Engineering PLGA Nanocomposite Matrices: Influence of Polymer Structure on Drug Release Kinetics and Ocular Pharmacokinetics

Abstract

The study emphasizes the role of PLGA as a biodegradable polymeric matrix governing drug release through diffusion and polymer erosion mechanisms, thereby functioning as a polymer–drug nanocomposite system. The structural and physicochemical properties of the polymer matrix play a critical role in controlling drug encapsulation and release kinetics. The solvent evaporation technique was utilized to fabricate PLGA nanoparticles, and a 3² factorial design was implemented for optimization. The optimized combination exhibited a zeta potential of −21.5 ± 2.6 mV, a polydispersity index of 0.182 ± 0.03, and an average particle size of 178.6 ± 12.4 nm. The drug loading was determined to be 14.6 ± 1.2%, while the drug entrapment efficiency was found to be 82.3 ± 3.7%. The biphasic release pattern was demonstrated in in vitro release studies. The initial burst release transpired within 6 hours, with a release rate of 21.4 ± 2.1%. The second burst release transpired within 72 hours, yielding a cumulative release rate of 88.7 ± 3.5%. Investigations into the permeability of nanoparticles in goat corneas revealed a 1.97-fold enhancement in the permeability coefficient, with drug infiltration from nanoparticles significantly exceeding that from drug suspension (68.2 ± 4.3% versus 34.6 ± 3.1%; p < 0.001). In vivo research on the pharmacokinetics of medicine absorption and ocular residence time in New Zealand albino rabbits (n = 6) demonstrated that PLGA nanoparticles significantly enhanced both parameters. The nanoparticle formulation exhibited a peak drug concentration (C_max) of 3.84 ± 0.42 µg/mL in aqueous humor, whereas the suspension demonstrated a concentration of 1.76 ± 0.28 µg/mL (p < 0.001). The extended duration to achieve maximum concentration (T_max) (4.0 ± 0.5 h vs. 1.5 ± 0.3 h) indicates a sustained release pattern. The nanoparticles exhibited a 2.2-fold enhancement in bioavailability, evidenced by a much larger area under the curve (AUC₀-24h) of 28.6 ± 3.2 µg·h/mL, in contrast to the suspension's 12.9 ± 2.1 µg·h/mL. The results indicate that PLGA nanoparticles offer superior therapeutic efficacy, prolonged drug release, and improved bioavailability as a carrier system for sustained ocular delivery of dexamethasone. The study emphasizes how polymer matrix density, interfacial stabilization, and crystallinity govern diffusion pathways and degradation-controlled release.