The Application Cyclodextrins in Drug Delivery

1. The ApplicationCyclodextrinsin DrugDelivery O. Sayed 1*, A. Saied1, J. Hadgraft2, M. E. Lane 2 1 DepartmentofPharmaceuticsandIndustrialPharmacy,FacultyofPharmacy,BeniSuefUniversity,Egypt 2 DepartmentofPharmaceutics,TheSchoolofPharmacy,UniversityofLondon,WC1N1AX,UK. * E-mail: Ossama.Sayed@live.pharmacy.ac.uk Introduction Mosapride citrate is a novel benzamide gastrointestinal prokinetic agent which is sparingly soluble in water. The poor solubility and wettability of the drug give rise to difficulties in pharmaceutical formulation for oral use, which may lead to variation in bioavailability. To overcome these difficulties, increased aqueous solubility is an important goal hence in this investigation, inclusion complexes of mosapride citrate were prepared with natural and modified cyclodextrins (CDs). Figure 1: Phase-solubility profiles for the inclusion complexes mosapride citrate - β-CD and mosapride citrate – SBE7 β-CD. Figure 2: X-ray diffraction patterns of mosapride citrate - β-CDbinary mixtures prepared by different methods. Objectives In this study, an attempt was made to improve the solubility and dissolution rate of mosapride citrate via the formation of inclusion complexes with β-CD and Sulfobutyl Ether7 β-cyclodextrin (SBE7 β-CD), thereby increasing its bioavailability and therapeutics efficiency. • Materials & Methods • Materials: • Mosapride citrate was obtained as a gift from MarcyrlPharma (Egypt), β-cyclodextrin (Kleptose ®) was obtained as a gift sample from Roquette (France), Sulfobutyl Ether7 β-cyclodextrin (SBE7β-cyclodextrin or Captisol ®) was obtained as a gift sample from Cydex Pharmaceuticals (USA), all other ingredients and solvents used were of analytical grade. • Methods: • Phase solubility studies: • The effects of CDs on the solubility of mosapride citrate were investigated according to the phase solubility technique established by Higuchi and Connors (1).The complexation efficiency (CE), which reflects the solubilizing power of the CDs towards the drug, was calculated from the straight line of the phase solubility diagrams according to the following equation • CE= So K1:1 = slope /1- slope • Where So represents the drug solubility in the absence of CDs, K1:1 is the apparent stability constant, where K1:1 = slope/So (1- slope). • Preparation of inclusion complexes: (1:1) Molar ratio • This was done by Physical mixing, Kneading and Freeze drying. • Characterization of the formed inclusion complexes: • The characterization of the formed inclusion complexes form every method was done using X-ray Diffraction, FT-IR spectroscopy, DSC analysis, Apparent solubility determination and Dissolution studies. Figure 4: Apparent solubilities of mosapride citrate binary mixtures prepared by different methods using β-CD and SBE 7 β-CD Figure 3: X-ray diffraction patterns of mosapride citrate - SBE7 β-CD binary mixtures prepared by different methods. Figure 6: Dissolution profiles of mosapride citrate binary mixtures prepared by different methods using SBE 7 β-CD. Figure 5: Dissolution profiles of mosapride citrate binary mixtures prepared by different methods using β-CD. Table 2: Values of IDR and DE 60 min of the release profiles of binary mixtures with CDs prepared by different methods.(IDR: InitialDissolution Rate, DE60 min: Dissolution Efficiency) Conclusions From the above results, it is possible to conclude that both CDs were able to form true inclusion complexes with mosapride citrate at a molar ratio of 1:1 using the freeze-drying technique. The dissolution of mosapride citrate was markedly enhanced in both systems, showing an initial burst effect of more than 85% in the first 5 min. A significant difference was found between the two systems at p ≤ 0.05. Therefore, the freeze dried system of mosapride citrate with SBE7 β-CD prepared at a molar ratio of 1:1 could be chosen for the formulation of mosapride citrate mucoadhesive buccal tablets. Results Table 1 and Figure 1 show the phase solubility curve of mosapride citrate in β-CD and SBE7 β-CD as well as the stability constant K1:1 and the complexation efficiency of both complexing agents. Figures 3 & 4 shows the X-ray diffraction of drug with both CDs, from which we can see the complete disappearance of the drug characteristic peaks with the complex formed with SBE7 β-CD with freeze drying technique. Figure. 5 shows the apparent solubility of the drug in saliva simulated buffer pH 6.8. Figures 6,7 and Table 2 describe the dissolution profile of mosapride citrate form its inclusion complexes. References 1- Higuchi T., Connors K.A.1965: “Phase Solubility Techniques”, in: C.N. Reilly (Ed.), Advances in Analytical and Chemistry Instrumentation, vol. 4, Wiley Interscience, New York, pp. 117–212. Table. 1: Values of CE and K1:1 of inclusion complexes of mosapride citrate - β-CD and mosapride citrate – SBE7 β-CD. (CE: Complexation Efficiency, K1:1: Stability Constant, S.D: Standard Deviation) Acknowledgments The authors wish to acknowledge MarcyrlPharma (Egypt) for providing mosapride citrate. The authors are grateful to Cydex Pharmaceuticals (USA) for providing Captisol® as a gift sample. The authors are also grateful to Roquette (France) for gift sample of β- cyclodextrin.