Developing oral formulations for protein and peptide drugs

The vast majority of protein/peptide drugs are not available orally. Their oral delivery is hindered by intestinal instability and limited permeability. The aim of this project was to gain an understanding of the stability of a large protein, lactase, a small protein, insulin, and a newly discovered peptide throughout the intestinal tract. This was used for the rational design of their oral formulations. Lactase was completely denatured at gastric pH within 10 minutes but was stable with intestinal enzymes. Encapsulation in enteric Eudragit L100 microparticles using a method previously used to encapsulate low molecular weight drugs produced small particles with a high yield and encapsulation efficiency, >90%. They restricted lactase release in acid but did not protect it from denaturation. Porosity and particle morphology investigations using an SEM with a new type of detector revealed surface structures which disappeared upon dispersal in acid and an inner porous structure which may allow acid entry and lactase denaturation. Co-encapsulation of an antacid preserved almost 10% of lactase activity in acid, superior to existing oral lactase supplements. Insulin was not hydrolysed at gastric pH but was immediately and completely digested by gastrointestinal enzymes. To protect it from pepsin insulin was encapsulated in Eudragit L100 microparticles. The particles produced were <100μm with a yield and encapsulation efficiency of >70%. After incubation with pepsin they protected 80% of encapsulated insulin. A small peptide, peptide 1 was gradually degraded in the intestinal fluids. To provide protection and increase its permeability peptide 1 was encapsulated in PLGA nanoparticles but 15% of the encapsulated peptide was immediately released in vitro. Encapsulation of the nanoparticles in Eudragit L100 microparticles successfully prevented any burst release in acid. This should minimise gastric digestion of peptide 1 and concentrate nanoparticle release in the small intestine providing a higher probability of permeation.