Theoretical Prediction of Induction Period from Transient Pore Evolvement in Polyester-Based Microparticles AIYING ZHAO, 1 S.K. HUNTER, 2 V.G.J. RODGERS 3 1 Department of Chemical and Biochemical Engineering, The University of Iowa, Iowa City, Iowa 52242 2 Department of Obstetrics and Gynecology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52241 3 B2K Group (Biotransport & Bioreaction Kinetics Group), Department of Bioengineering, University of California, A237 Bourns Hall, Riverside, California Received 6 May 2009; revised 25 February 2010; accepted 2 March 2010 Published online 13 May 2010 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22167 ABSTRACT: A model was developed and compared to experimental results for prediction of the induction period during drug delivery from various compositions of biodegradable copolymer PLGA microparticles. The uniqueness of this model is that it considers transient pore evolve- ment and uses the kinetic parameters of polymer degradation, which are independent of experimental measurements of microparticle erosion, in its analysis. Delivery data from PLGA microparticles (50:50, 75:25, and 85:15) releasing ovalbumin (OVA, 46 kDa) and bovine serum albumin (BSA, 66 kDa) were determined and used as the model systems. Experimental mea- surements were carried out from 85 to 150 days depending on the PLGA characteristics. The predicted induction periods were approximately 45, 70, and 105 days for the release of both OVA and BSA from 50:50, 75:25, and 85:15 PLGA microparticles, respectively. Overall, these values were in very good agreement with experimentally estimated results. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4477–4487, 2010 Keywords: mathematical modeling; induction time; polymer degradation; transient pore evolvement; bulk erosion kinetics; hindered transport; polyesters; microparticles; probabilistic model INTRODUCTION Polyester-based microparticles undergoing bulk ero- sion, especially poly lactic-co-glycolic acid (PLGA)- based microparticles are potential delivery vehicles for pulsatile release. 1–3 A number of factors influence the overall release profiles including water intrusion into the device, polymer degradation, diffusion of protein molecules and polymer degradation products, microenvironmental pH changes, osmotic effects, adsorption/desorption process, 4,5 and protein decom- position/denaturation. 6,7 Understanding the governing mechanisms can provide the foundation for predict- ability of long-term release profiles during controlled drug delivery. This can have particular significance for scenarios requiring rapid protocol adjustments for administration of a variety of vaccines. As systems such as PLGA microparticles undergo bulk erosion, hydration is imminent and polymer chains are simultaneously cleaved throughout the microparticles. Thus, polymer degradation and trans- port processes are two major interacting factors in determining drug release profiles. 1,8,9 The inner morp- hologies of the microparticles under bulk erosion, which is related to polymer degradation and significantly influence various transport processes, have been found to be very complex and usually heterogeneous. 10–12 In addition, the spontaneous pore opening, closing and coalescence during erosion make it difficult to predict the transient pore structure of the microparticles. 13 The morphological limiting effect of polymer erosion is the main cause to the induction period (or dead time), which is defined as the time interval between two pulses in drug delivery. The induction period is one of the most important parameters in controlled drug release which largely determines the overall release profile. In addition to polymer erosion, other factors affect the induction period including geometric proper- ties of the polymeric systems, such as particle size, size distribution and internal structure properties; physi- cochemical properties and molecular weight of the entrapped drug/protein. Geometric factors directly influence the availability of particle contact points, porosity, viscosity, and tortuosity of matrices, which of all determines the effective surface area. Effective Correspondence to: V.G.J. Rodgers (Telephone: 951-827-6241; Fax: 951-827-6416; E-mail: victor.rodgers@ucr.edu) Journal of Pharmaceutical Sciences, Vol. 99, 4477–4487 (2010) ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010 4477