Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Mater Sci Eng C Mater Biol Appl. 2020 Jul;112:110895. doi: 10.1016/j.msec.2020.110895. Epub 2020 Mar 23.
Tuberculosis (TB) is one of the top ten causes of death worldwide and a leading cause of death in HIV patients. Rifampicin (Rif), a low water-soluble drug, is a critical first-line treatment and the most effective drug substance for therapy of drug-susceptible TB. However, Rif has high interindividual pharmacokinetic variability, mainly due to its highly variable absorption caused by its poor solubility. Drug nanocrystals are a promising technology to overcome this variability by increasing the surface area. This strategy allows for increasing the dissolution rate and improving the bioavailability of this BCS class II drug. In this study, Rif nanocrystals were prepared by a wet-bead milling method. A 3-factor, 3-level Box-Behnken design was used to investigate the independent variables: the concentration of rifampicin, the concentration of the stabilizing agent (Povacoat® type F), and the mass of zirconia beads. Two optimized formulations, F1-Rif and F2-Rif, were characterized by determining their particle size and size distribution, morphology, crystal properties, and antimicrobial activity. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) revealed that rifampicin's polymorph II crystal structure was unchanged. The reduced particle size of <500 nm (100-fold decrease) increased the saturation solubility and dissolution rate up to 1.74-fold. The novel polymer, Povacoat®, demonstrated to be a suitable stabilizer to maintain the physical stability of nanosuspensions over two years. The Rif nanocrystals showed antimicrobial activity (0.25 μg/mL) not significantly different from standard rifampicin powder. However, the low cytotoxicity of the nanosuspensions in HepG2 cells was determined. When compared to the commercial product, the nanosuspension increased the rifampicin concentration 2-fold. In conclusion, the Rif nanosuspension allows half the needed volume of administration, which might increase compliance among children and elderly patients throughout the long-term treatment of TB.
结核病（TB）是全球十大死因之一，也是艾滋病毒感染者的主要死因之一。利福平（Rif）是一种水溶性低的药物，是治疗耐多药结核病的关键一线治疗药物，也是最有效的治疗药物。然而，Rif 的个体间药代动力学变异性很大，主要是由于其溶解度差导致吸收变异性很大。药物纳米晶体是一种有前途的技术，可以通过增加表面积来克服这种变异性。该策略可以提高这种 BCS 类 II 药物的溶解速率并提高其生物利用度。在这项研究中，通过湿磨珠方法制备了 Rif 纳米晶体。采用 3 因素 3 水平 Box-Behnken 设计研究独立变量：利福平浓度、稳定剂（Povacoat®型 F）浓度和氧化锆珠的质量。通过测定粒径和粒径分布、形态、晶体性质和抗菌活性对两种优化配方 F1-Rif 和 F2-Rif 进行了表征。差示扫描量热法（DSC）和粉末 X 射线衍射（PXRD）表明利福平 II 型多晶晶体结构没有变化。粒径减小至<500nm（降低 100 倍）可将饱和溶解度和溶解速率提高 1.74 倍。新型聚合物 Povacoat®被证明是一种合适的稳定剂，可以在两年内保持纳米混悬剂的物理稳定性。 Rif 纳米晶体显示出抗菌活性（0.25μg/mL），与标准利福平粉末无显著差异。然而，确定了纳米混悬剂在 HepG2 细胞中的低细胞毒性。与商业产品相比，纳米混悬剂使 Rif 浓度增加了 2 倍。总之，Rif 纳米混悬剂可减少一半的给药体积，这可能会提高儿童和老年患者在结核病长期治疗过程中的顺应性。
