The Pharmacokinetics And Relative Bioequivalence Of Nefopam Hydrochloride Sustain-released Tablet In Healthy Volunteers

Objective:The present study on the sustain-released nefopam hydrochloride tablet was performed in 20 health male volunteers so as to clarify its pharmacokinetics properties such as absorption, disposion, metablism ,etc. and investigate the bioequivalence of it ,which was evaluated to provide scientifical data for direction of applicating it clinically.Methods:The present study was divided into three parts including methodology, pharmacokinetics and bioequivalence.The first was to set up analytic methodology named liquid chromatography-mass spectrometry which was effectively used to assay the plasma concentration of nefopam hydrochloride. The mobile phase consisted of 500ml methanol, realesed liquid (40/60,v/v) and the flow rate was 1.0ml.min-1 .To evaluate the methodology by detecting the limit of quantitation for gatifloxacin in plasma, method recovery rate, draw recovery rate, RSD of inter-precision and intra-precision, selectivity and ruggedness to prove whether it could be useful to study the pharmacokinetics and bioequivalence of nefopam hydrochloride or not.The second part was to study phannacokinetics and bioequivalence of nefopam hydrochloride following single 60mg dose orally in health volunteers.According to an open, randomized two-period crossover with seven days washout design, 20 male volunteers were randomly distributed into two groups. Prior to initial trial, no food was allowed until 4h after dose administration. Water intake was allowed after 2h of dose; water, lunch and dinner were given to all volunteers according to a time schedule. A single oral dose was administered. nefopam hydrochloride and added internal standard Plasma concentrations was assayed by the HPLC-MS up to 48h after oral administration. Approximately 3ml of blood samples assay were drawn before (Oh) and at 0.5,1,1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24h after the common tablet while 3ml of blood samples were drawn before (Oh) and at 1,2, 3, 4, 5, 6, 8, 10, 12,14,24, 48h after the sustain-released tablet. The drug safety was monitored.The third part was based on the second part to further study what phannacokinetics after multi oral dose.The common tablet was administered per 20mg at 8:00, 16: 00, 24: 00 everyday for six days while the sustained-released tablet was given per 60mg at 8:00 for six days.Its plasma samples were drawed at the 4^th ,5^th ,6^th day. At the sixth day moring,both formulation were administered again and its 3 ml of blood samples assay were drawn before (Oh) and at 0.5,1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24h after the common tablet while 3ml of blood samples were drawn before (Oh) and at 1,2,3, 4, 5, 6, 8, 10, 12, 14, 24, 48h after the sustain-released tablet. The drug safety was monitored.Results:1.In the experiment, The way of assaying was very high sensitive,the method was linear in the scope of 2 and 150μg/L between blood concentration and area under curve. correlation coefficient of calibration curve were 0.9998,the minmum limit was 2μg/L in plasma under this condition. The method recovery rate of high concentration, middle concentration and low concentration were as (103. 41 ± 1. 01) % , (50. 61 ± 2. 33 ) % , (4. 75 ± 0. 26 ) % respectively; and the drawn recovery rates were as (103. 41 ± 1. 01) %,(50. 61 ± 2. 33 ) % ,(4. 75 ± 0. 26 ) %; and RSD of inter-precision were 1.71%,1. 96%, 3.48%; intra-precision were 1.36%,2. 46%, 1.47% respectively;2.The pharmacokinetics parameters of sustained release tablet or common tablet obtained from Single oral dose study were as following: C_max were (71.9±18.0) and (104.7±24.8)μg/L,Tpeak were (5.1 ±0.6), (2.1±0.7) h ,respectively; AUC_0-24h were (907.1±340.1)and (865.0±287.3) μg .h/L;3.The pharmacokinetics parameters of sustained release tablet or common tablet obtained from multi oral dose study were as following: AUC^SS(0-24h) were (1307.6±312.8) and (503.9±109.1) μg.h/L,C_max were (100.7±20.4) and(113.5±27.5)μg/L, C_min were (29.4± 13.4) and (20.1 ± 11.9) μg/L.The F value (bioavailability) of the drug is 88. 4%± 10. 7%.Conclusions:1.As shown from the figure of chromatography and mass, there is no obivious something disturbing the nefopam in plasma and the limit of quantitation for nefopam was 2ng.mL^-1 in plasma under given assaying condition.This analysis method has some good character such as high sensitivity, accuracy, wonderful specificity and the good linearity in the scope...