Pharmacodynamics In Analgesics Of Ketoprofen Injectable In Situ Forming Gel And Pharmacokinetics In Dogs

Ketoprofen(Ketoprofen,KPF)is one of non-steroidal anti-inflammatory drugs(NSAIDs),which has good antipyretic,analgesic and anti-inflammatory effects.Compared with other phenylpropionic acid NSAIDs,not only does KPF have strong analgesic effect for inflammatory pain and postoperative pain,but the adverse reaction of it is silght.In the medical clinical,the KPF is mainly used to treat the inflammatory pain,which are induced by various arthritis,tenosynovitis,synovitis,ankylosing spondylitis and so on.At the same time,it can be used for the treatment of trauma and postoperative pain.The control and prevention of the related disease in the pet has not yet been reported in China.The analgesic effect and pharmacokinetics of ketoprofen injectable in situ gel were studied in this paper.The details are as follows:1.Pharmacodynamics study of 10%KPF injectable in situ gel1.1 Guinea pigs skin pimples experiment Choose 48 clean level guinea pigs,half male and female,and were divided into 6 groups randomly.Except the blank group,other groups were respectively given normal saline,100 mg/kg metamizole sodium injection,8 mg/kg lidocaine hydrochloride injection,25 mg/kg KPF injectable in situ gel,and 50 mg/kg KPF injectable in situ gel by intradermal injection.The painless reaction rate of acupuncturing pichel was regarded as the evaluation index to evaluate the analgesic effect.The results showed that compared with normal saline control group,the two dosage groups of KPF injectable in situ gel displayed very significantly abirritation on pain induced by intradermal pimples in guinea pigs at 0.25?60 h(P<0.01).Among them,and the middle dosage group of KPF injectable in situ gel was better than the low dosage group,whose painless response rate reached more than 90%at 0.25?56 h.The results indicated that the low dosage and middle dosages of KPF injectable in situ gel both had obviously abirritation,and the analgesic effect of the middle dosage was better.1.2 Mice body torsion experiment Choose 50 clean level mice,half male and female,and were divided into 5 groups randomly.Except the model control group,other groups were respectively given normal saline,800 mg/kg metamizole sodium injection,100 mg/kg KPF injectable in situ gel,and 200 mg/kg KPF injectable in situ gel by subcutaneous injection.The body torsion reaction number was regarded as the evaluation index to evaluate the analgesic effect.The results showed that compared with normal saline control group,the two dosage groups of KPF injectable in situ gel could very significantly inhibit twisty response in mice induced by acetic acid at 0.5?60 h(P<0.01).Among them,and the middle dosage group of KPF injectable in situ gel was better than the low dosage group,whose analgesic rate reached more than 80%at 0.5-60 h.The results indicated that the low and middle dosages of KPF injectable in situ gel both had obviously abirritation,and the analgesic effect of the middle dosage was better.1.3 Analgesic experiment of partial enterectomy and end-to-end intestinal anastomosis in the rabbits Choose 30 clean level rabbits,half male and female,and divide them into 5 groups randomly.Except the model group,other groups were respectively given 2.5 mg/kg morphine hydrochloride after the operation,20 mg/kg KPF injectable in situ gel before the operation,20 mg/kg KPF injectable in situ gel after the operation,20 mg/kg KPF injectable in situ gel before the operation joint with 2.5 mg/kg morphine hydrochloride after the operation by subcutaneous injection.Evaluate the analgesic effect of persistent pain caused by surgery,according to the criteria evaluation of the pain scale of Melbourne university.The results showed that compared with model group,the three dosage groups of KPF injectable in situ gel displayed very significantly abirritation at 0?48 h(P<0.01)and significantly abirritation in rabbits at 60 h(P<0.05)on the pain induced by surgery in rabbits.KPF injectable in situ gel had a clear long-acting analgesic action.The results indicated that the KPF injectable in situ gel had obviously abirritation.2.Pharmacokinetics study of 10%KPF injectable in situ gel2.1 Establishment of high performance liquid chromatography(HPLC)detection method to quantify KPF concentration in plasma Chromatographic conditions:mobile phase was methanol;0.01 mol/L phosphate buffer salt(43:57,adjusted to pH=3.3 using phosphoric acid),flow rate was set at 0.85 mL/min,detection wavelength was at 255 nm,column temperature was set at 35 ?,sample size was 20 ?L.KPF concentration was of good linear relationship at 0.05?25 ?g/mL for the liner regression equation was Ar=80.221C-0.2851(R~2=1);the method was specific;limit of detection was 0.02 ?g/mL and quantitation limit was 0.05 ?g/mL;precision and recoveries were all in line with the methodology requirements.Plasma samples were extracted with acetonitrile.This extraction and derivation method was of high recovery rate,high degree of separation and no impurity peaks.2.2 Determination the pharmacokinetics parameters of 10%KPF injectable in situ gel in dogs Twelve healthy dogs were administrated a single subcutaneously injected with 10 mg/kg of KPF in situ gel.Plasma concentration analyzed by method of HPLC.Then the plasma concentration-time data were performed using pharmacokinetic software WinNonlin with non-compartment model.The main pharmacokinetic parameters were as followed:For KPF injectable in situ gel,Tmax was 3.17±0.98 h;Cmax was 11.62±1.64?g/mL;T1/2?z was 16.19±13.27 h;MRT was 13.75±2.42 h;AUC0?t was 167.55± 10.83 h·?g/mL;AUC0?? was 167.68±10.77 h·?g/mL.The results indicated that the effective blood drug concentration of the KPF injectable in situ forming gel could maintain a long time,and the acting time was prolonged.