姜黄素固体脂质纳米粒干粉吸入剂的体外释药、体内急性毒性及对哮喘模型小鼠炎症反应的影响  

Drug Release in vitro and Acute Toxicity in vivo of Curcumin Solid Lipid Nanoparticles Dry Powder Inhaler and Its Effects on Inflammatory Response in Asthmatic Model Mice

作　　者：李楠[1] 李旭[1] 刘伟伟[1] 李锡晶[1] 刘洪斌[1] LI Nan;LI Xu;LIU Weiwei;LI Xijing;LIU Hongbin(Tianjin Institute of Pharmaceutical Science,Tianjin 300020,China)

机构地区：[1]天津市医药科学研究所,天津300020

出　　处：《中国药房》2019年第3期332-338,共7页China Pharmacy

基　　金：天津市自然科学基金资助项目(No.18JCQNJC13500)

摘　　要：目的:研究姜黄素(Cur)固体脂质纳米粒(SLN)干粉吸入剂(DPI)的体外释药性能、小鼠体内急性毒性及对哮喘模型小鼠炎症反应的影响。方法:采用喷雾干燥法将微乳法制备的Cur-SLN混悬液微粉化后与乳糖(200目)等充分混匀制成Cur-SLN-DPI。采用动态膜透析法考察体外释药情况,比较Cur原料药、Cur-SLN、Cur-SLN-DPI分别在3种释放介质[含1.0%十二烷基硫酸钠(SDS)的磷酸盐缓冲液(PBS,pH 7.4)、含0.2%聚山梨酯80的PBS(pH 7.4)、生理盐水-20%乙醇溶液]中释放5、15、30 min和1、1.5、3、6、8、12、18、24、36、48 h的释放曲线,并筛选合适的释药模型。按急性毒性试验要求考察尾静脉注射最大剂量2 000 mg/kg Cur-SLN-DPI对KM小鼠的影响。将KM小鼠随机分为正常对照组、模型组、阳性药物组(布地奈德3 mg)和Cur-SLN-DPI高、低剂量组(100、50 mg/kg),每组7只,以卵蛋白(OVA)为致敏原复制哮喘模型,每周1、3、5雾化OVA激发哮喘前30 min雾化给药,连续3周。末次激发24 h内,计数肺泡灌洗液(BALF)中白细胞总数、淋巴细胞数、中性粒细胞数和嗜酸性粒细胞数,观察支气管和肺组织的病理学变化。结果:与Cur原料药比较,Cur-SLN和Cur-SLN-DPI均具有缓释作用,且Cur-SLN-DPI在3种释放介质中的缓释更平稳,释药特征均符合Weibull模型。尾静脉注射2 000 mg/kg Cur-SLN-DPI对小鼠无明显的急性毒性。与正常对照组比较,模型组小鼠BALF中白细胞总数、淋巴细胞数、中性粒细胞数、嗜酸性粒细胞数均明显增加(P<0.01),支气管黏膜上皮被覆假复层纤毛柱状细胞,周围炎症细胞浸润严重,肺淤血,中度间质性肺炎;与模型组比较,各给药组小鼠BALF中上述细胞数均明显降低(P<0.01),Cur-SLN-DPI低、高剂量组小鼠气管病变均改善,肺部淤血减轻,且高剂量组减轻更明显。结论:Cur-SLN-DPI具有体外缓释作用,对小鼠无明显急性毒性,可改善哮喘模型小鼠的气管炎症反应和肺�OBJECTIVE:To study in vitro drug release and acute toxicity in vivo of Curcumin(Cur)solid lipid nanoparticles(SLN)dry powder inhaler(DPI)and its effects of inflammatory response in asthmatic model mice.METHODS:Cur-SLN-DPI was obtained with spray-drying method by micronizing the Cur-SLN suspension prepared by the microemulsion method and thoroughly mixing with lactose(200 mesh)etc.The drug release in vitro was investigated by dynamic membrane dialysis.Accumulative release rates(Q)of Cur raw material,Cur-SLN and Cur-SLN-DPI in 3 kinds of release mediums[phosphate buffer solution(PBS,pH 7.4)containing 1.0%sodium dodecyl sulfate(SDS),PBS(pH 7.4)containing 0.2%tween 80,normal saline-20%ethanol solution]were compared 5,15,30 min and 1,1.5,3,6,8,12,18,24,36,48 h after releasing.Drug release model was fitted.The effects of intravenous injection of maximal dose 2 000 mg/kg Cur-SLN-DPI via tail vein on KM mice were investigated by acute toxicity test.KM mice were randomly divided into normal control group,model group,positive drug group(budesonide 3 mg),Cur-SLN-DPI high-dose and low-dose groups(100,50 mg/kg),with 7 mice in each group.The ovalbumin(OVA)was used as sensitizer to induce asthma model;the model mice were given relevant medicine with aerosol administration 30 min before aerosol administration of OVA inducing asthma on Monday,Wednesday and Friday per week,for consecutive 3 weeks.Within 24 h after last induction,total number of leukocyte,the number of lymphocyte,neutrophil and eosinophil were counted in broncho alveolar lavage fluid(BALF);the pathological changes of bronchus and lung tissue were observed.RESULTS:Compared with Cur raw material,Cur-SLN and Cur-SLN-DPI showed good sustained-release effect,and Cur-SLN-DPI had more stable sustained release in 3 kinds of release mediums.The characteristics of drug release conformed to the Weibull model.Intravenous injection of 2 000 mg/kg Cur-SLN-DPI via tail vein had no significant acute toxicity in mice.Compared with normal control group,total number of leukocyte,the

关 键 词：姜黄素 固体脂质纳米粒 干粉吸入剂 体外释药性能 急性毒性 抗炎 小鼠 

分 类 号：R943[医药卫生—药剂学] R965[医药卫生—药学]