(261d) Design of PLGA Microparticle Drug Delivery Systems Using Mechanistic Reaction-Diffusion Model

Proteins and pharmaceuticals can be encapsulated into biodegradable polymer microspheres of controlled size. Core-shell microparticles and microcapsules can also be fabricated uniformly, and present important options for encapsulating drugs for delivery in a multi-stage pulsatile release fashion or for protecting proteins from being deactivated by suspension in an aqueous core for time-delayed delivery after polymer microcapsule degradation. The precision particle fabrication technique can reproducibly yield highly uniform distributions of microparticles with tight control of the specific sizes and thicknesses of core-shell microparticles and microcapsules. Controlled-release drug delivery systems are being developed as an alternative to conventional medical drug therapy regimens that require frequent injections or oral dosages. Also, some pharmaceuticals have poor oral bioavailability which means that the drug compounds are not readily absorbed by the body through the digestive system. Controlled-release systems have the potential to provide better control of drug concentrations and reduce the side effects of current drug therapies. These systems can be designed to provide specific drug concentrations over extended periods of time that are optimal for effectiveness of the drug and avoid both ineffective low and potentially harmful high drug concentrations. Controlled-release systems can also be administered locally to the part of the body where the drug is needed. Although controlled-release devices have clear advantages, their design depends heavily on trial-and-error experiments due to incomplete understanding of the mechanisms that regulate the release processes. An accurate computational model of drug release from polymer microspheres would be useful for determining the optimal parameters for fabrication of the microspheres to yield a desired drug concentration profile. A successful mechanistic model of this type would be a useful tool for planning experiments, and once thoroughly validated, it could be used in the design of pharmaceutical manufacturing of microspheres.

A mechanistic model developed to capture the degradation heterogeneities observed in PLGA microspheres of different sizes due to autocatalytic polymer hydrolysis is compared to experiments for microspheres, core-shell microparticles, and microcapsules. The mechanistic model is also used to predict drug release profiles for a variety of formulation variables in order to optimally design biodegradable polymeric microparticles for controlled release. Changing the design variables such as the core diameter and shell thickness along with the distribution of molecular weights and pore sizes enables the design of microparticles to produce a large spectrum of obtainable release profiles. These profiles include zeroth-order release and pulsatile release with a range of shapes for the individual pulses. The model also determines the pH as a function of position within the microparticle, which can be used to design microparticles that limit the pH to ranges in which the released molecule is stable. The mechanistic model can also be used to compute an optimal distribution of microparticles.