Danazol-beta-cyclodextrin binary system: a potential application in emergency contraception by the oral route.
This study explored the potential of beta-cyclodextrin to improve the aqueous solubility and dissolution of danazol, investigated a simple and less expensive method for preparation of a danazol-beta-cyclodextrin binary system, and explored the potential application of a danazol-beta-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 beta-cyclodextrin indicated solubilization capability of beta-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 beta-cyclodextrin. (1)H-nuclear magnetic resonance analysis suggested that the protons of the steroidal skeleton of danazol display favorable interactions with the beta-cyclodextrin cavity. The danazol-beta-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-beta-cyclodextrin binary system prepared by the freeze-drying and milling (in the presence of 13% moisture) methods. In a mouse model, the danazol-beta-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-beta-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-beta-cyclodextrin binary system could serve as a new therapeutic application: an oral emergency contraceptive at a physiologically acceptable single dose.
Jadhav
Ganesh S
GS
Pharmaceutical Division, Mumbai University Institute of Chemical Technology, Matunga, Mumbai, India.
Vavia
Pradeep R
PR
Nandedkar
Tarala D
TD
D000818:Animals; D002942:Circular Dichroism; D003276:Contraceptives, Oral / Q000008:administration & dosage / Q000737:chemistry*; D003281:Contraceptives, Postcoital / Q000008:administration & dosage / Q000737:chemistry*; D003613:Danazol / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D010064:Embryo Implantation / Q000187:drug effects; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011374:Progesterone / Q000097:blood; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D047392:beta-Cyclodextrins / Q000737:chemistry*
D003276:Contraceptives, Oral; D003281:Contraceptives, Postcoital; D047392:beta-Cyclodextrins; D011374:Progesterone; C031215:betadex; D003613:Danazol