Injectable Multi-Drug Formulation for the Postoperative Management of Ocular Surgery

Abstract

In this dissertation, the interaction between particles or particles and polymers were examined. In addition, outcomes of such studies were used to develop drug delivery formulations. Initially, by carrying out Brownian dynamics (BD) simulations binding kinetics between two spheres in the dilute limit under shear flow for the entire Pe values (measure of flow strength) was studied. Effects of Pe, hydrodynamic interactions, inter-particle potential and surface anisotropy were studied. Results were in agreement with previous literature that had limited range of applicability including zero and infinite shear rate Smoluchowski limits, as well as high Pe perturbation results of Feke and Schowalter [J. Fluid Mech. 133, 17-35 (1983)]. Next, developing a drug delivery system for the postoperative management of ocular surgery was considered. In routine care after cataract surgery, patients are required to receive antibiotics for a week and steroids for at least a month. Later during postoperative treatment period, ocular pressure increases and could be managed by administration of ocular hypotensives, which adds to postoperative treatment burden. Currently, the required drug molecules in the postoperative treatment are delivered mainly by eye drops, which have significant shortcomings, such as poor patient compliance, low drug bioavailability and allergic reactions. Hence, different routes were pursued to make a formulation that reduces reliance on the patients to use eye drops. Initially, layer-by-layer (LbL) assembly of nanoparticles (NPs) and polyelectrolytes was considered as a viable strategy. The goal was to layer different sheets of LbL films with different drug loaded NPs in order to fine-tune the drug release profile. The effect of different parameters on the growth of LbL films was studied and the optimal conditions to grow thick LbL films with inexpensive blank NPs were attained. Unfortunately, by switching from blank polystyrene NPs to biodegradable poly(D,L-lactide-co-glycolide) (PLGA) NPs, the growth of LbL films was interrupted. Therefore, we were faced with the challenge of modifying our research to find a more robust solution for postoperative management following cataract surgery. In a subsequent attempt, the multidrug release system was developed utilizing thermoresponsive polymer solutions. The invented drug release system is composed of microparticles incorporated into a bulk hydrogel that was engineered to be in liquid form at room temperature for simple delivery into the eye and form a hydrogel network at physiological body temperatures to act as a depot release platform. The delivery platform was designed to mimic current topical application of postoperative ocular formulations, releasing the antibiotic for up to a week, and the corticosteroid and the ocular hypotensive agents for at least a month. Different means to finely tune drug release was demonstrated. To ensure the most linear drug release, more hydrophobic blocks such as PLCL should be used in the triblock copolymer. Increasing the hydrophobicity of the polymer encapsulating the drug molecules, it was possible to prolong the release duration of drugs substantially. Finally, preliminary results on overcoming the poor bioavailability of free drug molecules to be used for the treatment of ocular diseases and cancer were examined. Two anti-hypoxia inducible factors (anti-HIFs) were successfully loaded in PLGA NPs with small particle size and considerable drug loading. Next, drug release from NPs was evaluated, in vitro. Finally, the effect of NPs on inhibiting HIF expression and blocking angiogenesis were examined in vivo. Results demonstrate significant improvements using NPs compared to free drug.