共晶技术改善氯诺昔康溶出行为及可压片性的研究

Enhanced dissolution and tabletability of lornoxicam by cocrystallization

氯诺昔康是一种具有解热镇痛和抗炎作用的非甾体抗炎药,属于生物药剂学分类系统(BCS) II类药物,水溶性差,口服生物利用度低。此外,氯诺昔康本身的可压片性较差,限制了其口服固体制剂的开发。本研究通过减压旋转蒸发法制备氯诺昔康-葛根素共晶,以提高氯诺昔康的溶出度及可压片性。利用X-射线粉末衍射法、差示扫描量热分析、傅里叶变换红外光谱法和热重分析等手段进行表征,并对所制备共晶的溶出行为、可压片性和稳定性进行考察。粉末溶出实验及特性溶出实验表明氯诺昔康-葛根素共晶较单独氯诺昔康有更高的溶出速率。平衡溶解度实验表明,氯诺昔康-葛根素共晶可以显著提高氯诺昔康(约4.0倍)及葛根素(约1.5倍)在水中的溶解度。并且,氯诺昔康形成共晶后表现出显著改善的可压片性。稳定性实验发现,该共晶在40℃和25℃/75%RH条件下放置60天后,含量均无明显变化,化学稳定性良好。

Lornoxicam(LOR) is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory and antipyretic effects. As a biopharmaceutics classification system(BCS) class II drug, it has poor aqueous solubility and then low bioavailability after oral administration. In addition, the tabletability of LOR itself is also poor and could not form the tablet after compression, which seriously limits the development of its oral solid dosage. The current study aims to improve dissolution and tabletability of LOR by cocrystallization technique with small molecule puerarin(PUE). LOR cocrystal with the co-former PUE was prepared via the solvent-evaporation method and characterized by powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and thermo-gravimetric analyzer. The dissolution behavior, tabletability and stability of the prepared cocrystal were also further investigated. In comparison to pure LOR, LOR-PUE cocrystal showed higher apparent and intrinsic dissolution rate. Moreover, after cocrystallization, the solubility of LOR and PUE showed 4.0-fold and 1.5-fold increase compared to the raw ones in water, respectively. LOR-PUE cocrystal showed significantly improved tabletability compared to LOR alone under a wide compression range of 75-375 MPa. In addition, such cocrystal exhibited superior chemical stability with no change of drug contents for at least 60 days under the conditions of 40 ℃ and 25 ℃/75% RH.