The ultimate goal of this project is to understand the underlying factors responsible for in vivo release of parenteral microsphere drug products and to develop a rational mechanism-based approach to create in vitro-in vivo correlations. To summarize this approach-In order to identify potential release mechanisms we propose to (a) determine the characteristic times governing key physical-chemical and/or biological processes that could be rate-limiting to the drug reaching the circulation, (b) the characteristic times identified in (a) will be measured both in vitro and in vivo while monitoring the release (and/or retention) kinetics of model drug-loaded microspheres to elucidate the release mechanism, (c) the in vitro conditions (solution chemistry, mixing, and temperature) will be adjusted between reasonable limits to encompass the rate- controlling characteristic times observed in vivo to identify suitable in vitro conditions for an in vitro-in vivo correlation (IVIVC), and (d) at the same time PK data will be used to confirm direct measurements, to determine if additional rate limits exist (e.g., tissue binding or metabolism) after release from the implant and to establish an IVIVC. The mechanistic evaluation will be conducted using two model drugs a steroid and LHRH agonist. Two formulations for each drug corresponding to two different release mechanisms will be selected for in vitro and in vivo characterization and the development of the IVIVC model. If successful, this proposal has the potential to create a path toward standardization of controlled release assays and rational development of IVIVCs.

Public Health Relevance

This project studies biodegradable polymer microparticles that are injected in patients and deliver drugs for one week to six months. Bydureon, a type 2 diabetes drug and Lupron Depot, a product for prostate cancer, are examples of many of such implants approved by the US Food and Drug Administration (FDA). This proposal responds to a special request by the FDA to develop a standard method to characterize how drugs come out of polymer at the bench that could predict how drugs will come out of polymer after injection in patients. This research is designed to lead to creation of new FDA guidelines to allow faster approval of generic and branded versions of polymer microparticle products.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZFD1-SRC (99))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
Zip Code
Schwendeman, Steven P; Shah, Ronak B; Bailey, Brittany A et al. (2014) Injectable controlled release depots for large molecules. J Control Release 190:240-53