Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.
Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.
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DOI：
10.1007/s11095-022-03393-w
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发表时间：
2022-12
影响因子：
3.7
通讯作者：
Hickey, Anthony J.
中科院分区：
文献类型：
--
作者：
Stewart, Ian E.;Durham, Phillip G.;Sittenauer, Jacob M.;Barreda, Aranza P.;Stowell, Grayson W.;Moody, Carmella;Mecham, Jeffery B.;Simpson, Catherine;Daily, Sharon;Maloney, Sara E.;Williams, Mark D.;Severynse-Stevens, Diana;Hickey, Anthony J.
结核病（TB）仍然是由单一生物体引起的最严重的疾病之一。多重（MDR）和广泛（XDR）耐药疾病对全球健康构成威胁，需要新药和/或创新的治疗方法。许多药物已被提议作为肺结核的吸入疗法，通常通过喷雾干燥制备。CPZEN-45是一种新型抗结核药物，口服生物利用度较差，但在吸入给药时显示出前景。无辅料的CPZEN-45 HCl已被喷雾干燥成粉末，具有理化特性、空气动力学粒度分布和递送剂量，适合作为吸入产品考虑。RS-01吸入器释放的粉末的质量中值空气动力学直径（MMAD）和几何标准差（GSD）分别为2.62 ± 0.04 μm和1.76 ± 0.09。此外，该粉末在环境条件下储存>1.5年后具有物理和化学稳定性，粒度与新鲜制造的产品相似。将喷雾干燥粉末中的过量物料回收至粉末中，并重新喷雾至制剂中，同样导致质量变化可忽略不计，因此可根据需要进行进一步的临床前表征。使用中试规模的制造设备按比例放大CPZEN-45，其中增加粉末的密度以促进更大的递送剂量而不影响空气动力学性能特性。喷雾干燥粉末适合于药代动力学、功效和临床前毒理学研究。最终生产方法可直接用于CGMP颗粒生产，以支持IND和I期临床试验及以后。在线版本包含补充材料，可通过10.1007/s11095-022-03393-w获得。
Tuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation. Excipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 μm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties. The spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond. The online version contains supplementary material available at 10.1007/s11095-022-03393-w.
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