Novel polymers with enhanced hydrophilicity for the sustained delivery of therapeutic proteins

The main objective of this work was to evaluate novel polyphosphoester matrices with enhanced hydrophilicity, for the delivery of a representative therapeutic protein, protein C. Specifically, polyphosphoester polymers were characterized using Nuclear Magnetic Resonance (NMR), Gel Permeation Chromatography (GPC) and Differential Scanning Calorimetry (DSC) to understand their structure and thermal properties. One dimensional 1H and two-dimensional 1H-1H COSY (Correlational Spectroscopy) NMR indicated that the polymer had a structure concurrent to the predicted structure. The phosphate groups had a plasticizing effect on the polymer, leading to a decrease in the glass transition temperatures, in accordance with the Fox theory of copolymers. In vitro degradation of the polymers was studied in detail to understand the kinetics of degradation. The phosphate groups participated directly in the degradation process, leading to accelerated degradation as compared to polylactide. A smooth mass loss profile was observed which could be a direct result of enhanced solubilization of oligomers caused by the presence of phosphate.; The surface properties of the polymer were studied with reference to the polymer hydrophilicity and specific interactions with protein C. It was seen that hydrophilicity is a critical parameter governing the activity and release of protein C from the polymer. The hydrophobic polylactides led to a multilayer adsorption of protein C, which is consistent with a combined Langmuir-Freundlich isotherm model. This multilayer adsorption further led to a decrease in activity of the protein presumably due to conformational changes. The enhanced hydrophilicity of polyphosphoesters on the other hand reduced the interactions between the polymer and protein, allowing for a smooth release profile for the protein. In addition, the surfactant-like properties of polyphosphosesters facilitated better encapsulation efficiencies for protein C.; The effect of processing conditions on the protein activity was studied in detail. The presence of excipients, specifically human serum albumin, was seen to be critical for preservation of protein C activity during low temperature sonication as well as to minimize adsorption of protein C onto sample vial surfaces. The amphiphilic environment provided by a combination of polyphosphoesters and human serum albumin provided conditions feasible for maintenance of protein activity and allow sustained release.