(108f) 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.¹The 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