Human Body Bioequivalence And Pharmacodynamics Comparative Study Of Propofol In Medium And Long Chain Triglyceride Emulsion Injection

Propofol has become one of the most clinical applications of intravenous anesthetics since1989s, because of it’s the advantages compared to other intravenous anesthetics, but local injection pain is one of the more prominent adverse reactions, high incidence of28%to90%. The propofol injection pain is a common problem in clinical procedure, although it will not be included in the drug of serious complications, but the propofol injection pain will occur to the patients with increased pain, fear and the hemodynamic changes by affected blood pressure, heart rate of patients, even directly affect the anesthesia safety and quality after evoked the potential risk. Although the mechanism of Injection pain is not clear, but most studies suggest that mechanisms of propofol injection pain generating:on the one hand, propofol may directly stimulate nociceptors within the vascular wall, on the other hand, propofol does not dissolve in water because highly lipophilic, cause to activation of the kinin release enzyme system after exposure of endothelial cells in a blood vessel, leading to the plasma bradykinin levels and vascular permeability changes, and ultimately stimulates nerve endings and produce ache. Therefore, how to effectively control the injection pain of propofol has become an important problem that always was in its clinical application.There have been many reports related clinical reduces propofol injection pain in the literature, common methods include various drugs were given before propofol was injected.such as fentanyl, sufentanil, lidocaine, ketamine, diluting or cooling propofol injection, slow down the speed of propofol injection, change the propofol concentration of formulation, choose a large vein to inject and so on, but these methods are slightly trouble and not applicable. Recently, Most of researchers prevent patients from injection pain by mixing of lidocaine and propofol, but pulmonary embolism caused by lidocaine combined with propofol injection have been reported in the literature,since it probably enlarge drug particle diameter size.at same time,it will beworthy to pay more attention that overdose lidocaine combined with propofol will produces synergistic effect by inhibiting central nervous system.Along with the clinical research and observation, it was recognized that the best choice of reduce injection pain is change agent composition, and has gradually become the focus of research. Propofol formulations containing fat emulsion, can increase the propofol lipid solubility, decreases the water free propofol, thereby significantly reducing injection pain.Propofol MCT/LCT injection and propofol LCT injection, containing more triglycerides. Medium chain Triglyceride are characterized by long chain triglyceride metabolism have faster speed than LCT in the body, after administration in vivo in patients plasma glycerin three greases concentration level is lower than LCT propofol fat emulsion injection, propofol medium and long chain fat emulsion injection is suitable for adult patients also applicable to newborn infants. Foreign human trials have shown, and standard propofol fat emulsion injection compared, propofol medium and long chain fat emulsion injection of propofol pharmacokinetics and pharmacodynamics of almost no change, but the medium and long chain fat emulsion injection on moderate and intense pain on injection of patients with long chain fat emulsion injection was significantly reduced, induced by injection of pain was markedly relieved. Propofol LCT injection has a higher incidence of side effects for injection pain, hyperlipemia,.Due to decreased of free propofol concerntration with propofol MCT injection, it can significantly reduce the pain on injection, the medicine have better compliance.Because the medium/long chain glycerin three greases hydrolysis, metabolic clearance rate was significantly higher than that of long chain glycerin three greases, after long time intravenous infusion of propofolMCT/LCT injection, plasma glycerin three greases levels rapidly returned to normal levels, and cause hyperlipidemia risk decreased significantly, and reducing the burden of liver.Use of propofol MCT/LCT injection have more quickly memory recovery,and propofol MCT/LCT injection can be used for more than1months child anesthesia.This study selected20healthy male subjects using random, single blind, two stage two formulations of the cross-over positive control experimental design method, a single intravenous injection of propofol medium and long chain fat emulsion injection test preparation and reference preparation, using high performance liquid chromatography-mass spectrometry (LC/MS/MS) method for the determination of plasma samples obtained pharmacokinetic parameters and record its pharmacodynamic targets, and to observe the drug safety index, study consists of two parts as following.PurposeUsing marketed propofol MCT/LCT injection (Fresenius Kabi) as a reference preparation, inspection pharmacokinetic parameters of healthy male volunteers after a single intravenous injection of propofolMCT/LCT of test preparation (domestic), comparing two formulations in human pharmacokinetic bioequivalence, and provide reference for clinical application.Methods20healthy male subjects, divided into two groups randomly, using a rand omized, single blind, two stage two formulations of the cross-over positive con trol experimental design method, during the week washout period of7days. T he subjects were fasting for venous injection of propofol test preparation or ref erence preparation2mg/kg dose on the morning, collecting venous blood of3mL in2,3,4,6,8,10,20.30,60,90.150,210,360min, the heparin ant icoagulant tube, mixing,3000r min-12min, centrifugal, separating