Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet ...Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.展开更多
文摘目的采用网状Meta分析的方法比较安贝生坦、波生坦、西他生坦和马西替坦四种内皮素受体拮抗剂治疗肺动脉高压的疗效和耐受性。方法计算机检索Pub Med、EMBASE、Cochrane Library和中国生物医学文献数据库、中国知网、万方数据库,检索时间截至2014年1月31日,纳入比较四种内皮素受体拮抗剂治疗肺动脉高压的随机对照试验,主要结局指标为疗效和耐受性,次要结局指标为病死率和临床恶化率。研究筛选、数据提取及方法学质量评价均由两人独立完成。分别使用Rev Man 5.2和GEMTC软件进行直接比较和网状Meta分析。结果纳入12篇文献,包含13个随机对照试验,总计2191例患者。直接Meta分析结果显示,4种内皮素受体拮抗剂疗效均优于安慰剂,在耐受性方面,只有安贝生坦的效果优于安慰剂,其余药物与安慰剂的比较差异无统计学意义。网状Meta分析结果显示:在疗效方面,安贝生坦和波生坦的疗效优于安慰剂,西他生坦及马西替坦与安慰剂比较以及各种药物的互相比较差异均无统计学意义。等级概率图显示:安贝生坦效果最佳,其次为波生坦、西他生坦,马西替坦疗效最差。在耐受性方面,安贝生坦与西他生坦优于安慰剂,其余药物与安慰剂的比较以及各类药物之间的比较差异均无统计学意义。等级概率图显示:耐受性最好的药物为安贝生坦,其余依次为西他生坦、马西替坦,最差为波生坦。结论在治疗肺动脉高压的4种内皮素受体拮抗剂中,安贝生坦在疗效和耐受性方面均优于其他3种药物。在未来的研究中,应该更多关注安贝生坦及其他药物在病死率和临床恶化率方面的效果,此外,应注重探讨不同药物剂量、不同类型肺动脉高压患者的具体疗效。
基金the management of Sinotherapeutics Inc. for supporting this study
文摘Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.
