Preparation Of Praziquantel-hydroxypropyl-β-cyclodextrin Inclusion Compound And Its Pharmacokinetics In Dogs

Praziquantel is a broad-spectrum drug against flukes and tapeworms,which has a particularly good therapeutic effect on schistosomiasis.Due to its poor palatability,low solubility and bioavailability,praziquantel is limited in its clini-cal application and application in pets.In order to improve the solubility and bioavailability of praziquantel,to cover its bitter taste,and to facilitate drinkingwater administration,hydroxypropyl-β-cyclodextrin was used as the drug carrierin this test.Praziquantel-hydroxypropyl-β-cyclodextrin inclusion compound,the best preparation process was obtained by orthogonal test;Fourier transform infrared spectroscopy,scaning electron microscopy and nuclear magnetic resonance spectroscopy were used to identify the phases;by praziquantel-hydroxypropyl-β-Study on the stability of cyclodextrin inclus-ion compound and pharmacokinetic research in dogs,which can improve the refere nce for the preservation of the preparation and the rational use of pet clinical med icine.The results are as follows:1.Preparation of praziquantel-hydroxypropyl-β-cyclodextrin inclusion complex.（1）Orthogonal test results show that the best conditions for inclusion of praziquan-tel-hydroxypropyl-β-cyclodextrin are:n（praziquantel）:n（hydroxypropyl-β-cyclodextrin）=1:3,inclusion temperature 65℃,inclusion time 3h,stirring speed 600r/min;（2）The results of phase identification showed that praziquantelhad characteristic absorption peaks of different intensities in the infrared spectrum.These characteristic absorption peaks were in the praziquantel-hydroxypropyl-β-cyclodextrin inclusion complex.The absorption intensity was reduced.In the scanning electron microscope,praziquantel was granular,hydroxypropyl-β-cyclodextrin was cystic,and praziquantel-hydroxypropyl-β-cyclodextrin inclusion complexes were complex.Spherical,the aromatic part and cyclohexane part of praziquantel in NMR spectrum are embedded in hydroxypropyl-β-cyclodextrin.The identification of the above three phases shows that praziquantel has been hydroxypropyl-β-cyclodextrin inclusion,praziquantel-hydroxypropyl-β-cyclo-dextrininclusion complex has been formed.（3）praziquantel-hydroxypropyl-β-cyclodext rin.The solubility of the refined inclusion compound was 27mg/m L.The dissolution rate of praziquantel-hydroxypropyl-β-cyclodextrin complex reached 84%at 2minutes,and the maximum cumulative dissolution rate reached 91%at 30 minutes.The dissolution effect of praziquantel was significantly improved;（4）stable Sexual investigation shows that the content of praziquantel-hydroxypropyl-β-cyclodextrin in clusion compound under high temperature（60℃）,high humidity（RH90±5%）,light（4500±500lx）and long-term storage conditions And dissolution stability is better.2.Pharmacokinetic study of praziquantel-hydroxypropyl-β-cyclodextrin inclu-si on compound in dogs.（1）A HPLC method was developed for the determination o f praziquantel in dog plasma.The mobile phase was acetonitrile:water（60:40,V/V）,the detection wavelength was 210nm,the column temperature was 30℃,and the flow rate was 1.0m L/min.The concentration of praziquantel in plasma was in the range of 0.1-12μg/m L,the standard working curve was y=79416x-6732.9,R²=0.9996,the limit of quantification was 0.1μg/m L,and the detection limit was 0.05μg/m L.The recovery of praziquantel in blank plasma was 99.29±1.72%～103.81±3.83%,the intraassay coefficient of variation was 1.73%-4.15%,and the inter-assay coef ficient of variation was 2.66%-3.97%.Theresults show that the method for dog pl asma drug extraction and concentration determination established in this experiment is stable and reliable,and can be used to detect the concentration of praziquantel in the plasma of healthy dogs.（2）Twelve healthy Chinese pastoral dogs weighing about 4 kg were randomly divided into two groups,and praziquantel and its hydro-xypropyl-β-cyclodextrin inclusion were administered at a single dose of 5 mg/kg.After the administra-tion,the drug-free feed was fed.Blood was collected once at0.25,0.5,0.75,1,2,3,4,6,8,12,24,36,48 and 72h time points before and after administ-ration,and dog plasma drug concentrations were determined by HPLC.The results showed that the drug-hour data of dogs administered praziquantel and its hydroxy-propyl-β-cyclodextrin inclusion compound were consistent with the two-compartme nt model of first order absorption.The pharmacokinetic parameters of praziquantel and its hydroxypropyl-β-cyclodextrin inclusion complex in healthy dogs are:T_maxis2.05h and 1.57h;C_maxis 0.51μg/m L and 4.82μg/m L;AUC It is 20.63μg·h/m L and98.06μg·h/m L;t_1/2kais 1.26h and 2.60h,t_1/2αis 1.28h and 2.56h;t_1/2βis 13.32h and18.82h;CL is 242.37L/kg/h and 50.99L/kg/h;F is 475%.In summary,the praziquantel-hydroxypropyl-β-cyclodextrin inclusion compo-und prepared in this test has high solubility,good palatability,convenien drinking water administration,good stability,high dissolution efficiency,and slowrelease effect relativ e bioavailability is high.