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首页> 外文期刊>Crystal growth & design >Enhanced Bioavailability in the Oxalate Salt of the Anti-Tuberculosis Drug Ethionamide
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Enhanced Bioavailability in the Oxalate Salt of the Anti-Tuberculosis Drug Ethionamide

机译：抗结核药乙硫酰胺的草酸盐中生物利用度的提高

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摘要

Ethionamide (ETH) is an anti-tuberculosis (TB) Biopharmaceutics Classification System class II drug of poor aqueous solubility. The objective of the present study was to evaluate the solubility and bioavailability parameters of ETH cocrystals/salts with Generally Regarded as Safe (GRAS) coformers. Five cocrystals, namely, ETH-GLA (glutaric acid), ETH-ADP (adipic acid), ETH-SBA (suberic acid), ETH-SEBA (sebacic acid), ETH-FA (fumaric acid), and one salt ETH-OA (oxalic acid) were prepared by liquid-assisted grinding, and their structural characterization was carried out using spectroscopic, thermal, and powder X-ray diffraction techniques. The crystal structures of ETH-ADP, ETH-SBA, ETH-FA, and ETH-OA were confirmed by X-ray diffraction. The three cocrystal structures are sustained by the robust acid center dot center dot center dot pyridine synthon, while the ETH-OA salt has an ionic N-H center dot center dot center dot O hydrogen bond between carboxylate and pyridinium ions. The ETH-OA salt exhibited the highest dissolution compared to ETH (25 times), and its cocrystals (10 to 2 times higher). The intrinsic dissolution rates are ETH-OA > ETH-GLA > ETH-FA > ETH-SBA > ETH-ADP > ETH-SEBA > ETH. The best crystal form of ETH-OA was administered orally and exhibited 2.5 times enhanced plasma concentration in rats with C-max of 4.08 +/- 0.2 mu g mL(-1) at T-max of 30 min, and AUC((08h)) increased 1.9 fold to 6.49 +/- 0.19 mu g mL(-1) h(-1) compared to ETH. The oxalate salt exhibits the highest bioavailability enhancement for BCS class II drug ethionamide.
机译：乙硫磷（ETH）是抗结核性（TB）生物药物分类系统的II类药物，水溶性差。本研究的目的是评估ETH共晶体/盐与一般公认安全（GRAS）共形成物的溶解度和生物利用度参数。五个共晶体，即ETH-GLA（戊二酸），ETH-ADP（己二酸），ETH-SBA（丁二酸），ETH-SEBA（癸二酸），ETH-FA（富马酸）和一种盐ETH-通过液体辅助研磨制备OA（草酸），并使用光谱，热和粉末X射线衍射技术对其结构进行表征。通过X射线衍射确认了ETH-ADP，ETH-SBA，ETH-FA和ETH-OA的晶体结构。这三个共晶体结构由坚固的酸中心点中心点中心点吡啶合成子维持，而ETH-OA盐在羧酸根和吡啶鎓离子之间具有离子N-H中心点中心点中心点O氢键。与ETH（25倍）相比，ETH-OA盐表现出最高的溶解度，并且其共晶体（高10至2倍）。固有溶解速率为ETH-OA> ETH-GLA> ETH-FA> ETH-SBA> ETH-ADP> ETH-SEBA> ETH。最好的ETH-OA晶体形式是口服给药，在C-max为4.08 +/- 0.2μg mL（-1），T-max为30分钟和AUC（（08h ））与ETH相比增加了1.9倍，达到6.49 +/- 0.19μg mL（-1）h（-1）。草酸盐对于BCS II类药物乙酰胺具有最高的生物利用度提高。

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