Clofazimine (CFZ) is highly active against mycobacterium, including resistant Mycobacterium tuberculosis, but its therapeutic efficacy via the oral route is limited by severe adverse effects, poor aqueous solubility, and slow onset of action. Pulmonary delivery of CFZ is an attractive alternative to target mycobacterium-harboring alveolar macrophages. This study explores the use of air jet milling to develop a respirable, cost-effective CFZ formulation. Jet milled CFZ was readily dispersed from an off-the-shelf dry powder inhaler without the need for additional excipients or carrier particles. Additionally, milled CFZ was internalized by J774.A1 alveolar macrophages within 8 h, with evidence of intracellular biotransformation of the CFZ crystals and macrophage sequestration by 24 h. Less macrophage toxicity was noted in comparison to solubilized drug. Compared to macrophage uptake rate, dissolution of milled CFZ was limited, thereby potentially reducing systemic absorption and subsequent side effects. These results suggest that jet milling is an effective manufacturing method in the development of a CFZ formulation for pulmonary delivery and alveolar macrophage targeting.

中文翻译：

---

通过空气喷射微粉化法对氯氟嗪明进行无辅料的肺部递送和巨噬细胞靶向

氯法齐明（CFZ）对分枝杆菌具有高度活性，包括耐药结核分枝杆菌，但通过口服途径的治疗功效受到严重的不良反应，水溶性差和起效缓慢的限制。CFZ的肺部递送是靶向携带分枝杆菌的肺泡巨噬细胞的一种有吸引力的替代方法。这项研究探索了使用空气喷射研磨技术开发出可呼吸，具有成本效益的CFZ配方的方法。喷射研磨的CFZ可以很容易地从现成的干粉吸入器中分散出来，而无需其他赋形剂或载体颗粒。此外，碾碎的CFZ在8小时内被J774.A1肺泡巨噬细胞内在化，有证据表明CFZ晶体在细胞内发生了生物转化，并在24 h内被巨噬细胞隔离。与增溶药物相比，注意到巨噬细胞毒性较小。与巨噬细胞摄取率相比，碾磨过的CFZ的溶解受到限制，从而有可能减少全身吸收和随后的副作用。这些结果表明，喷射研磨是开发用于肺部递送和肺泡巨噬细胞靶向的CFZ制剂的有效制造方法。