME(INS)-PiP-Alb in comparison to ME(INS)-PiP. Similarly, the pharmacokinetic studies also revealed similar to 1.6 fold higher AUC for ME(INS)-PiP-Alb than ME(INS)-PiP. Thus, in vivo results suggested that Alb as a stabilizer can assist in improving the hypoglycemic effect of the developed ME with PiP. Hence, this strategy can also be extrapolated for delivering other bio-macromolecules orally. (C) 2020 Elsevier B.V. All rights reserved.

Automated summary

In this study, a novel oral insulin microemulsion was developed with piperine as a permeation enhancer and albumin as a stabilizer. The microemulsion showed small droplet size and good stability, maintaining INS stability in simulated gastrointestinal fluids and showing improved uptake and permeation compared to free INS. Animal studies demonstrated a significantly higher hypoglycemic effect and pharmacokinetic studies revealed higher AUC for the microemulsion with albumin as a stabilizer, suggesting its potential for oral delivery of bio-macromolecules.