Exploring the potential of redispersible nanocomplex-in-microparticles for enhanced oral insulin delivery.

Polyelectrolyte nanocomplex (PEC) is a promising carrier for insulin encapsulation. However, tenacious enzymatic degradation and insufficient penetration in mucus and enterocyte are the dominating obstacles for their oral insulin delivery. Besides, the rate of insulin release should be tuned to achieve desired therapeutic effect and meanwhile with scale-up potential. Thus, PEC embedded microparticles were fabricated in this study to solve the above dilemma. First of all, insulin loaded PEC with sodium dodecyl sulfate (SDS) coating was prepared by self-assembly method and then spray-dried using different ratio chitosan (CS)/ polyvinyl alcohol (PVA) as the matrix to obtain the microparticles. Influence of the CS/PVA ratio on the in vitro and in vivo properties of the redispersed PEC was investigated systemically. It was demonstrated that when CS 50 kDa was used in the matrix, all the PEC could be well redispersed with particle size less than 250 nm, and good stability in the gastrointestinal tract, further improved enzymatic stability was achieved by nanoparticles-in-microparticles design, with CS/PVA 1:1 and 4:1 groups showing better and comparable protection. Insulin release from the microparticles decreased with the increase of CS ratio in the CS/PVA matrix. Spray-dried microparticles had less influence on the mucus penetration of the in situ redispersed PEC, with enhanced insulin permeation observed in different intestinal segments in a CS/PVA ratio dependent manner. And the CS/PVA 1:1 group, which presented good enzymatic stability, enhanced mucus penetration and moderate insulin release rate, exhibited the highest relative pharmacological availability of 6.80%. In conclusion, PEC in microparticles design using CS/PVA as the composite matrix is a potential platform for enhanced oral insulin delivery.