Date of Award
Master of Science (MS)
Luvinov , Igor
Vyavahare , Narendra
Protein drugs are typically administered intravenously, but this practice has clear disadvantages such as widespread circulation and swift clearance from the body. Orally delivered protein drugs are not yet available but potentially offer improved distribution, retention, and activity by use of protective matrices and cell-specific targeting. Much work has been done on delayed release formulations for the upper intestine, but there has not been overwhelming evidence of protection of peptides from gastric conditions. In many instances the large intestine may be a better release target due to lower proteolytic activity. Afflictions of the colon such as Inflammatory Bowel Disease and colon cancer would benefit most directly from colon targeted drug release.
Orally delivered colon-targeted protein drugs need protection and a release mechanism to withstand the upper GI and be dispersed along the inflamed areas of the lower intestine. This sort of delayed release has been proven with low molecular weight drugs, but has yet to be shown with peptides which also need protection from the acidic and proteolytic conditions of digestion. This work aims to distribute protein drugs throughout the colon while retaining protein activity.
Pellets containing active peptides are synthesized from dextran modified with methacrylate. Dextranase, formed by bacteria and found in increasing amount in the lower intestines, gradually degrades these pellets allowing steady transport of drug from the pellet. These pellets are further coated in an acrylic copolymer (supplied by Evonik) designed to protect from acidic pH of the stomach and degrade within the upper intestines. Polylactide nanoparticles loaded in these constructs were found to release steadily under conditions simulating the colon over 25-40 hours.
Lysozyme was incorporated into pellets as a model protein drug and showed an estimated 10% activity after a complete digestion simulation. α-MUC1 was utilized similarly and imaged on epithelial cells, demonstrating feasibility of delivering antibody drugs orally. As many cancers overexpress MUC1 and inflamed cells are believed to as well, MUC1 is a potential drug target for CD and colitis. In vivo data using a mice colitis model showed mitigation of symptoms when administered with antacids. Overall this drug delivery platform has demonstrated colon targeting and potential efficacy of orally delivered enzyme, antibody, and other complex peptide drugs.
Blichmann, Paul, "ORAL DELIVERY OF PEPTIDE DRUGS FOR MITIGATION OF CROHN'S DISEASE" (2012). All Theses. 1486.