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Encapsulation of cyclodextrin complexed simvastatin in chitosan nanocarriers: A novel technique for oral delivery

  • Amber Vyas
  • Shailendra Saraf
  • Swarnlata Saraf
Original Article

Abstract

The purpose of the present work was to design and investigate the potential of novel hydroxylpropyl-beta-cyclodextrin (HP-β-CD) and chitosan nanocarriers (NCs) for effective delivery of model, poorly water soluble drug simvastatin. The prepared system was characterized for particle size, particle size distribution (PDI), zeta potential, differential scanning calorimetery, x-ray diffraction, encapsulation efficiency and drug release studies. The results revealed that among the selected ratios of tripolyphosphate/chitosan, ratio 1:4 and 1:5 proved to be optimum in terms of particle size, particle distribution and drug release profile. The average size of nanoparticles increased from 516 to 617 and 464 to 562 nm for ratio 1:4 and 1:5 with increase in drug/HP-β-CD amount. To assess interactions and whether the simvastatin was incorporated in the NCs in its crystalline or amorphous form DSC and XRD were performed. These results suggest that the encapsulation process produces a marked decrease in crystallinity of simvastatin and/or confers to a nearly amorphous state of drug in NCs. Results reveled that with increase in the amount of HP-β-CD/drug the final loading of the NCs increased due to increased solubilization of simvastatin in the presence of HP-β-CD. The in vitro release profile of prepared NCs showed initial fast release (burst effect) followed by a delayed release pattern. In conclusion, these nanocarriers constitute a novel and efficient system for encapsulation and oral delivery of poorly soluble drugs.

Keywords

Hydroxylpropyl-beta-cyclodextrin (HP-β-CD) Nanocarrier Chitosan Tripolyphosphate Novel drug delivery system 

Notes

Acknowledgment

The authors are thankful to AICTE [F.No.: 8023/BOR/RPS-153/2006-07] New Delhi for financial assistance. Authors are thankful to Ranbaxy, India for providing pure drug and Dr. Denis Simon and Emilie Van- Oudendycke of Roquette, Lestrem, France for providing hydroxypropyl-beta-cyclodextrin. Authors also extend their gratitude to Head, University Institute of pharmacy, Pt., Ravishankar Shukla University, Raipur, Chhattisgarh, India for providing facilities to carry out research work.

