Technical strategies for improved oral bioavailability of poorly water soluble ezetimibe

Abstract

ABSTRACT PART 1

Improved oral bioavailability of poorly water-soluble ezetimibe via a solid self-nanoemulsifying drug delivery system, a solvent evaporated solid dispersion and a surface modified solid dispersion.

Rehmana Rashid College of Pharmacy Graduate School of Hanyang University

The objective of this study was to compare the physicochemical characteristics, solubility, dissolution and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), a surface modified solid dispersion (SMSD) and a solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. For the liquid SNEDDS formulation, Capryol 90, Cremophore EL and Tween 80 were selected as the oil, surfactant and cosurfactant, respectively, on the basis of their compatibility with the drug and their solubility. The optimized liquid SNEDDS formulation was composed of the drug, Tween 80, Cremophore EL and Capryol 90 (5/10/35/55, w/v/v/v) and was chosen on the basis of the emulsion-forming region sketched by a pseudo ternary phase diagram and the reduced emulsion size. It was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray-drying technique with water, various amounts of HPC and Tween 80; the drug solubility was investigated, leading to selecting the composition ezetimibe/HPC/Tween 80 (3/1.5/1.5, w/w/w) as the optimized SMSD formulation. The optimized SESD formulation was prepared with the same composition of SMSD using a mixture of water and ethanol (1:1, v/v) instead of only water. The aqueous solubility, dissolution, physicochemical properties and pharmacokinetics of all the formulations were investigated in rats and compared with the drug powder. The drug existed in the unchanged crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD. Solid SNEDDS, SESD and SMSD gave particle sizes of about 11, 6 and 24 µm, respectively. All these formulations significantly improved the aqueous solubility as compared to the drug powder. Moreover, the aqueous solubility and dissolution in water, and solutions at pH 1.2, pH 4.0 and pH 6.8 increased in the order of solid SNEDDS > SESD > SMSD. All the formulations showed a total higher plasma concentration than the drug powder. Unlike the order of aqueous solubility, the AUC increased in the order of SESD > solid SNEDDS = SMSD, with significantly greater AUC values compared to the drug powder (P<0.05). Thus, SESD provided greater oral bioavailability of ezetimibe than SMSD and solid SNEDDS, even though these formulations were not significantly different. In particular, SESD improved drug solubility by about 110-fold and oral bioavailability by 2-fold because of the reduced particle size and change in crystallinity. Amongst the various formulations tested in this study, the SESD system formulated with HPC and Tween 80 is strongly recommended as a drug delivery system for the oral administration of weakly water soluble ezetimibe. ABSTRACT PART 2

Effect of hydroxypropylcellulose and Tween 80 on physicochemical properties and oral bioavailability of ezetimibe-loaded solid dispersion

Rehmana Rashid College of Pharmacy Graduate School of Hanyang University

The purpose of this research was to evaluate the effect of the HPC (polymer) and tween 80 (surfactant) on the physicochemical properties and oral bioavailability of an ezetimibe-loaded binary and ternary solid dispersions. The binary and ternary solid dispersions were prepared with drug, various amounts of hydroxypropyl cellulose and Tween 80 via the solvent evaporation method. The effect of HPC and Tween 80 on the drug solubility and dissolution were investigated. Their physicochemical properties were determined by the scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). In addition, their pharmacokinetic study was carried out in rats as compared to the drug powder. All the binary and ternary solid dispersions significantly improved the drug solubility and dissolution as compared to the drug powder. As the ratio of HPC was increased in the binary solid dispersions to 10-fold, the drug solubility and dissolution were increased. However, the binary solid dispersions with 10- and 20-fold increase in HPC had no significant differences in them. Similarly, up to 0.1 fold, Tween 80 increased the drug solubility in the ternary solid dispersions followed by no significant change. But, Tween 80 hardly affected the drug dissolution. In particular, the ternary solid dispersion composed of drug, HPC and Tween 80 at the weight ratio of 1:10:0.1 showed the highest drug solubility and dissolution. The ezetimibe-loaded binary and ternary solid dispersion were in spherical shape and the drug in them existed in amorphous form. The ezetimibe-loaded binary and ternary solid dispersions gave 1.6 and 1.8 fold increased oral bioavailability in rats, respectively, as compared to the drug powder; however, these values were not significantly different from each other. Thus, HPC greatly affected the solubility, dissolution and oral bioavailability of drug, but Tween 80 hardly did. Furthermore, this ezetimibe-loaded binary solid dispersion prepared only with HPC would be suggested as a potential formulation for oral administration of ezetimibe.