Controlled Release of Exendin-4 from PLGA Micropheres with Convective Blood Flow
Chen, Yuen Ching (Brenda); Kim, Justin; Lee, Jae Dong; Song, Sang Hoon
Type 2 diabetes is a metabolic disease characterized by high blood glucose due to insulin resistance and relative insulin deficiency. Primarily affecting those suffering from obesity, it comprises approximately 90% of all cases of diabetes. Currently, insulin and metformin injections are the most common methods of lowering blood glucose levels in type 2 diabetics. However, there are several disadvantages to these treatments, including the need for several injections a day and the risks associated with improper dosage or deviation from injection schedule. One proposed alternative treatment is to deliver microspheres embedded with exendin-4, an insulin secretagogue with glucoregulatory effects on the body, via a single subcutaneous injection. Bioerodible microspheres allow for a slow, sustained release of drug that will decrease the required frequency of administration and subsequently improve patient compliance. This paper documents the release of exendin-4 from poly(lactic-co-glycolic acid) (PLGA) microspheres into the bloodstream and the phenomena that influence its transport, namely the diffusion through the polymer matrix and bloodstream and the convective mass transfer effected by the flow of blood in the vessel. Because the motivation behind using microspheres as the preferred method of delivery is to eliminate the need for repeated administration, it is necessary to achieve a controlled, prolonged delivery of the desired dosage of exendin-4. The goal of this study is to find the optimal formulation properties for a steady release of exendin-4 into the bloodstream for an extended period of treatment. To this end, we developed a 2D-axisymmetric geometry in COMSOL to model a single microsphere in the human artery. A time varying boundary condition was implemented to simulate the changing radius of the microsphere, which steadily decreases due to surface degradation. A variety of parameters (e.g. PLGA composition, initial drug concentration, microsphere radius) were simulated using a series of parametric sweeps, and the effects of parametric changes were observed using sensitivity analysis. We found that the determination of the optimal diffusivity of exendin-4 in the PLGA microsphere depends on the desired balance between steadiness of release rate and total amount released after three weeks. Higher ratios of glycolic acid resulted in undesired bursts of drug release, whereas higher ratios of lactic acid did not result in appreciable rates of diffusion through the polymer matrix and thus did not achieve complete release by the end of the administration period. For any given composition of PLGA, we determined that an initial concentration of 1.505 mol/m3 (247 mg/mL) provided flux values within the reasonable range for effective delivery of exendin-4 over the desired period of administration. Our model does not provide conclusive evidence that the delivery of exendin-4 embedded in PLGA microspheres will achieve adequate therapeutic results. However, computational analysis of the concentration profiles attainable in the bloodstream provides a rough estimate of the formulation conditions required for controlled drug release; subsequent experiments will be conducted to evaluate its viability as a safer, less invasive alternative to periodic direct insulin injections for the treatment of type 2 diabetes.
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