MECHANISTIC STUDIES TO ELUCIDATE THE ROLE OF LIPID VEHICLES ON SOLUBILITY, FORMULATION AND BIOA VAILABILITY OF POORLY SOLUBLE COMPOUNDS

Lipids have been utilized to increase the bioavailability of poorly soluble drugs which resulted in with advent of High Throughput Screening (HTS). Although lipids have been used to improve bioavailability of a few drugs for almost twenty years, they are still not well characterized. There are limited publications about the effects of physicochemical properties of the lipid vehicle, such as class of lipid (i.e. glyceride, propylene glycol ester), fatty acid chain length, MW and polarity on lipid solubility, formulation and bioavailability of poorly soluble drugs. Knowledge of such relationship can improve quick screening of these vehicles. The goals of this study are to identify physicochemical properties of the lipids, to investigate the relationship of these properties with solubility of the model drugs, namely nifedipine and griseofulvin, to design lipid-drug formulations with Cremophor EL, to evaluate in vitro dissolution of selected formulations and to compare the bioavailability of nifedipine from the formulations tested. It has been shown that the lipids used improved the solubility of nifedipine and griseofulvin compared to the solubility of drugs in water. Calculated solubility parameter was not sufficient to predict the solubility of the drugs in the lipids. Calculated and measured properties of lipids analyzed with stepwise regression analyses showed that MW, dielectric constant, surface tension and fatty acid chain length are the common factors that govern the lipid solubility. However. the estimates of each factor were different for each drug indicating that the nature of the drug played an important role in lipid solubility. Incorporation of Cremophor EL. a nonionic surfactant into lipid-based nifedipine formulation enhanced the solubility and dissolution of nifedipine. The solubility of (( nifedipine showed a linear correlation with increasing surfactant concentration. While solution rate was dependent on the type of lipid used, the nature of the lipid had no affect on the dissolution of nifedipine in presence of the surfactant. Dissolution of nifedipine from the lipids showed that as the fatty acid chain length increases, the dissolution rate increases. This is due to lower solubility of nifedipine in the lipids that have longer chain length. The effect of lipids on dissolution rate and extent of nifedipine showed that even though physicochemical properties of lipids (HLB, interfacial tension, viscosity, density) and solubility of nifedipine in lipids play a role, only partitioning of the drug from lipid to the dissolution medium and the particle size of the formulation in dissolution medium provided a good correlation with dissolution extent of nifedipine. The bioavailability of nifedipine obtained with different lipid formulations in beagle dogs showed that the type lipid and surfactant used in the formulation play important roles. Dissolution is a good predictor for in vivo performance of nifedipine lipid formulation when it was formulated with non digestible lipids (mostly mono-glycerides). Although, the solubility of nifedipine in lipids, the particle size of the formulation in dissolution medium and partitioning of the drug from the formulation to dissolution medium seem to affect the in vivo performance of the drug, dissolution performance of the formulation and digestibility of the lipid used in the formulation are the major factors in bioavailability of nifedipine from the lipid-based formulations