Parumasivam T, Chan J G Y, Pang A, Quan D H, Triccas J A, Britton W J, Chan H K
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia.
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia; JHL Biotech, Inc., Hsinchu County, Taiwan.
Eur J Pharm Biopharm. 2016 Oct;107:205-14. doi: 10.1016/j.ejpb.2016.07.014. Epub 2016 Jul 12.
Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine. Formulation 1 is a combination of amorphous thioridazine and crystalline rifapentine, while Formulation 2 consisted of both drugs as amorphous forms. Both thioridazine-rifapentine formulations were found suitable for inhalation with a total fine particle fraction (<5μm) of 68-76%. The two powders had similar MIC90 to rifapentine alone, being 0.000625μg/mL and 0.005μg/ml against Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv, respectively. In contrast, thioridazine alone had a MIC90 of 12.5μg/mL and 500μg/mL, against M. tuberculosis H37Ra and M. tuberculosis H37Rv, respectively, demonstrating no synergistic anti-TB activity. However, thioridazine and rifapentine in a ratio of 1:3 enhanced the killing of M. tuberculosis H37Ra within the human monocyte-derived macrophages (THP-1) compared to the single drug treatments. Both powders showed an acceptable half maximal inhibitory concentration (IC50) of 31.25μg/mL on both THP-1 and human lung epithelial (A549) cells. However, Formulation 1 showed greater chemical stability than Formulation 2 after three months of storage under low humidity (vacuum) at 20±3°C. In conclusion, we have demonstrated a novel inhalable powder consisted of amorphous thioridazine and crystalline rifapentine (Formulation 1) with a good aerosol performance, potent anti-TB activity and storage stability, which deserves further in vivo investigations.
硫利达嗪是一种口服抗精神病药物，具有治疗耐药结核病（TB）的潜力。然而，当硫利达嗪以200mg/天的有效口服剂量用于治疗结核病时，已报告有药物引起的不良心脏效应。硫利达嗪的肺部给药可能是一种合理的方法，既能减少剂量相关的副作用，又能在感染的主要部位实现高药物浓度。本研究比较了由硫利达嗪和一线抗结核药物利福喷丁组成的两种可吸入粉末的体外气溶胶性能、储存稳定性、体外抗菌活性和细胞毒性。配方1是无定形硫利达嗪和结晶利福喷丁的组合，而配方2由两种药物的无定形形式组成。两种硫利达嗪-利福喷丁配方均被发现适合吸入，总细颗粒分数（<5μm）为68-76%。这两种粉末对单独的利福喷丁具有相似的MIC90，对结核分枝杆菌H37Ra和结核分枝杆菌H37Rv的MIC90分别为0.000625μg/mL和0.005μg/ml。相比之下，单独的硫利达嗪对结核分枝杆菌H37Ra和结核分枝杆菌H37Rv的MIC90分别为12.5μg/mL和500μg/mL，表明没有协同抗结核活性。然而，与单一药物治疗相比，硫利达嗪和利福喷丁以1:3的比例增强了人单核细胞衍生巨噬细胞（THP-1）内结核分枝杆菌H37Ra的杀伤作用。两种粉末在THP-1和人肺上皮（A549）细胞上均显示出可接受的半数最大抑制浓度（IC50）为31.25μg/mL。然而，在20±3°C的低湿度（真空）下储存三个月后，配方1显示出比配方2更高的化学稳定性。总之，我们已经证明了一种新型的可吸入粉末，由无定形硫利达嗪和结晶利福喷丁（配方1）组成，具有良好的气溶胶性能、强大的抗结核活性和储存稳定性，值得进一步进行体内研究。
