Development of Meloxicam Salts with Improved Dissolution and Pharmacokinetic Behaviors in Rats with Impaired Gastric Motility
Development of Meloxicam Salts with Improved Dissolution and Pharmacokinetic Behaviors in Rats with Impaired Gastric Motility
复制标题
开发美洛昔康盐，改善胃动力受损大鼠的溶出度和药代动力学行为
DOI：
10.1007/s11095-012-0878-2
复制
发表时间：
2013
影响因子：
3.7
通讯作者：
Satomi
中科院分区：
文献类型：
--
作者：
Ochi;Masanori; Inoue;Ryo; Yamauchi;Yukinori; Yamada;Shizuo; Onoue;Satomi
目的美洛昔康(Meloxicam，MEL)在酸性溶液中的溶解性较差，对胃动力受损的剧烈疼痛患者，其口服吸收和疗效可能降低。本研究旨在开发盐形态以克服这些缺点。方法在用8个反离子筛选Mel盐的基础上，得到5个Mel盐。对这些MEL盐的物理化学性质进行了表征，重点考察了它们的形态、结晶度、热行为、溶解度和化学/光稳定性。结果所有Mel盐的溶出行为均明显好于晶态MEL，尤其是二水精氨酸MEL的初始溶出度(MEL/Arg)约为晶态MEL的14倍。MEL/Arg在化学和物理上都是稳定的。口服晶状MEL(1.0 mg-MEL/kg)大鼠的AUC0-4比正常大鼠减少约18倍。而口服美尔/精氨酸(1.0 mg/kg)后，正常大鼠和丙氨酸组大鼠的AUC0-4仅相差约3倍。结论MEL/Arg可改善重度疼痛患者的口服吸收。
PurposeBecause of its poor solubility in acidic solution, oral absorption and efficacy of meloxicam (MEL) may be reduced in severe pain patients with impaired gastric motility. The present study aimed to develop salt forms to overcome these drawbacks.MethodUpon MEL salt screening with eight counterions, five MEL salts were obtained. The physicochemical properties of these MEL salts were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and chemical/photo-stability. Pharmacokinetic profiling of an orally administered MEL salt was also carried out in both normal rats and rats treated with propantheline for the suppression of gastric motility.ResultsDissolution behaviors for all obtained MEL salts were markedly better than that of crystalline MEL; in particular, the initial dissolution rate of arginine MEL dihydrate (MEL/Arg) was ca. 14-fold higher than that of crystalline MEL. MEL/Arg was found to be chemically and physically stable. There was ca. 18-fold reduction of AUC0–4for orally dosed crystalline MEL (1.0 mg-MEL/kg) in propantheline-treated rats compared with that in normal rats. In contrast, there was only a ca. 3-fold difference in AUC0–4between normal and propantheline-treated rats after oral administration of MEL/Arg (1.0 mg-MEL/kg).ConclusionFrom these findings, MEL/Arg may provide improved oral absorption in severe pain patients.