乙磺酸尼达尼布雾化吸入制剂的制备及评价

Preparation and evaluation of nebulized inhalation preparation of nitanib ethanesulfonate

目的:研究乙磺酸尼达尼布(nintedanib ethanesulfonate,NE)雾化吸入制剂的处方工艺,并对其进行体内外评价。方法:通过筛选抗氧剂、渗透压调节剂、pH等确定其最优处方;测定NE雾化吸入制剂的雾化动态粒径;通过液相色谱测定NE雾化吸入制剂的体内药代动力学;以肺功能、羟脯氨酸(hydroxyproline,HYP)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、转化生长因子-β1(transforming growth factor-β1,TGF-β1)等为指标评价体内治疗效果。结果:确定NE吸入溶液的最终处方为NE 10 mg,亚硫酸氢钠4 mg,丙二醇50 mg,水2 mL,盐酸调pH至4.0;NE雾化吸入制剂的平均粒径约为3.3μm;SD大鼠体内药代动力学结果显示,NE吸入溶液的体内消除半衰期为5.27 h,生物利用度显著提高,达到63.71%;吸入制剂后肺纤维化模型小鼠肺功能各项参数(气管收缩参数、50%潮气量呼气流量和呼吸速率等)及肺干/湿重比、HYP、TNF-α等指标均有显著改善。结论:NE雾化吸入制剂可有效改善肺功能参数,提高其生物利用度。

Objective:To study the optimized formulation of nidanib ethanesulfonate(NE)solution for inhalation and evaluate the formulation in vitro and in vivo.Methods:The prescription of NE solution was studied by optimizing the amount of the antioxidants,osmotic pressure regulators and pH value.The dynamic particle size of NE nebulized inhalation formulations was measured.The in vivo pharmacokinetics of NE nebulized inhalation formulations was determined by high performance liquid chromatography.Lung function,hydroxyproline(HYP),tumor necrosis factor-α(TNF-α),transforming growth factor-β1(TGF-β1)were used as indicators to evaluate the therapeutic effect in vivo.Results:Optimized prescription was obtained:NE:10 mg,sodium bisulfite:4 mg,propylene glycol:50 mg,water:2 mL.The pH of the solution was adjusted to 4.0.The average particle size of NE nebulized inhalation was about 3.3μm.The in vivo pharmacokinetic results in SD rats showed that the elimination half-life of NE inhalation preparation was 5.27 h.The bioavailability was significantly improved,reaching 63.71%.Pulmonary function parameters(tracheal contraction parameters,50%tidal volume expiratory flow rate,respiratory rate)and lung dry/wet weight ratio,HYP,TNF-αin mice with pulmonary fibrosis model after inhalation administration had been significantly improved.Conclusion:NE inhalation can greatly improve lung function parameters and increase its bioavailability.