Int. J. Pharm. Investigation, 2020; 10(3) : 326-331 Int.J. Pharm. Investigation, Vol 10, Issue 3, Jul-Sep, 2020 326 Original Article INTRODUCTION Irritable bowel syndrome (IBS), a chronic gastrointestinal disorder, is characterized by abdominal pain and an erratic bowel habit. 1,2 Mebeverine hydrochloride (MBH) is an antispasmodic agent that has a direct musculotropic action on the smooth muscles of the gastrointestinal tract; especially the colon. 3 For many years, MBH has been considered the drug of choice for the management of IBS. 4,5 Nevertheless, following oral administration, MBH is rapidly absorbed from the upper part of gastrointestinal tract and undergoes extensive hepatic metabolism. 6 Tis adversely hinders the delivery of MHB to the site of action; colon, in appropriate concentrations. Accordingly, development of drug delivery systems that are capable of delivering MBH to the diseased organ (colon) in adequate concentrations is urgently needed in order to enhance the overall therapeutic efcacy along with reducing the incidence of adverse side efects. Recently, colon targeted drug delivery systems have gained enormous attention as means for delivering drugs specifcally into the colon. 7-9 Targeting of drugs to colon is valuable approach for treating diseases associated with the colon such as colorectal cancer, ulcerative colitis, Crohn’s disease, amebiosis, infammatory bowel disease and irritable bowel syndrome. 10,11 Nevertheless, for successful targeted drug delivery to the colon, the delivery vehicle should protect the drug from degradation, release and absorption in stomach and small intestine and should allow the selective/controlled release in the proximal colon. Tis can be accomplished by the use of well-designed delivery vehicles that can shield the drug during its transit to the colon. Polymeric micro-particles represent one of the promising delivery vehicles that have been recognized for their potential as therapeutic carriers to the colon. 12,13 Tey can be prepared using diferent kinds of polymers. Among them, naturally occurring biodegradable polymers, especially polysaccharides, have been extensively explored for their potential in colon-specifc drug delivery. 14,15 Polysaccharides, such as chitosan, pectin, inulin, dextran and guar gum, show the potential to be retained intact in the environment of the stomach and small intestine, while being degraded by polysaccharidases upon arrival in the colon. Chitosan is one of the non-toxic biodegradable polysaccharide that is obtained from the alkaline deactivation of chitin. 16 Chitosan shows a propensity to dissolve in acidic pH of the stomach but get swollen in the intestinal pH. Tis gelling property retards drug release from the dosage form, making it more susceptible to degradation in the colon. 17,18 Consequently, chitosan serves as an efective polymer for the preparation of colon-specifc drug delivery systems. Te aim of the present study was, therefore, to formulate and optimize chitosan microspheres loaded with MBH for colon-specifc drug targeting using a 3-factor, 3-level Box Behnken design. In addition, the in vivo fate of the optimized MBH chitosan microspheres was evaluated in rabbits following oral administration. Mebeverine Hydrochloride Loaded Chitosan Microspheres as Potential Treatment Targeting Irritable Bowel Syndrome: Box-Behnken Design Optimization Azza Ali Hasan 1 , Rasha Mohamed Samir 1 , Samir Sayed Abu-Zaid 1 , Amr Selim Abu Lila 2, * 1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zigzag University, Zagazig, EGYPT. 2 Department of Pharmaceutics, College of Pharmacy, Hail University, Hail, SAUDI ARABIA. ABSTRACT Objective: Mebeverine hydrochloride is an antispasmodic agent that has a direct musculotropic action on the smooth muscles of the gastrointestinal tract; especially the colon.Therefore, the current study aimed at formulating and optimizing colon targeted mebeverine hydrochloride microspheres for treatment of chronic gastrointestinal disorder. Methods: Mebeverine hydrochloride-loaded chitosan microspheres were formulated adopting emulsion cross-linking method using glutaraldehyde as a cross linking agent. A 3 3 Box Behnken design was utilized in formulating the micro- spheres and investigating the effect of different formulation factors such as drug: polymer ratio (X 1 ), stirring speed (X 2 ) and the surfactant concentration (X 3 ) on particle size (Y 1 ), the entrapment ef fciency percentage (Y 2 ) and the cumulative release percentage of mebeverine hydrochloride after 8 h (Y 3 ). Result: The particle size and entrapment ef fciency were signifcantly affected by tested formulation parameters. The release of mebeverine hydrochloride from optimized formula was pH dependent. In simulated gastric fuid, less than 10% of entrapped mebeverine hydrochloride was released, while, a relatively high amount of the drug (> 65%) was released in simulated colonic fuid (pH 7.4). The in vivo pharmacokinetic study revealed that the optimized formula of microspheres exhibited increased oral absorption of mebeverine hydrochloride, compared to free drug (C max 168.51±20.05 ng/ml vs. 126.45±29.46 ng/ml, respectively). In addition, the optimized formula exerted a remarkably higher systemic bioavailability, compared to the free drug. Conclusion: These results underscore the applicability of cross-linked chitosan microspheres as a promising carrier for colon targeted delivery of mebeverine hydrochloride for treating diseases associated with the colon such as irritable bowel syndrome. Key words: Box-Behnken design, Chitosan, Irritable bowel syndrome, Mebeverine hydrochloride, Microspheres. Correspondence Dr. Amr S. Abu Lila, Associate Professor, Department Department of Pharmaceutics, College of Pharmacy, Hail University, Hail-81442, SAUDI ARABIA. Phone: +966-565434262 Email: amr_selim78@yahoo.com; ORCID: http://orcid.org/0000-0001-7385-868X DOI: 10.5330/ijpi.2020.3.58 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.