References

  1. 1.
    Radtke, M.: Nanopure TM: pure drug nanoparticles for the formulation of poorly soluble drugs. New Drugs 3, 62–68 (2001)Google Scholar
  2. 2.
    Muller, R.H., Bohm, B.H.L.: Nanosuspensions. In: Muller, R.H., Bentia, S., Bohm, B.H.L. (eds.) Emulsions & nanosuspensions for the formulation of poorly soluble drugs, pp. 149–174. Medpharm Scientific Publishers, Stuttgart, Germany (1998)Google Scholar
  3. 3.
    Muller, R.H., Jacobs, C., Kayser, O.: Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future. Adv. Drug Deliv. Rev. 47(1), 3–19 (2001)CrossRefGoogle Scholar
  4. 4.
    Liversidge, E.M., Liversidge, G.G., Cooper, E.R.: Nanosizing: a formulation approach for poorly water-soluble compounds. Eur. J. Pharm. Sci. 18(2), 113–120 (2003)CrossRefGoogle Scholar
  5. 5.
    Rabinow, B.E.: Nanosuspensions in drug delivery. Nat. Rev. Drug Discov. 3(9), 785–796 (2004)CrossRefGoogle Scholar
  6. 6.
    Patravale, V.B., Date, A.A., Kulkarni, R.M.: Nanosuspensions: a promising drug delivery strategy. J. Pharm. Pharmacol. 56(7), 827–840 (2004)CrossRefGoogle Scholar
  7. 7.
    Gref, R., Minamitake, Y., Perracchia, M.T., Trubeskoy, V., Torchilin, V., Langer, R.: Biodegradable long-circulating polymeric nanospheres. Science 263, 1600–1603 (1994)CrossRefGoogle Scholar
  8. 8.
    Florence, A.T., Hillery, A.M., Hussain, N., Jani, P.U.: Nanoparticles as carriers for oral peptide absorption: studies on particle uptake and fate. J. Control. Release 36, 39–46 (1995)CrossRefGoogle Scholar
  9. 9.
    Allemann, E., Gurny, R., Deolker, E.: Drug loaded nanoparticles: preparation methods and drug targeting issues. Eur. J. Pharm. Biopharm. 39, 173–191 (1993)Google Scholar
  10. 10.
    Tiyaboonchai, W.: Chitosan nanoparticles: a promising system for drug delivery. Naresuan Univ. J. 11(3), 51–66 (2003)Google Scholar
  11. 11.
    Aspden, T.J., Mason, J.D., Jones, N.S.: Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers. J. Pharm. Sci. 86, 509–513 (1997)CrossRefGoogle Scholar
  12. 12.
    Lehr, C.M., Bouwstra, J.A., Schacht, E., Junginger, H.E.: In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharm. 78, 43–48 (1992)CrossRefGoogle Scholar
  13. 13.
    Dumitriu, S., Chornet, E.: Inclusion and release of proteins from polysaccharide-based polyion complexes. Adv. Drug Deliv. Rev. 31, 223–246 (1998)CrossRefGoogle Scholar
  14. 14.
    Takeuchi, H., Yamamoto, H., Niwa, T., Hino, T., Kawashima, Y.: Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes. Pharm. Res. 13, 896–901 (1996)CrossRefGoogle Scholar
  15. 15.
    Janes, K.A., Calvo, P., Alonso, M.J.: Polysaccharide colloidal particles as delivery systems for macromolecules. Adv. Drug Deliv. Rev. 47, 83–97 (2001)CrossRefGoogle Scholar
  16. 16.
    Bhumkar, D.R., Pokharkar, V.B.: Studies on effect of PH on cross-linking of chitosan with sodium tripolyphosphate: a technical note. AAPS PharmSciTech. 7(2), E1–E6 (2006)CrossRefGoogle Scholar
  17. 17.
    Aral, C., Akbug˘ a, J.: Alternative approach to the preparation of chitosan beads. Int. J. Pharm. 168, 9–15 (1998)CrossRefGoogle Scholar
  18. 18.
    Mi, F.L., Shyu, S.S., Chen, C.T., Schoung, J.Y.: Porous chitosan microsphere for controlling the antigen release of Newcastle disease vaccine: preparation of antigen-adsorbed microsphere and in vitro release. Biomaterials 20, 1603–1612 (1999)CrossRefGoogle Scholar
  19. 19.
