In vitro and in vivo studies of controlled release of novel peptide from in situ polymer precipitation delivery system
Lim, Soo Ghim
Date of Issue2014
School of Materials Science and Engineering
The in situ polymer precipitation delivery system has generated much interest over the last two decades. The ease of manufacturing and administering the delivery system are key advantages that have contributed to its increasing preference as a mode of drug delivery. Although much research has been performed on this system, the number of studies that have translated into animal models and subsequently into clinical trials is much lower than desired. This study aimed to investigate and understand the release mechanism and kinetics involved in peptide release from an in situ polymer precipitation system. Moreover, this study aimed to establish a correlation between the in vitro- and in vivo-derived data. The ultimate aim was to identify a delivery system that can be used to deliver a novel therapeutic peptide, CD-NP, for the treatment of heart failure conditions. This study can be divided into 3 broad categories. First, in vitro studies were performed to characterise systemically the delivery system and its efficacy at achieving the prolonged release of the drug Cenderitide. Various gel formulation parameters were tested, i.e., the effect of polymer concentration, co-solvent, drug-loading and injected volume. The co-solvent system using the gel formulation 40% PLGA / 40% NMP / 20% triacetin was the most suitable for achieving the desired linear peptide release profile. Investigation of the solvent efflux and its influence on the drug release profile and shell structure formation morphology were also investigated. The solvent efflux and shell structure formation were found to be inter-dependent and affected the drug release profile. Second, feasibility studies were performed on both healthy and diseased Wistar rats. As a preliminary feasibility study, the peptide release from an in situ polymer precipitation delivery system was performed on healthy rats. The results suggested that the delivery system was efficacious. In addition, the peptide bioactivity was preserved until the end of the prescribed study. The results from the diseased rat model correlated with the feasibility studies. The acute myocardial infarction rat model was created through left ventricular ligation. As expected, the preservation of peptide bioactivity was observed at the study endpoint. More important, in this disease model, the peptide delivery system effectively attenuated the heart failure syndrome, demonstrated by the distinct preservation of cardiac functionality and structural integrity. Last, a simplified in vitro and in vivo correlation was established. Furthermore, it was established that the shape of the injected depot contributed to the initial peptide release. As such, a proper correlation between the in vitro and in vivo data during the solidification phase of the injected gel could not be established. However, following the complete solidification of the polymer depot, a steady peptide concentration was observed in the plasma. The estimated steady-state peptide plasma concentration was consistently 2.5x higher than that of the actual measured values. This phenomenon was attributed to the simplified single compartment diffusion model that was used to establish this relationship.