Development of Poly(Lactide-Co-Glycolide) Microspheres for Controlled Release of Thymosin Beta-4 in the Heart

Thymosin beta-4 is of great importance because it improves heart function after heart attack in animal models. In order to limit the number of interventions in Thymosin beta-4 therapy, a localized and controlled release formulation is necessary. Our goal was to generate controlled release microsphere formulations of poly(lactic-co-glycolic acid) that overcame a common problem of burst-release and to establish a method to modulate the release rates between formulations. Burst-release is the rapid release of drug from the formulation occurring in the initial 24 hours of elution. This event causes undesirable loss and potentially toxic levels of therapeutic from the microsphere. Modulation of release is of particular importance in these studies because little is known regarding the therapeutic dose of Thymosin beta-4 in humans. A class of non-ionic surfactants, alkyl glucosides, were used as excipients in preparation of poly(lactic-co-glycolic acid) double-emulsion microspheres for controlled release of the protein albumin or the peptide Thymosin beta-4. We specifically chose octyl-glucopyranoside and decyl-glucopyranoside for their ability to stabilize the primary emulsion step during microsphere synthesis. We demonstrate that the addition of alkyl glucosides of differing hydrocarbon chain length can modulate the rate of protein and peptide release from these microspheres. In albumin formulations, octyl-glucopyranoside reduced overall release compared to decyl-glucopyranoside and formulations prepared without surfactant, whereas in TB4 formulations decyl-glucopyranoside reduced overall release. In albumin containing microspheres burst release was high in formulations that did not contain any surfactant, 23%. Addition of decyl-glucopyranoside reduced burst release to 6% while addition of octyl-glucopyranoside further reduced burst release to 3%. Thin sections revealed smaller and more uniform internal porosity in microspheres containing surfactant, of which octyl-glucopyranoside porosity was less than decyl-glucopyranoside porosity. This difference in porosity corresponds with the reduction in initial burst release and overall release of albumin. With these surfactants we established a group of formulations with differing drug release rates. This research suggests that formulations containing Thymosin beta-4 can be beneficially used in future in vivo testing to determine a controlled release profile capable of generating a therapeutic response in ischemic heart disease.