| M-11 is anti-cholinesterase drug,used for postoperative recovery after surgery in clinical.The current preparation of M-11 is the sugar-coated tablet, the clinical administration needs three times a day for a long cycle. In order to reduce delivery times and to avoid not achieve the anticipated effect because of adnimistration missing by the patient, improve the compliance of adnimistration for patient, this study decided to preparat M-11 sustained-release tablets.The study include following components:In first secion,HPMC as the block material,MCC,LAC as the diluent agent, single-factor method was used to investigated the relationship between the in vitro accumulated release of M-11 and the types and the amounts of HPMC. The results show only use HPMC II as the block agent at the amount of 50% in the formulation, the accumulated release of M-11 in 2 hours was 33.32±0.006%,exist a burst release effective.To avoid the burst release effective,wrapped EQ film on the core to control drug release was taken in this study.Orthogonal design method was used to investigate the relationship among the M-11 in vitro accumulated release and the coating weight,the porogen agent level,and the amount of anti-adhesion agent in coating system.The results show that when coating weight was 10% of the tablet weight, porogem agent was 3% of the coating system, anti-adhesive agnet was 0.1% of the coating system, the in vtitro accumulated release of M-11 in 2 hours,4hours,8hours respectively were 19.52±0.72%,42.31±0.61%,86.50±0.72%.The release time of M-11 in vitro was uptill to 12 hours, successfully avoid the burst release effect,prolonged the drug release time.In section two,established the determination method of M-11 in vitro release, investigated the in vitro cumulated drug release of M-11,fitted the drug release kinetics model using the in vitro release data of M-11. Established a UV method to determination the in vitro drug release,the standard curve concentration ranged from 11.95μg / m L~ 39.84μg / mL,A=0.158*C+0.0204,r=0.9999,recovery was 100.14±0.018%. f 2as the factor to investigate the in vitro release of M-11 in different device, different stirring speed and different release medium pH value, the results show that there was no significant different in the vitro release of M-11 under such conditions.Fitted the drug release kinetic model with the data of drug release from 0 hour to 12hours,the reslut show that drug release macth the Higuchi model,the drug release eqation was Q=0.3788t1/2-0.2731,r=0.9965.In section three,study the stability od sustained-release tablet.The results show that the factor of temperature and light han no significal effect on the stability of suntained-release tablet,sustained-release tablet was sensitive to moistrue;accelaration experiments show that the temperature,humidity and light had no significant effect on the stdbility of sustained-release tablet. Long-term experimental results show that sustained-release tablet was steady.In section four,established the method to deternimate the plasma drug concertration of M-11,caculated the in vito pharmacokinetics of M-11 in rabbit, and preliminary evaluated the bioequivalence of sustained-release tablet.RP-HPLC ion pair method was used to deternimate the plasma concertration of M-11 in rabbit, the standard curve was C=0.025*R-0.0066,r=0.9991,linear range was 0.25μg / mL ~ 100μg / mL.The average recovery was 97.41±0.34%,extraction recovery was 96.36±1.26%,LOD was 30 ng/mL,LOQ was 100 ng/mL.DAS2.0 program was used to caculate the pharmacokinetics parameter of M-11,the result show that the phaemacokinetic model of sustained-release tablet in vito fitted the two-compartment model.The pharmacokinetic equation of sustained-release tablet of single-dosage was C=35.534e-0.268t-7.101e-0.065t, F=102.90%, The pharmacokinetic equation of sustained-release tablet of multi-dosage was C=35.534e-0.268t-7.101e-0.065t,F=104.46%.Anova and t-test were used to analysis AUC(0-∞),Cmax after logarithmically transformed,nonparametric rank sum test was used to analysis Tmax,the Anova and t-test results show that the sustaied-release tablet had the same bioequivalence compaired with the conventional tablets either in single-doasge test nor in multi-dosage test. nonparametric rank sum test show that bioequivation between sustaied-release tablet and conventional tablet was not equal either in single-dosage test nor in multi-dosage test. 90% confidence interval of AUC(0-∞) and Cmax in single-dosage test were respectively 81%~98%,95%~114% in multi-dosage test were 91%~ 99 %,82%~98%.Loo-Riegelamn method was used to caculate the absorbtion in vito and investigated IVIVC, the result show that M-11 sustaind-release tablet had a good relationship in IVIVC, Fa= 2.4182Fr + 2.0735, r=0.9918.This study successfully develoment a M-11 sustained-release tablet. The accumulated release in vitro meet the regulation under the item of sustained-release preparation in Chinese Pharmacopoeia 2005 edition.Compared with conventional tablet, the sustained-release tablet had the low fluctuation in plasma concertration,longer effective time and better IVIVC relationship.The method and result in this study provide a scientific evidence for application and theory research of sustained-release drug delivery system,also has the significant value both in academic and practise.
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