Laboratoire de Pharmacie Galénique et de Biopharmacie, Institut de Pharmacie, Université Libre de Bruxelles , boulevard du triomphe, CP207, 1050 Brussels, Belgium.
Eur J Pharm Sci. 2010 Mar 18;39(5):402-11. doi: 10.1016/j.ejps.2010.01.010. Epub 2010 Jan 25.
The aim of this study was to compare the efficacy of local drug delivery by inhalation to intravenous delivery in a B16F10 melanoma metastatic lung model. Temozolomide was formulated as a suspension, which was elaborated and evaluated in terms of particle size, shape and agglomeration. An endotracheal administration device was used to aerosolise the suspension. This mode of delivery was evaluated at different temozolomide concentrations and was optimized for the uniformity of delivered dose, the droplet size distribution and the distribution of droplets in vivo. Of the particles in the stabilised suspension, 79% were compatible with the human respirable size range, and this formulation retained 100% in vitro anticancer activity as compared to temozolomide alone in three distinct cancer cell lines. The pulmonary delivery device provided good reproducibility in terms of both the dose delivered and the droplet size distribution. Most of the lung tissues that were exposed to aerosol droplets contained the particles, as revealed by fluorescent microscopy techniques. The global in vivo antitumour activity of the inhaled temozolomide provided a median survival period similar to that for intravenous temozolomide delivery, and three out of 27 mice (11%) survived with almost complete eradication of the lung tumours. The present study thus shows that inhalation of a simple liquid formulation is well tolerated and active against a very biologically aggressive mouse melanoma pulmonary pseudo-metastatic model. This inhalation delivery could be used to deliver other types of anticancer drugs.
本研究旨在比较局部药物输送（吸入）与静脉注射在 B16F10 黑色素瘤肺转移模型中的疗效。替莫唑胺被制成混悬剂，从粒径、形态和聚集等方面进行了阐述和评估。采用经气管给药装置使混悬剂雾化。在不同替莫唑胺浓度下评估了这种给药方式，并对输送剂量的均匀性、液滴尺寸分布和体内液滴分布进行了优化。在稳定的混悬剂中，79%的颗粒符合人体可吸入的粒径范围，与单独使用替莫唑胺相比，该制剂在三种不同的癌细胞系中保持了 100%的体外抗癌活性。肺部输送装置在输送剂量和液滴尺寸分布方面都具有良好的重现性。通过荧光显微镜技术，暴露于雾化液滴的大部分肺组织都含有颗粒。吸入替莫唑胺的整体体内抗肿瘤活性提供了与静脉注射替莫唑胺相似的中位生存时间，27 只小鼠中有 3 只（11%）存活，肺部肿瘤几乎完全消除。因此，本研究表明，吸入简单的液体配方具有良好的耐受性，并对非常具有生物侵袭性的小鼠黑色素瘤肺假转移性模型具有活性。这种吸入式给药方法可用于输送其他类型的抗癌药物。
