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Abstract:

Purpose: lansoprazole has been found to form inclusion complexes with Hp-- cyclodextrin (Hp--CD) in solid state. The present study was undertaken to determine a suitable method for scaling up lansoprazole Hp --CD inclusion complex formation and to evaluate the effect of some parameters on the efficiency of complexation. Method: The solid inclusion complexes of lansoprazole and Hp--cyclodextrin were prepared at a molar ratio of 1:1 and 1:2 by mixing, kneading, on small and large scales. Characterization was performed using infrared spectroscopy, X-ray diffractometry, and dissolution studies. In vitro release studies were carried out in phosphate buffer (pH 6.8). Result: Kneading methods of preparation of complexes were found to be useful in increasing the solubility of lansoprazole except mixing method where the rise in solubility was not significant. Both kneading and co-precipitation methods in 1:2 molar ratios were found to be equally effective in improving the solubility of lansoprazole. The formation of inclusion complexes was evident in these formulations as shown by IR and XRD studies. But when carried out on a large scale. Moreover percent recovery of complexes in the kneading method was found to be 98.76% . Conclusion: Drug content studies, IR spectroscopic studies, X-Ray diffractometry studies and in vitro dissolution study data indicated that inclusion complexes prepared by kneading method in 1:2 molar ratios were suitable for improving the solubility of lansoprazole. The same formulation was prepared at large scale and optimum formulation conditions were established. Keywords: lansoprazole, Inclusion complexes,Hp- -cyclodextrin, Kneading method.

INTRODUCTION; Lansoprazole (LPZ), (2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridine- 2-pyridinyl] methyl] sulfinylsulphinyl]-1H-benzimidazole), is a proton pump inhibitor that acts on the membrane H+/K+-ATPase in gastric parietal cells [1,2]. It has been widely used for the treatment of a variety of acid-related disorders, including peptic ulcers (duodenal and gastric) [3,4], symptoms of gastroesophageal reflux disease [5], erosive esophagitis [6], drug-induced ulcers [7], hypersecretory syndromes like ZollingerEllison [8] and Helicobacter pylori infection [9]. LPZ can come as a tablet, an oral suspension and a disintegrating capsule [10]. However, LPZ is unstable in the stomach, i.e., gastric acid, it need to be protected from the destructive effects of gastric acid when administered orally. Various types of enteric coating have been developed to protect LPZ, but they all delay LPZ absorption [1012]. In addition, LPZ belongs to class II drugs of the Biopharmaceutical Classification System (BCS) characterized by practically high permeability, poor solubility. Therefore, even if it is protected from the destruction of gastric acid, there is a possibility that it is not well dissolved in the small intestine from which most drugs are absorbed into the systemic circulation [8]. In fact, oral administration of LPZ has been known to show a marked individual variation of absolute bioavailability in human subjects [13]. This is not only attributed to the genotype of CYP2C19 involved in the metabolism of LPZ in the patients [14,15], but also to the gastric degradation, the dissolution and limited solubility of LPZ in water [8]. One of the most important tasks in drug discovery and development is to enhance the oral bioavailability by improving the dissolution of poorly water soluble drugs. Salt formation, solubilization, particle-size reduction, and solid dispersion formation are the approaches most often used to reach this goal. The formulation of hydrophobic drugs as solid dispersions is a significant area of research aimed at improving their dissolution and thus enhancing the bioavailability [16]. In the solid dispersion system, the solubility of drug can be improved by changing drug crystallinity to an amorphous state and reducing particle size for better wettability [17]. On the other hand, the presence of the carrier might also cause the creation of a microenvironment in which the drug solubility is improved [18,19]. Cyclodextrins (CDs) are cyclic oligosaccharides, containing a minimum of six D-(+)glycopyranose units attached by -1,4- linkages produced by the action of the cyclodextrintrans-glycosidase enzyme on a medium containing starch. It has a hydrophobic central cavity and a hydrophilic outer surface1. CDs have been found to be very useful in enhancing the solubility of poorly water-soluble drugs owing to the formation of inclusion complex of the drug in its hydrophobic cavity2-6. The most common natural CDs are -cyclodextrin, -

cyclodextrin and -cyclodextrin, which are formed by six, seven, and eight glucose units, respectively. Apart from these naturally occurring CDs, various derivatives are also available7,8 which may produce better solubility when complexed9,10 but cost and toxicity factors poses limitation in their use. Amongst the various available CDs, -cyclodextrins (CD) are the cheapest and are nontoxic for oral use11.
EXPERIMENTAL

Materials Hydroxy propyl - Cyclodextrin gifted by glain mark mumbai and Lansoprazole was received from Cipla private Ltd., Indore, India, as gift samples. Potassium dihydrogen phosphate (35.084 g) and disodium hydrogen phosphate (28.80 g) were dissolved in 1000 ml of water to produce phosphate buffer of pH 6.8. All the reagents and solvents were analytical grade, and double distilled water was used. Method
Preparation of physical mixtures The physical mixtures of lansoprazole withHP -CD were prepared by mixing appropriate amounts (1:1 ratio) in a mortar using the geometric dilution technique. The resulting mixtures were sieved through 0.25mm sieve, collected and stored in a closed container away from the light and humidity until use. Preparation of solid dispersion complex Dispersion complexes of LSP withHP -CD containing 1:1 ratio was prepared by the kneading method. Appropriate amount of -CD and HPC were added to DMP in a mortar and the powder mixture was wetted with a minimum volume of water and kneaded thoroughly with a pestle to obtain a paste, which was then dried under vacuum at room temperature. The resultant dispersion complex was pulverized, and sieved through 0.25mm sieve and stored in a closed container away from the light and humidity until use.