A Study Of Acetamido-avermectin In Situ Gel Injection

Eprinomectin(EPR)is a macrolide antiparasitic drug,approved by the U.S.Food and Drug Administration(FDA)for use in animals during pregnancy and lactation.There is no drug withdrawal period after administration.In-situ gel injection is a new type of long-acting sustained-release preparation.It has a simple preparation process and convenient administration.It is a low-viscosity liquid before administration and forms a solid implant after being injected into the body.It releases the drug slowly,reduces the frequency of administration,and increases Patient compliance.In this topic,referring to the marketed preparation LONGRANGE?,the antiparasitic drug EPR is combined with the controlled release polymer material polylactic acid-glycolic acid(PLGA)to prepare the In-situ gel injection of EPR with lower burst release,and investigate the release and degradation of the gel through in vivo experiments in SD rats.In the pre-prescription research,an in vitro release content analysis method of EPR in-situ gel injection was established.The specificity,precision,and recovery rate of the method meet the requirements.The physical and chemical properties of EPR were investigated,the pH value was 7.4.Phosphate buffered saline(PBS)is used as the in vitro release medium,the in vitro release characteristics of EPR in-situ gel injections are investigated by sample separation method.This method can accurately predict the release of in-situ gel in vivo.According to single factor experiments,the impact of the burst release,viscosity,cumulative release and implant formation of in-situ gel injections of different molecular weights,concentrations,types of polymers and different additives within 24 hours was investigated.Liquid chromatography,rotational viscometer and scanning electron microscope were analyzed and characterized.A prescription for in-situ gel injection with a drug content of 5%(w/v)was determined,with 5%(w/v)PLGA polymer added,1%(w/v)antioxidant 2,6-di-tert Butyl toluene(BHT),65%(v/v)hydrophilic organic solvent N-methylpyrrolidone(NMP),35%(v/v)hydrophobic solvent triacetin(GTA),through the release of continuous three batches is tested for concentration,and the prescription,which has good reproducibility.The Sprague-Dawley rats were selected as the animal model,and the pharmacokinetic experiment and the mechanism of in-situ gel degradation were carried out respectively.The plasma drug concentration in SD rats was measured by high performance fluorescent liquid chromatography,the morphology of the implant was observed by scanning electron microscope,and the molecular weight of the polymer was measured by gel liquid chromatography.The drug-time curve was drawn,and the drug-time curve was processed by DAS3.0 software.The pharmacokinetic parameters of the EPR in situ gel injection are as follows:The AUC_0-t is(1690.498±18.676)d·ng/mL,the AUC_0??is(1859.847±37.876)d·ng/mL,the t_1/2?z is(13.636±1.982)d,the t_max is(11.667±2.466)d,the C_max is(27.168±7.475)ng/mL;the MRT is(28.063±6.544)d.The effective blood concentration of EPR in situ gel injection can be maintained for four months,achieving the purpose of long-acting drug release.After investigating the injection site and injection speed of the in-situ gel,the administration method of slow subcutaneous injection at the back of the neck of SD rats was determined.Combined with Plasma drug concentration curves,morphologies and molecular weight changes at different time points,the release can divide into four parts:(1)The initial stage,which is mainly reflected in the drug burst release.All the drugs close to the surface are dissolved in the surrounding water medium and released quickly from the interconnected pores;(2)Under the action of body fluids,the hydrolysis of PLGA and the erosion of the gel run through the second stage,entering slowly and slowly.The stable release phase(3)is the third phase,which is the second burst of drug release.With the continuous progress of polymer autocatalysis,the acidity inside the matrix continues to increase,degrades into small fragments,and the specific surface area continues to increase,resulting in a large amount of drug release.(4)Finally,the matrix degradation continues,but due to the lower drug concentration,the release The speed decreases until the implant is completely degraded.This study solved the problem of burst release of the in-situ gel to a certain extent,but after injection into the body,the variability of the shape of the solid implant is still not well resolved,and follow-up research is needed.