APPLICATION OF ENGINEERING PRINCIPLES TO THE DESIGN OF BIODEGRADABLE POLYMER MATRICES FOR CONTROLLED RELEASERothstein, Sam N. (2013) APPLICATION OF ENGINEERING PRINCIPLES TO THE DESIGN OF BIODEGRADABLE POLYMER MATRICES FOR CONTROLLED RELEASE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractControlled release formulations improve drug safety and address patient adherence, barriers that are responsible for 10% of hospitalizations and over $100 billion in annual medical expenses. These benefits apply to medications that require consistent dosing over days, weeks, or months, a category accounting for over 90% of prescription drugs sales. Yet, the use of controlled release formulations remains comparatively sparse because their design requires months of costly experimentation. Significant scholarship has been devoted to facilitating formulation development and to understanding controlled release behavior, particularly in the realm of mathematical modeling. However, each modeling study to date has only focused on predicting the performance of an extremely limited number of “drug”-polymer combinations, vehicle geometries and excipient types. Researchers have yet to arrive at one general theory of controlled release applicable to a wide range of drug delivery systems and have even begun to doubt that one will be developed. To define the underlying mechanisms of controlled release, we studied data from formulations encapsulating a wide variety of agents. Analysis began with poly(lactic-co-glycolic) (PLGA) acid microparticles, yielding a set of equations that predicted the release behavior of neutral or anionic, water-soluble agents from small molecule drugs (~300Da) to viruses. Building from this foundation, new layers of diffusion/reaction equations were added to enable predictions for implant systems and sparingly soluble drugs. These predictions compared favorably to in vitro data from implants that underwent either dissolution-limited or degradation-controlled release. The new predictive models of controlled release enable analytical interpretation of in vitro release data. Their predictions have identified rates and durations of drug release in over 20 systems to date. Calculations of in vitro release also aid in targeting precise release behaviors ranging abrupt bursts to sustained, constant release. These behaviors were realized in a delayed release vaccine, capable of masking antigen from the body until a specific point in time, and as a sustained release formulation that delivered the HIV entry inhibitor, enfuvirtide, for one month. The in vitro and in vivo data from these two proof-of-concept applications support the use of predictive modeling in the design of long-acting controlled release formulations. Share
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