A synthetic polymer matrix for the delayed or pulsatile release of water-soluble peptides

Abstract

The design of a polymeric peptide release system with a controlled delay time and a burst-free pre-release phase is described. In general, the system consists of a blend of a tyrosine-derived polyarylate and a fast-degrading copolymer of lactic and glycolic acid (PLGA). Due to the peptide-like structure of the polyarylate backbone, peptide–polymer interactions prevented the release of peptide from neat polyarylate films. The addition of PLGA acts as a ‘delayed’ excipient: as PLGA degrades, it generates acidic degradation products that cause a drop in the internal pH of the polyarylate matrix. This drop in pH weakens the peptide–polymer interactions and causes the release of peptide to commence. The initial molecular weight of PLGA can be used to control the length of time before degradation occurs. Consequently, this parameter can also be used to control the duration of the delay period prior to peptide release. As a specific model system, blends of poly(DTH adipate) with three different copolymers of lactic and glycolic acid were prepared and used for the delayed release of Integrilin™, a synthetic water-soluble heptapeptide (clinically used in antithrombic injections) that acts as a highly potent glycoprotein IIb/IIIa antagonist. Blends composed of a 1:1 weight ratio of poly(DTH adipate) and PLGA and containing Integrilin™ (15%, w/w) were prepared. In vitro release studies were conducted in phosphate buffered solution at 37°C and the release of Integrilin™ was followed by HPLC. As the initial molecular weight of PLGA varied from 12 000 to 62 000, the duration of the delay period prior to release increased from 5 to 28 days.