Abstract
Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with β-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of β-cyclodextrin concentration, resulting in AL type phase solubility diagram which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M1. The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.
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Abdel-Moety, E. M., Khattab, F. I., Kelani, K. M., and AbouAI-Alamein, A. M., Chromatographie determination of clotrimazole, ketoconazole and fluconazole in pharmaceutical formulations.Farmaco., 57, 931–938 (2002).
Abosehmah-Albidy, A. Z., York, P. Wong, V., Losowsky, M. S., and Chrystyn, H., Improved bioavailability and clinical response in patients with chronic liver disease following the administration of a spironolactone: β-cyclodextrin complex.Brit. J. Clin. Pharmacol., 44, 35–39 (1997).
Ahmed, M. O., El-Gibaly, I., and Ahmed, S. M., Effects of cyclodextrins on the physicochemical properties and antimycotic activity of clotrimazole.Int. J. Pharm., 171, 111–121 (1998).
Ammar, H. O., Ghorab, M., El-nahhas, S. A., Omar, S. M., and Ghorab, M. M., Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. 5. Theophylline,Pharmazie, 51,42–46 (1996).
Becket, G, Schep, L. J., and Tan, M. Y, Improvement of thein vitro dissolution of praziquantel by complexation with a-, β-, and y-cyclodextrins.Int. J. Pharm., 179,65–71 (1999).
Bekers, O., Uijtendaal, E. V., Beijnen, J. H., Bult, A., and Underberg, W. J. M., Cyclodextrins in the pharmaceutical field.Drug Dey. Ind. Pharm., 17,1503–1549 (1991).
Chang, J. Y, Oh, YK., Kong, H. S., Kim, E. J., Jang, D. D., Nam, K. T., and Kim, C. K., Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis.J. Control. Release, 82, 39–50 (2002).
Choi, H. G, Kim, D. D., Jun, H. W., Yoo, B. K., and Yong, C. S., Improvement of dissolution and bioavailability of nitrendipine by inclusion in hydroxypropyl-â-cyclodextrin,Drug Dev. Ind. Pharm., 29, 1085–1094 (2003).
Choi, H. G, Lee, B. J., Yong, C. S., Rhee, J. D., Han, J. H., Lee, M. K., Park, K. M., and Kim, C. K., Terfenadine-â-cyclodextrin inclusion complex with the anti-histaminic activity enhancement,Drug. Dev. Ind. Pharm., 27, 857–862 (2001).
Davis, N. M., Wang, G, and Tucker, I. G, Evaluation of a hydro-cortisone/hydroxypropyl-β-cyclodextrin solution for ocular drug delivery.Int. J. Pharm., 156, 201–209 (1997).
Ficarra, R., Ficarra, P., Di Bella, M. R., Raneri, D., Tommasini, S., Calabro, M. L., Villari, A., and Coppolino, S., Study of the Inclusion Complex of Atenolol with β-Cyclodextrin.J. Pharm. Biomed. Anal., 23, 231–236 (2000).
Gandhi, R. B. and Karara, A. H., Characterization, Dissolution and Diffusion Properties of Tolbutamide-β-cyclodextrin Complex System.Drug Dev. Ind. Pharm. 14, 657–682 (1988).
Grant, D. J. W. and Higuchi, W., Techniques of Chemistry (Weissberger, A. (Ed): Solubility Behaviour of Organic Compounds;Wiley, New York, Vol. 21, 440–473 (1990).
Hassan, M. A., Suleiman, M. S., and Najib, N. M., Improvement of thein vitro Dissolution Characteristics of Famotidine by Inclusion in β-Cyclodextrins.Int. J. Pharm., 58,19–24 (1990).
]Higuchi, T and Conners, K. A., Phase-solubility Techniques.Adv. Anal. Chem. Instrument, 117-212 (1965).
Jarvinen, T, Jarvinen, K., Schwarting, N., and Stella, V. J., β- Cydodextrin derivatives, SBE4-β-CD and HP-β-CD, increase the oral bioavailability of cinnarizine in beagle dogs.J. Pharm. Sci., 84, 295–299 (1995).
Kimura, E., Bersani-Amado, C. A., Sudo, S. U., Santos, S. R. J., and Oga, S., Pharmacokinetic Profile of Piroxicam-β- cyclodextrin, in Rat Plasma and Lymph.General Pharmacol., 28,695–698(1997).
Lee, S. W., Kim, M. H., and Kim, C. K., Encapsulation of ethanol by spray drying technique: effects of sodium lauryl sulfate.Int. J. Pharm., 187,193–198 (1999).
Linares, M., de Bertorello, M. M., and Longhi, M., Solubilization of Naphthoquinones by Complexation with Hydroxypropyl-β- cyclodextrin.Int. J. Pharm., 159,13–18 (1997).
Memisoglu, E., Bochot, A., Ozalp, M., Sen, M., Duchene, D., and Hincal, A. A., Direct formation of nanospheres from amphiphilic beta-cyclodextrin inclusion complexes.Pharm. Res., 20,117–125 (2003).
Nakai, Y, Yamamoto, K., Terada K., and Akimoto, K., The dispersed states of medicinal molecules in ground mixtures with a- or β-cyclodextrin.Chem. Pharm. Bull., 32, 685–691 (1984).
Ning, M., Gu, Z., Pan, H., Yu, H., and Xiao, K., Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antifungal drug clotrimazole.Indian J. Exp. Biol., 43, 150–157 (2005).
özkan, Y, Atay, T., Dikmen, N., Isimer, A., and Aboul-Enein, H. Y, Improvement of water solubility andin vitro dissolution rate of gliclazide by complexation with β-cyclodextrin.Phar- maceutica. Acta. Helvetiae., 74, 365–370 (2000).
Pedersen, M., Effect of hydrotropic substances on the complexation of clotrimazole with b-cyclodextrin.Drug Dev. Ind. Pharm., 19, 439–448 (1993).
Pedersen, M., The bioavailability difference between genuine cyclodextrin inclusion complexes and freeze-dried or ground drug cyclodextrin samples may be due to supersaturation differences.Drug Dev. Ind. Pharm., 23, 331–335 (1997).
Pedersen, M., Bjerregaard, S., Jacobsen, J., and Sørensen, A. M., A genuine clotrimazole y-cyclodextrin inclusion complex - isolation, antimycotic activity, toxicity and an unusual dissolution rate.Int. J. Pharm., 176, 121–131 (1998).
Stella, V. J. and Rajewski, R. A., Cydodextrins: their future in drug formulation and delivery.Pharm. Res., 14, 556–567 (1997).
Wojtulewski, J. A., Gow, P. J., Walter, J., Grahame, R., Gibson, T, Panayi, G. S., and Mason, J., Anti-inflammatory effect of clotrimazole.Ann. Rheum., 39, 469–472 (1980).
Wong, J. W. and Yuen, K. H., Improved oral bioavailability of artemisinin through inclusion complexation with β- and γ- cyclodextrin.Int. J. Pharm., 227,177–185 (2001).
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Prabagar, B., Yoo, BK., Woo, JS. et al. Enhanced bioavailability of poorly water-soluble clotrimazole by inclusion with β-cyclodextrin. Arch Pharm Res 30, 249–254 (2007). https://doi.org/10.1007/BF02977701
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DOI: https://doi.org/10.1007/BF02977701