| Among the different types of drug delivery systems that have been developed, the colloidal drug delivery system has a great potential for solving common problems encountered in the normal drug development process. The most widely used colloidal drug delivery systems are microemulsions. Recently, much attention has been focused on surfactant and lipid based formulations to improve the oral bioavailability of poorly water soluble drug compounds. In fact, the most popular approach is the incorporation of the drug compound into inert lipid vehicles such as oils, surfactant dispersions, self-emulsifying formulations, emulsions, and liposomes with particular emphasis on self-microemulsifying drug delivery systems (SMEDDS).;In the first part of this work, the effects of co-surfactants, formulation, pH, temperature and drug loading (for ibuprofen and benzocaine) on the stability of m croemulsions on dilution with water were studied. From those results, a SMEDDS consisting of n-decane and an Smix (surfactant/co-surfactant mix) of Tween 40 plus n-butanol in a 1:1 ratio was selected for further studies.;One part of the study evaluated the loading effects and distribution of ibuprofen. It was found that the free drug concentration in the external aqueous phase was described in terms of the total drug concentration using a first order fit. The distribution coefficient KD was 5673 for 10°C and decreased to 4200 at 25°C and 3277 at 37°C. The Cmax for 10°C was 0.04296 mg/mL and increased to 0.0746 mg/mL for 37°C.;Another part of the study focused on the effects of the aqueous phase pH and temperature on the drug distribution. The drug benzocaine (a weak base with pKa of 2.5-2.7) was used for this study. It was seen that the distribution coefficient KD decreased with increasing temperature. It was also seen that the KD values decreased as the pH was lowered. It was also seen that the KD changed with pH starting as high as 5-7, when the benzocaine is essentially completely unionized in the water phase. In other words, even when the amount of ionized drug is negligible in the aqueous phase, there was an observed pH effect on KD. However, these effects were not explainable in terms of Henderson-Hasselbalch (H-H) arguments. It was assumed that the H-H equation could be used in the aqueous phase, but it was found that effects opposite to the H-H predictions resulted in the Smix (surfactant plus co-surfactant) phase.;A thermodynamic model was developed, in which the chemical potential changes in the aqueous and Smix phases associated with dissolution and distribution of the dissolved neutral and ionized forms of the drug, and setting the chemical potentials of each form equal in each phase. From the model, it was found that there were energy differences due to non-ideal dissolution behavior, which were characterized using interaction parameters (denoted as chi nj, where n = 1 and 3 denote the neutral drug form in the aqueous and Smix phases, respectively, and n = 2 and 4 denote the ionized form in the aqueous and Smix phases).;It was concluded that addition of drugs affected the stability of microemulsions formed from SMEDDS. In addition, the drug distribution was affected by the choice of drug and drug loading, as well as the temperature and pH of the external phase. (Abstract shortened by UMI.)... |
