The effect of size, charge and cyclization of model peptides on their in vitro release from DL-PLGA microspheres

This study was designed to examine the effects of size, charge and conformation on the release of peptides from microspheres of poly (D,L-lactic-co-glycolic) acid 50:50 (DL-PLGA). These microspheres were prepared using a double emulsion technique and were characterized for size, morphology and peptide release kinetics. The influence of formulation variables such as water volume of the internal-phase and excipient loading were also investigated. The linear hexapeptides (Ac-Trp-Ala-Gly-Gly-X-Ala-NH2, X=Asp, Asn, Lys) used in this study were chosen because of their ability to form p-turn structures in solution. To determine what effect restricting the conformational flexibility would have on the release of peptide, a series of cyclic hexapeptides (cycle [Trp-Ala-Gly-Gly-X-Ala], X=Asp, Asn, Lys), which exist primarily in compact, beta-turn solution conformations, were also studied. The capped-amino acids (Ac-X-NH2, X=Asp, Asn, Lys) were used to determine the effect that size (MW, hydrodynamic volume) and charge have on their release from DL-PLGA microspheres. The volume of water used as the internal-phase has a significant effect on the release of the linear hexapeptide Ac-Trp-Ala-Gly-Gly-Asp-Ala-NH2. For example, when no water is added, the release appears to be erosion-controlled. In contrast, when 150, 500 or 1000 mu l of water is added, the release shifts to a diffusion-controlled mechanism. Changing the size, charge and conformational flexibility of the model peptides had no significant effect on their release kinetics. The differences in release kinetics that were observed for the neutral capped amino acid and the positively-charged cyclic hexapeptide are due to unique specific interactions between these compounds and DL-PLGA. (C) 1997 Elsevier Science B.V.