- 1:30 PM

Towards the Rational Design of Controlled Release Therapeutics

Sam N. Rothstein, William Federspiel, and Steven Little. Department of Chemical Engineering, University of Pittsburgh, 1237 Benedum Hall, Pittsburgh, PA 15261

Controlled release technology presents solutions to the problems of patient compliance and sub-optimal dosing that often plague modern pharmaceuticals. This technology is commonly manifested as biodegradable matrices that gradually release drug as the structure degrades and dissolves, obviating the need for removal. As therapeutics, these matrices, which form the basis of a $110 billion dollar industry, have simplified dosing schedules from daily to monthly or even biannual treatments. However, the design of controlled release therapeutics remains largely heuristic despite nearly 30 years of research, resulting in substantial development costs in the form of exploratory, in vitro release studies. At present, thousands of medications that could offer improved performance as controlled release formulations await development.

We have recently reported the first, broadly applicable, predictive model for biodegradable matrices composed of the most widely used polymers (e.g. polyesters and polyanhydrides). Unlike prior attempts to predict release, the published model uses readily measured design parameters to calculate the in vitro release profiles for a wide variety of agents, including small molecules, peptides and proteins without regression. As all these parameters can be controlled or set with standard microparticle fabrication methods (single/double emulsion processing, melt casting, ect.), it should be possible to produce formulations to match particular release profiles.

As one example, the model suggests that it is possible to precisely control the magnitude and timing of subsequent doses in a burst-lag-burst release profile (e.g. the duration of the lag phase). Such a profile has significant potential to replicate proven vaccine dosing schedules without repeat injections. To date, formulations where the timing of controlled release bursts match the desired vaccine dosing schedule have proven elusive. Using the published model, design parameters were computed for microspheres based on a common murine vaccination schedule. When fabricated to these specifications, release assays showed that dosing from these microspheres did indeed match the desired schedule within the bounds of experimental error.

As another example, theoretical predictions from this model also suggest that a sustained, constant rate of drug delivery may be obtained from bulk eroding polyester microspheres. This release behavior was previously thought to only be obtainable using surface eroding systems. Efforts are currently underway to experimentally confirm such precise specifications for microparticle formulations.

In conclusion, initial experimental evidence shows that our newly published model can serve as a powerful tool for the inexpensive and rapid design of select therapeutics. Using this model to guide matrix fabrication, it may be possible to both improve upon current formulations and also enable the design of new formulations to address clinical needs in the area of controlled release.