Formulation and Optimization of Nanosuspensions for Enhancing Simvastatin Dissolution Using Central Composite Design

Simvastatin is a poorly water-soluble drug, and bioavailability from its crystalline form is very low. The purpose of this investigation was to increase the solubility and dissolution rate of simvastatin by the preparation of nanosuspensions with Pluronic F127 and zirconium oxide (ZrO2) beads using a wet-milling technique at the laboratory scale. Prepared nanosuspensions were evaluated for particle size and in vitro dissolution. A 3 central composite design was employed to study the effect of the independent variables (i.e., amount of Pluronic F127, X1, and amount of ZrO2, X2) on the dependent variables (i.e., particle size [nm] and percentage of drug released after 10 min, Q10). The relationship between the dependent and independent variables was further elucidated using multiple liner regression analysis (MLRA) and contour plots. The results show that nanosuspensions prepared with the higher concentrations of Pluronic F127 and the higher quantities of ZrO2 (up to 8 g) reduced the particle size and enhanced the dissolution rate of the formulation. The dissolution rate of the optimized nanosuspension was enhanced (64% in 10 min) relative to that of a micronized suspension of simvastatin (3.5% in 10 min), mainly because of the formation of nanosized particles. These results show that the preparation of simvastatin-loaded nanosuspensions significantly improved the in vitro dissolution rate, thus possibly enhancing the fast onset of therapeutic drug effect. INTRODUCTION The design and formulation of a dosage form require consideration of the physical, chemical, and biological characteristics of all the drug substances and pharmaceutical ingredients to be used in its preparation. An important property of a drug substance is solubility, especially aqueous system solubility (1). The solubility–dissolution behavior of a drug is a key factor to its oral bioavailability. An improvement in the solubility of poorly water-soluble drugs remains one of the most challenging tasks of drug development. The techniques that can generally overcome the problem of solubility are salt formation, micronization, use of surfactant, and use of prodrugs. However, all these techniques have certain limitations. Over the last ten years, nanoparticle engineering processes have been developed and reported for pharmaceutical applications (2, 3). Various approaches have been developed to improve bioavailability by increasing drug dissolution rate and solubility. For example, nanosizing techniques have been used to enhance dissolution rate by increasing drug surface area, thereby improving the oral bioavailability of poorly water-soluble drugs (4, 5). Nanosuspensions are submicron colloidal dispersions of pure drug particles in an outer liquid phase. Nanoparticle engineering enables poorly soluble drugs to be formulated as nanosuspensions either alone or with a combination of pharmaceutical excipients. The nanosuspension engineering processes currently used are precipitation (6), high-pressure homogenization (7), and pearl milling (8), either in water or in mixtures of water and water-miscible liquids or in nonaqueous media (9). In the present study, a wet-milling technique was used to prepare nanosuspensions; an aqueous suspension was formulated with ZrO2 as a milling medium. As the beads rotated, they flew to the grinding vial interior and impacted against the sample on the opposite grinding vial wall. The combination of frictional forces and impact forces led to a high degree of particle size reduction. Cavitation fields generated inside the chambers also contributed to particle size reduction. The main advantage of this technique is that no hazardous solvents are used (10, 11). Simvastatin (SIM) is a lipid-lowering agent derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, SIM, an inactive lactone, is hydrolyzed to the corresponding β-hydroxy acid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3methylglutaryl-coenzyme-A (HMG Co-A) reductase, the enzyme that catalyses an early and rate-limiting step in the biosynthesis of cholesterol (12). SIM is a white, crystalline, nonhygroscopic powder, insoluble in water and 0.1 N HCl (30 μg/mL and 60 μg/mL, respectively). It is generally considered that compounds with very low aqueous solubility will show dissolution-rate-limited absorption. Improvement of aqueous solubility in such cases is a valuable goal to improve therapeutic efficacy. The dissolution rate is a function of the solubility and the surface area of the *Corresponding author diss-18-03-05.indd 40 8/31/2011 1:35:24 PM dx.doi.org/10.14227/DT180311P40