INTELLECTUAL 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.
We have targeted one of the most important and impactful issues in biomaterials science, that of enhancing the solubility of poorly-soluble drugs in water, and thereby enhancing their ability to pass from the gastrointestinal tract (the "gut") into circulation (the blood). The ability for drugs to do this is termed "bioavailability". This step is essential for oral medications to function properly; if they don’t dissolve in the gut and pass into the blood, they can’t reach their sites of action in various organs in the body, and so can’t cure diseases or mitigate symptoms. This problem is of huge importance; oral drugs are the most prevalent, patient-preferred, and inexpensive, and an estimated 50% of existing drugs and 70% of those in development share this problem of low solubility, that can lead to low bioavailability. Unfortunately, the methods in existence to deal with this problem are inadequate; the results for patients are that drug costs are too high (doses have to be increased due to the poor bioavailability), there are too many side effects (because of the high doses), pills are too big (same reason), and the effect from a given dose is too variable. We have a solution to this problem, in that we can mix the drug with a polymer on a molecular level; a so-called "amorphous solid dispersion" or ASD, in which molecules of polymer sit between the drug molecules and prevent them from coming together to make a crystal. Crystalline forms of things are always less soluble than those that are "amorphous" (in other words, not crystalline), so if we can prevent crystallization, we can make drugs much more soluble. Trouble is, pharmaceutical companies have been working almost entirely with old polymers that weren’t designed for these ASDs, so don’t work very well for the purpose. We came up with an idea that natural, renewable polysaccharides (natural polymers based on sugars) would be the perfect basis for designing ASD polymers that work from the ground up, so to speak. The lab of Professor Lynne Taylor at Purdue knows drug chemistry, and the lab of Professor Kevin Edgar at Virginia Tech knows the chemistry of polysaccharides. Working together, we have figured out what kind of polysaccharide-based material we need to make ASDs work, have figured out how to test whether they work using only the small samples of polysaccharide-based material we can make in the lab, and then have made a wide range of materials based on cellulose, one of the safest and most abundant polysaccharides. All of the groups that we have attached to cellulose to tailor its properties are either already present in the human body, or are part of our diet; therefore we designed our new materials to be harmless for human ingestion, and are hopeful that toxicity testing down the road will prove that to be the case. Even more exciting is that we have used this wide range of materials to do experiments that have taught us what type of materials work for high-performance ASDs, and how to optimize our designs to best increase drug solubility and bioavailability. This has allowed us to do a few rounds now of making a range of materials, testing performance vs. structure, using the data to help us design a refined set of new materials, and then test again. As a result, we have developed a small set of polymers that work better at ASD of several model drugs than any existing polymer, whether based on natural materials or not. We find that a couple of features of these polymers predict very well whether they are going to work well in ASDs; one is whether the polymer "likes" oil (olive oil, for example), "likes" water, or is somewhere in between those extremes. We find that it’s best to be somewhere in the middle, and to be as similar in that respect to the drug as possible. Another characteristic is whether the polymer is charged in water; in other words, is it positive or negative, or neither? We find that more charge is better. We have tested our top materials for ASD of a variety of drug structures; no drug delivery system works for every drug structure, but we have found that our best polymers work to enhance solubility of a wide range of drugs, across a range of characteristics that encompass a large percentage of the drug candidates now coming out of pharmaceutical companies. These new polymers, designed for this purpose, promise to work for a wide range of drugs to make them much more soluble, hence effective at much lower doses, cutting costs, keeping patients healthier, and making it easier for patients to take the drugs that they need.
