Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan 410013, PR China.
Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, PR China; Guangdong Institute of Semiconductor Micro-Nano Manufacturing Technology, Foshan 528200, PR China.
Int J Pharm. 2023 Mar 25;635:122707. doi: 10.1016/j.ijpharm.2023.122707. Epub 2023 Feb 9.
There is a great interest to develop co-amorphous drug delivery systems to enhance the solubility of biopharmaceutics classification system (BCS) class II and IV drugs. However, most reported systems only resulted in severalfold solubility improvement. Tranilast (TRA) is an anti-allergic drug used to treat bronchial asthma and allergic rhinitis. It is a BCS class II drug and its poor aqueous solubility affects its absorption in vivo. To address this issue, a natural alkaloid matrine (MAR) with interesting biological activities was chosen to form a co-amorphous system with TRA, based on the solubility parameter and phase solubility experiment. The TRA-MAR drug-drug co-amorphous system was prepared by the solvent evaporation method, and further characterized by powder X-ray diffraction and modulated temperature differential scanning calorimetry. Fourier transform infrared spectroscopy, FT-Raman, and X-ray photoelectron spectroscopy revealed the formation of salt and the presence of strong intermolecular interactions in the TRA-MAR co-amorphous system, which are also supported by molecular dynamics simulations, showing ionic and hydrogen bonding interactions. This co-amorphous system exhibited excellent physical stability at both 25 °C and 40 °C under anhydrous silica gel condition. Finally, co-amorphous TRA-MAR showed greatly enhanced solubility (greater than 100-fold) and rapid release behavior in the vitro release experiments. NMR spectroscopy revealed the strong intermolecular interactions between TRA and MAR in both DMSO‑d and DO. Our study resulted in a TRA-MAR co-amorphous drug system with significant solubility improvement and showcased the great potential to improve the dissolution behaviors of BCS class II and IV drugs through the co-amorphization approach.
开发共无定形药物传递系统以提高生物药剂学分类系统（BCS）II 类和 IV 类药物的溶解度具有重要意义。然而，大多数报道的系统仅导致溶解度提高几倍。曲尼司特（TRA）是一种用于治疗支气管哮喘和过敏性鼻炎的抗过敏药物。它是一种 BCS 类 II 药物，其较差的水溶解度影响其体内吸收。为了解决这个问题，选择了具有有趣生物学活性的天然生物碱苦参碱（MAR）与 TRA 形成共无定形系统，基于溶解度参数和相溶解度实验。TRA-MAR 药物-药物共无定形系统通过溶剂蒸发法制备，并通过粉末 X 射线衍射和调制差示扫描量热法进一步表征。傅里叶变换红外光谱、FT-Raman 和 X 射线光电子能谱揭示了 TRA-MAR 共无定形系统中盐的形成和强分子间相互作用的存在，分子动力学模拟也支持这些相互作用，显示离子和氢键相互作用。该共无定形系统在无水硅胶条件下在 25°C 和 40°C 下均表现出优异的物理稳定性。最后，共无定形 TRA-MAR 在体外释放实验中表现出出色的溶解度提高（大于 100 倍）和快速释放行为。NMR 光谱揭示了 TRA 和 MAR 在 DMSO-d 和 DO 中均存在强分子间相互作用。我们的研究得到了 TRA-MAR 共无定形药物系统，显著提高了溶解度，并展示了通过共无定形化方法改善 BCS 类 II 和 IV 类药物溶解行为的巨大潜力。
