Co-encapsulation by Flash NanoPrecipitation of Insulin, Trypsin Inhibitor and Caprate Permeabilization Enhancer for Oral Administration

Abstract

We describe inverse-Flash NanoPrecipitation as a new scalable platform for co-encapsulation of insulin (a model therapeutic peptide) with soybean trypsin inhibitor (a peptidase inhibitor) and so-dium caprate (a permeation enhancer) forming 300 nm particles for oral delivery. The co-encapsulation of the protein therapeutic with a protease inhibitor and a permeation enhancer into nanoparticles addresses enzymatic attack on the protein drug and the transport across the gastroin-testinal tract barrier. Inverse-Flash NanoPrecipitation (iFNP) encompasses two sequential precipita-tion processes. First, insulin, soybean trypsin inhibitor (SBTI), and hydroxypropyl methylcellulose acetate-succinate polymer (HPMCAS, a stabilizing block copolymer)(at mass ratios of 1:4:5) are rapidly precipitated into an organic antisolvent forming the inverted nano-core (iNC) with 50 wt% insulin and SBTI. Encapsulation efficiencies are greater than 98%. The second step involves the precipitation of sodium caprate and a stabilizing polymer coating onto the iNCs surface. HPMCAS, chitosan, and PEG polymers are used to coat the iNCs to generate nanoparticles with anionic, cation-ic, and neutral surfaces, respectively. This demonstrates that the iFNP platform can encapsulate complex biologics mixtures at high loadings into particles with customizable surface properties.