Study On Tolerability,safety And Pharmacokinetics Of Meloxicam Suspension Injection In Chinese Healthy Subjects After Formulation Optimization

Purpose（1）Establish an LC-MS/MS method to determine the concentration of meloxicam in human plasma;（2）To investigate the pharmacokinetic characteristics and safety of meloxicam suspension injection in Chinese healthy subjects,and provide a theory for the rational use of meloxicam suspension injection in patients with moderate to severe postoperative pain in clinical practice in accordance with.MethodThe study is divided into two parts:single-dose study and multiple-dose study.There are 4 groups（A,B,C,and D）in the single dose study,corresponding to the doses of meloxicam suspension injection of 7.5 mg,15 mg,30 mg,and 60 mg,respectively.Among them,the A group adopts a random,open,positive control（different dosage form of the same active ingredient）,a two-cycle crossover test design,and the pharmacokinetics of meloxicam suspension injection 7.5 mg and Mobic?7.5 mg For a comparative study,the cleaning period was 14 days.The three dose groups B,C,and D adopted an open and parallel experimental design,and a single fasting administration study of meloxicam suspension injection was carried out.The dosage of meloxicam suspension injection in the multiple-dose group was 30 mg（1.2 ml）,once a day,for 5 consecutive days,for a total of 5 administrations.Twelve healthy subjects,half male and half female,were enrolled in the single dose four dose group and the multiple dose group,half of them male and female.After the administration,blood samples were collected at the specified time,and an LC-MS/MS method was established to determine the blood concentration of meloxicam in human plasma.The non-compartmental model（NCA）was used to calculate the pharmacokinetic parameters,and SAS 9.4 was used for statistical analysis of the pharmacokinetics.During the trial,vital signs were monitored,safety physical examinations,adverse events and combined medications were recorded,and incidence rates of adverse events were calculated.Result（1）In the LC-MS/MS method established in this study,the plasma concentration of meloxicam has a good linearity in the range of 10～10000pg/m L,and the LLOQ is 10 pg/m L.The maximum value of the endogenous substance in the blank matrix interference to the analyte is2.50,and the endogenous substance has no interference to the internal standard.Except for LLOQ QC,the intra-run precision and accuracy of all concentration quality control%CV is 3.10,and LLOQ QC%CV is5.20.The total extraction recovery rate of the analyte is 103.00%.The stability test results show that the meloxicam plasma quality control sample has good stability.（2）The plasma concentration of meloxicam suspension injection reaches the maximum rapidly after a single intravenous bolus injection（Tmax is about 2～5 min）.Compared with the tablet,the T_maxof the suspension injection is significantly earlier,and the C_maxwas significantly higher than the early exposure(AUC_0-6h～AUC_0-48h);but the overall exposure of the two drugs(AUC_0-tand AUC_0-∞)was equivalent,and the drug distribution and elimination related parameters(V_z,t_1/2z),CL_zwere also not significant different.（3）A single bolus of meloxicam suspension injection showed linear pharmacokinetic characteristics within the dose range of 7.5 mg to 60 mg.The exposure of meloxicam in healthy subjects(C_maxand AUC)increase with the dose of meloxicam,and there was basically no difference in drug distribution and elimination-related parameters(V_z,t_1/2z),CL_zbetween each dose group.After a single intravenous bolus injection of 7.5 mg-60mg meloxicam suspension in healthy subjects,the Cmax and AUC_0-∞of men were about 18%and 27%lower than those of women,and the V_zand CL_zwere lower,respectively.It is 18%and 36%higher than that of women,and there is no significant difference in elimination half-life between genders.（4）After continuous intravenous bolus injection of meloxicam suspension,the blood concentration of meloxicam reached a steady state before the third day of administration,the accumulation factor Rac,AUC_0-τwas about 1.72,and It accumulates slightly in the body.The average volume of distribution（V_z）is about 10 L,the average elimination half-life(t_1/2)is about 24 h,and the average plasma clearance rate(CL_ss)is about 5 m L/min.No significant gender difference trend was observed after multiple administrations.（5）The slow elimination of meloxicam suspension injection in MLXK-B006 subjects may be related to the slow metabolism caused by mutations in the CYP2C9*3 gene.（6）Adverse events in single and multiple-dose trials were mild,no treatment were performed,and no serious adverse events occurred.There was no obvious trend in the incidence of adverse events among dose levels.The main adverse reactions of meloxicam suspension injection were abdominal pain,positive occult blood,constipation and blood pressure reduction,which were similar to those reported in the instructions of the marketed tablets.ConclusionA single administration of meloxicam suspension injection showed a linear kinetic trend in the dose range of 7.5 mg to 60 mg,and the exposure of the multiple administration group(AUC_0-τand AUC_0-∞)was about that of a single administration 2 times,C_maxis about 1.5 times that of a single dose,and its distribution and elimination related parameters are basically the same.In healthy subjects,a single intravenous bolus of7.5 mg-60 mg and a continuous intravenous bolus of 30 mg of meloxicam suspension injection for 5 days have good overall safety.