Alfonsi R, Attivi D, Astier A, Socha M, Morice S, Gibaud S
Équipe CITHEFOR (EA3452), université de Lorraine, 5, rue Albert-Lebrun, 54000 Nancy, France.
Ann Pharm Fr. 2013 May;71(3):186-92. doi: 10.1016/j.pharma.2013.02.001. Epub 2013 Mar 15.
Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushing's syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p'-DDD was compared to its regioisomer (i.e. p,p'-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate.
米托坦（邻，对'-二氯二甲基二氯乙烷[邻，对'-DDD]）用于治疗肾上腺皮质癌，偶尔也用于治疗库欣综合征。这种药物在水中的溶解度非常低，口服给药后，约60%的剂量以未改变的形式在粪便中回收。制备具有改善生物利用度的可溶制剂（即通过与环糊精络合）是这项工作的目标。使用相溶解度方法和核磁共振实验研究了米托坦在甲基-β-环糊精中的包合情况。为了阐明包合机制，将邻，对'-DDD与其区域异构体（即对，对'-DDD）进行了比较。结果表明，两个二甲基-β-环糊精（DMβCD）可以与芳环络合。从相溶解度图中，我们观察到两种情况非常不同：K（1:1）在37000至85000 mol·l⁻¹之间，而K（1:2）在5.3至32 mol·l⁻¹之间。核磁共振实验证实了包合，但也深入了解了解离动力学：邻氯部分在核磁共振时间尺度上处于缓慢交换，而对氯部分处于快速交换速率。
