Khan, Isaac John. The utility of L-tyrosine based polycarbonate copolymers containing poly(ethylene glycol) as a degradable carrier for the release of a hydrophobic peptide molecule. Retrieved from http://dx.doi.org/doi:10.7282/T33778W2
DescriptionThe utility of biodegradable polymers as localized drug delivery carriers is an ongoing area of research where investigators attempt to deliver a wide range of hydrophobic small molecules and peptides. The long-term (> 1 year), controllable and sustained release of such molecules from these solid carriers has not been demonstrated due to the complexity of the reaction-diffusion mechanisms that occur in these hydrated polymers. The goal of the present research was to characterize the release of the hydrophobic peptide voclosporin from a class of biodegradable amorphous polymers based on desaminotyrosyl-tyrosine alkyl ester (DTR) and desaminotyrosyl-tyrosine ester, (DT), and the monomer polyethylene glycol (PEG). Four areas of study were presented: (i) the modulation of drug release and polymer erosion as a function of poly(DTR-co-y % DT-co-z % PEG1K carbonate) homo-, co- and terpolymer compositions, (ii) the changes in polymer morphology and a proposed theory to account for drug retention exhibited by these polymers after prolonged hydration, (iii) the instability of voclosporin in the presence of the terpolymer carriers and the need for formulations containing antioxidants and (iv) the demonstration of selected PEG-containing polycarbonate formulations as a drug delivery vehicle for potential ophthalmic applications. The polycarbonate terpolymers were shown to undergo hydration-induced microphase separation, where the mobility of the PEG1K length in the composition enabled this behavior. The limited access of water to regions containing only PEG was believed to cause both drug retention and a slowdown in polymer erosion in these matrices. Drug-polymer interaction between DTE-co-DT segments of the polymer and voclosporin was also suspected to play a role in drug retention. In vivo in vitro correlation (IVIVC) values of 3 to 4 obtained from rabbit implantation studies implied that both drug release and polymer resorption would be enhanced if these carriers were placed within the human body. Select tyrosine-based polycarbonate terpolymer matrices were well tolerated in the sensitive regions of the rabbit’s eye. An outcome of this research is the development of a polymer platform that can serve as an implantable medical device matrix to deliver drugs to patients for the treatment of chronic diseases and disorders of the eye.