Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice
Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice
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DOI：
10.1016/j.ejpb.2012.04.019
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Williams, Robert O., III
中科院分区：
文献类型：
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作者：
Beinborn, Nicole A.;Du, Ju;Williams, Robert O., III
人们的注意力开始集中在针对侵袭性真菌感染的抗真菌药物的肺部输送上，因为吸入真菌孢子通常是许多这些感染（包括侵袭性肺曲霉病（IPA））发病机制的第一步。尽管目前有全身（口服或静脉注射）治疗，但免疫功能低下患者的 IPA 死亡率仍很高。在这项研究中，使用薄膜冷冻（TFF）（一种能够生产低密度多孔聚集颗粒的颗粒工程工艺）设计了具有适合吸入特性的伏立康唑（VRC）颗粒制剂。尽管 VRC 是一种水溶性较差的化合物，但 VRC 的纳米结构无定形形态在体外和体内不如微结构晶体形态有利。使用 Handihaler (R) 干粉吸入器 (DPI)，微结构结晶 TFF-VRC 和纳米结构非晶 TFF-VRC-PVP K25 (1:3) 的细颗粒分数分别为 37.8% 和 32.4%，质量中值空气动力学直径分别为 4.2 和 5.2 μm。在 ICR 小鼠中进行单剂量 24 小时药代动力学研究。将10mg/kg剂量的TFF-VRC直接吹入小鼠肺部后，肺组织和血浆中的AUC(0-24h)分别为452.6μg·h/g湿肺重和38.4μg·h/mL，而肺组织和血浆中的AUC(0-24h)分别为232.1μg·h/g湿肺重和18.6 在吹入 10 mg/kg 剂量的 TFF-VRC-PVP 1(25 (1:3) 后，分别为 mu g h/mL。肺组织中高浓度的 VRC 加上临床相关的血浆浓度表明，微结构晶体 VRC 的肺部递送可能是对侵袭性肺部真菌感染患者给予 VRC 的有益策略。 (C) 2012 Elsevier B.V. 保留所有权利。
Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections, including invasive pulmonary aspergillosis (IPA). IPA in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. In this study, particulate voriconazole (VRC) formulations were designed with suitable properties for inhalation using thin film freezing (TFF), a particle engineering process capable of producing low-density porous aggregate particles. Nanostructured amorphous morphology of VRC was less favorable in vitro and in vivo than microstructured crystalline morphology, despite being a poorly water-soluble compound. Using a Handihaler (R) dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K25 (1:3) had fine particle fractions of 37.8% and 32.4% and mass median aerodynamic diameters of 4.2 and 5.2 mu m, respectively. Single dose 24-h pharmacokinetic studies were conducted in ICR mice. AUC(0-24h) in the lung tissue and plasma was 452.6 mu g h/g wet lung weight and 38.4 mu g h/mL, respectively, following a 10 mg/kg insufflated dose of TFF-VRC directly into the lungs of the mice, while AUC(0-24h) in the lung tissue and plasma was 232.1 mu g h/g wet lung weight and 18.6 mu g h/mL, respectively, following a 10 mg/kg insufflated dose of TFF-VRC-PVP 1(25 (1:3). High concentrations of VRC in lung tissue coupled with clinically relevant plasma concentrations suggest that pulmonary delivery of microstructured crystalline VRC could potentially be a beneficial strategy for administration of VRC to patients with invasive pulmonary fungal infections. (C) 2012 Elsevier B.V. All rights reserved.