Construction And In Vivo/In Vitro Evaluation Of Menantine Hydrochloride Oral Liquid Sustained Release Drug Delivery System

Menantine Hydrochloride（MH）is a noncompetitive N-methyl-D-aspartic acid（NMDA）receptor antagonist,can effectively prevent NMDA receptor excitation caused by too high concentration of glutamic acid,and prevent neuronal damage caused by abnormal increase of glutamic acid concentration.It is the first drug approved for the treatment of severe Alzheimer’s disease.At present,MH pharmaceutical dosage forms listed in China and abroad are mainly ordinary tablets,oral liquid and slow-release capsules.MH is easily absorbed by oral administration and has a long half-life.Since most of the drug users are the elderly,the dosage will vary according to the degree of illness of patients.To develop a MH liquid preparation with slow-release effect will help patients with medication compliance.In this study,ion exchange resin（IER）was used as the carrier for drug delivery,and MH was selected as the model drug.A drug-resin composite containing MH was prepared by ion exchange,and then the coated microcapsules were prepared using the emulsion-solvent evaporation coating technology to prepare the memantine hydrochloride sustained-release suspension.1.P reparation of memantine hydrochloride drug resin complexFirst,MH was derivatized with benzoyl chloride and triethylamine,and then an in vitro analytical method for MH was established by HPLC,the methodology of this method is investigated.In this chapter,ion exchange technology was used to combine MH with resin to form MH-DRC,Finally,the static method was adopted to prepare MH-DRC.The optimal preparation conditions were as follows:200 m L of 5.0 mg·m L^-1MH solution was placed on a constant-speed magnetic stirrer for stirring,and 1000 mg of Amberlite^?IRP69 was added thereto.The reaction temperature was maintained at 25.0±0.5℃for 2 h.After the reaction,the drug loading（Q_∞）was 0.83mg MH/1 mg resin,with a drug utilization E of 83.34%.2.Study on the binding mechanism and in vitro release of MH-DRCSEM was used to observe the morphology of MH-DRC,and the combination mechanism was explored by XRD and FTIR.The various characterizations fully confirmed the combination mode between MH and IER,which was the MH-DRC formed by ion exchange rather than physical adsorption.The factors affecting the release rate of MH-DRC in vitro were also investigated,including the temperature of the medium,the volume of the medium,the type and intensity of ions in the medium,and the rotation speed of the paddle.Based on the released amount and f₂,the optimal conditions for in vitro release were screened out as follows:900 m L0.15 M Na Cl solution was used as the dissolution medium,the solution temperature was controlled at 37.0±0.5℃,and the rotation speed of the paddle was maintained at 50 r·min^-1.3.Study on coating technology and prescription of MH-DRCIn order to prevent the sudden release of MH in water after coating,the MH-DRC was impregnated with an impregnant before coating.Then,based on the emulsification-solvent evaporation method,the MH-CM coated microcapsules were prepared using Utrecht quaternary ammonium salt as the blocking material.The single factor method was used to explore the influencing factors of the coating prescription process.The in vitro release rate and f₂factor were selected as evaluation indexes,and the prescription was optimized by orthogonal test,and the optimal preparation process was selected as follows:curing temperature 40℃,curing time 4 h,Eudragit RL100 resin as the retardant material,the ratio of drug to retardant material 10:1,the concentration of coating solution 5.0 mg m L^-1,and the concentration of plasticizer 5%.The release mechanism of MH-CM was also explored.The linear fitting results showed that the release of MH-CM was mainly controlled by membrane,supplemented by particle diffusion.4.Preparation of MH sustained-release suspensionIn this chapter,the properties of MH-CM were investigated to determine whether its particle size and wettability met the standards,and the formulation of suspension was screened.The sedimentation volume ratio and heavy dispersibility were selected as the evaluation basis to screen the appropriate formulation.The content,in vitro release and f₂factor,and drug leakage were selected as the evaluation basis,and the stability of the self-made dosage form was tested.The test results of the self-made sample met the requirements.5.In vivo pharmacokinetic study of MH sustained-release suspensionIn this chapter,the pre-column derivatization method was used to treat MH drugs.The reagent selected was benzoyl chloride.Then the in vivo analytical method was established by HPLC,and the standard of the analytical method was examined.The test results showed that the established HPLC pre-column derivatization in vivo analytical method met the relevant requirements of pharmacokinetics.The SD rats were intragastrically administered with two different preparations of commercial capsule and homemade suspension respectively.According to the test results,t the relevant pharmacokinetic parameters were calculated and the drug-time curve was drawn.The results showed that compared with the commercial preparations,the homemade sustained-release suspension t_1/2of MH delayed by 4.35 h,C_maxdropped from 4.667μg·m L^-1to 3.56μg·m L^-1,indicating that the homemade preparation had a significant effect in the regulation of blood drug concentration,which prolonged the time for MH to exert its efficacy in vivo.The AUC of the self-made and commercial preparations were 101.68μg·m L^-1and 87.24μg·m L^-1,respectively,and the relative bioavailability was 116.65%,which was within the required 80～125%range for the sustained and controlled release preparations,indicating that the self-made and commercial preparations were bioequivalent.