Kotta Sabna, Aldawsari Hibah Mubarak, Badr-Eldin Shaimaa M, Binmahfouz Lenah S, Bakhaidar Rana Bakur, Sreeharsha Nagaraja, Nair Anroop B, Ramnarayanan Chandramouli
Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Pharmaceutics. 2021 Nov 3;13(11):1851. doi: 10.3390/pharmaceutics13111851.
Excessive architectural re-modeling of tissues in pulmonary fibrosis due to proliferation of myofibroblasts and deposition of extracellular matrix adversely affects the elasticity of the alveoli and lung function. Progressively destructive chronic inflammatory disease, therefore, necessitates safe and effective non-invasive airway delivery that can reach deep alveoli, restore the surfactant function and reduce oxidative stress. We designed an endogenous surfactant-based liposomal delivery system of naringin to be delivered as an aerosol that supports pulmonary mechanics for the management of pulmonary fibrosis. Phosphatidylcholine-based liposomes showed 91.5 ± 2.4% encapsulation of naringin, with a mean size of 171.4 ± 5.8 nm and zeta potential of -15.5 ± 1.3 mV. Liposomes with the unilamellar structure were found to be spherical and homogeneous in shape using electron microscope imaging. The formulation showed surface tension of 32.6 ± 0.96 mN/m and was able to maintain airway patency of 97 ± 2.5% for a 120 s test period ensuring the effective opening of lung capillaries and deep lung delivery. In vitro lung deposition utilizing Twin Stage Impinger showed 79 ± 1.5% deposition in lower airways, and Anderson Cascade Impactor deposition revealed a mass median aerodynamic diameter of 2.35 ± 1.02 μm for the aerosolized formulation. In vivo efficacy of the developed formulation was analyzed in bleomycin-induced lung fibrosis model in rats after administration by the inhalation route. Lactate dehydrogenase activity, total protein content, and inflammatory cell infiltration in broncho-alveolar lavage fluid were substantially reduced by liposomal naringin. Oxidative stress was minimized as observed from levels of antioxidant enzymes. Masson's Trichrome staining of lung tissue revealed significant amelioration of histological changes and lesser deposition of collagen. Overall results indicated the therapeutic potential of the developed non-invasive aerosol formulation for the effective management of pulmonary fibrosis.
由于肌成纤维细胞增殖和细胞外基质沉积导致的肺纤维化中组织过度的结构重塑，会对肺泡弹性和肺功能产生不利影响。因此，这种进行性破坏性慢性炎症疾病需要安全有效的非侵入性气道给药方式，该方式能够到达深部肺泡，恢复表面活性剂功能并降低氧化应激。我们设计了一种基于内源性表面活性剂的柚皮苷脂质体递送系统，以气雾剂形式递送，用于支持肺力学以治疗肺纤维化。基于磷脂酰胆碱的脂质体对柚皮苷的包封率为91.5±2.4%，平均粒径为171.4±5.8 nm，zeta电位为-15.5±1.3 mV。使用电子显微镜成像发现，具有单层结构的脂质体呈球形且形状均匀。该制剂的表面张力为32.6±0.96 mN/m，在120秒的测试期内能够维持97±2.5%的气道通畅性，确保肺毛细血管有效开放和深部肺递送。利用双级冲击器进行的体外肺部沉积显示，在下呼吸道的沉积率为79±1.5%，安德森级联冲击器沉积显示雾化制剂的质量中值空气动力学直径为2.35±1.02μm。通过吸入途径给药后，在博来霉素诱导的大鼠肺纤维化模型中分析了所开发制剂的体内疗效。脂质体柚皮苷可显著降低支气管肺泡灌洗液中的乳酸脱氢酶活性、总蛋白含量和炎性细胞浸润。从抗氧化酶水平观察到氧化应激最小化。肺组织的Masson三色染色显示组织学变化明显改善，胶原蛋白沉积减少。总体结果表明，所开发的非侵入性气雾剂制剂在有效治疗肺纤维化方面具有治疗潜力。
