Danazol-β-cyclodextrin binary system: A potential application in emergency contraception by the oral route

This study explored the potential of β-cyclodextrin to improve the aqueous solubility and dissolution of danazol, investigated a simple and less expensive method for preparation of a danazol-β-cyclodextrin binary system, and explored the potential application of a danazol-β-cyclodextrin binary system as a single-dose emergency contraceptive. Phase solubility analysis indicated formation of a first-order soluble complex with stability constant 972.03 M−1, while Job's plot affirmed 1∶1 stoichiometry. The hyperchromic shift in the UV-Vis spectrum of danazol in the presence of β-cyclodextrin indicated solubilization capability of β-cyclodextrin for danazol. The extrinsic Cotton effect with a negative peak at 280.7 nm confirmed the inclusion of danazol in the asymmetric locus of β-cyclodextrin.1H-nuclear magnetic resonance analysis suggested that the protons of the steroidal skeleton of danazol display favorable interactions with the β-cyclodextrin cavity. The danazol-β-cyclodextrin binary system was prepared by kneading, solution, freeze-drying, and milling methods. The extent of the enhancement of dissolution rate was found to be dependent on the preparation method. Dissolution studies showed a similar relative dissolution rate (2.85) of the danazol-β-cyclodextrin binary system prepared by the freeze-drying and milling (in the presence of 13% moisture) methods. In a mouse model, the danazol-β-cyclodextrin binary system at 51.2 mg/kg (equivalent to a 400-mg human dose) showed 100% inhibition of implantation when given postcoitally. Moreover, the danazol-β-cyclodextrin binary system is safe up to 2000 mg/kg in the mouse (15.52 g/70 kg human) as a single oral dose. Thus, the danazol-β-cyclodextrin binary system could serve as a new therapeutic application: an oral emergency contraceptive at a physiologically acceptable single dose. Similar content being viewed by others

Kistner RW, ed.Gynecology: Principles and Practice, Chicago, IL: Year Book Medical Publishers; 1971. Dmowski WP. Endocrine properties and clinical applications of danazol.Fertil Steril. 1979;31:237–251. Dmowski WP, Cohen MR. Antigonadotropin (danazol) in the treatment of endometriosis. Evaluation of post-treatment fertility and three-year follow-up data.Am J Obstet Gynecol. 1978;130:41–48. Lauersen NH, Wilson KH. The effect of danazol in the treatment of chronic cystis mastitis,Obstet Gynecol. 1976;48:93–98. Lee PA, Thompson RG, Migeon CJ, Blizzard RM. The effect of danazol in sexual precocity.Johns Hopkins Med J. 1975;137:265–269. Chimbira TH, Cope E, Anderson AB, Bolton FG. The effect of danazol on menorrhagia, coagulation mechanism, hematological indices and body weight.Br J Obstet Gynaecol. 1979;86:46–50. Chen X, Vaughn JM, Yacaman MJ, Williams RO, Johnston KP. Rapid dissolution of high-potency danazol particles produced by evaporative precipitation into aqueous solution.J Pharm Sci. 2004;93:1867–1878. Webb AM, Russell J, Elstein M. Comparison of Yuzpe regimen, danazol, and mifepristone (RU486) in oral postcoital contraception.BMJ. 1992;305:927–931. Davison C, Banks W, Fritz A. The absorption, distribution and metabolic fate of danazol in rats, monkeys and human volunteers.Arch Int Pharmacol Ther. 1976;221:294–310. Yalkowsky SH.Techniques of Solubilization of Drugs. New York, NY: Marcel Dekker; 1981. Blanco J, Vila-Jato JL, Otero F, Anguiano S. Influence of method of preparation on inclusion complexes of naproxen with different cyclodextrins.Drug Dev Ind Pharm. 1991;17:943–957. Fucile M, Mazzitelli G, Ratti D, et al. Inclusion complex of isosorbide-5-mononitrate in β-cyclodextrin: comparison of preparation methods and assessment of analytical techniques.Eur J Pharm Biopharm. 1992;38:140–144. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins, 1: drug solubilization and stabilization.J Pharm Sci. 1996;85;1017–1025. Loftsson T. Pharmaceutical applications of β-cyclodextrins.Pharm Technol Eur. 1999;11:20–32. Hedges AR. Industrial applications of cyclodextrins.Chem Rev. 1998;98:2035–2044. Oguchi T, Matsumoto K, Yonemochi E, Nakai Y, Yamamoto K. Dissolution studies in organic solvents for evaluating hydrogen bond matrix of cellulose in the ground mixture.Int J Pharm. 