Development of P(TMC)-Based Polymers for Sustained Delivery of Acid-Sensitive Drugs

Abstract

Peptides are a quickly growing drug class, which continue to garner attention in pharmaceutical research due to their applications in the treatment of a variety of diseases. The major challenge when working with these drugs is their rapid degradation in vivo and poor membrane-permeability. This makes simple administration via oral routes infeasible and necessitates the use of a localized drug delivery system. One example of such a system is to load the peptide into a biodegradable polymer which is then injected close to the drug’s site of action. The polymer provides extended drug release, before degrading and being removed by the body. This is done commercially by a polymer called poly(lactide-co-glycolide), or PLG. However, PLG breaks down to form highly acidic by-products, which react with the peptide and alter the drug’s chemistry. Depending on the peptide, this can lead to reduced effectiveness or inactivation. In this work, a P(TMC)-based polymer containing pendant hydroxyl and butyrate groups was synthesized and assessed as a delivery vehicle for acid-sensitive drugs. P(TMC-HTMC-BtTMC) copolymers with varying compositions and molecular weights were examined. Ultimately, a low molecular weight viscous liquid formulation was the most feasible delivery option, and its degradation was characterized. Release of a representative peptide drug, octreotide, from the polymer was also studied. Increasing the HTMC content resulted in increased degradation, but complete degradation of the polymers was not achieved after 8 weeks, with degradation slowing considerably as HTMC content approached 15%. Modification of the octreotide was reduced in comparison to studies done using PLG, however, instead of acylation a small amount of glyceration occurred. Release of the octreotide from the polymers was also relatively short when compared to PLG, with the longest release period observed lasting less than ten days.