Bioinspired Symmetrical Lipids For Controlled Drug Delivery
Designing new drug delivery systems requires tight control of drug release kinetics. Historically, polymers have been strong contenders in the field. However, achieving a narrow polydispersity and reducing batch-to-batch variability in synthesis can be difficult. Therefore researchers have expanded to other materials such as lipids, which mat have more favorable drug release properties. Lipids are a chemically unique category of molecules that plays a role in functionality and architecture of all living cells. Thus when used as materials for design of drug delivery systems, they will be considered biodegradable and biocompatible. In addition they offer more robust control over design of molecular architecture and thus directly impact the release kinetics of model drugs. The aim of this study was to better understand the mass transport mechanism involved in controlled release of a model drug from lipid based parenteral delivery systems. A family of dihydroxyacetone (DHA) derived symmetrical lipids with varying hydrocarbon chain length was synthesized to systematically analyze how lipid chain length influences drug release kinetics. Our results showed that microparticles prepared using solvent emulsification are porous and polydisperse in size. The effects of several formulation and processing parameters (lipid and surfactant concentration) on the resulting release kinetics were measured. As expected smaller particles (less than 25mu-m) showed faster release kinetics possibly due to shorter diffusion pathway length compared to the larger particles ([25-40] mu-m and greater than 40 mu-m). Our results showed that porosity controls the release kinetics of the anti-inflammatory drug piroxicam more strongly than hydrophobicity. Further investigation of parenteral delivery systems made from DHA derived symmetrical diglcycerides showed that protein release is dependent on the hydrophobicity of the matrix. With lysozyme as a model protein drug, long chain diglycerides (C16 and C14) showed slower release compared to short chain, less hydrophobic diglycerides (C10 and C12). As with solid microparticles, the effect of varying formulation and processing parameters (e.g. lysozomal loading, compression force) was studied. SDS gel electrophoresis and enzymatic study in M. lysodeikticus suspensions were used to study the structural integrity and activity of dispersed model drug. The results showed that there is slight aggregation and loss of activity possibly as a result of heat generation during compression. Furthermore diglyceride implants showed acute inflammatory response in early time points of the biocompatibility study conducted using rat animal models. The inflammatory response subsided for later time points. Histological inspection of the tissues showed presence of granulomas but no sign of tissue necrosis.
dissertation or thesis