Development Of Ranolazine Dihydrochioride Floating Delayed-onset Sustained-release Tablets

Objective：To design and decelopment the floating delayed—onset sustained-release tablets withranolazine dihydrochioride as the modle drug by using floating technology、 delaytechnology and sustained technology.Methods：UV and HPLC methods were developed for assaying ranolazine dihydrochioride andranolazine dihydrochioride floating delayed—onset sustained-release tablets. The coretablets were prepared by wet process compression method,and the ranolazinedihydrochioride floating delayed—onset sustained-release tablets were prepared by wetprocess compression method or direct powder compression technique.The material of outershell was screened by invitron floatation and releasem. The preparation factors of outershell influencing the floatation and release were studied through single-factor experiments,the optimized formulation was determined by the central composite design-responsesurface methodology. The quality standards were established to evaluate the quality of thetablets prepared by the optimum formulation and technology, and Preliminary Study ontheir release mechanism.Results：1. The HPLC methodology study showed that there was no impact of excipients onranolazine dihydrochioride assay under the established chromatography condition; The system suitability lest was good, the exclusive was strong; The concentration of ranolazinedihydrochioride was good linear with area(15.30-305.90μg/mL)，the precision(RSD＜1.00%) and recovery rate(>97%) of ranolazine dihydrochioride in mobile test met therequirement of ranolazine dihydrochioride assay.2. The UV mwthodology study showed that there was no impact of excipients onranolazine dihydrochioride assay, the concentration of carvedilol was good linear with peakarea(14.6-204.4μg/ml), the precision(＜3.00%) of ranolazine dihydrochioride in releasemedia met the requirement of ranolazine dihydrochioride assay.3. The results of pre-formulation study showed that ranolazine dihydrochioride wasstable at strong light、hight tempreture and high humidity. Its aqueous solution was stable in24hours; Its solubility was decreased with the increasing pH of dissolution medium, butit could completely meet the conditions to determine the release in water、0.1mol/Lhydrochloric acid solution and pH6.8phosphate buffer solutions.4. The ranolazine dihydrochioride floating delayed—onset sustained-release tabletswere coated-core tablets that were consisted of core of containing drug and outer shell.Thecore tavblets were a mixture of main drug、sone microcrystalline cellulose and lactose,witch weighted350mg. Composition of prescription for outer shell was different becuace ofthe different preparation process. HPMC K4M and K15M(mass ratio of K4M/K15M=2:1)were chosed as the gel matrices，and NaHCO3as bubble—resulting excipient when outershell was prepared by wet granulation method. PEO WSR301and carbomer980(P)NFwere used as the gel matrices，and NaHCO3as bubble—resulting excipient when outer shellwas prepared by the method of power directly mixing. It was showed that amount ofhydrophilic gels and NaHCO3were the influencing factors from the floatation and releaseof agent. Based on these found, Central composition design was conductcd to optimized thefmulation, and the results were as follows: the amounts of HPMC accounted for107.37%of the weight of tablet core, the amounts of NaHCO3accounted for107.37%of the weightof outer shell when the agent was prepared by wet granulation method; the amounts of PEOWSR301accounted for93.69%of the weight of tablet core, the amounts of carbomer980(P)NF accounted for17.77%of the weight of tablet core, the amounts of NaHCO3 accounted for20.22%of the weight of outer shell when the agent was prepared by anothermethod.5. It was showed that the power derictly dry—compression coating technique was themost optimum process; the drug releasa of ranolazine dihydrochioride floating delayed—onset sustained-release tablets witch were prepared by the most optimum process either inthe same batch or batch to batch were homogeneous,and it was showed that the process wasstable and highlu reproducible. Primarily stability study showed that ranolazinedihydrochioride floating delayed—onset sustained-release tablets were stable under thecondition of hight temperature(60℃)、hight humidity(RH75%) and strong light. Theaccelerated study showed that ranolazine dihydrochioride floating delayed—onsetsustained-release tablets were stable for3months under the comdition of40℃,RH75%.6. It was showed that in vitro drug release of ranolazine dihydrochioride floatingdelayed—onset sustained-release tablets followed first order kinetics equation. The drugrelease mechanism of this formulation was matrix diffusion and erosion verified byRitger-Peppas equation.Conclusion：The formulation of ranolazine dihydrochioride floating delayed—onsetsustained-release tablets is reasonable, and the preparation process is stable.The in vitrofloatation and release can be Continuous for12hours, the lag time is not less than4hours,and drug releases with law. It can basically meet the rquirements of floating delayed—onset sustained-release tablets witch have the characteristics of longer retention time instomach，delayed-releasa and sustained-release.This new formulation can ultimately greatly play the application potentiality onclinical, and have higher value of science and technology and good application prospects.