Preparation And Evaluation Of Quick-release And Sustained-release Bilayer Tablets Of Loxoprofen Sodium

[Object]Loxoprofen sodium（LXP）,which is used in the treatment of rheumatoid arthritis,was selected as the model drug.In order to establish and maintain the steady-state blood concentration as soon as possible,to achieve better clinical therapeutic effect,LXP quick-release bilayer tablets were prepared.Optimize the formulation of LXP bilayer tablets and determine the best preparation process;explore the in vitro release behavior of LXP bilayer tablets;study the quality and influence factor test of LXP bilayer tablets;study the pharmacokinetics of LXP bilayer tablets in New Zealand rabbits.[Method]The content determination and in vitro analysis methods of LXP bilayer tablets were established,and the methodological investigation was completed respectively.Using the single factor test method,taking the release rate of LXP in bilayer tablets as the index,the main factors affecting the drug release of each layer were determined,and the prescription was further optimized by Box-behnken method to determine the best process parameters.The cumulative drug release rate of LXP bilayer tablets was calculated,the release behavior was studied,and the mathematical model was used to fit the drug release mechanism.The quality standard of LXP bilayer tablets was established according to the2020 edition of Chinese Pharmacopoeia,and the influence factor test was carried out.The drug concentration in plasma was determined by high performance liquid chromatography（HPLC）,and the pharmacokinetics of LXP bilayer tablets was studied in New Zealand rabbits.[Result]The optimal formulation for the preparation of LXP bilayer tablets was selected.The quick release layer was as follows:sodium carboxymethyl cellulose 3.05 mg,lactose41.30 mg,microcrystalline cellulose 37.76 mg;sustained release layer:hydroxypropyl methyl cellulose 112.65 mg,ethyl cellulose 60.70 mg,microcrystalline cellulose 30.76 mg.The results of in vitro release experiments showed that the LXP bilayer tablets prepared by the optimal prescription had a good early release effect,with a release amount of 20.77%at30 min,and then released slowly for 12 h,which met the expected release requirements;the release process conformed to the Ritger-Peppas equation and belonged to the synergistic effect of diffusion and dissolution.The results of quality study on LXP bilayer tablets show that the preparation process and quality are stable and reliable,which conforms to the relevant regulations of Chinese Pharmacopoeia（2020 edition）.The influence factor test results show that the LXP double-layer sheet has good stability.The results of pharmacokinetics in vivo showed that compared with the common LXP preparation,t_1/2increased significantly（1.300±0.229 h,3.009±1.219 h,respectively）,indicating that the elimination of LXP bilayer tablets in vivo was slow,and the T_maxwas significantly prolonged（0.542±0.102 h,5.167±0.408 h,respectively）,C_maxwas relatively lower(5.338±0.371mg·L^-1,2.612±0.101mg·L^-1,respectively),indicating that the LXP in the bilayer tablets achieved the expected sustained release effect.Compared with ordinary tablets,MRT and AUC were significantly increased,indicating that the retention time of LXP bilayer tablets in vivo was prolonged and the degree of absorption and utilization was better.[Conclusion]The established LXP analysis method in vivo and in vitro is stable and feasible;the optimal formulation for the preparation of LXP bilayer tablets was successfully screened;the 12h release rate of the preparation was more than 90%,which met the requirements of the sustained release preparation;its quality standard and influence factor test all met the requirements.The formulation of LXP bilayer tablets prepared by twice pressing method is reasonable and the process is feasible,which can provide a reliable scientific basis for the development of related preparations of LXP.