Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Paul M. Bummer

Abstract

Lipid-based drug delivery systems (LBDDSs) are becoming an increasingly popular approach to improve the oral absorption of poorly-water soluble drugs. Several possible mechanisms have been proposed to explain the means by which LBDDSs act in vivo to enhance absorption. The goal of the current dissertation is to provide a better understanding of one proposed mechanism; the capability of lipoidal components in LBDDS formulations to create and maintain a drug in a supersaturated state under simulated GI conditions. Moreover, molecular details of equilibrium solubilization of a drug in a series of model lipid assemblies were examined. The results of these studies will aid formulators in choosing the optimal LBDDS to improve oral absorption of poorly water-soluble drugs.

Time-dependent solubilization behavior of progesterone, 17β-estradiol and nifedipine in a simple model LBDDS composed of Polysorbate 80 was assessed employing the in vitro dynamic lipolysis model. The results illustrated the extent to which the supersaturated state was dependent on the extent of lipolysis of Polysorbate 80 and the initial drug concentration. Area-under-the curve-supersaturation was proposed as a means of quantifying the time-dependent extent of supersaturation in LBDDSs in simulated intestinal conditions.

Concurrently, a series of model mixed micellar solutions, composed of Polysorbate 80 and oleic acid, were prepared to represent the lipid assemblies produced during the lipolysis experiments. The ability of these aggregates to solubilize progesterone, 17β-estradiol and nifedipine were evaluated and the aggregate/water partition coefficients were determined. The Treinor model was found to successfully fit the partition coefficients of the drugs in a range of mixed micelles. The equilibrium solubility of drugs in the mixed micelles was calculated and compared to that found under lipolytic conditions. The best agreement between calculated and experimental conditions was observed for nifedipine. These studies have established a foundation for the evaluation of time-dependent extent of supersaturation with more complex LBDDS formulations exposed to lipolytic conditions.

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