地西泮在体鼻腔吸收动力学及薄荷醇对其吸收促进作用的研究

Intranasal Absorption Kinetics of Diazepam and Promoting Effect of Menthol on The Absorption of Diazepam

目的:研究地西泮鼻腔吸收的主要影响因素、吸收动力学及促透剂薄荷醇对其吸收的影响。方法:建立家兔在体鼻腔循环吸收的动物模型,取样时间为0、5、10、15、30、45、60、75、90 min,计算药物吸收速率常数K、吸收半衰期(t1/2)及药物吸收率。研究在鼻腔灌流液体积、循环液流速和pH值一定的条件下,地西泮的质量浓度、吸收促进剂薄荷醇对地西泮鼻腔吸收的影响。结果:在鼻腔灌流液体积为5 ml,循环液流速2.0 ml/min,循环液的pH值在5.9～6.1的中性吸收环境下,地西泮质量浓度在0.25～1.00 g/L时,随着地西泮质量浓度的增加,药物吸收速率常数K增加不明显,t1/2及药物吸收率变化不大;薄荷醇含量为0.2%时对地西泮鼻腔吸收有最佳的促进效果[药物吸收速率常数K为(0.442 4±0.002 3)/h],且能加快地西泮的吸收[t1/2为(0.32±0.07)h)],缩短地西泮的t1/2;0.2%～0.4%范围内,随薄荷醇质量浓度的增加,药物吸收速率常数K反而减小。结论:地西泮可以经鼻腔吸收,鼻腔吸收的机制为被动扩散;0.2%薄荷醇能促进地西泮的鼻腔吸收。

OBJECTIVE： To study the factors associated with intranasal absorption of diazepam, its absorption kinetics and the effect of the penetration enhancer menthol on its absorption. METHODS： The in vivo nasal recirculation rabbit model was established. Sampling was scheduled at 0, 5, 10, 15, 30, 45, 60, 75 and 90 min. Intranasal absorption rate constant K, t1/2 （ half time of absorption） and absorption rate were computed. Under a certain condition of nasal perfusate volume, circulation fluid flow rate and pH value, the effects of mass concentration of diazepam and the penetration enhancer menthol on intranasal absorption of diazepam were investigated. RESULTS ： At a nasal perfusate volume of 5 ml, recirculation flow rate of 2 mL/min, pH value （ of the circulation fluid） of 5.9-6. 1 （ neutral absorption environment）, the concentration of diazepam at a concentration range of between 0. 25 g/L and 1.00 g/L, the increase of the concentration of diazepam was associated with insignificant increase of intranasal absorption rate constant （k） and insignificant change in tl/2 （half time of absorption）. At a content of 0.2%, menthol exhibited optimal promoting effect on the absorption of diazepam [ k = （0. 442 4 ±0. 002 3 ）/h ] and it contributed to the fast absorption of diazepam [ t1/2 = （0.32 ± 0.07）h] and shortening of tl/2of diazepam; within the concentration range of 0.2%-0.4%, with menthol concentration increasing, k decreased. CONCLUSION： Diazepam can be absorbed intranasally. The mechanism underlying the intranasal absorption is passive diffusion. 0. 2% menthol couldfacilitate the intranasal absorption of diazepam.