Factorial Design Studies and Biopharmaceutical Evaluation of Simvastatin Loaded Solid Lipid Nanoparticles for Improving the Oral Bioavailability

Statins are HMG-CoA reductase inhibitors, which lower the cholesterol level through reversible and competitive inhibition; they are involved in the biosynthesis of cholesterol and other sterols. Simvastatin exhibits poor oral bioavailability (<5%) and undergoes extensive microsomal metabolism by CYP enzymes. CYP3A4 is the major metabolizing enzyme that metabolizes lactone form of simvastatin and significantly lowers intestinal uptake. The hydrophobic properties of simvastatin prevent complete dissolution of the drug in the intestinal fluid which also contributes to its lower bioavailability. SLNs are alternative carrier system to polymeric nanoparticles. SLNs are in submicron size range (1–1000？nm). To overcome the hepatic first pass metabolism and to enhance the bioavailability, intestinal lymphatic transport of drugs can be exploited. In the present study, attempt has been made to prepare solid lipid nanoparticles of simvastatin to improve the bioavailability. SLNs of simvastatin were prepared with Trimyristin by hot homogenization followed by ultrasonication method. The SLNs were characterized for various physicochemical properties and analytical techniques like PXRD, DSC to study thermal nature and morphology of formulation and excipients. Promising results of the study indicated the applicability of simvastatin solid lipid nanoparticles as potential tools for improvement of bioavailability of poorly soluble drugs. 1. Introduction Simvastatin is an antihyperlipidemic drug with plasma half-life of 3？hrs and poor oral bioavailability (<5%) due to the extensive first pass metabolism. Possible methods to avoid first pass metabolism include transdermal, buccal, rectal, and parenteral routes of administration. Oral route is the most commonly used and preferred route for the delivery of drugs, although several factors like pH of GIT, residence time, and solubility can affect drug absorption or availability by this route. Lymphatic delivery is an alternative choice to avoid first pass metabolism in oral drug delivery. Enhanced lymphatic transport of drugs avoids the hepatic first pass metabolism and improves bioavailability, because intestinal lymph vessels drain directly into thoracic duct and further into the venous blood, thus bypassing the portal circulation. The main function of the lymphatic system is to facilitate absorption of long chain fatty acids via chylomicron formation. Two different lipid-based approaches are known to enhance the lymphatic transport, which includes construction of a highly lipophilic prodrug and incorporation of drug in a