1 Institute of Pharmacy, Nirma University , Gujarat, Ahmedabad, India .
2 Centred'étude des Pathogènes et Biotechnologies pour la Santé , Montpellier, France .
J Aerosol Med Pulm Drug Deliv. 2017 Dec;30(6):388-398. doi: 10.1089/jamp.2017.1379. Epub 2017 May 16.
The delivery of antitubercular drugs through direct lung targeting can lead to reduction in the dose as well as side effects of the drug. In the present investigation, carrier (lactose)-based dry-powder inhaler of rifampicin was prepared to achieve direct targeting of the drug into the lungs.
The dry powder inhaler formulation was prepared by simply mixing micronized rifampicin with coarse and fine lactose preblend. Preliminary blends of the drug were prepared with various lactose grades (Inhalac, Respitose, and Lactohale). Rotahaler and Revolizer were evaluated for the performance. The 3 factorial design was used to optimize the amount of drug (X) and amount of fine lactose (X). In vitro lung deposition was carried out using Andersen Cascade Impactor. The % cell viability studies of the formulation were carried out using murine macrophage J774 cell lines. The in vivo toxicity was determined using histopathology. Further in vivo pulmonary pharmacokinetics of the developed dry-powder inhaler (DPI) formulation was carried out in comparison to the marketed formulation in the rat lungs.
Based on preliminary trials, Inhalac 230 and Inhalac 400 were selected as coarse and fine lactose grades, respectively. Rotahaler exhibited better DPI performance with the evaluated drug blends. The mass median aerodynamic diameter (MMAD) was in the range of 4.3-5.8 μm with the maximum fine particle fraction of 28.9%. The formulation exhibited negligible cytotoxicity on macrophage J774 cell lines with about 75%-80% cell viability at 6- and 12-hour exposure. The histopathological examination revealed negligible toxicity of DPI in comparison to the marketed formulation. The in vivo pulmonary pharmacokinetic studies of the DPI formulation in rats showed higher drug concentration in lungs in comparison to the marketed formulation.
The carrier-mediated dry-powder inhaler of rifampicin could serve as an improved and efficient system for local targeting of drugs into the lungs.
通过直接肺部靶向输送抗结核药物可以减少药物的剂量和副作用。在本研究中，制备了基于载体（乳糖）的利福平干粉吸入剂，以实现药物直接靶向肺部。
通过简单地将微粉化利福平与粗、细乳糖预混物混合，制备干粉吸入剂配方。用不同等级的乳糖（Inhalac、Respitose 和 Lactohale）制备药物初步混合物。评估 Rotahaler 和 Revolizer 的性能。使用 3 因素设计优化药物（X）和细乳糖（X）的量。使用 Andersen 级联撞击器进行体外肺部沉积研究。用鼠巨噬细胞 J774 细胞系进行制剂的%细胞活力研究。通过组织病理学确定体内毒性。进一步在大鼠肺部进行开发的干粉吸入剂（DPI）制剂与市售制剂的体内肺部药代动力学比较。
基于初步试验，选择 Inhalac 230 和 Inhalac 400 作为粗和细乳糖等级。Rotahaler 对评价药物混合物表现出更好的 DPI 性能。质量中值空气动力学直径（MMAD）在 4.3-5.8 μm 范围内，最大细颗粒分数为 28.9%。该制剂对巨噬细胞 J774 细胞系的细胞毒性可忽略不计，在 6 小时和 12 小时暴露时，细胞存活率约为 75%-80%。组织病理学检查显示，与市售制剂相比，DPI 制剂的毒性可忽略不计。大鼠体内肺部药代动力学研究表明，DPI 制剂在肺部的药物浓度高于市售制剂。
载体制剂的利福平干粉吸入剂可作为一种改进的、高效的肺部局部靶向药物输送系统。
