Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Int J Pharm. 2023 Jan 5;630:122428. doi: 10.1016/j.ijpharm.2022.122428. Epub 2022 Nov 24.
Dapsone (DAP)is a dual-function drug substance; however, its limited water solubility may impair its bioavailability. Drug nanocrystals are an alternative to overcome this limitation. Herein, a DAP nanosuspension was prepared using adesign space approach aiming to investigate the influence of raw material properties and process parameters on the critical quality attributes of the drugnanocrystals. Optimized nanocrystals with 206.3 ± 6.7 nm using povacoat™ as stabilizer were made. The nanoparticles were characterized by dynamic light scattering, laser diffraction, scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and saturation solubility. Compared to the raw material, the nanocrystals were 250-times smaller. Meanwhile, its crystalline state remained basically unchanged even after milling and drying. The nanosuspension successfully maintained its physical stability inlong-termandaccelerated stability studiesover, 4 and 3 months. Furthermore, toxicity studiesshowed low a toxicity at a20 mg/kg. As expected for nanocrystals, the size reduction improvedsaturation solubility3.78 times in water. An attempt to scale up from lab to pilot scale resulted nanocrystals of potential commercial quality. In conclusion, the present study describes the development of dapsone nanocrystals for treating infectious and inflammatory diseases. The nanocrystal formuation can be scaled up for commercial use.
双氨苯砜（DAP）是一种双功能药物物质；然而，其有限的水溶性可能会影响其生物利用度。药物纳米晶体是克服这一限制的一种替代方法。本文采用设计空间方法制备了 DAP 纳米混悬剂，旨在研究原料药性质和工艺参数对药物纳米晶体关键质量属性的影响。使用 povacoat™作为稳定剂，优化得到了 206.3 ± 6.7nm 的纳米晶体。纳米颗粒通过动态光散射、激光衍射、扫描电子显微镜、差示扫描量热法、X 射线粉末衍射和饱和溶解度进行了表征。与原料药相比，纳米晶体小了 250 倍。同时，即使在研磨和干燥后，其结晶状态基本保持不变。纳米混悬剂在长期和加速稳定性研究中成功地保持了物理稳定性，超过 4 个月和 3 个月。此外，毒性研究表明，在 20mg/kg 的剂量下，毒性较低。正如纳米晶体所预期的那样，其在水中的溶解度提高了 3.78 倍。从实验室到中试规模的放大尝试得到了具有潜在商业质量的纳米晶体。总之，本研究描述了用于治疗感染性和炎症性疾病的双氨苯砜纳米晶体的开发。纳米晶体制剂可放大用于商业用途。
