RESUMO
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 number of lymphocyte， neutrophil and eosinophil were increased significantly （P＜0.01）； bronchial mucosal epithelium was covered with pseudostratified ciliated columnar cells， with severe infiltration of inflammatory cells， pulmonary congestion and moderate interstitial pneumonia. Compared with model group， the number of above cells in BALF of mice were decreased significantly in administration group （P＜0.01）； tracheal lesions of mice were improved in Cur-SLN-DPI low-dose and high-dose groups； pulmonary congestion of them were alleviated， and that of high-dose group was alleviated more significantly. CONCLUSIONS： Cur-SLN-DPI shows sustained-release effect in vitro and has no obvious acute toxicity to mice. Cur-SLN-DPI can improve the inflammatory response of the airway and the degree of pulmonary congestion in asthmatic model mice.
RESUMO
OBJECTIVE:To prepare the curcumin solid lipid nanoparticles. METHODS:Microemulsion method was adopted to prepare curcumin solid lipid nanoparticles (SLN) and pseudo-ternary phase diagrams was conducted to optimize the preferable three-phase microemulsion factors. The optimal conditions were determined,and then hot microemulsion was dispersed in cold wa-ter to prepare SLN. After the preliminary screening of the factors (emulsifiers,lipid materials,amount of lipids,drug-to-lipid ra-tio,cold water phase temperature and the holding temperature of microemulsion)by single-factor test,with the index of encapsula-tion efficiency,the orthogonal test was conducted to optimize the formulation,followed by the verification test. RESULTS:The best microemulsion was produced at 65 ℃ with three phases consisting of stearic acid(oil phase),polysorbate 80(emulsifier)and ethanol (co-emulsifier) and the Km ratio of 1∶4. The optimal conditions for SLN were as follows as curcumin dosage of 50 mg, stearic acid of 0.5 g,cold water phase temperature of 2 ℃,holding temperature of microemulsion of 65 ℃. The encapsulation effi-ciency was 87.73% for solid lipid nanoparticles prepared,drug-loading rate was 7.72%,particle size was(156.9±2.2)nm,poly-dispersity coefficient was 0.480,average Zeta potential was -24.8 mV(RSD<2%,n=3). CONCLUSIONS:The microemulsion method to prepare SLN is simple and feasible.