Abstract
Objective: The present research aims to design and optimize gastroretentive floating pellets of anagliptin (a dipeptidyl peptidase-4 inhibitor), so as to reduce P-Glycoprotein (PGP)–mediated efflux in the intestine hence to improve oral bioavailability.
 Methods: The drug-containing core pellets were prepared by extrusion and spheronization process followed by subsequent coating with three successive layers i.e. Eudragit RS 100, sodium bicarbonate (NaHCO3): hydroxypropyl methylcellulose E5LV (HPMC E5LV) and Eudragit RL 100 using fluidized bed processor. A 3 level 3 factor box-behnken design was adopted to investigate the effect of Eudragit RS 100, NaHCO3: HPMC E5LVand Eudragit RL 100 on floating lag time and drug release at 10 h. Desirability function under numerical optimization technique was used to identify the optimum formulation.
 Results: The study reveals the significant effect of the amount of NaHCO3 and coating level of polymers on floating lag time and drug release. The optimum system could float within 4 min and exhibited more than 85% drug release in 10 h. The pharmacokinetic study conducted in male Wistar rats indicated 2.51 fold increase in relative bioavailability of optimized formulation compare to anagliptin drug. Formulated anagliptin pellets were evaluated in cafeteria diet-induced metabolic syndrome model in male Wistar rats. Anagliptin floating pellets treatment compared to cafeteria diet group significantly inhibited increase in body weight (238.79±2.52 g vs. 277.98±3.69 g, P<0.001), calorie intake (2283.99 kcal vs. 3086.05 kcal, P<0.05) and serum levels of total cholesterol (95.19±0.61 mg/dl vs. 110.04±1.31 mg/dl, P<0.01), triglycerides (96.12±1.25 mg/dl vs. 105.99±1.29 mg/dl, P<0.01) while high-density lipoproteins levels were improved (42.15±0.92 mg/dl vs. 30.92±0.77 mg/dl, P<0.01) indicated its hypophagic and anti-hyperlipidemic effects.
 Conclusion: The gastroretentive floating pellets of anagliptin was obtained and could be a promising technique to deliver anagliptin with improved bioavailability in the management of the metabolic syndrome.
Highlights
The urbanization and sedentary lifestyles of 21st century leads to increase the prevalence of metabolic syndrome and is becoming a major public health concern
The floating system consisted of drug loaded pellets coated with three successive layers, release retardant Eudragit RS 100 as internal coat over which NaHCO3: HPMC E5LV layered as effervescent coat and gas entrapped Eudragit RL 100 as top coat indicated in
To maintain the flotation the hydrated coat should be flexible to avoid rupturing and impermeable to the generated CO2 [37]. Due to these reasons the higher flexible, water permeable and gas impermeable Eudragit RL 100 was chosen as a gas entrapped outer polymeric membrane
Summary
The urbanization and sedentary lifestyles of 21st century leads to increase the prevalence of metabolic syndrome and is becoming a major public health concern. Among all the gastroretentive systems, due to minimum effect on GIT motility, floating drug delivery systems (FDDS) are considered suitable and preferable [11,12,13]. These systems are useful for drugs having absorption in upper GIT, drugs which are unstable in the intestine and exhibits poor solubility in intestinal pH [14]. Designing sustained release multiparticulate drug delivery system of anagliptin with prolonged residence time in the stomach using FDDS approach can significantly improve the overall bioavailability
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