Design of pH Sensitive Materials for On/Off Release of Thrombolytic and Anticoagulant Drugs
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Design of pH Sensitive Materials for On/Off Release of Thrombolytic and Anticoagulant Drugs Angela M. Thornton and Christopher S. Brazel The University of Alabama, Department of Chemical Engineering Tuscaloosa, AL 35487, U.S.A. ABSTRACT An experimental study was conducted to determine the mechanisms of transport for delivery of cardiovascular agents using a pH-sensitive hydrogel as the carrier. Copolymer gels based on hydrophilic (2-hydroxyethyl methacrylate) and polybasic (N,N-diethylaminoethyl methacrylate) monomers were formed as membranes and analyzed for their potential to control the diffusion of model solutes as well as heparin and streptokinase. The polybasic materials were selected because they would allow drug delivery to be triggered by microenvironmental pH fluctuations around the site of a blood clot. In slightly basic solutions, the polymers remained in a thermodynamic state of phase-separation, while the polymer absorbed more solution and the mesh size increased once the pH was less than the pKb of the polybasic moiety. The hydrogels’ equilibrium swelling ratios were determined as a function of pH, and the mesh sizes were determined by rubber elasticity measurements. Diffusion of model solutes, as well as heparin, was studied using side-by-side diffusion cells to determine the influence of gel morphology and mesh size on the screening of the solutes. Streptokinase release from these gels was modulated by environmental pH. INTRODUCTION Two of the two primary causes of death in the United States are heart attack and stroke1, resulting from thromboembolisms. The anticoagulant and thrombolytic drugs currently used are successful at breaking up or preventing the formation of blood clots. Unfortunately, these drugs also pose the threat of hemorrhage during follow-up surgeries, due to blood thinning2. One potential solution is targeted delivery to localize treatment to the fibrin clot while minimizing drug concentration throughout the cardiovascular system. The ideal cardiovascular drug delivery system would meet rigid requirements for biocompatibility, size, targeting ability and effectiveness, as described in Table 1. Each requirement is necessary for effective localized treatment using existing medications. In addition to preventing drug side-effects and lowering treatment cost by reducing the quantities of drugs needed per patient, controlled release systems also improve the effective half-lives of cardiovascular drugs, such as streptokinase which loses 50 % of its efficacy in 15-20 minutes3. In the past, researchers have sought to create drug delivery systems for cardiovascular medications that can respond to triggering mechanisms such as pH and temperature, focusing on polyacidic materials, which swell in basic solutions, and alkylacrylamides, which display temperature-sensitivity4-7. The research herein describes an effort to achieve some of the goals for cardiovascular controlled delivery - namely, the use of pH-sensitive polybasic polymers to trigger release locally, the development of carriers with
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