Jadhav Ganesh S, Vavia Pradeep R, Nandedkar Tarala D
Pharmaceutical Division, Mumbai University Institute of Chemical Technology, Matunga, Mumbai, India.
AAPS PharmSciTech. 2007 May 11;8(2):Article 35. doi: 10.1208/pt0802035.
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.
本研究探讨了β-环糊精改善达那唑水溶性和溶出度的潜力，研究了一种制备达那唑-β-环糊精二元体系的简单且成本较低的方法，并探索了达那唑-β-环糊精二元体系作为单剂量紧急避孕药的潜在应用。相溶解度分析表明形成了稳定性常数为972.03 M⁻¹的一级可溶性复合物，而Job曲线证实化学计量比为1:1。在β-环糊精存在下，达那唑紫外可见光谱中的增色位移表明β-环糊精对达那唑具有增溶能力。在280.7 nm处出现负峰的外在科顿效应证实达那唑被包合在β-环糊精的不对称位点。氢核磁共振分析表明，达那唑甾体骨架的质子与β-环糊精腔表现出良好的相互作用。通过捏合、溶液法、冷冻干燥和研磨法制备了达那唑-β-环糊精二元体系。发现溶出速率提高的程度取决于制备方法。溶出度研究表明，通过冷冻干燥和研磨（在13%水分存在下）方法制备的达那唑-β-环糊精二元体系具有相似的相对溶出速率（2.85）。在小鼠模型中，达那唑-β-环糊精二元体系以51.2 mg/kg（相当于400 mg人体剂量）在交配后给药时显示出100%的着床抑制。此外，达那唑-β-环糊精二元体系作为单次口服剂量在小鼠中高达2000 mg/kg（15.52 g/70 kg人体）是安全的。因此，达那唑-β-环糊精二元体系可作为一种新的治疗应用：一种生理上可接受的单剂量口服紧急避孕药。
