Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong Special Administrative Region.
Department of Chemistry, Faculty of Science, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region.
Int J Pharm. 2024 Mar 25;653:123896. doi: 10.1016/j.ijpharm.2024.123896. Epub 2024 Feb 10.
The therapeutic potential of pharmaceutical cocrystals in intranasal applications remains largely unexplored despite progressive advancements in cocrystal research. We present the application of spray freeze drying (SFD) in successful fabrication of a favipiravir-pyridinecarboxamide cocrystal nasal powder formulation for potential treatment of broad-spectrum antiviral infections. Preliminary screening via mechanochemistry revealed that favipiravir (FAV) can cocrystallize with isonicotinamide (INA), but not nicotinamide (NCT) and picolinamide (PIC) notwithstanding their structural similarity. The cocrystal formation was characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and unit cell determination through Rietveld refinement of powder X-ray analysis. FAV-INA crystalized in a monoclinic space group P2/c with a unit cell volume of 1223.54(3) Å, accommodating one FAV molecule and one INA molecule in the asymmetric unit. The cocrystal was further reproduced as intranasal dry powders by SFD, of which the morphology, particle size, in vitro drug release, and nasal deposition were assessed. The non-porous flake shaped FAV-INA powders exhibited a mean particle size of 19.79 ± 2.61 μm, rendering its suitability for intranasal delivery. Compared with raw FAV, FAV-INA displayed a 3-fold higher cumulative fraction of drug permeated in Franz diffusion cells at 45 min (p = 0.001). Dose fraction of FAV-INA deposited in the nasal fraction of a customized 3D-printed nasal cast reached over 80 %, whereas the fine particle fraction remained below 6 % at a flow rate of 15 L/min, suggesting high nasal deposition whilst minimal lung deposition. FAV-INA was safe in RPMI 2650 nasal and SH-SY5Y neuroblastoma cells without any in vitro cytotoxicity observed. This study demonstrated that combining the merits of cocrystallization and particle engineering via SFD can propel the development of advanced dry powder formulations for intranasal drug delivery.
尽管在共晶研究方面取得了进展，但药物共晶在鼻腔应用中的治疗潜力在很大程度上仍未得到探索。我们介绍了喷雾冷冻干燥（SFD）在成功制备法匹拉韦-吡啶甲酰胺共晶鼻用粉末制剂中的应用，该制剂可能用于广谱抗病毒感染的治疗。通过机械化学初步筛选发现，法匹拉韦（FAV）可以与异烟酰胺（INA）共晶，但不能与烟酰胺（NCT）和吡啶甲酰胺（PIC）共晶，尽管它们的结构相似。共晶形成通过差示扫描量热法、傅里叶变换红外光谱法和粉末 X 射线分析的 Rietveld 精修确定的晶胞测定进行了表征。FAV-INA 结晶为单斜空间群 P2/c，晶胞体积为 1223.54(3) Å，在不对称单元中容纳一个 FAV 分子和一个 INA 分子。该共晶通过 SFD 进一步制成鼻腔干粉，评估了其形态、粒径、体外药物释放和鼻腔沉积。无孔片状 FAV-INA 粉末的平均粒径为 19.79±2.61μm，适合鼻腔给药。与原料药 FAV 相比，FAV-INA 在 45 分钟时 Franz 扩散池中的累积渗透药物分数高 3 倍（p=0.001）。在 15 L/min 的流速下，定制 3D 打印鼻腔铸型的鼻腔部分沉积的 FAV-INA 剂量分数超过 80%，而细颗粒分数仍低于 6%，提示鼻腔沉积高而肺部沉积低。FAV-INA 在 RPMI 2650 鼻腔和 SH-SY5Y 神经母细胞瘤细胞中是安全的，没有观察到任何体外细胞毒性。本研究表明，通过 SFD 结合共晶化和颗粒工程的优点，可以推动鼻腔给药的先进干粉制剂的发展。
