Optimization and Evaluation of Gastroretentive Ranitidine HCl Microspheres by Using Factorial Design with Improved Bioavailability and Mucosal Integrity in Ulcer Model

The purpose of our investigation was to develop and optimize the drug entrapment efficiency and bioadhesion properties of mucoadhesive chitosan microspheres containing ranitidine HCl prepared by an ionotropic gelation method as a gastroretentive delivery system; thus, we improved their protective and therapeutic gastric effects in an ulcer model. A 3 x 2(2) full factorial design was adopted to study the effect of three different factors, i.e., the type of polymer at three levels (chitosan, chitosan/hydroxypropylmethylcellulose, and chitosan/methylcellulose), the type of solvent at two levels (acetic acid and lactic acid), and the type of chitosan at two levels (low molecular weight (LMW) and high molecular weight (HMW)). The studied responses were particle size, swelling index, drug entrapment efficiency, bioadhesion (as determined by wash-off and rinsing tests), and T80% of drug release. Studies of the in vivo mucoadhesion and in vivo protective and healing effects of the optimized formula against gastric ulcers were carried out using albino rats (with induced gastric ulceration) and were compared to the effects of free ranitidine powder. A pharmacokinetic study in rabbits showed a significant, 2.1-fold increase in theAUC(0-24)of the ranitidine microspheres compared to free ranitidine after oral administration. The optimized formula showed higher drug entrapment efficiency and mucoadhesion properties and had more protective and healing effects on induced gastric ulcers in rats than ranitidine powder. In conclusion, the prolonged gastrointestinal residence time and the stability of the mucoadhesive microspheres of ranitidine as well as the synergistic healing effect of chitosan could contribute to increasing the potential of its anti-gastric ulcer activity.