Skip to main content
SpringerLink
Log in

Co-Administration of a Water-Soluble Polymer Increases the Usefulness of Cyclodextrins in Solid Oral Dosage Forms

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The aim of this study was to investigate the effect of cyclodextrins (β-CD, HP-β-CD and (SBE)7m-β-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs.

Methods. Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs.

Results. Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for β-CD and an Ap-type diagrams for both of the β-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-β-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/β-CD/HPMC and glibenclamide/(SBE)7m-β-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-β-CD) or 40% (in the case of β-CD) less cyclodextrin was used.

Conclusions. The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. In J. E. F. Reynolds (eds.), Martindale The Extra Pharmacopoeia 29 th edition, The Pharmaceutical Press, London, 1989, pp. 389.

    Google Scholar 

  2. L. Groop, E. Wåhlin-Boll, K.-J. Tötterman, A. Melander, E.-M. Tolppanen, and F. Fyhrqvist. Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetes. Eur. J. Clin. Pharmacol. 28:697–704 (1985).

    Google Scholar 

  3. J. B. Chalk, M. Patterson, M. T. Smith, and M. J. Eadie. Correlations between in vitro dissolution, in vivo bioavailability and hypoglycaemic effect of oral glibenclamide. Eur. J. Clin. Pharmacol. 31:177–182 (1986).

    Google Scholar 

  4. O. Shaheen, S. Othman, I. Jalal, A. Awidi, and W. Al-Turk. Comparison of pharmacokinetics and pharmacodynamics of a conventional and a new rapidly dissolving glibenclamide preparation. Int. J. Pharm. 38:123–131 (1987).

    Google Scholar 

  5. M. T. Esclusa-Diaz, J. J. Torres-Labandeira, M. Kata, and J. L. Vila-Jato. Inclusion complexation of glibenclamide with 2-hydroxypropyl-β-cyclodextrin in solution and in solid state. Eur. J. Pharm. Sci. 1:291–296 (1994).

    Google Scholar 

  6. N. M. Sanghavi, H. Venkatesh, and V. Tandel. Solubilization of glibenclamide with β-cyclodextrin & its derivates. Drug Dev. Ind. Pharm. 20:1275–1283 (1994).

    Google Scholar 

  7. A. Mitrevej, N. Sinchaipanid, V. Junyaprasert, and L. Warintornuwat. Effect of grinding of β-cyclodextrin and glibenclamide on tablet properties. Part I. in vitro. Drug Dev. Ind. Pharm. 22:1237–1241 (1996).

    Google Scholar 

  8. A. Gerlóczy, M. Vikmon, J. Szemán L. Jicsinszky, D. Acerbi, P. Ventura, M. Pasini, and J. Szejtli. Absorption Studies on Glibenclamide/Sodium/ β-Cyclodextrin complex in Rabbits. In P. Couvreur, D. Duchêne, I. Kalles (eds.), Minutes of the Formulation of Poorly-available Drugs for Oral Administration, Editions de Santé, Paris, 1996, pp. 257–260.

    Google Scholar 

  9. V. J. Stella and R. A. Rajewski. Cyclodextrins: Their future in drug formulation and delivery. Pharm. Res. 14:556–567 (1997).

    Google Scholar 

  10. R. A. Rajewski and V. J. Stella. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J. Pharm. Sci. 85:1142–1169 (1996).

    Google Scholar 

  11. T. Loftsson, H. Fridriksdóttir, A. M. Sigurdadóttir, and H. Ueda. The effect of water-soluble polymers on drug-cyclodextrin complexation. Int. J. Pharm. 110:169–177 (1994).

    Google Scholar 

  12. T. Loftsson, H. Fridriksdóttir, and T. K. Gudmundsdóttir. The effect of water-soluble polymers on aqueous solubility of drugs. Int. J. Pharm. 127:293–296 (1996).

    Google Scholar 

  13. H. Fridriksdóttir, T. Loftsson, and E. Stefánsson. Formulation and testing of methazolamide cyclodextrin eye drop solutions. J. Contr. Rel. 44:95–99 (1997).

