Enhanced Solubility and Bioavailability of Sibutramine Base by SolidDispersion System with Aqueous Medium

摘要

To develop a novel sibutramine base-loaded solid dispersion with improved solubility bioavailability, varioussolid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acidusing spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibu-tramine was investigated. The physicochemical properties of solid dispersion were investigated using scanningelectron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolu-tion and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloridemonohydrate-loaded commercial product (Reductil). The sibutramine base-loaded solid dispersion gave twotype forms. Like conventional solid dispersion system, one type appeared as a spherical shape with smooth sur-face, as the carriers and drug with relatively low melting point were soluble in water and formed it. The otherappeared as an irregular form with relatively rough surface. Unlike conventional solid dispersion system, thistype changed no crystalline form of drug. Our results suggested that this type was formed by attachinghydrophilic carriers to the surface of drug without crystal change, resulting from changing the hydrophobicdrug to hydrophilic form. The sibutramine-loaded solid dispersion at the weight ratio of sibutramine base/HPMC/poloxamer/citric acid of 5/3/3/0.2 gave the maximum drug solubility of about 3 mg/ml. Furthermore, itshowed the similar plasma concentration, area under the curve (AUC) and C. of parent drug, metabolite I andII to the commercial product, indicating that it might give the similar drug efficacy compared to the sibutraminehydrochloride monohydrate-loaded commercial product in rats. Thus, this solid dispersion system would be use-ful to deliver poorly water-soluble sibutramine base with enhanced bioavailability.