Crystalline adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved residence time in the lungs
Crystalline adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved residence time in the lungs
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DOI：
10.1016/j.ejps.2019.104961
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发表时间：
2019-08-01
影响因子：
4.6
通讯作者：
Das, Shyamal C.
中科院分区：
文献类型：
--
作者：
Eedara, Basanth Babu;Tucker, Ian G.;Das, Shyamal C.
制备了抗结核药物莫西沙星和反式肉桂酸（1：1摩尔比（MCA（1：1）））的结晶加合物，通过降低药物的溶解度和溶出速率来延长药物在肺部的停留时间。加合物是盐还是共晶体尚未明确确定。加合物 (MCA(1:1)) 在磷酸盐缓冲盐水 (PBS, pH 7.4) 中的平衡溶解度和固有溶出速率测量显示莫西沙星的溶解度显着降低 (从 17.68 +/- 0.85 mg mL(-1) 至 6.10 +/- 0.05 mg mL(-1)) 和固有溶出速率 (从 0.47 +/- 0.04 mg cm(-2))与提供的莫西沙星相比，min(-1) 至 0.14 +/- 0.03 mg cm(-2) min(-1))。使用下一代冲击器对来自吸入器装置 Aerolizer (R) 的加合物进行气雾化行为，结果显示细颗粒分数为 30.4 +/- 1.2%。使用定制的溶出装置在少量静止粘液中评估收集的可吸入颗粒的细颗粒剂量的溶出行为。与提供的莫西沙星相比，可吸入加合物颗粒显示出较低的溶出度（显微镜观察）和渗透性。结晶加合物MCA(1:1)的溶解度和溶出速率比莫西沙星低，可以提高莫西沙星在肺部的局部停留时间和治疗作用。
A crystalline adduct of the anti-tubercular drug, moxifloxacin and trans-cinnamic acid (1:1 molar ratio (MCA(1:1))) was prepared to prolong the residence time of the drug in the lungs by reducing its solubility and dissolution rate. Whether the adduct is a salt or cocrystal has not been unequivocally determined. Equilibrium solubility and intrinsic dissolution rate measurements for the adduct (MCA(1:1)) in phosphate buffered saline (PBS, pH 7.4) revealed a significant decrease in the solubility of moxifloxacin (from 17.68 +/- 0.85 mg mL(-1) to 6.10 +/- 0.05 mg mL(-1)) and intrinsic dissolution rate (from 0.47 +/- 0.04 mg cm(-2) min(-1) to 0.14 +/- 0.03 mg cm(-2) min(-1)) compared to the supplied moxifloxacin. The aerosolization behaviour of the adduct from an inhaler device, Aerolizer (R), using a Next Generation Impactor showed a fine particle fraction of 30.4 +/- 1.2%. The dissolution behaviour of the fine particle dose of respirable particles collected was assessed in a small volume of stationary mucus fluid using a custom-made dissolution apparatus. The respirable adduct particles showed a lower dissolution (microscopic observation) and permeation compared to the supplied moxifloxacin. The crystalline adduct MCA(1:1) has a lower solubility and dissolution rate than moxifloxacin and could improve the local residence time and therapeutic action of moxifloxacin in the lungs.