Gastroretentive Orlistat Microspheres: Formulation, Characterization, and In Vitro Evaluation

The present study involves the preparation and evaluation of floating microspheres of orlistat for improving drug bioavailability by prolongation of gastric residence time. The microspheres were prepared by a solvent diffusion–evaporation technique using inert polymers (Eudragit RL100, cellulose acetate, and ethyl cellulose). The effect of three formulation variables (i.e., drug/polymer ratio [D/P], polymer amount, and stirring speed) on floatability, encapsulation efficiency, percentage fines, and release mechanism were studied. The results of Fourier transform infrared spectroscopy show no interaction between the drug and the polymers. In vitro dissolution studies were performed in 0.1 N HCl (pH 1.2) for 12 h, and samples were analyzed by HPLC using a UV–vis detector at 205 nm. The grading curve was constructed for the selected formulations, and D30, D60, and D90 values were determined to characterize the size distribution. A comparison of r values for Higuchi, Korsmeyer–Peppas, and zero-order kinetic models for different batches of microspheres shows Fickian and non-Fickian diffusion kinetics. The orlistat microspheres prepared with cellulose acetate (D/P 1:2) at the stirring speed of 900 rpm show maximum floatability and optimum encapsulation efficiency, and exhibited a prolonged release for almost 12 h with a Fickian diffusion release mechanism. INTRODUCTION Dyslipidemia is a disorder of lipoprotein metabolism. Dyslipidemia is the elevation of plasma cholesterol, triglycerides, or both. It can also be manifested by the elevation of low-density lipoprotein (LDL) cholesterol and the decrease of high-density lipoprotein (HDL) cholesterol in the blood (1). Dyslipidemia is a primary risk factor that contributes to the development of atherosclerosis in the general population and in diabetic patients. Most people with high serum cholesterol also have elevated LDL because much of the serum cholesterol is transported in LDL. The concept therefore has emerged that LDL is the predominant atherogenic lipoprotein. The remarkable finding that LDLlowering therapy reduces the risk for subsequent coronary events even in patients with advanced atherosclerotic disease discloses a role for LDL in late stages of atherogenesis (2). Orlistat, [(1S)-1-[(2S, 3S)-3-hexyl-4-oxo-oxetan -2-y1] methyl] dodecyl] (2S)-2-formamido-4-methyl–pentonate (Figure 1), also known as tetrahydrolipstatin, is designed to treat obesity. It reduces the LDL concentration in the blood by inhibiting gastric and pancreatic lipases (the enzymes that break down triglycerides in the intestine). The primary effect of orlistat is local lipase inhibition within the GI tract after an oral dose. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids and are excreted undigested instead, thereby reducing caloric intake (3, 4). A single dose of orlistat will prevent approximately 30% of dietary fat from being absorbed, which indicates its effectiveness in controlling dyslipidemia. It also exhibits antiproliferative and antitumor properties in prostate and breast tissues (5). In a study conducted in an obese population over four years, the incidence of type-2 diabetes was reduced with orlistat (6.2%) when compared with placebo (6, 7). Hence, orlistat is an important drug in prophylactic management of obesity and for the management of type-2 diabetes. Orlistat has a short half-life (<2 h) and requires administration multiple times a day. The absorption window is restricted to the upper part of the gastrointestinal tract, which may lead to variability and nonuniform absorption, and makes the bioavailability unpredictable (8). The shorter residence time of the conventional dosage form in the stomach and the variable gastrointestinal transit time may affect the efficacy of this drug. Hence, a beneficial delivery system would be one that can control and prolong the gastric emptying time and deliver drugs in higher concentration to the absorption site. One such approach is a multiparticulate spherical dosage form having a density less than that of gastric fluids (9). A formulation that can deliver the drug for a prolonged time would be ideal. Recently, Jain et al. (10) evaluated a floating delivery system of orlistat using calcium silicate. Such dosage forms are better because they reduce the *Corresponding author. diss-18-03-09.indd 72 8/31/2011 1:45:05 PM dx.doi.org/10.14227/DT180311P72