Innovation Centre for Science and Technology, North Sichuan Medical College, Nanchong, Sichuan 637100, P. R. China.
Innovation Centre for Science and Technology, North Sichuan Medical College, Nanchong, Sichuan 637100, P. R. China; Institute of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637100, P. R. China.
Eur J Pharm Biopharm. 2024 Oct;203:114475. doi: 10.1016/j.ejpb.2024.114475. Epub 2024 Aug 30.
Sulfasalazine (SULF), a sulfonamide antibiotic, has been utilized in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) since its discovery. However, its poor water solubility causes the high daily doses (1---3 g) for patients, which may lead to the intolerable toxic and side effects for their lifelong treatment for RA and IBD. In this work, two water-soluble natural anti-inflammatory alkaloids, matrine (MAR) and sophoridine (SPD), were employed to construct the co-amorphous systems of SULF for addressing its solubility issue. These newly obtained co-amorphous forms of SULF were comprehensively characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). We also investigated their dissolution behavior, including powder dissolution, in vitro release, and intrinsic dissolution rate. Both co-amorphous systems exhibited superior dissolution performance compared to crystalline SULF. The underlying mechanism responsible for the enhanced dissolution behaviors in co-amorphous systems were also elucidated. These mechanisms include the inhibition of nucleation, complexation, increased hydrophilicity, and robust intermolecular interactions in aqueous solutions. Importantly, these co-amorphous systems demonstrated satisfactory physical stability under various storage conditions. Network pharmacological analysis was utilized to investigate the potential therapeutic targets of both co-amorphous systems against RA, revealing similar yet distinct multi-target synergistic therapeutic mechanisms in the treatment of this condition. Our study suggests these drug-drug co-amorphous systems hold promise for optimizing SULF dosage in the future and providing a potential drug combination strategy.
柳氮磺胺吡啶（SULF）是一种磺胺类抗生素，自发现以来一直用于治疗类风湿关节炎（RA）和炎症性肠病（IBD）。然而，其较差的水溶性导致患者需要服用高剂量（1---3 g），这可能导致他们终生治疗 RA 和 IBD 时出现无法耐受的毒性和副作用。在这项工作中，两种水溶性天然抗炎生物碱，苦参碱（MAR）和槐定碱（SPD）被用于构建 SULF 的共无定形系统，以解决其溶解度问题。这些新获得的 SULF 共无定形形式通过粉末 X 射线衍射（PXRD）、温度调制差示扫描量热法（mDSC）、傅里叶变换红外光谱（FTIR）和 X 射线光电子能谱（XPS）进行了全面表征。我们还研究了它们的溶解行为，包括粉末溶解、体外释放和内在溶解速率。与晶态 SULF 相比，这两种共无定形系统均表现出优越的溶解性能。还阐明了共无定形系统中增强溶解行为的潜在机制。这些机制包括抑制成核、络合、增加亲水性以及在水溶液中形成稳定的分子间相互作用。重要的是，这些共无定形系统在各种储存条件下均表现出令人满意的物理稳定性。网络药理学分析用于研究这两种共无定形系统治疗 RA 的潜在治疗靶点，揭示了它们在治疗这种疾病时具有相似但又不同的多靶点协同治疗机制。我们的研究表明，这些药物-药物共无定形系统有望在未来优化 SULF 的剂量，并提供一种潜在的药物联合策略。