plasma, f inally.save for test at-20degrees. at the same time, observing records of p harmacodynamics, vital signs and safety index. Blood samples using high-perfo rmance liquid chromatography-mass spectrometry/mass spectrometry (LC/MS/MS) method for the determination of propofol concemtration. Chromatog raphic conditions including:pre column:C18(4mm2.0mm m,3); analytical column:C18protective column (50mm2.1mm3.5m,); mobile phase of methanol:0.1%ammonia solution; flow rate:0.4mL/min; sample size:10L; column temperature:40C, ESI negative ion mode detection;Using thymol as internal standard to determination of the concentration of propofol in plasma, u sing DAS2.1software for pharmacokinetic parameters calculation and statistical analysis, and draw the plasma concentration-time curve. Pharmacokinetic par ameters of two kinds of drug was transformed by logarithmic,then caculate ana lysis of variance during the week, individual between three factors, double unil ateral t test (alpha=0.05) and (1-2alpha) confidence interval analysis we re conducted to evaluate bioequivalence of. the test preparation and reference p reparation ResultsBlood samples of propofol MCT/LCT injection by high performance liquid chromatography-mass spectrometry (HPLC-MS) method for the determination of plasma concentration of sample in the10.05-12060ng/mL inside of a good relationship (r=0.9967). the lowest limit of quantification was10.05ng/mL, the extraction rate of greater than84.1%, determination day and inter-day precision is less than15%, plasma samples at room temperature.4h,8h and31days and freeze thaw were under stable conditions (RE in15%.). The method has the advantages of high sensitivity, good accuracy can meet the requirements of propofol MCT/LCT injection testing requirements, applicable to the pharmacokinetic and bioequivalence studies.20healthy male subjects after single intravenous dose propofol test prepar ation or reference preparation2mg/kg dose, pharmacokinetic parameters were:T1/2:115.636±26.672min,113.598±21.443min;Tmax:2.250±0.444min,2.45±0.470min Cmax:6532.850±1905.995ng/mL,6414.700±1765.466ng/mlAUC0-t:78585.265±12236.419ng/ml*min,79773.880±11718.066ng/ml*min,AUC0-oo:84353.781±13456.027n g/ml*min,85674.040±12882.424ng/ml*min. The test preparation and reference pr eparation of AUCO-t, AUC0-∞, Cmax, for after log transformation by analysis o f variance and bidirectional unilateral t test. Test preparation (AUCO-t), In (AUCO-oo)[1-2alpha] confidence intervals were94.3%～102.8%,94.2%102.6%, all in the range of80%～125%,it showed that two agents in absorpt ion extent bioequivalent; In (Cmax)[1-2alpha] for a confidence interval of94.4%～108.2%, in the70%to143%range, showed that two agents in the p eak concentration of bioequivalence of test and reference preparation; Tmax of preparation by non-parametric tests, the results of P>0.05, showed no statist ical significance, indicted that two agents in the peak time of Bioequivalence. Conclusion Taking Listed drug propofol MCT/LCT injection (Fresenius Kabi) as the reference preparations. Guangdong Gabo Qingyuan Pharmaceutical Company Limited production of MCT/LCT injection for the test preparation, Study of two formulation in20healthy male subjects were designed as randomized, two stage single blind, cross-over positive control testing, the results show that two formulations were bioequivalent.in healthy human.PurposeTake listed drug propofol MCT/LCT injection (Fresenius Kabi) as a control drug, to testify clinical drug effect and drug safety.of domestic propofol injection with same formulation (Guangdong Gabo Qingyuan Pharmaceutical Company Limited) in healthy volunteers after a single venous injection.MethodsThe experiment uses a single center, randomized, single-blind, two stage two drug cross-over positive control design methods, each subject is divided into two stages of intravenous administration of two drugs, during the washout period of7d;20healthy adult male volunteers were randomly divided into A, B in two groups of10, the group A first stage inject test drug, the second stage inject control drug, B group is the opposite. According to2mg/kg dose intravenous injection of two formulations, continuous recording of BIS values, loss of consciousness, consciousness recovery time (t-LOC) time (t-ROC), loss of consciousness duration (d-LOC), the minimum BIS value emergence time (t-BISmin). Monitoring subjects of the vital signs, including heart rate (HR), noninvasive systolic blood pressure (SBP), noninvasive diastolic blood pressure (DBP), respiratory rate (RR), pulse oxygen saturation (SpO2); Using VAS scale to valuate injection pain of volunteers after waking up, observing adverse reaction of two kinds of drug through the study.Resultspharmacodynamic indications display that the rest of the BIS value of two drugs were not statistically different (P>0.05);,t-ROC, d-LOC, t-LOC. T-BISmin also had no statistical difference (P>0.05); except for minimu BIS value of test drug and control drug in group A has statistical difference (P=0.034)after study design as two phase.cross over,positive control. Results of drug safety characteristics show that various changes in vital signs have no statistical difference,and laboratory testing of blood, urine, stool routine, liver function, blood lipids, a total of29, after the administration of were not indicated abnormalities and clinical significance of the parametersr; Adverse reaction, injection pain VAS score of two formulation have no statistical difference (P>0.05). Besides,group A and group B have occurred5cases of breath choke after administration in phase Ⅰ,6cases of group A at in phase Ⅱ,4cases in group B, The rest of adverse reaction have not occurred.ConclusionControl drug and test drug have similar clinical drug effect and characteristics of safety after a single venous injection of two formulations in healthy volunteers.