    Shu, X.Z., Zhu, K.J.: A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled drug delivery. Int. J. Pharm. 201, 51–58 (2000)CrossRefGoogle Scholar
  20. 20.
    Ducheˆ ne, D., Ponchel, G., Wouassindjewe, D.: Cyclodextrins in targeting- Application to nanoparticles. Adv. Drug Deliv. Rev. 36(1), 29–40 (1999)CrossRefGoogle Scholar
  21. 21.
    Vyas, A., Saraf, S., Saraf, S.: Cyclodextrin based novel drug delivery systems. J. Incl. Phenom. Macrocycl. Chem. 62(1–2), 23–42 (2008)CrossRefGoogle Scholar
  22. 22.
    Higuchi, T., Connors, K.A.: Phase-solubility techniques. Adv. Anal. Chem. Instrum. 4, 117–212 (1965)Google Scholar
  23. 23.
    Brewster, M.E., Loftsson, T.: Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59, 645–666 (2007)CrossRefGoogle Scholar
  24. 24.
    Shu, X.Z., Zhu, K.J.: Chitosan/gelatin microspheres prepared by modified emulsification and ionotropic gelation. J. Microencapsul. 18, 237–245 (2001)CrossRefGoogle Scholar
  25. 25.
    Calvo, P., Remun˜a′n-Lo′ pez, C., Vila-Jato, J.L., Alonso, M.J.: Novel hydrophilic chitosan–polyethylene oxide nanoparticles as protein carriers. J. Appl. Polym. Sci. 63, 125–132 (1997)CrossRefGoogle Scholar
  26. 26.
    Calvo, P., Vila-Jato, J.L., Alonso, M.J.: Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers. Int. J. Pharm. 153, 41–50 (1997)CrossRefGoogle Scholar
  27. 27.
    Bodmeier, R., Chen, H., Paeratakul, O.: A novel approach to the oral delivery of micro- or nanoparticles. Pharm. Res. 6, 413–417 (1989)CrossRefGoogle Scholar
  28. 28.
    Ambike, A.A., Mahadik, K.R., Paradkar, A.: Spray-dried amorphous solid dispersions of simvastatin a low Tg drug: in vitro and in vivo evaluations. Pharm. Res. 22, 990–998 (2005)CrossRefGoogle Scholar
  29. 29.
    Kang, B.K., Lee, J.S., Chon, S.K., Jeong, S.Y., Yuk, S.H., Khang, G., Lee, H.B., Cho, S.H.: Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int. J. Pharm. 274, 65–73 (2004)CrossRefGoogle Scholar
  30. 30.
    Rajput, S.J., Raj, H.A.: Simultaneous spectroscopic estimation of ezetimibe and simvastatin in tablet dosage forms. Indian J. Pharm. Sci. 69, 759–762 (2007)CrossRefGoogle Scholar
  31. 31.
    Arayne, M.S., Sultana, N., Hussain, F., Ali, S.A.: Validated spectrophotometric method for quantitative determination of simvastatinin pharmaceutical formulations and human serum. J. Anal. Chem. 62, 536–541 (2007)CrossRefGoogle Scholar
  32. 32.
    Bhatia, N.M., Deshmukh, D.D., Kokil, S.U., Bhatia, M.S.: (2009) Simultaneous spectrophotometric estimation of simvastatin and ezetimibe in tablet formulation. J. Chem. 6(2), 541–544. http://www.e-journals.in/ Google Scholar
  33. 33.
    Zerrouk, N., Corti, G., Ancillotti, S., Maestrelli, F., Cirri, M., Mura, P.: Influence of cyclodextrins and chitosan, separately or in combination, on glyburide solubility and permeability. Eur. J. Pharm. Biopharm. 62, 241–246 (2006)CrossRefGoogle Scholar
  34. 34.
    Maestrelli, F., Garcia-Fuentes, M., Mura, P., Jose′ Alonso, M.: A new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin. Eur. J. Pharm. Biopharm. 63, 79–86 (2006)CrossRefGoogle Scholar
  35. 35.
    Patel, A.R., Vavia, P.R.: Effect of hydrophilic polymer on solubilization of fenofibrate by cyclodextrin complexation. J. Incl. Phenom. Macrocycl. Chem. 56, 247–251 (2006)CrossRefGoogle Scholar
  36. 36.
    Chowdary, K.P.R., Srinivas, S.V. Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl β-cyclodextrin. AAPS PharmSciTech. 7(3), E-1–E-6 (2006)Google Scholar
