Fabrication techniques for the preparation of orally administered insulin nanoparticles

The development of orally administered protein drugs is challenging due to their intrinsic unfavourable features, including large molecular size and poor chemical stability, both of which limit gastrointestinal (GI) absorption efficiency. Nanoparticles can overcome the GI barriers effectively and improve the oral bioavailability of proteins in the GI tract. They possess large surface area to volume ratio, and can facilitate the GI absorption of nanoparticles via the paracellular and transcellular routes. Nanoparticles can be prepared by various fabrication techniques that can encapsulate the fragile therapeutic proteins via hydrophobic bonding and electrostatic interaction. A desirable technique should involve minimal harsh conditions and encapsulate therapeutic proteins with preserved functionalities. The current review examines the characteristics of each preparation technique, and illustrates the examples of insulin-loaded nanoparticles that have been developed in each fabrication method. The following techniques, which include nanoprecipitation, hydrophobic conjugation, flash nanocomplexation, double emulsion, ionotropic gelation, and layer-by-layer adsorption, have been used to formulate ligand-modified nanoparticles for targeted delivery of insulin. Other techniques, including reduction, complex coacervation (polyelectrolyte complexation), hydrophobic ion pairing and emulsion solvent diffusion method, and sol-gel technology, were also discussed in the latter part of the review due to their extensive use in fabrication of insulin nanoparticles. This review also discusses the strategies that have been utilised during the formulation process to improve the stability and bioactivity of therapeutic proteins.