Over the last three decades, controlled drug release technology has attracted researchers around the world because it has proven to be an efficient means of administering bioactive agents to patients suffering from a variety of diseases. With genetic engineering products becoming increasingly available, controlled drug release systems have attained a new level of interest due to their high health and economic potential. Of the various modalities known to release drugs modalities known to release drugs at predictable rates, the erodible polymeric systems stand out because they do not have to be removed once implanted and many biocompatible polymers are known. Among the erodible systems, polyanhydrides have been studied extensively in controlled drug release applications to the point where polymer-drug matrices are now available for treating human brain tumors. However, most polyanhydrides are linear. Their backbone cleavage generally leads to the formation of """"""""internal"""""""" erosion fronts with variable drug release rates, and their use in humans is limited to short-term (one to two months) applications. The goal of this project is to develop a monolith-type, polymer -drug matrix based on cross-linked or branched, amino acid-containing polyanhydrides capable of releasing peptides and proteins at predictable rates for months and even years after implantation in animals and humans. The underlying hypothesis is that these new polyanhydrides can be made to degrade at the surface by altering their chemical structure or the matrix formulation procedure.
The specific aims are: 1) to synthesize and characterize cross-linked or branched poly(anhydride-co- imides) based on an amino acid-containing pre-polymer and a pre-polymer of a space molecule such as sebacic acid, glycolic acid, or L-lactic acid; 2) to formulate polymer-drug matrices based on the polymers synthesized and either porcine insulin or cyclosporin A as test proteins: 3) to incubate these matrices in aqueous media and determine the polymer degradation/drug release rates: 4) to determine the activity of the test proteins throughout the matrix formulation and incubation procedures; 5) to perform extensive mechanical tests on the polymer-drug matrices to assess their usefulness in vivo; and 6) to implant the polymer-drug matrices in diabetic (insulin-loaded matrices) and normal (cyclosporin A-loaded matrices) rates to determine the polymer degradation and drug release rates. The methods proposed include polymer synthesis and characterization using various chromatographic and spectrophotometric techniques; mechanical testing of freshly prepared and degraded polymer-drug matrices; activity testing of the entrapped peptides and protein using enzymatic and radioimmunoassay techniques; and in vivo implantation and follow-up of the polymer-insulin and polymer-cyclosporin A matrices in rats. The integrated approach involving fundamental polymer chemistry, as well as in vitro and in vivo testing, will lead to a more rational design of these polyanhydride-dug matrices and shed light on their potential use in long-term therapies for diabetes and immunosuppression.
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