治疗急性肺损伤的龙油乳剂雾化吸入溶液研究

Long oil emulsion nebulizers for the treatment of acute lung injury

急性肺损伤(acute lung injure,ALI)是一种严重的弥漫性肺部疾病,可由病原体感染、刺激性物质吸入等原因造成,严重者会发展成急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)。龙油(Long oil,LO)是一种从多种药用动植物中提取的油脂类混合物,临床已用于创伤修复。本研究制备了一种O/W型龙油乳剂(Long oil emulsions,LOE),由LO、Tween-80、丙二醇、黄原胶、水组成,乳滴大小为671.63±7.21 nm,zeta电位为−17.8±1.26 mV,粒径小且均一,稳定性好,经振动筛雾化器雾化后的气溶胶空气动力学粒径为2.25±0.05μm,1~5μm的粒子占81.40%,可有效沉积到肺深部,适合肺吸入给药。对于人胚肺成纤维细胞(MRC-5),LOE的安全剂量高达12.50μg·mL^(-1),在0.02~2.50μg·mL^(-1)内可促进小鼠成纤维L929细胞增殖和迁移。所有动物实验经军事科学院军事医学研究院辐射医学研究所伦理委员会批准且实验均按照相关指导原则和规定进行。小鼠经气管喷入LO(3.25 mg·kg^(-1))未见明显毒性。小鼠气管喷入LOE可显著减轻脂多糖致ALI,降低肺组织促炎细胞因子(肿瘤坏死因子-α、白介素-6)和总蛋白的释放。LOE有望成为治疗ALI的有临床应用价值的肺吸入制剂。

Acute lung injure(ALI)is a severe diffused lung disease,which is caused by pathogen-induced infections,inhalation of irritates,and so on.It could lead to acute respiratory distress syndrome(ARDS).Long oil(LO)is a lipidic mixture extracted from multiple medicinal animals and plants.It has been used for clinical wound repair.Here,an O/W LO emulsions(LOE)was prepared,which was composed of LO,Tween-80,propylene glycol,xanthan gum,and water.The droplet size of LOE was 671.63±7.21 nm,and the zeta potential was -17.8±1.26 mV.The size of LOE was small and homogenous,and the stability was satisfied.The aerosols had an aerodynamic diameter of 2.25±0.05μm after atomization of LOE with a vibrating screen atomizer,where the percentage of particle sizes within 1−5μm was 81.40%,indicating effective deep lung deposition and suitable pulmonary inhalation.The safe dose of LOE was high to 12.50μg·mL^(-1) on human embryonic lung fibroblast MRC-5 cells.In the range of 0.02-2.50μg·mL^(-1) of LOE,the proliferation and migration of mouse fibroblast L929 cells were improved.Animal experiments were approved by the Ethics Committee of Institute of Radiation Medicine,Academy of Military Medical Sciences,and the experiments were conducted by relevant guidelines and regulations.No significant toxicity was observed after intratracheal(i.t.)administration of LO(3.25 mg·kg^(-1))to mice.Mouse i.t.administration of LOE remarkably attenuated lung injury induced by lipopolysaccharide with mitigations of inflammatory factors(tumor necrosis factor-α,interleukin-6)and total proteins.LOE is a promising inhaled formulation for the treatment of ALI.