Pharmaceutical salt of BM635 with improved bioavailability

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• 作者：Giovanna Poce^a ; ^{giovanna.poce@uniroma1.it} ; Sara Consalvi^a ; Martina Cocozza^a ; Raquel Fernandez-Menendez^b ; Robert H. Bates^b ; Fá ; tima Ortega Muro^b ; David Barros Aguirre^b ; Lluis Ballell^b ; Mariangela Biava^a
• 关键词：Tuberculosis ; BM635 ; MmpL3 ; Pharmaceutical salts ; Drug development
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 March 2017
• 年：2017
• 卷：99
• 期：Complete
• 页码：17-23
• 全文大小：772 K
• 卷排序：99

文摘

BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12 μM against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1 h, allowing a reasonable maximum concentration (Cmax = 1.62 μM) and a moderate bioavailability (46%). The present study aimed to develop salt forms of BM635 with pharmaceutically accepted hydrochloric, methanesulphonic, phosphoric, tartaric, and citric acids to overcome these drawbacks. BM635 salts (BM635-HCl, BM635-Mes, BM635-PA, BM635-TA and BM635-CA) were evaluated for physicochemical as well as biopharmaceutical attributes.