  37. 37.
    Bibby, D.C., Davies, N.M., Tucker, I.G.: Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int. J. Pharm. 197, 1–11 (2000)CrossRefGoogle Scholar
  38. 38.
    Loftsson, T., Frioriksdottir, H., Siguroardottir, A.M., Ueda, H.: The effect of water-soluble polymers on drug–cyclodextrin complexation. Int. J. Pharm. 110, 169–177 (1994)CrossRefGoogle Scholar
  39. 39.
    Ammar, H.O., Salama, H.A., Ghorab, M., Mahmoud, A.A.: Formulation and biological evaluation of glimepiride–cyclodextrin–polymer systems. Int. J. Pharm. 309, 129–138 (2006)CrossRefGoogle Scholar
  40. 40.
    Pan, Y., Li, Y.J., Zhao, H.Y., Zheng, J.M., Xu, H., Wei, G., et al.: Int. J. Pharm. 349, 139–147 (2002)CrossRefGoogle Scholar
  41. 41.
    Papadimitriou, S., Bikiaris, D., Avgoustakis, K., Karavas, E., Georgarakis, M.: Chitosan nanoparticles loaded with dorzolamide and pramipexole. Carbohydr. Polym. 73, 44–54 (2008)CrossRefGoogle Scholar
  42. 42.
    Zhang, H., Oh, M., Allen, C., Kumacheva, E.: Monodisperse chitosan nanoparticles for mucosal drug delivery. Biomacromolecules 5(6), 2461–2468 (2004)CrossRefGoogle Scholar
  43. 43.
    Fernandez-Urrusuno, R., Calvo, P., Remunan-Lopez, C., Vila-Jato, J.L., Alonso, M.J.: Enhancement of nasal absorption of insulin using chitosan Nanoparticles. Pharm. Res. 16, 1576–1581 (1999)CrossRefGoogle Scholar
  44. 44.
    Kim, D.G., Jeong, Y.I., Choi, C., Roh, S.H., Kang, S.K., Jang, M.K., Nah, J.W.: Retinol-encapsulated low molecular water-soluble chitosan nanoparticles. Int. J. Pharm. 319, 130–138 (2006)CrossRefGoogle Scholar
  45. 45.
    Dhawan, S., Singla, A.K.: Nifedipine loaded chitosan microspheres prepared by emulsification phase separation. Biotech. Histochem. 78, 243–254 (2003)Google Scholar
  46. 46.
    Gupta, P., Bansal, A.K.: Devitrification of amorphous celecoxib. AAPS PharmSciTech. 6, E223–E230 (2005)CrossRefGoogle Scholar
  47. 47.
    Kausbal, A.M., Gupta, P., Bansal, A.K.: Amorphous drug delivery systems: molecular aspects, design, and performance. Crit. Rev. Ther. Drug Carrier Syst. 21(3), 133–193 (2004)CrossRefGoogle Scholar
  48. 48.
    Karavas, E., Georgarakis, E., Sigalas, M.P., Avgoustakis, K., Bikiaris, D.: Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions. Eur. J. Pharm. Biopharm. 66(3), 334–347 (2007)CrossRefGoogle Scholar
  49. 49.
    Karavas, E., Georgarakis, E., Docoslis, A., Bikiaris, D.: Combining SEM, TEM, and micro-Raman techniques to differentiate between the amorphous molecular level dispersions and nanodispersions of a poorly water-soluble drug within a polymer matrix. Int. J. Pharm. 340, 76–83 (2007)CrossRefGoogle Scholar
  50. 50.
    Shah, B., Kakumanu, V.K., Bansal, A.K.: Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J. Pharm. Sci. 95, 1641–1665 (2006)CrossRefGoogle Scholar
  51. 51.
    Jun, S.W., Kim, M.S., Kim, J.S., Park, H.J., Lee, S., Woo, J.S., Hwang, S.J.: Preparation and characterization of simvastatin/hydroxypropyl-β-cyclodextrin inclusion complex using supercritical antisolvent (SAS) process. Eur. J. Pharm. Biopharm. 66(3), 413–421 (2007)CrossRefGoogle Scholar
  52. 52.
    Boonsongrit, Y., Mitrevej, A., Mueller, B.W.: Chitosan drug binding by ionic interaction. Eur. J. Pharm. Biopharm. 62(3), 267–274 (2006)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.University Institute of Pharmacy, Pt. Ravishankar Shukla UniversityRaipurIndia

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