褪黑素鼻喷剂的吸收与生物利用度研究

 目的研究一种能够快速吸收、生物利用度高的褪黑素鼻喷剂。方法采用大鼠在体鼻循环法研究褪黑素的体外吸收规律,计算吸收速率常数;6只新西兰兔随机分为3组,进行3×3拉丁方实验,分别给予受试制剂T1,T2和参比制剂R,于不同时间点取血,清洗期为1周。采用反相高效液相色谱法测定血药浓度,计算药动学参数和绝对生物利用度。结果受试制剂T1,T2大鼠鼻腔吸收速率常数分别为0.006 8,0.002 7 min^-1,有显著性差异(P<0.05)。参比制剂R和受试制剂T1,T2的药-时曲线均符合二室模型,ρ_max分别为(676.9±133.1),(296.6±135.4)和(155.8±82.8)μg·L^-1,t_1/2β分别为(15.2±2.0),(14.6±1.3)和(16.3±3.0)min,AUC_0-60分别为(6 329.5±681.3),(5 307.6±1 424.9)和(2 736.4±620.0)μg·min·L^-1;受试制剂T1,T2的t_max分别为(4.29±2.32)和(6.40±3.46)min,K_a分别为(0.622±0.280)和(0.320±0.150)min^-1,绝对生物利用度分别为(85.2±26.3)%和(44.2±14.2)%。统计学结果表明,吸收速率常数Ka,绝对生物利用度在受试制剂间有显著性差异(P<0.05)。结论本研究制备的褪黑素鼻喷剂给药后快速吸收,绝对生物利用度高;大鼠在体鼻循环法与体内试验结果相关性好。

Study on Absorption and Absolute Bioavailability of the Melatonin Nasal Spray

OBJECTIVE To develop a high bioavailability nasal spray of melatonin absorbed rapidly.METHODS The in situ rat nasal recirculation methods were used in experimental animal model to study the rule of melatonin nasal absorption.The rate constants of absorption were evaluated.Six male New Zealand White rats were enrolled and divided into 3 groups in Tris-period-cross-over test by the three kinds of preparations exchanged every week.The blood samples were collected from the rabbits to measure the plasma drug concentration by HPLC-UV.The pharmacokinetic parameters and absolute bioavailability were evaluated.RESULTS The in vitro rate constants of absorption were(0.006 8),0.002 7 min^-1 for the rats in the groups treated with T1 and T2 respectively,and significantly different(P<0.05).In vivo,these generalized plots of melatonin concentration versus time of R and T1,T2 showed drug distribution and equilibration for a two-compartment model.The pharmacokinetic parameters were as follows:ρ_max(676.9±133.1),(296.6±135.4) and(155.8±82.8) μg·L^-1,t_1/2β(15.2±2.0),(14.6±1.3) and(16.3±3.0) min, AUC_0～60(6 329.5±681.3),(5 307.6±1 424.9) and(2 736.4±620.0) μg·min·L^-1,for the rabbits in the groups treated with R,T1 and T2,respectively.The pharmacokinetic parameters of the groups treated with T1 and T2 were followed as:t_max(4.29±2.32) and(6.40±3.46)min,K_a(0.622±0.280) and(0.320±0.150)min^-1.Absolute bioavailability(85.2±26.3)% and(44.2±14.2)%,respectively.Significant differences of K_a and absolute bioavailability between T1 and T2 were found(P<0.05).CONCLUSION The nasal spray of melatonin can be absorbed rapidly and have a high bioavailability.The correlation between in vitro and in vivo is good.