Preparation And In Vivo/in Vitro Evaluation Of Oseltamivir Phosphate Oral Sustained Release Suspension

Oseltamivir Phosphate（OP）is a prodrug used to treat influenza.Its active metabolite,oseltamivir carboxylate（OC）,prevents viral progeny from spreading from infected cells by inhibiting viral neuraminidase.Now,OP has been used to treat symptoms before and after exposure to the virus in children from 1 year old to adults.In the domestic market,there are granules,capsules and dry suspensions,all of which are common dosage forms.At present,Yichang East Sunshine Changjiang Pharmaceutical Co.,LTD.,the leader of OP,is applying for clinical application of sustained-release tablet dosage forms.For children under 12 years of age,the dosage is determined according to body weight,which requires a measured dose of drugs;Frequently released preparations can cause gastrointestinal side effects due to high local concentration in the body.Oseltamivir has a bitter taste and affects palatability,causing problems with oral medication compliance in children.Therefore,in this study,Amberlite^?IRP69 strong acid cation exchange resin was used as the carrier to load OP,and the oseltamivir phosphate sustained-release suspension was prepared by combining with the emulsification solvent coating technology.1.Oseltamivir Phosphate Drug Resin Complex（OP-DRC）was prepared by static method and dynamic method,respectively.The influencing factors of the two preparation methods were investigated separately by single factor method.Based on the comparative analysis of the two,the optimal process prescription was obtained as follows:300 mg OP was dissolved in deionized water to prepare a 3 mg/m L OP solution.During the magnetic stirring process,300 mg Amberlite^?IRP69cationic resin was added and stirred at 37.0℃±0.5℃for 3 h at constant temperature.The equilibrium drug loading Q_∞of the resin was 0.8 mg OP/1 mg resin,and the drug utilization ratio E was 80%.The morphology of OP-DRC was observed by scanning electron microscope（SEM）,and the binding mechanism was analyzed by X-ray diffraction（XRD）and attenuated total reflection flourier transformed infrared spectroscopy（ATR-FTIR）.The results showed that OP and resin were not simply physical mixing,but ion exchanged to form ionic bonds.To further elucidate the drug loading mechanism in OP-DRC,the ion exchange kinetics and thermodynamics were investigated.In addition,the release characteristics of OP-DRC under different in vitro media conditions were studied in this study.2.Based on emulsification and solvent volatilization method,OP-DRC was wrapped in acrylic resin,and ethanol was used to prepare OP-COATED microcapsules（OP-CM）instead of acetone.The drug release of OP-CM was detected in simulated body fluid（0.15mol/L Na Cl）,and screened by single factor method,f₂factor evaluation and orthogonal experimental design.The optimal preparation conditions of OP-CM were as follows:Eudragit RS100 was used as coating material,accounting for 12%of the OP resin;the plasticizer accounted for 8%of the capsule material;the capsule material accounted for 2.5%of ethanol,and the mixture was stirred at 40℃for 4h at constant temperature.The drug release model of OP-CM was fitted,and the results showed that the release was dominated by film diffusion and supplemented by particle diffusion.3.Based on the preliminary experiment and literature search,the preliminary formulation process of suspension was established.Then according to the sedimentation volume ratio and redispersity,the dosage of xanthan gum was screened,and the formulation process of suspension agent was finally determined.The stability test of OP sustained-release suspension was carried out,including drug leakage,sedimentation volume ratio,redispersion and release in vitro,and the results showed that the stability was good.4.In vivo detection method of oseltamivir carboxylate（OC）was established and methodological verification was carried out,which showed that all the methods met the requirements.The pharmacokinetic process of oseltamivir phosphate granules and OP sustained-release suspension in rats was studied in vivo by HPLC analysis and pharmacokinetic parameters were calculated by non-compartmental model fitting.Compared with commercially available granules,OP sustained-release suspension prepared in this paper showed obvious sustained-release characteristics.Pharmacokinetics showed that T_max was extended from 2h（commercially available）to 6h（self-administered）,and C_max decreased from 0.631μg/m L（commercially available）to 0.397μg/m L（self-administered）,and the time curve of self-administered drugs was more gentle than that of commercially available drugs.The relative bioavailability of the self-made sustained-release suspension is 101%compared with the commercially available conventional granules,which was in line with the design principle of controlled release preparation.