Collaborative Research: Polysaccharide Derivatives for Enhanced Drug Delivery

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Lead ID: DMR/BMAT(7623) 0804609 Lead PI: Taylor, Lynne ORG: PurdueNon-Lead ID: DMR/BMAT(7623) 0804501 Non-Lead PI: Edgar, Kevin ORG: Virginia TechTitle: COLLABORATIVE RESEARCH: Polysaccharide Derivatives for Enhanced Drug DeliveryINTELLECTUAL MERIT: The PIs propose synthesis, mechanistic study, and screening test development for the design of novel cellulosic biomaterials to ensure effective and safe delivery of water-insoluble drugs. The research promises to create fundamental understanding of amorphous matrices, leading to effective new amorphous matrix systems for delivery of highly active, poorly bioavailable drugs. It will thus address a key impediment to productive drug development. The proposal has the following specific objectives: (1) Elucidate key requirements for polymeric stabilization of the amorphous form of model drugs in both the solid and solution phases by mechanistic studies. (2) Create screening methods to rapidly evaluate novel cellulose derivatives. (3) Synthesize two novel families of cellulose derivatives designed for drug miscibility, slow release, and pH-triggered release, as well as safety. (4) Design second generation cellulose derivatives based on screening results and solubility testing of key drugs with solubility and bioavailability issues. The team at Virginia Tech will synthesize novel long chain ester derivatives of carboxymethyl cellulose, and novel adipate esters of cellulose, varying the degree of substitution of carboxymethyl and other substituents to provide a range of hydrophobicity and release rates. The team at Purdue will carry out polarized light optical microscopy of spin coated polymer/model drug films that will provide mechanistic understanding and ultimately a screening method for new polymer delivery systems. They will screen solution stabilization by visible and UV spectroscopy of drug in polymer solution, using 1H NMR spectroscopy of the solutions to provide mechanistic understanding. Mechanistic understanding of how amorphous drugs are stabilized in the solid state, and especially in solution, by polymeric matrices, and creation of novel stabilization screening methods will provide valuable new tools of general use in the field. Furthermore, the research will generate biomaterials forming the basis of new drug delivery systems for rescue of failed pipeline drugs, enhancing efficacy of marketed drugs, and enabling conversions of injectable formulations to oral for enhanced compliance.BROADER IMPACTS: Many important drugs, including several anticancer and antifungal agents, suffer from poor bioavailability due to the low aqueous solubility of their crystalline forms. One strategy for addressing this problem is to produce the drug in an amorphous modification, given the generally improved solubility of the amorphous material. This proposal develops a general approach to using cellulose derivatives to suppress drug crystallinity and enhance bioavailabilty. It will develop a systematic approach to understanding the mechanisms underlying this enhancement. The work could have very substantial impact inasmuch as effective delivery of many drugs represents a major impediment to their efficient implementation. The project provides an attractive multidisciplinary platform for the training of students, who will be associated not only with synthesis and characterization of materials but with developing drug formulations with practical utility. Minority undergraduate research participation will be encouraged at Purdue through the existing Pharmacy Multicultural Program, which provides 50% cost sharing for the student stipend. Past experience suggests that 3-5 students will be involved each year during the summers as well as the academic year.