Posaconazole nanocrystals dry powder inhalers for the local treatment of invasive pulmonary aspergillosis

Invasive pulmonary aspergillosis poses a significant threat to immunocompromised patients, characterized by high mortality rates. Posaconazole (PSZ), a second-generation triazole antifungal, exhibits broad-spectrum activity but suffers from limited pulmonary concentrations and notable systemic side effects when administered orally or intravenously. This study focuses on optimizing PSZ nanocrystals-agglomerated particles for dry powder inhalers (DPIs) to enhance solubility, dissolution rates, and pulmonary deposition, ultimately improving therapeutic efficacy while minimizing systemic adverse effects.

Highlights

• Posaconazole dry powder inhalers (DPIs) for pulmonary delivery mitigated adverse effects associated with systemic administration
• Posaconazole nanocrystal-agglomerated particles in DPIs exhibited improved solubility and dissolution.
• Optimized posaconazole DPIs demonstrated high pulmonary deposition and superior relative bioavailability in the lungs.
• High drug loading in posaconazole DPIs reduced excipient use and the total amount of inhalable powder needed.

We employed wet medium milling and spray-drying techniques to formulate PSZ nanocrystals-agglomerated DPIs. Various stabilizers including HPMC, HPC, Soluplus, and PVPK30, were systematically evaluated to optimize physicochemical properties. Aerosolization performance was assessed using the Next Generation Impactor, while antifungal efficacy was evaluated through in vitro and in vivo studies

The optimized PSZ DPIs demonstrated significant enhancements in solubility and dissolution rates, with a fine particle fraction (FPF) of 78.58 ± 3.21 %, ensuring optimal lung delivery. In vitro experiments revealed potent effects with minimal cytotoxicity to lung cells. In vivo studies indicated that the optimized formulation achieved a C_max/AUC_0→∞ ratio in lung tissues that was 27.32 and 6.76-fold higher than that of the oral suspension, highlighting increased local drug concentrations.

This approach presents a scalable, cost-effective strategy for the pulmonary delivery of PSZ, ensuring high drug loading and promising clinical outcomes in treating pulmonary fungal infections.

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Materials

PSZ was provided by Roubo Pharmaceutical and Chemical Co., Ltd. (Wuhan, China). Hydroxypropyl methylcellulose (HPMC) was supplied by Shin-Etsu Chemical Co., Ltd. (Shanghai, China). The source of hydroxypropyl cellulose (HPC) was Japan Caoda Co., Ltd. (Hongkong, China). Polycaprolactam polyvinyl acetate polyethylene glycol graft copolymer (Soluplus) was bought from BASF Co., Ltd. (Shanghai, China). The supplier of sodium dodecyl sulfate (SDS) was Damao Chemical Reagent Factory, located in Tianjin, China. Yuanye Bio-Technology Co., Ltd. (Shanghai, China) provided the polyvinylpyrrolidone (PVPK30). Candida albicans (ATCC number: 10231) and Aspergillus niger (ATCC number: 16404) were obtained from ATCC (USA).

Xuchun Li, Qing Wang, Jiewen Huang, Xiao Yue, Xuejuan Zhang, Xinxin Fan, Zhian Fang, Guanlin Wang, Zhenwen Qiu, Dandong Luo, Qiupin Guo, Alan Xiaodong Zhuang, Shaofeng Zhan, Qingguo Li, Ziyu Zhao, Posaconazole nanocrystals dry powder inhalers for the local treatment of invasive pulmonary aspergillosis, International Journal of Pharmaceutics, 2024, 124938, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124938.

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18 – 24 November 2024