الفهرس 
Preparation of mosapride citrate tablets using liquisolid techniqueOnly 14 pages are availabe for public view
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Abstract
MC is a class II water-insoluble drug and its dissolution rate and, consequently, absorption are dependent on the gastrointestinal pH. This results in a very high variability in bioavailability and related inter- and intra-subject absorption variations which present a major challenge that hinders the realization of an effective and uniform therapy. Our aim of work in this thesis was to produce MC in a solid dosage form that can increase its aqueous solubility and as a result improves its oral bioavailability. Achieving this goal will enable us to reduce the administered dose, which is advantageous, taking into consideration the adverse effects of the drug and the cost-treatment relationship. To achieve these goals, the work in this thesis was divided into three chapters: Chapter I: Preparation of msoapride citrate tablets using liquisolid technique. Chapter II: Preparation of msoapride citrate tablets using complexation technique. Chapter III: Bioavailability and pharmacokinetic study of mosapride citrate tablets in healthy human volunteers. In chapter I, it was hypothesized that the formulation of MC using liquisolid compacts technique may reduce the effect of pH variation on the drug dissolution rate. Solubilities of MC in propylene glycol, PEG
400, and glycerol formal were first measured and glycerol formal was selected due to its superiority in dissolving MC among the tested solvents. Several liquisolid tablet formulations containing various ratios of drug: glycerol formal (5% and 10% w/w) were prepared. The carriers used were microcrystalline cellulose, mannitol and lactose. The R factor of the coating powder material (Aerosil 200) was 25 and 30. The dissolution behavior of MC from liquisolid compacts was investigated in several buffered and biorelevant media with different pH values. The results showed that the drug release rates produced by liquisolid compacts prepared using Avicel with R factor 30 and 10% concentration of drug in glycerol formal were significantly higher and less affected by pH variation compared with marketed (Mosapride®) tablets. In conclusion, liquisolid compacts technique may be used as a tool to enhance solubility and dissolution and minimize the effects of pH variation on the dissolution rate of drugs with poor water solubility. In chapter II, the work included the physicochemical investigation of the complexation of MC with different cyclodextrins and the study of the cyclodextrin effect on both the solubility and dissolution profiles of MC. Two chemically modified cyclodextrins, namely; hydroxypropyl-β-cyclodextrin (HP- β-CD) and methyl-β-cyclodexrin (M- β -CD) were compared to the natural beta cyclodextrin (β-CD). The investigation of the binary complexation of MC with the three selected cyclodextrins in solution state was carried out using phase solubility studies method.
The phase solubility diagrams for MC with β-cyclodextrin, HP- β-cyclodextrin and M- β-cyclodextrin in distilled water a 37± 0.5 ° C are considered of the Ap type, indicating the formation of higher order complexes with respect to the selected cyclodextrins at higher cyclodextrin concentrations. Solid binary systems of MC with β-cyclodextrin, HP- β-cyclodextrin and M- β-cyclodextrin were prepared in molar ratios of 1:1 and 1:2 by kneading and freeze-drying techniques. Physical mixtures of the same molar ratios have been also prepared for comparison. The dissolution behavior of MC from inclusion complexes was also investigated in several buffered and biorelevant media with different pH values. The results showed that the dissolution rates produced by complexation using M-β-cyclodextrin with freeze-drying technique was significantly higher than marketed (Mosapride ®) tablets. Stability studies showed that aging has no effect on dissolution behavior of MC inclusion complex tablets. In chapter III, the two selected tablet formulae that showed the highest enhancement of MC in-vitro dissolution results namely; LS-4 and CX-15 were selected for in-vivo evaluation. Both formulae were compared to the marketed Mosapride ® tablets. The study was carried out using six healthy volunteers aged between 20 and 40 years. Randomized, single dose, three-way crossover open-label study was performed using three MC formulations viz. the prepared LS-4 tablets, CX-15 tablets and the marketed product. Venous blood samples were collected in glass tubes before
administration of the dosage form, and at 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, and 12.00 hours after drug administration. Plasma concentration-time data of MC were analyzed for each subject by non-compartmental pharmacokinetic models using kinetica® software (version 4.4.1). The mean values for the maximum plasma concentration (Cmax) were 35.38 ± 4.52, 45.86 ± 3 and 42.64 ± 6.27 ng/ml after the oral administration of the marketed product, LS-4 and CX-15 to the volunteers, respectively. In addition, the mean values for time to reach peak plasma concentration (Tmax) were 0.71± 0.1, 0.5± 0 and 0.5±0.16 hours while the mean values for the area under the plasma concentration-time curve AUC(0-12) were 133.77 ± 22.79, 162.12 ±9.62 and 155.24 ± 21.57 ng.hr/ml, for the three aforementioned formulae, respectively. Both the selected LS-4 and CX-15 showed enhanced relative oral bioavailability of MC with respect to the marketed Mosapride® tablets with respective values of 121.20and 116.0%. This indicates the possibility of dose reduction and hence reduced side effects of Mc.