    Google Scholar 

  14. M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed., Marcel Dekker Inc., New York, 1982.

    Google Scholar 

  15. T. Higughi and K. A. Connors. Phase-solubility techniques. Adv. Anal. Chem. Instr. 4:117–212 (1965).

    Google Scholar 

  16. D. O. Thompson. Cyclodextrins-Enabling Excipients: Their Present and Future Use in Pharmaceuticals. In S. Bruck (ed.), Crit. Rev. Ther. Drug Carr. Syst. 14:1–104 (1997).

  17. M. D. Johnson, B. L. Hoesterey, and B. D. Anderson. Solubilization of a tripeptide HIV protease inhibitor using a combination of ionization and complexation with chemically modified cyclodextrins. J. Pharm. Sci. 83:1142–1146 (1994).

    Google Scholar 

  18. K. Okimoto, R. A. Rajewski, K. Uekama, J. A. Jona, and V. J. Stella. The interaction of charged and uncharged drugs with neutral (HP-β-CD) and anionically charged (SBE7-β-CD) β-cyclodextrins. Pharm. Res. 13:256–264 (1996).

    Google Scholar 

  19. T. Loftsson, T. K. Gudmundsdóttir, and H. Fridriksdóttir. The influence of water-soluble polymers and pH on hydroxypropyl-β-cyclodextrin complexation of drugs. Drug Dev. Ind. Pharm. 22:401–405 (1996).

    Google Scholar 

  20. L. S. Goodman and A. Gilman. The Pharmacological Basis of Therapeutics, Pergamon Press, New York, 1990.

    Google Scholar 

  21. K. Uekama, S. Narisawa, F. Hirayama and M. Otagiri. Improvement of dissolution and absorption characteristics of benzodiazepines by cyclodextrin complexation. Int. J. Pharm. 16:327–338 (1983).

    Google Scholar 

  22. T. Järvinen, K. Järvinen, N. Schwarting, and V. J. Stella. β-Cyclodextrin Derivatives, SBE4-β-CD and HP-β-CD, Increase the oral bioavailability of cinnarizine in beagle dogs. J. Pharm. Sci. 84:295–299 (1995).

    Google Scholar 

  23. C. J. Betlach, M. A. Gonzalez, B. C. McKiernan, C. Neff-Davis, and N. Bodor. Oral pharmacokinetics of carbamazepine in dogs from commercial tablets and a cyclodextrin complex. J. Pharm. Sci. 82:1058–1060 (1993).

    Google Scholar 

  24. M. E. Brewster, W. R. Anderson, D. Meinsma, D. Moreno, A. I. Webb, L. Pablo, K. S. Estes, H. Derendorf, N. Bodor, R. Sawchuk, B. Cheung, and E. Pop. Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-β-cyclodextrin based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions. J. Pharm. Sci. 86:335–339 (1997).

    Google Scholar 

  25. J. K. Kristinsson, H. Fridriksdóttir, S. Thórisdóttir, A. M. Sigurdardóttir, E. Stefánsson, and T. Loftsson. Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Invest. Ophthalmol. Vis. Sci. 37:1199–1203 (1996).

    Google Scholar 

  26. H. Fridriksdóttir, T. Loftsson, J. A. Gudmundsson, G. J. Bjarnason, M. Kjeld, and T. Thorsteinsson. Desing and in vivo testing of 17β-estradiol-HPβCD sublingual tablets. Pharmazie 51:39–42 (1996).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Jouko Savolainen, Hannu Taipale, Pekka Jarho & Tomi Järvinen

  2. Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Kristiina Järvinen

  3. Department of Pharmacy, University of Iceland, P.O. Box 7210, IS-127, Reykjavik, Iceland

    Thorsteinn Loftsson

Authors
  1. Jouko Savolainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristiina Järvinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hannu Taipale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pekka Jarho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thorsteinn Loftsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomi Järvinen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Savolainen, J., Järvinen, K., Taipale, H. et al. Co-Administration of a Water-Soluble Polymer Increases the Usefulness of Cyclodextrins in Solid Oral Dosage Forms. Pharm Res 15, 1696–1701 (1998). https://doi.org/10.1023/A:1011900527021

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1011900527021

Search

Navigation