(537a) Modeling of Dynamic Hindered Diffusion of Drugs From Biodegradable PLGA Microspheres with Evolving Porous Structure

Controlled-release drug delivery systems provide alternatives to conventional medical drug therapy regimens which require frequent dosages due to short pharmaceutical in vivo half-life and poor oral bioavailability. Controlled-release systems have the potential to enhance control of drug concentrations, reduce side effects, and improve compliance as compared to conventional regimens.

Poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres are the controlled-release drug delivery system modeled in this work. Biodegradable PLGA microspheres have been extensively studied as drug delivery devices [1-3]. Modeling of the drug release from the devices must consider the interdependent phenomena that contribute to drug release. The microspheres encapsulate drug molecules dispersed throughout the polymer. The polymer undergoes autocatalytic hydrolysis, breaking the polymer bonds and generating smaller polymer chains with acidic end groups that catalyze further hydrolysis of the degradation products. Autocatalytic hydrolysis is more significant in the interior of large microspheres where the diffusion of degradation products is more limited [4-6]. Sufficiently small oligomers produced by the degradation are water-soluble and can diffuse out of the polymer microspheres through water-filled pores. The resulting polymer mass loss increases the pore volume in the microspheres. Encapsulated drug molecules diffuse through the aqueous pores in the polymer by hindered diffusion [7]. As the pore network in the microspheres evolves, the effective diffusivity of the drug increases.

A reaction-diffusion model has been developed to investigate the degradation heterogeneities observed in PLGA microparticles of different sizes due to autocatalytic polymer hydrolysis and polymer erosion. The model considers the coupling between the hydrolysis reactions, the diffusion of polymer oligomers, and the dynamic effective diffusivity of the drug. The unique contribution of the modeling work is that it combines autocatalytic PLGA degradation mechanisms [8-9] with hindered diffusion in aqueous pores [10] having variable pore sizes. Simulations using the model capture microsphere-size-dependent release phenomena observed experimentally and show the dependence of drug release profiles on polymer morphology.

References

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