Molecular and Biomolecular Physics Department, National Institute for R&D of Isotopic and Molecular Technologies, 67-103 Donat, 400293 Cluj-Napoca, Romania.
TeraCrystal, 67-103 Donat, 400293 Cluj-Napoca, Romania.
Mol Pharm. 2020 Mar 2;17(3):919-932. doi: 10.1021/acs.molpharmaceut.9b01178. Epub 2020 Feb 7.
The 1:1 cocrystal of the antifungal agent ketoconazole with -aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurements revealed a 10-fold aqueous solubility increase that induces a 6.7-fold oral bioavailability improvement compared to ketoconazole. cell assays showed a good toxicity profile of the cocrystal with lower oxidative stress and inflammation and enhanced antifungal activity against several species. The study of the cocrystal indicated similar pharmacokinetic profiles and liver toxicity with increased transaminases, as reported for ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over ketoconazole, together with the improved antifungal activity and good / toxicity, indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a successful approach for bioavailability improvement of poorly soluble drugs.
抗真菌药酮康唑与 - 氨基苯甲酸的 1:1 共晶已成功结晶，并从物理和药理学的角度进行了系统的表征。晶体结构测定证实了共晶的身份，充分了解了其晶体堆积和无序程度。粉末溶解测量显示水溶解度增加了 10 倍，与酮康唑相比，口服生物利用度提高了 6.7 倍。细胞试验表明，与酮康唑相比，共晶具有更好的毒性特征，氧化应激和炎症减轻，抗真菌活性增强，对多种 种属有效。对共晶的研究表明，与酮康唑相似的药代动力学特征和肝毒性，转氨基酶升高。值得注意的是，除了轻微的炎症迹象外，未发现肝实质的形态变化或纤维化和坏死的迹象。与酮康唑相比，共晶的溶解度和口服生物利用度提高，抗真菌活性增强，毒性降低，表明其作为母体药物的替代抗真菌药物具有潜在用途。我们的结果证明了共晶化作为提高难溶性药物生物利用度的成功方法。
