The Application Cyclodextrins in Drug Delivery
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The Application Cyclodextrins in Drug Delivery O. Sayed 1* , A. Saied 1 , J. Hadgraft 2 , M. E. Lane 2 1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Egypt 2 Department of Pharmaceutics, The School of Pharmacy, University of London, WC1N 1AX, UK. * E-mail: [email protected] 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). 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 (SBE 7 β-CD), thereby increasing its bioavailability and therapeutics efficiency. Materials & Methods Materials: Mosapride citrate was obtained as a gift from Marcyrl Pharma (Egypt), β-cyclodextrin (Kleptose ®) was obtained as a gift sample from Roquette (France), Sulfobutyl Ether7 β-cyclodextrin (SBE 7 β- 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 re ects the solubilizing power of the CDs towards fl the drug, was calculated from the straight line of the phase solubility diagrams according to the following equation CE= S o K 1:1 = slope /1- slope Where So represents the drug solubility in the absence of CDs, K1:1 is the apparent stability constant, where K 1:1 = 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. 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 SBE 7 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. 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 SBE 7 β-CD prepared at a molar ratio of 1:1 could be chosen for the formulation of mosapride citrate mucoadhesive buccal tablets. 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. Acknowledgments The authors wish to acknowledge Marcyrl Pharma (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. β-CD conc. (mole/L) Mosapride citrate conc. (mole/L) (Average ± S.D) SBE 7 β-CD conc. (mole/L) Mosapride citrate conc. (mole/L) (Average ± S.D) 0.002 0.00069 ± 8.39E-07 0.002 0.00171 ± 2.36E-05 0.004 0.00082 ± 4.25E-07 0.004 0.00315 ± 4.82E-05 0.006 0.00099 ± 2.89E-07 0.006 0.00429 ± 2.71E-05 0.008 0.00105 ± 5.62E-07 0.008 0.00525 ± 2.14E-05 0.010 0.00122 ± 1.61E-07 0.010 0.00664 ± 3.78E-05 Slope = 0.0643 Slope = 0. 5978 Intercept = 0.0006 Intercept = 0.0006 CE = 0.069 CE = 1.486 K 1:1 = 114.53 mole -1 K 1:1 = 2477.21 mole -1 Table. 1: Values of CE and K1:1 of inclusion complexes of mosapride citrate - β-CD and mosapride citrate – SBE 7 β-CD. (CE: Complexation Efficiency, K 1:1 : Stability Constant, S.D : Standard Deviation) CD type Method IDR (% dissolved/min) ± S.D DE 60 min (%) ± S.D β-CD Freeze Drying 17.33 ± 0.22 90.47 ± 1.58 Kneading 15.40 ± 0.37 82.13 ± 2.08 Physical Mixing 8.46 ± 0.60 44.09 ± 2.08 SBE 7 β-CD Freeze Drying 19.43 ± 0.20 97.50 ± 0.93 Kneading 17.80 ± 0.19 89.65 ± 1.34 Physical Mixing 9.46 ± 0.56 49.06 ± 3.20 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-CD binary mixtures prepared by different methods. Figure 3: X-ray diffraction patterns of mosapride citrate - SBE7 β-CD binary mixtures prepared by different methods. Figure 4: Apparent solubilities of mosapride citrate binary mixtures prepared by different methods using β-CD and SBE 7 β-CD Figure 5: Dissolution profiles of mosapride citrate binary mixtures prepared by different methods using β- CD. Figure 6: Dissolution profiles of mosapride citrate binary mixtures prepared by different methods using SBE 7 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 : Initial Dissolution Rate, DE 60 min : Dissolution Efficiency)
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The Application Cyclodextrins in Drug Delivery. O. Sayed 1* , A. Saied 1 , J. Hadgraft 2 , M. E. Lane 2 1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Egypt - PowerPoint PPT Presentation
Transcript of The Application Cyclodextrins in Drug Delivery
The Application Cyclodextrins in Drug DeliveryO. Sayed 1*, A. Saied1, J. Hadgraft2, M. E. Lane 2
1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Egypt
2 Department of Pharmaceutics, The School of Pharmacy, University of London, WC1N 1AX, UK.
* E-mail: [email protected] 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).
ObjectivesIn 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 & MethodsMaterials: Mosapride citrate was obtained as a gift from Marcyrl Pharma (Egypt), β-cyclodextrin (Kleptose ®) was obtained as a gift sample from Roquette (France), Sulfobutyl Ether7 β-cyclodextrin (SBE7 β-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.ResultsTable 1 and Figure 1 show the phase solubility curve of mosapride citratein 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 theapparent solubility of the drug in saliva simulated buffer pH 6.8. Figures6,7 and Table 2 describe the dissolution profile of mosapride citrate form its inclusion complexes.
ConclusionsFrom the above results, it is possible to conclude that both CDs were ableto form true inclusion complexes with mosapride citrate at a molar ratio of1:1 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.
References1- 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.
AcknowledgmentsThe authors wish to acknowledge Marcyrl Pharma (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.
β-CD conc. (mole/L)
Mosapride citrate conc. (mole/L) (Average ± S.D)
SBE7 β-CDconc. (mole/L)
Mosapride citrate conc. (mole/L) (Average ± S.D)
0.002 0.00069 ± 8.39E-07 0.002 0.00171 ± 2.36E-050.004 0.00082 ± 4.25E-07 0.004 0.00315 ± 4.82E-050.006 0.00099 ± 2.89E-07 0.006 0.00429 ± 2.71E-050.008 0.00105 ± 5.62E-07 0.008 0.00525 ± 2.14E-050.010 0.00122 ± 1.61E-07 0.010 0.00664 ± 3.78E-05
Slope = 0.0643 Slope = 0. 5978Intercept = 0.0006 Intercept = 0.0006
CE = 0.069 CE = 1.486K1:1 = 114.53 mole-1 K1:1 = 2477.21 mole-1
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)
CD type Method IDR (% dissolved/min) ± S.D DE 60 min (%) ± S.D
β-CD
Freeze Drying 17.33 ± 0.22 90.47 ± 1.58
Kneading 15.40 ± 0.37 82.13 ± 2.08
Physical Mixing 8.46 ± 0.60 44.09 ± 2.08
SBE7 β-CD
Freeze Drying 19.43 ± 0.20 97.50 ± 0.93
Kneading 17.80 ± 0.19 89.65 ± 1.34
Physical Mixing 9.46 ± 0.56 49.06 ± 3.20
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-CD binary mixtures prepared by different methods.
Figure 3: X-ray diffraction patterns of mosapride citrate - SBE7 β-CD binary mixtures prepared by different methods.
Figure 4: Apparent solubilities of mosapride citrate binary mixtures prepared by different methods using β-CD and SBE 7 β-CD
Figure 5: Dissolution profiles of mosapride citrate binary mixtures prepared by different methods using β-CD.
Figure 6: Dissolution profiles of mosapride citrate binary mixtures prepared by different methods using SBE 7 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: Initial Dissolution Rate, DE 60 min: Dissolution Efficiency)
