273889 Modeling of Drug Delivery From PLGA Microspheres Using Reaction-Diffusion Equations with Hindered Diffusion

Tuesday, October 30, 2012: 12:30 PM
327 (Convention Center )
Ashlee N. Ford Versypt1,2, Daniel W. Pack2 and Richard D. Braatz1, (1)Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, (2)Chemical & Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL

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 mathematical model has been developed for the simultaneous treatment of PLGA degradation and erosion and diffusive drug release with autocatalytic effects and nonconstant effective diffusivity of the drug [8-9]. A mechanistic reaction-diffusion model with pore evolution coupled to hydrolysis and related to the effective diffusivity through hindered diffusion theory is proposed. The unique contribution of the modeling work is that it combines autocatalytic PLGA degradation mechanisms [10-11] with hindered diffusion in aqueous pores [12] 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.


[1] J. M. Anderson and M. S. Shive. Biodegradation and Biocompatibility of PLA and PLGA Microspheres. Advanced Drug Delivery Reviews, 28(1):5-24, 1997.

[2] N. K. Varde and D. W. Pack. Microspheres for Controlled Release Drug Delivery. Expert Opinions on Biological Therapy, 4(1):35-51, 2004.

[3] S. Freiberg and X. X. Zhu. Polymer Microspheres for Controlled Drug Release. International Journal of Pharmaceutics, 282(1-2):1-18, 2004.

[4] J. Siepmann, K. Elkharraz, F. Siepmann, and D. Klose. How Autocatalysis Accelerates Drug Release from PLGA-Based Microparticles: A Quantitative Treatment. Biomacromolecules,  6(4):2312-2319, 2005.

[5] C. Berkland, E. Pollauf, C. Raman, R. Silverman, K. Kim, and D. W. Pack. Macromolecule Release from Monodisperse PLG Microspheres: Control of Release Rates and Investigation of Release Mechanism. Journal of Pharmaceutical Sciences, 96(5):1176-1191, 2007.

[6] D. Klose, F. Siepmann, K. Elkharraz, and J. Siepmann. PLGA-Based Drug Delivery Systems: Importance of the Type of Drug and Device Geometry. International Journal of Pharmaceutics, 354(1-2): 95-103, 2008.

[7] A. Zhao, S. K. Hunter, and V. G. J. Rodgers. Theoretical Prediction of Induction Period from Transient Pore Evolvement in Polyester-Based Microparticles. Journal of Pharmaceutical Sciences, 99(11):4477-4487, 2010.

[8] A. N. Ford, D. W. Pack, and R. D. Braatz. Multi-Scale Modeling of PLGA Microparticle Drug Delivery Systems. In E. N. Pistikopoulos, M. C. Georgiadis, and A. C. Kokossis, editors, 21st European Symposium on Computer Aided Process Engineering: Part B, pages 1475–1479. Interscience, New York, 2011.

[9] A. N. Ford Versypt. Modeling of Controlled-Release Drug Delivery from Autocatalytically Degrading Polymer Microspheres. Ph.D. Dissertation, University of Illinois at Urbana-Champaign, Urbana, IL, 2012.

[10] H. Antheunis, J. C. van der Meer, M. de Geus, W. Kingma, and C. E. Koning. Improved Mathematical Model for the Hydrolytic Degradation of Aliphatic Polyesters. Macromolecules, 42(7):2462-2471, 2009.

[11] S. Lyu, R. Sparer, and D. Untereker. Analytical Solutions to Mathematical Models of the Surface and Bulk Erosion of Solid Polymers. Journal of Polymer Science Part B: Polymer Physics, 43(4):383-397, 2005.

[12] P. Dechadilok and W. M. Deen. Hindrance Factors for Diffusion and Convection in Pores. Industrial and Engineering Chemistry Research, 45(21):6953-6959, 2006.

Extended Abstract: File Not Uploaded