Skip to main content
SpringerLink
Log in

Comparative study of itraconazole-cyclodextrin inclusion complex and its commercial product

  • Research Articles
  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Itraconazole (ITZ) solid complex using hydroxypropyl-β-cyclodextrin (ITZ-HP-β-CD) with 20% polyvinylpyrrolidone was prepared by a co-evaporation method. The complex improved antifungal activity against C. parapasilosis and C. albicans. The complex demonstrated good flow and compressibility characteristics. The complex was formulated as a capsule dosage form and drug release was evaluated. Capsules containing ITZ-HP-β-CD at a molar ratio of 1:3 with 20% polyvinylpyrrolidone have a faster dissolution rate than commercial capsules (Sporanox®). About 88% of ITZ was released in less than 30 min and the initial dissolution rate exhibited a 3.5-fold increase compared to the commercial product. UV spectrophotometeric, HPLC, and antimicrobial methods were used to determine ITZ concentration in the release medium and the results obtained by these methods are reported. It was found that HPLC analysis is a suitable and reliable method for determination of the drug concentration with a coefficient of variation less than 10%. The intraday precision showed a coefficient of variation less than 3.96%, and that for interday was less than 4.99%. The HPLC method was more accurate and precise than the antimicrobial and UV-spectrophotometric methods for determination of ITZ concentration present in the release medium.

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

  • Ahmed, M. O., El-Gibaly, I., and Ahmed, S. M., Effect of cyclodextrins on the physicochemical properties and antimycotic activity of clotrimazole. Int. J. Pharm., 171, 111–121 (1998).

    Article  CAS  Google Scholar 

  • Alanazi, F. K., Ahmed, S. M., Alhamed, S. S., Mowafy, H. A., Alsarra, I. A., and Bayomi, M. A., Inclusion complexation of Itraconazole with cyclodextrin derivatives: phase solubility and physicochemical characterization. Mansoura J. Pharm. Sci., 23, 177–194 (2007).

    CAS  Google Scholar 

  • Al-Marzouqi, A. H., Elwy, H. M., Shehadi, I., and Adem, A., Physicochemical properties of antifungal drug-cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques. J. Pharm. Biomed. Anal., 49, 227–233 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Al-Meshal, M. A., Ramadan, M. A., Lotfi, K. M., and Shibl, A. M., Determination of meropenem in plasma by high performance liquid chromatography and a microbioloical method. J. Clin. Pharm. Ther., 20, 159–163 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Alsarra, I. A., Alanazi, F. K., Alhamed, S. S, Ahmed, S. M, and Mowafy, H. A., Preparation and evaluation of itraconazole-cyclodextrin complexes in solid state. Alex. J. Pharm. Sci., 21, 47–55 (2007).

    CAS  Google Scholar 

  • Amidon, G. L., Lennernäs, H., Shah, V. P., and Crison, J. R., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 12, 413–420 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Ammar, H. O., Salama, H. A., Ghorab, M., and Mahmoud, A. A., Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy. Int. J. Pharm., 320, 53–57 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Ancarani, F., Incidence and prevalence of Candida nonalbicans in oral Candida infections. Clinician, 11, 6–10 (1993).

    Google Scholar 

  • Aulton, M. E., Pharmaceutics: The Science of Dosage Form Design. New York, USA, (1988).

  • Banker, G. S., Anderson, N. R., Tablets, In Lachman, L., Liberman, H. A., and Kanig, J. I. (Eds.), The Theory and Practice of Industrial Pharmacy. Lea and Febiger, Philadelphia, pp. 293–345, (1986).

    Google Scholar 

  • Bettinetti, G. P., Mura, P., Liguori, A., Bramanti, G., and Giordano, F., Solubilization and interaction of naproxen with cyclodextrins in aqueous solution and in the solid state. Farmaco Prat., 43, 331–343 (1988).

    CAS  PubMed  Google Scholar 

  • Brewster, M. E., Vandecruys, R., Peeters, J., Neeskens, P., Verreck, G., and Loftsson, T., Comparative interaction of 2-hydroxypropyl-beta-cyclodextrin and sulfobutyletherbeta-cyclodextrin with itraconazole: phase-solubility behavior and stabilization of supersaturated drug solutions. Eur. J. Pharm. Sci., 34, 94–103 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Cappello, B., De Rosa, G., Giannini, L., La Rotonda, M. I., Mensitieri, G., Miro, A., Quaglia, F., and Russo, R., Cyclodextrin-containing poly(ethyleneoxide) tablets for the delivery of poorly soluble drugs: Potential as buccal delivery system. Int. J. Pharm., 319, 63–70 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Cirri, M., Maestrelli, F., Corti, G., Furlanetto, S., and Mura, P., Simultaneous effect of cyclodextrin complexation, pH, and hydrophilic polymers on naproxen solubilization. J. Pharm. Biomed. Anal., 42, 126–131 (2006).

    Article  CAS  PubMed  Google Scholar 

  • De Beule, K. and Gestel, J. V., Pharmacology of itraconazole. Drugs, 61, 27–37 (2001).

