Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
Nanotechnology Institute, Jordan University of Science and Technology, Irbid, Jordan.
AAPS PharmSciTech. 2023 Aug 11;24(6):172. doi: 10.1208/s12249-023-02627-3.
Hydroxychloroquine (HCQ) was repurposed for COVID-19 treatment. Subtherapeutic HCQ lung levels and cardiac toxicity of oral HCQ were overcome by intratracheal (IT) administration of lower HCQ doses. The crosslinker-free supercritical fluid technology (SFT) produces aerogels and impregnates them with drugs in their amorphous form with efficient controlled release. Mechanistic physiologically based pharmacokinetic (PBPK) modeling can predict the lung's epithelial lining fluid (ELF) drug levels. This study aimed to develop a novel HCQ SFT formulation for IT administration to achieve maximal ELF levels and minimal cardiac toxicity. HCQ SFT formulation was prepared and evaluated for physicochemical, in vitro release, pharmacokinetics, and cardiac toxicity. Finally, the rat HCQ ELF concentrations were predicted using PBPK modeling. HCQ was amorphous after loading into the chitosan-alginate nanoporous microparticles (22.7±7.6 μm). The formulation showed a zero-order release, with only 40% released over 30 min compared to 94% for raw HCQ. The formulation had a tapped density of 0.28 g/cm and a loading efficiency of 35.3±1.3%. The IT administration of SFT HCQ at 1 mg/kg resulted in 23.7-fold higher bioavailability, fourfold longer MRT, and eightfold faster absorption but lower CK-MB and LDH levels than oral raw HCQ at 4 mg/kg. The PBPK model predicted 6 h of therapeutic ELF levels for IT SFT HCQ and a 100-fold higher ELF-to-heart concentration ratio than oral HCQ. Our findings support the feasibility of lung-targeted and more effective SFT HCQ IT administration for COVID-19 compared to oral HCQ with less cardiac toxicity. Graphical abstract.
羟氯喹（HCQ）被重新用于 COVID-19 的治疗。通过气管内（IT）给予较低剂量的 HCQ，克服了口服 HCQ 的治疗窗下限肺水平和心脏毒性。无交联剂的超临界流体技术（SFT）生产气凝胶，并以无定形形式将药物浸渍其中，实现高效控制释放。机制生理基于药代动力学（PBPK）模型可以预测肺上皮衬里液（ELF）中的药物水平。本研究旨在开发一种新型 HCQ SFT 制剂，用于 IT 给药，以实现最大 ELF 水平和最小的心脏毒性。制备并评估了 HCQ SFT 制剂的理化性质、体外释放、药代动力学和心脏毒性。最后，使用 PBPK 模型预测了大鼠 HCQ ELF 浓度。HCQ 在负载到壳聚糖-海藻酸钠纳米多孔微球中后呈无定形（22.7±7.6 μm）。该制剂表现出零级释放，与原料药 HCQ 相比，仅在 30 分钟内释放 40%，而原料药 HCQ 释放 94%。该制剂的振实密度为 0.28 g/cm，载药量为 35.3±1.3%。与口服原料药 HCQ（4 mg/kg）相比，IT 给予 SFT HCQ（1 mg/kg）导致生物利用度提高 23.7 倍，MRT 延长 4 倍，吸收速度加快 8 倍，但 CK-MB 和 LDH 水平降低。PBPK 模型预测 IT SFT HCQ 给药 6 小时可达到治疗性 ELF 水平，ELF 与心脏的浓度比是口服 HCQ 的 100 倍。这些发现支持与口服 HCQ 相比，肺部靶向且更有效的 SFT HCQ IT 给药治疗 COVID-19 的可行性，同时心脏毒性更低。
