An evaluation of the drug delivery applications of the tyrosine-derived polyarylates: The development of pulsatile release systems for a model water-soluble peptide

The members of the library of tyrosine-derived polyarylates are degradable polymers designed particularly for biomedical applications. The uniqueness of this library lies in the combinatorial chemistry approach to the synthesis of these structurally related materials. It has been demonstrated that the systematic variation of structural groups between the members permits precise control over polymer properties. It was postulated that such control of polymer properties would be useful in drug delivery applications and prompted the studies reported here. It would permit the design or selection of particular materials with specific characteristics to suit an active agent and the desired release profile. This approach is in direct contrast with the current trend which focuses on optimizing the properties of one material, poly(lactide-co-glycolide) (PLGA), for use with all water-soluble active agents.; In the drug release studies reported here, IntegrilinTM was used as the model water-soluble peptide. Although the peptide is water-soluble, only trace amounts of peptide were released from the polymer during in vitro studies. Further investigation indicated that due to the peptide-like structure of the polymer, hydrogen bond and hydrophobic forces developed between the peptide and the polymer inhibiting release.; The reduction of the pH of the polymer matrix weakened these interactions. This sensitivity to pH was used to formulate delayed and pulsatile release systems. In one system, low molecular weight PLGA was blended into the formulation. This blend delayed the release of the peptide until the PLGA degraded sufficiently to reduce the pH of the polymer matrix. Initial molecular weight of PLGA was used to control the lag time preceding release; This delayed release effect was also accomplished by copolymerizing with a free-acid containing monomer. It was observed that a critical mole percent of this monomer was necessary for release and that the length of the lag time decreased with increasing acid content.; Organization within the polymer matrix also weakened these interactions. Consequently, the polymer that was associated with long range ordering was also associated with release of the peptide, and the release rate increased with increasing percent crystallinity within the polymer matrix.