    Article  PubMed  Google Scholar 

  • Dupont, B. and Drouhet, E., Early experience with itraconazole in vitro and in patients: Pharmacokinetic studies and clinical results. Rev. Infect. Dis., 9, S71–S76 (1987).

    PubMed  Google Scholar 

  • El-Maradny, H. A., Mortada, S. A., Kamel, O. A., and Hikal, A. H., Characterization of ternary complexes of meloxicam-HP β CD and PVP or L-arginine prepared by the spray-drying technique. Acta Pharm., 58, 455–466 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Espinel-Ingroff, A., Shadomy, S., and Gebhart, R. J., In vitro studies with R 51,211 (Itraconazole). Antimicrob. Agents Chemother., 26, 5–9 (1984).

    CAS  PubMed  Google Scholar 

  • Farmaki, E., Evdoridou, J., Pouliou, T., Bibashi, E., Panagopoulou, P., Filioti, J., Benos, A., Sofianou, D., Kremenopoulos, G., and Roilides, E., Fungal colonization in the neonatal intensive care unit: risk factors, drug susceptibility, and association with invasive fungal infections. Am. J. Perinatol., 24, 127–135 (2007).

    Article  PubMed  Google Scholar 

  • Fromtling, R. A., Galgiani, J. N., Pfaller, M. A., Espinel-Ingroff, A., Bartizal, K. F., Bartlett, M. S., Body, B. A., Frey, C., Hall, G., Roberts, G. D., Nolte, F. B., Odds, F. C., Rinaldi, M. G., Sugar, A. M., and Villareal, K., Multicenter evaluation of a broth macrodilution antifungal susceptibility test for yeasts. Antimicrob. Agents Chemother., 37, 39–45 (1993).

    CAS  PubMed  Google Scholar 

  • Gennaro, A. R., Der Marderosian, A. H., Hanson, G. R., and Medwick, T., Remington: The Science and Practice of Pharmacy. Philadelphia, USA, (2000).

  • Gubbins, P. O., Gurley, B. J., and Bowman, J., Rapid and sensitive high performance liquid chromatographic method for determination of itraconazole and hydroxy-metabolite in human serum. J. Pharm. Biomed. Anal., 16, 1005–1012 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Hassan, H. A., Al-Marzouqi, A. H., Jobe, B., Hamza, A. A, and Ramadan, G. A., Enhancement of dissolution amount and in vivo bioavailability of itraconazole by complexation with beta-cyclodextrin using supercritical carbon dioxide. J. Pharm. Biomed. Anal., 45, 243–250 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Hegde, R. P., Rheingold, J. L., Welch, S., and Rhodes, C. T., Studies of powder flow using a recording powder flow-meter and measurement of the dynamic angle of repose. J. Pharm. Sci., 74, 11–15 (1985).

    Article  CAS  PubMed  Google Scholar 

  • Hikal, A. H., Shibl, A., and El-Houfy, S., Determination of sodium fusidate and fusidic acid in dosage forms by high performance liquid chromatography and a microbiological method. J. Pharm. Sci., 71, 1297–1298 (1982).

    Article  CAS  PubMed  Google Scholar 

  • Hostetler, J. S., Heykants, J., Clemons, K. V., Woestenborghs, R., Hanson, L. H., and Stevens, D. A., Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: Studies of interpatient variations in concentrations. Antimicrob. Agents Chemother., 37, 2224–2227 (1993).

    CAS  PubMed  Google Scholar 

  • Hufford, C. D., Funderburk, M. J, Morgan, J. M., and Robertson, L. W., Two antimicrobial alkaloids from heartwood of Liriodendron tulipifera L. J. Pharm. Sci., 64, 789–792 (1975).

    Article  CAS  PubMed  Google Scholar 

  • Hwang, C.-C. and Lee, W.-C., Chromatographic resolution of the enantiomers of phenylpropanolamine by using molecularly imprinted polymer as the stationary phase. J. Chromatogr. B Biomed. Sci. Appl., 765, 45–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Jung, J. Y., Yoo, S. D., Lee, S. H., Kim, K. H., Yoon, D. S., and Lee, K. H., Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique. Int. J. Pharm., 187, 209–218 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Khan, K. A., The concept of dissolution efficiency. J. Pharm. Pharmacol., 27, 48–49 (1975).

    CAS  PubMed  Google Scholar 

  • Loftsson, T. and Brewster, M. E., Pharmaceutical applications of cyclodextrins. I. Drug solubilization and stabilization. J. Pharm. Sci., 85, 1017–1025 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Miro, A., Quaglia, F., Giannini, L., Cappello, B., and La Rotonda, M. I., Drug/cyclodextrin solid systems in designing hydrophilic matrices: A strategy to modulate drug delivery rate. Curr. Drug Deliv., 3, 373–378 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Miyake, K., Irie, T., Arima, H., Hirayama, F., Uekama, K., Hirano, M., and Okamaoto, Y., Characterization of itraconazole/ 2-hydroxypropyl-β-cyclodextrin inclusion complex in aqueous propylene glycol solution. Int. J. Pharm., 179, 237–245 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Mura, P., Bettinetti, G., Melani, F., and Manderioli, A., Interaction between naproxen and chemically modified β-cyclodextrins in the liquid and solid state. Eur. J. Pharm. Sci., 3, 347–355 (1995).