1995;113: 97–102. Yamamoto K, Oguchi T, Yonemochi E, Matsumura Y, Nakai Y. Fluorometric study of the molecular states of 2,5-diphenyloxazole in ground mixtures with γ-cyclodextrin.Pharm Res. 1994;11:331–336. Oguchi T, Kazama K, Yonemochi E, et al. Specific complexation of ursodeoxycholic acid with guest compounds induced by co-grinding.Phys Chem Chem Phys. 2000;2:2815–2820. Higuchi T, Connors K, eds.Phase Solubility Techniques: Advances in Analytical Chemistry and Instrumentation. New York, NY: Interscience Publishers; 1965. Job P. Formation and stability of inorganic complexes in solution.Ann Chim. 1928;9:113–203. Khan KA. The concept of dissolution efficiency.J Pharm Pharmacol. 1975;27:48–49. Reel JR, Hild-Petito S, Blye RP. Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple, or continuous doses to rats,Contraception. 1998;58:129–136. Laurence DR, Bacharach AL, eds.Evaluation of Drug Activities: Pharmacometrics. New York, NY: Academic Press; 1964. OECD Series on Testing and Assessment. Number 24: Guidance Document on Acute Oral Toxicity Testing (2001). Organization for Economic Cooperation and Development (OECD) Web site. Accessed January 3, 2004. Engle AR, Purdie N, Hyatt JA. Induced circular dichroism study of the aqueous solution complexation of cello-oligosaccharides and related polysaccharides with aromatic dyes.Carbohydr Res. 1994;265: 181–195. Ventura CA, Puglisi G, Zappla M, Mazzone G. A physicochemical study on the interaction between papaverine and natural and modified β-cyclodextrins.Int J Pharm. 1998;160:163–172. Otagiri M, Uekama K, Ikeda K. Inclusion complexes of β-cyclodextrin with tranquilizing drugs phenothiazines in aqueous solution.Chem Pharm Bull (Tokyo). 1975;23:188–195. Balogh G, Csizer E, Ferenczy GG, et al. Estimation of impurity profiles of drugs and related materials, 12: isolation and identification of an isometric impurity in danazol,Pharm Res. 1995;12:295–298. Schneider HJ, Hacket F, Rudiger V, Ikeda H. NMR studies of cyclodextrins and cyclodextrin complexes.Chem Res. 1998;98:1755–1786. Wongmekiat A, Tozuka Y, Oguchi T, Yamamotto K. Formation of fine drug particles by cogrinding with cyclodextrins, I: the use of β-cyclodextrin anhydrate and hydrate.Pharm Res. 2002;19:1867–1872. Tozuka Y, Wongmekiat A, Sakata K, Moribe K, Oguchi T, Yamamotto K. Co-grinding with cyclodextrin as a nanoparticle preparation method of a poorly water soluble drug.J Inclusion Phenom Macro Chem. 2004;50:67–71. Wongmekiat A, Tozuka Y, Oguchi T, Yamamotto K. Formation of fine drug particle by cogrinding with cyclodextrins, Part II: the influence of moisture condition during cogrinding process on fine particle formation.Int J Pharm. 2003;265:85–93. Uekama K, Narisawa S, Hirayama F, Otagiri M. Improvement of dissolution and absorption characteristics of benzodiazepines by cyclodextrin complextation.Int J Pharm. 1983;16:327–338. Mura P, Facucci MT, Parrini PL. Effects of grinding with microcrystalline cellulose and cyclodextrins on the ketoprofen physicochemical properties.Drug Dev Ind Pharm. 2001;27:119–128. Djedaini F, Lin SZ, Perly B, Wouessidjewe D. High-field nuclear magnetic resonance techniques for the investigation of a beta-cyclodextrin: indomethacin inclusion complex.J Pharm Sci. 1990;79:643–646. Linn SY, Kao YH, Yang JC. Grinding effect on some pharmaceutical properties of drugs by adding β-cyclodextrin.Drug Dev Ind Pharm. 1988;14:99–118. Ahmed MO, Nakai Y, Aboutaleb AES, Yamamoto K, Rahman AAZA, Saleh SI. Complex formation of nitrazepam in coprecipitating and in co-grinding with methylated β-cyclodextrins.Chem Pharm Bull (Tokyo). 1990;38:3423–3427. Nash RA. Cyclodextrins. In: Kibbe AH, ed.Handbook of Pharmaceutical Excipients. London: Pharmaceutical Press and Washington, DC: American Pharmaceutical Association; 2000: 165–168. Author information Authors and Affiliations Corresponding author Additional information Published: May 11, 2007 Rights and permissions About this article Cite this article Jadhav, G.S., Vavia, P.R. & Nandedkar, T.D. Danazol-β-cyclodextrin binary system: A potential application in emergency contraception by the oral route. AAPS PharmSciTech 8, 35 (2007). https://doi.org/10.1208/pt0802035 Received: Accepted: DOI: https://doi.org/10.1208/pt0802035