(475a) Tethered pH Responsive Biomaterials for Mucoadhesive Oral Controlled Release Drug Delivery Systems

Significant effort has been spent on identifying ways to slow down the GI transit of the therapeutic especially that of the small intestine, the location where the majority of absorption occurs. The two main areas of thrust for research pertaining to increasing the bioavailability of drugs possessing narrow absorption windows are retaining the dosage form in the stomach (gastroretentive) and slowing down transit time in the small intestine (mucoadhesive). Gastroretentive dosage forms maintain the drug delivery system above the absorption window and release the drug accordingly. Mucoadhesion affords the ability to slow upper GI transit by maintaining the dosage form at the site of absorption through some type of interaction with the intestinal mucosa. The motility of the gastrointestinal tract plays a major role in appropriately engineering a dosage form. The delivery system must be designed so that it works with the digestive system to accomplish the goal of targeting the area where the narrow absorption window of the therapeutic exists.

Smart biomaterials composed of pH responsive polymers, poly((meth)acrylic acid), were synthesized using a precipitation polymerization technique. The microparticles were grafted with linear polymer chains (PEG) that are capable of complexing with the hydroxyl groups of the polyacid and interpenetrating into the mucus gel layer upon entry into the small intestine. Upon introduction of an alkaline solution, these materials imbibe a significant amount of water and create a highly viscous solution. The gelled materials serve as both a control release membrane and resist the inertial forces associated with motility, thereby effectively slowing down the transit of the dosage form. The amount and length of the linear chain were varied to investigate their effects on the release behavior of theophylline.

Formulations composed of anhydrous lactose, theophylline, Cab-O-Sil, magnesium stearate, and the pH responsive polymer microparticles were formulated into mintablets. The release behavior of these capsule formulations was assessed using dissolution in varying pH buffers. Thermal analysis of the formulations was performed using DSC, and the physical mixtures were evaluated using FT-IR spectroscopy.

Dissolution studies conducted indicated that the polymer particles are capable of controlling the release of the therapeutics which is dependent on the medium's pH. At high concentrations of PEG, the effective diffusion coefficient of the model drug is significantly reduced due to complexation that occurs between the ether oxygens and hydroxyl groups. Higher degrees of crosslinking cause the drug to be released at a more rapid rate due to the lowered swelling capacity of the microparticles.

This work was supported by a Department of Homeland Security Graduate Research Fellowship (to JBT) and a grant from the National Institutes of Health (EB-000246).