Tuberculosis (TB) is a life threatening pulmonary infection caused by Mycobacterium tuberculosis (MTB). Current treatments are complex, lengthy, and associated with severe side effects that decrease patient compliance and increase the probability of the emergence of drug resistant strains. Thus, more effective drugs with little to no side effects are needed to diversify the armamentarium against the global TB epidemic. SHetA2, an anticancer compound with null toxicity at doses much higher than the effective dose, was recently discovered to be active against MTB. In the present study, a dry powder formulation of SHetA2 for pulmonary delivery was developed to overcome its poor aqueous solubility and to maximize its concentration in the lungs, the main site of TB infection. Using quality by design (QbD) methodology, three different formulations of SHetA2 microparticles (MPs) were designed, manufactured, and optimized, SHetA2 alone, SHetA2 PLGA, and SHetA2 mannitol MPs, to maximize the drug dose, target alveolar macrophages, and increase drug solubility, respectively. The resulting three SHetA2 MP formulations had spherical shape with particle size ranging from 1 to 3 μm and a narrow size distribution, suitable for uniform delivery to the alveolar region of the lungs. Upon dispersion with the Aerolizer dry powder inhaler (DPI), all three SHetA2 MP formulations had aerodynamic diameters smaller than 3.3 μm and fine particle fractions (FPF_4.46) greater than 77%. SHetA2 remained chemically stable after MP manufacture by spray drying, but the drug transformed from the crystalline to the amorphous form, which significantly enhanced the solubility of SHetA2. Using a custom-made dissolution apparatus, the FPF_4.46 of SHetA2 MP dissolved much faster and to a greater extent (21.19 ± 4.40%) than the unprocessed drug (3.51 ± 0.9%). Thus, the physicochemical characteristics, in vitro aerosol performance, and dissolution rate of the optimized SHetA2 MPs appear to be suitable to achieve therapeutic concentrations in the lungs.

中文翻译：

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SHetA2结核干粉气雾剂：通过设计获得的质量保证的配方，设计和优化

结核病（TB）是由结核分枝杆菌引起的危及生命的肺部感染（MTB）。当前的治疗是复杂，冗长的，并伴有严重的副作用，这些副作用降低了患者的依从性并增加了耐药菌株出现的可能性。因此，需要更有效的药物而几乎没有副作用，以使军备库多样化以应对全球结核病流行。最近发现SHetA2是一种无效毒性的抗癌化合物，其剂量远高于有效剂量，它对MTB具有活性。在本研究中，开发了用于肺部输送的SHetA2干粉制剂，以克服其差的水溶性，并最大程度地提高其在肺部结核感染的主要部位的浓度。使用设计质量（QbD）方法，设计，制造和优化了三种不同的SHetA2微粒（MPs）配方，分别是SHetA2，SHetA2 PLGA，和SHetA2甘露醇MP分别最大化药物剂量，靶向肺泡巨噬细胞和增加药物溶解度。所得的三种SHetA2 MP制剂具有球形形状，粒径范围为1至3μm，并且粒径分布较窄，适合于均匀递送至肺泡区域。在用Aerolizer干粉吸入器（DPI）分散后，所有三种SHetA2 MP制剂的空气动力学直径均小于3.3μm，并且微粒级分（FPF_4.46）大于77％。通过喷雾干燥制造MP后，SHetA2保持化学稳定，但药物从结晶形式转变为无定形形式，从而显着提高了SHetA2的溶解度。使用定制的溶出度仪，SHetA2 MP的FPF _4.46的溶出度比未加工的药物（3.51±0.9％）快得多，溶出度更高（21.19±4.40％）。因此，优化的SHetA2 MP的理化特性，体外气溶胶性能和溶出速率似乎适合于在肺中达到治疗浓度。