    Article  CAS  Google Scholar 

  • Mura, P., Faucci, M. T., and Bettinetti, G. P., The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-β-cyclodextrin. Eur. J. Pharm. Sci., 13, 187–194 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Ng, T. K., Chan, R. C., Adeyemi-Doro, F. A., Cheung, S. W., and Cheng, A. F., Rapid high performance liquid chromatographic assay for antifungal agents in human sera. J. Antimicrob. Chemother., 37, 465–472 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Peeters, J., Neeskens, P., Tollenaere, J. P., van Remoortere, P., and Brewster, M. E., Characterization of the interaction of 2-hydroxypropyl-beta-cyclodextrin with itraconazole at pH 2, 4, and 7. J. Pharm. Sci., 91, 1414–1422 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Raghavan, S. L., Schuessel, K., Davis, A., and Hadgraft, J., Formation and stabilization of triclosan colloidal suspension using supersaturated systems. Int. J. Pharm., 261, 153–158 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Rao, V. M., Nerurkar, M., Pinnamaneni, S., Rinaldi, F., and Raghavan, K., Co-solubilization of poorly soluble drugs by micellization and complexation. Int. J. Pharm., 319, 98–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Reeves, D. S., Wise, R., Andrews, J. M., and White, L. O., Clinical Antimicrobial Assays. Oxford, (1999).

  • Rodriguez-Hornedo, N. and Murphy, D., Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J. Pharm. Sci., 88, 651–660 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Serajuddin, A. T., Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci., 88, 1058–1066 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Shibl, A. M., Tawfik, A. F., El-Houfy, S., and Al-Shammary, F. J., Determination of lomefloxacin in biological fluids by high performance liquid chromatography and a microbioloical method. J. Clin. Pharm. Ther., 16, 353–359 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Shim, S. Y., Ji, C. W., Sah, H., Park, E. S., and Lee, B. J., Characterization of itraconazole semisolid dosage forms prepared by hot melt technique. Arch. Pharm. Res., 29, 1055–1060 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Six, K., Daems, T., de Hoon, J., Van Hecken, A., Depre, M., Bouche, M. P., Prinsen, P., Verreck, G., Peeters, J., Brewster, M. E., and van den Mooter, G., Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. Eur. J. Pharm. Sci., 24, 179–186 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Strickley, R. G., Solubilizing excipients in oral and liquid formulations. Pharm. Res., 21, 201–230 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Truant, A. L., Manual of Commercial Methods in Clinical Microbiology. Virginia, USA, (2002).

  • Valero, M., Pérez-Revuelta, B.I., and RodrÍguez, L. J., Effect of PVP K-25 on the formation of the naproxen:beta-ciclodextrin complex. Int. J. Pharm., 253, 97–110 (2003).

    Article  CAS  PubMed  Google Scholar 

  • van Doorne, H. and Bosch, E. H., Stability and in vitro activity of nystatin and its γ-cyclodextrin complex against Candida albicans. Int. J. Pharm., 73, 43–49 (1991).

    Article  Google Scholar 

  • Venkateswarlu, K., Denning, D. W., and Kelly, S. L., In-vitro activity of D0870, a new triazole antifungal drug, in comparison with fluconazole and itraconazole against Aspergillus fumigatus and Candida krusei. J. Antimicrob. Chemother., 39, 731–736 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Warnock, D. W., Turner, A., and Burke, J. Comparison of high performance liquid chromatographic and microbiological methods for determination of itraconazole J. Antimicrob. Chemother., 21, 93–100 (1988).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Ibrahim A. Alsarra, Fars K. Alanazi, Sayed M. Ahmed, Ahmed A. Bosela, Suliman S. Alhamed & Hammam A. Mowafy

  2. Center of Excellence in Biotechnology Research, King Saud University, Riyadh, 11451, Saudi Arabia

    Ibrahim A. Alsarra

  3. Kayyali Chair for Pharmaceutical Industry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Fars K. Alanazi

  4. Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, PA, 19104, USA

    Steven H. Neau

Authors
  1. Ibrahim A. Alsarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fars K. Alanazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sayed M. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ahmed A. Bosela
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Suliman S. Alhamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hammam A. Mowafy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven H. Neau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ibrahim A. Alsarra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alsarra, I.A., Alanazi, F.K., Ahmed, S.M. et al. Comparative study of itraconazole-cyclodextrin inclusion complex and its commercial product. Arch. Pharm. Res. 33, 1009–1017 (2010). https://doi.org/10.1007/s12272-010-0706-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-010-0706-3

Key words

Search

Navigation