(666a) Mechanistic Modeling of PLGA Microsphere Drug Delivery: Analytical Autocatalytic Degradation of Polymer and Hindered Diffusion of Drug | AIChE

(666a) Mechanistic Modeling of PLGA Microsphere Drug Delivery: Analytical Autocatalytic Degradation of Polymer and Hindered Diffusion of Drug


Ford Versypt, A. N. - Presenter, Massachusetts Institute of Technology
Braatz, R. D., Massachusetts Institute of Technology
Pack, D. W., University of Illinois Urbana-Champaign

Controlled release drug delivery is a category of pharmaceutical administration techniques where the concentration of medicine in a patient’s body is sustained for an extended period of time with a single dose. Controlled-release drug delivery devices such as polymer microspheres composed of poly(lactic-co-glycolic acid) (PLGA) are alternatives to conventional pharmaceutical dosage forms such as pills or injections that require repeated doses or complicated dosing regimens. Controlled-release drug delivery alleviates the pressure on patients to adhere to strict dosing schedules, thus improving the compliance with the prescribed treatment. Controlled-release drug delivery also can enhance the control of drug concentrations in a patient and reduce side effects associated with frequent doses, missing doses, or peaks and valleys in drug concentration.

Biodegradable PLGA microspheres have been extensively studied as drug delivery devices [1-4]. Modeling of the drug release from the devices must consider the interdependent phenomena that contribute to drug release [1,5]; the most significant of the phenomena are autocatalytic polymer degradation and drug diffusion. 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 severe in the interior of large microspheres where the diffusion of degradation products is more limited [5-9]. 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 [10-11]. As the pore network in the microspheres evolves, the effective diffusivity of the drug increases, thus enhancing the diffusion of drug through the microspheres and accelerating drug release.

A mathematical reaction-diffusion model [12] is defined and solved analytically for the concentration of carboxylic acid end groups of the polymer chains in PLGA microspheres as a function of radial position and time. The model treats simultaneous diffusion and first-order degradation to capture the microsphere-size-dependent effects of autocatalysis on PLGA erosion. The analytical expression is useful for predicting the conditions under which drug release from PLGA microspheres transitions from diffusion-controlled to erosion-controlled release, for understanding the dynamic coupling between the PLGA degradation and erosion mechanisms, and for designing drug release particles. The model is the first to provide an analytical prediction for the dynamics and spatial heterogeneities of PLGA degradation and erosion within a spherical particle. The analytical solution is general and can be applied to other spherical systems with simultaneous diffusive transport and first-order generation by reaction.

The analytical expression for the autocatalytic polymer degradation and erosion is coupled to a model of pore evolution, which is related to the effective diffusivity through hindered diffusion theory, and subsequent diffusive drug release [12-13]. The unique contribution of the modeling work is that it combines autocatalytic PLGA degradation mechanisms [10-11] with hindered diffusion in aqueous pores [14-15] having variable pore sizes. The model performance for the case of drug release from microspheres of different sizes is presented to highlight the capability of the model for predicting size-dependent, autocatalytic effects on the polymer and the release of drug.


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