Soliman Lomass, Party Petra, Nagy Attila, Farkas Árpád, Paróczai Dóra, Burián Katalin, Ambrus Rita
Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Eötvös utca 6, 6720 Hungary.
Department of Applied and Nonlinear Optics, HUN-REN Wigner Research Centre for Physics, Konkoly-Thege Miklós St. 29-33, 1121 Budapest, Hungary.
Eur J Pharm Sci. 2025 Jun 1;209:107109. doi: 10.1016/j.ejps.2025.107109. Epub 2025 Apr 23.
The emergence of novel carrier systems for dry powder inhalers is an attractive research subject. Additionally, the site-specific pulmonary delivery of theophylline (THN) remains challenging. Therefore, the present research aims to assess the potential enhancement of THN local delivery to the deep lung via powder inhalation for asthma treatment by developing appropriate fine carriers utilizing the well-established spray-drying technique. The preliminary study aimed to develop novel trehalose-based carrier systems combined with amino acids leucine, glycine, and arginine. Aqueous feedstock solutions were spray-dried, and the obtained microparticulate carriers were assessed. Subsequently, therapeutic powders were produced by spray drying ethanol 10 % solutions of THN combined with candidate-developed carriers. Following each sample preparation, it was subjected to structural, thermal, morphological, rheological, aerodynamic, and particle size distribution characterization. Furthermore, THN solubility was determined. In vitro drug release and diffusion, in vitro and in silico simulated lung deposition, and aerodynamic particle count were analyzed by applying samples equivalent to 10 mg of THN. To summarize the outcomes, carriers composed of trehalose with either leucine or a leucine-glycine combination demonstrated superior respirable properties and were considered candidates for further development. THN co-spray-dried samples showed less crystalline structure and particle size of 4-5 µm, leading to profound solubility enhancement (⁓20 fold) and rapid drug release compared to the pure THN (⁓100 % in 5 min). The in vitro and in silico aerodynamic measurements demonstrated that the THN-trehalose-leucine combination had a significantly enhanced fine particle fraction (43 %), leading to higher deep lung deposition (36 %), and the aerodynamic counter confirmed the development of fine particles (mean=3.61 µm). Moreover, the in vitro experiments on the A549 cells demonstrated that the optimized formulation has a low cytotoxicity profile. In conclusion, the acquired characteristics suggest that inhalable co-spray-dried THN with the trehalose-leucine fine carrier may be a practical approach for local asthma therapy.
新型干粉吸入器载体系统的出现是一个引人关注的研究课题。此外，茶碱（THN）的肺部靶向递送仍然具有挑战性。因此，本研究旨在通过利用成熟的喷雾干燥技术开发合适的精细载体，评估通过粉末吸入增强THN在肺部深处的局部递送用于哮喘治疗的潜力。初步研究旨在开发与氨基酸亮氨酸、甘氨酸和精氨酸结合的新型海藻糖基载体系统。对水性原料溶液进行喷雾干燥，并对获得的微粒载体进行评估。随后，通过喷雾干燥10%乙醇的THN溶液与候选开发的载体来制备治疗性粉末。每次样品制备后，对其进行结构、热、形态、流变学、空气动力学和粒度分布表征。此外，还测定了THN的溶解度。通过应用相当于10mg THN的样品，分析了体外药物释放和扩散、体外和计算机模拟的肺部沉积以及空气动力学颗粒计数。总结结果，由海藻糖与亮氨酸或亮氨酸-甘氨酸组合组成的载体表现出优异的可吸入性能，被认为是进一步开发的候选物。THN共喷雾干燥样品显示出较少的晶体结构，粒径为4-5μm，与纯THN相比，溶解度显著提高（约20倍），药物释放迅速（5分钟内约100%）。体外和计算机模拟的空气动力学测量表明，THN-海藻糖-亮氨酸组合的细颗粒分数显著提高（43%），导致肺部深处沉积更高（36%），空气动力学计数证实了细颗粒的形成（平均=3.61μm）。此外，对A549细胞的体外实验表明，优化后的制剂具有低细胞毒性。总之，所获得的特性表明，可吸入的共喷雾干燥THN与海藻糖-亮氨酸精细载体可能是局部哮喘治疗的一种实用方法。
