Affinity-Based Thermoset Biodegradable Polymer

        Crosslinked polymers have received widespread attention for use in vascular and osseous tissue. Not only do they have chemical diversity and the ability to show the same biodegradability as linear polymers, but crosslinked polymers also have the capacity to adjust mechanical strength across several orders of magnitude. Crosslinked polymers have become commonplace in medical procedures and implants, such as drug delivery, although there is much room for improvement.

        Last year, we presented on a novel, thermoset crosslinked polymer made from citric acid and glycerol, which are renewable and biocompatible reagents.¹ The degree of crosslinking in the polymer could be easily controlled by altering the reaction conditions. The drug delivery rate was found to be a function of the degree of crosslinking, showing significant therapeutic release for over 3 days. While the fairly rapid release of the previous polymer had some applications, including wound dressings, the therapeutic window needed to be increased to an order of weeks to translate these materials to implantable devices.

        In this work, we will present an improvement of the previously reported drug delivery system. Glycerol was replaced with a cyclodextrin (CD) monomer, also a biocompatible reagent, which we and others have shown to be capable of forming inclusions with small molecule drugs, delaying their release beyond that of diffusion alone. By taking advantage of the molecular affinity that drives this inclusion formation, we are able to deliver drugs in a more linear and sustained release profile. Previous work with cyclodextrin polymers has been in non-degradable polymers; therefore, this represents the first work in a degradable formulation of CD-based polymers that still have the capacity for long-term release. The primary crosslinking reaction is the esterification of a carboxylic acid (citric acid or PEG bis-carboxcylic acid 250) with the hydroxyl groups of a cyclodextrin (hydroxyl propyl b-cyclodextrin or b-cyclodextrin) in dimethylformamide (DMF). The crosslinked cyclodextrin biodegradable polymers are then rinsed extensively in water to remove DMF and unreacted components.

        Prior to crosslinking, novobiocin, a heat-stable antibiotic, was added to the formulation. While novobiocin has a secondary hydroxyl and two amides that could also participate in the reaction, these reaction groups are less favorable than cyclodextrin. We will show data demonstrating drug release profiles and zone-of-inhibition assays (Kirby-Bauer Assays) from various formulations, with the most effective release lasting over 21 days.

References:

1)      J.M. Halpern, R.T. Mathers, H.A. von Recum. “Biodegradable Antibiotic Delivery Materials Developed from Renewable and Biocompatible Reagents.” Oral Presented at 2012 American Institute of Chemical Engineers Fall Annual Meeting. #536h. Pittsburgh, PA