地西泮固体脂质纳米粒的制备及大鼠经鼻腔给药的药动学研究

 目的 制备地西泮固体脂质纳米粒，评价其制剂学性质，并探讨其经鼻腔给药后的药动学过程。方法 用高温乳化-低温固化法制备地西泮固体脂质纳米粒，考察了其包封率、体外释药、粒径分布、Zeta电位和形态；大鼠经鼻腔给予固体脂质纳米粒或静脉给予地西泮注射液后经股动脉插管采集血样，采用HPLC测定血药浓度，以DAS1.0软件估算药动学参数。结果 制备的地西泮固体脂质纳米粒形态为类球形，平均粒径为(104.4±0.56 nm；Zeta电位为(-18.50±0.98 mV；包封率为(98.8±3%。经鼻腔给药后，地西泮固体脂质纳米粒的t_max为11 min，ρ_max为(0.33±0.01 μg·mL^-1，绝对生物利用度为67.01%。结论 鼻腔给予地西泮固体脂质纳米粒后吸收迅速，绝对生物利用度较高，有望成为治疗癫痫持续状态的新型制剂。

Preparation of Diazepam Solid Lipid Nanoparticles and Its Pharmacokinetics after Intranasal Administration in Rats

OBJECTIVE To prepare diazepam solid lipid nanoparticles, evaluate the pharmacy characters and study the pharmacokinetics after intranasal administration. METHODS Diazepam solid lipid nanoparticles were prepared by high temperature emulsification-low temperature solidification method. The entrapment efficiency, particle size distrubtion, Zeta potential and morphology were measured. After administrating solid lipid nanoparticles in intranasal routes or diazepam parenteral solution via intravenous, the blood samples were collected from the femoral artery. Drug concentration in plasma were analyzed by HPLC method. The concentration-time curves were obtained, and pharmacokinetic parameters were obtained by DAS 1.0. RESULTS The morphology of diazepam solid lipid nanoparticles obtained were appoximately spherical. The average particle size was (104.4±0.56 nm. The Zeta potential was (-18.50±0.98 mV. Encapsulating efficiency was（98.8±3%. After intranasal aministration of diazepam solid lipid nanoparticles, t_max was 11 min， ρ_max was (0.33±0.01 μg·mL^-1， and the absolute bioavailability was 67.01%. CONCLUSION The rapid absorption and high absolute bioavailability were obtained after nasal administration of diazepam solid lipid nanoparticle. It is a promising approach for the treatment of status epilepticus.