Preparation And Study Of Gliclazide Extended-release Pellet Capsule

Objective: To prepare gliclazide extended-release pelletscapsule(EPC) which could prolong retention time of thegliclazide in vivo and the time of maintaining effectiveconcentration of drug in plasma, keep the concentration-timecurve steady, decrease the occurrencing rate of hypoglycemiamal-response and rise the reliability of medication.Method: EPC was filled with the pellets prepared byextrusion/spheronization with microcrystalline cellulose(MCC),ethylcellulose(EC) and stearic acid as framework. The mainfactors inspected involved factors of prescription(dose ofMCC,EC, stearic acid, excerption and dose of adhesive )andfactors of technique ( speed of extrusion, speed ofspheronization, time of spheronization ) which influencedformation and release of pellets. The orthogonal experiment wasdesigned to screen prescription and technique in which the doseof MCC, EC, stearic acid and the time of spheronization weretaken as four influential factors and three different levels wereselected to part , each conformation of prescription andtechnique was selected refer to the L9(3⁴) orthogonal designtable based on the inspection of the main factors. By theanalysis of range, the optimization of prescription and techniquewere definited with the colligation evaluation of formation andrelease of pellets.The dissolution test of gliclazide EPC was established referto the dissolution test of gliclazide tablet recorded in C.P. pH8.6phosphate buffer was taken as release medium, gliclazide insample was determined by ultraviolet spectrophotography(UV)at the wave-length of 233 nm. The colligation marker P=f (therecovery of pellets at 18-24 category)-2Φ(critical angle of plan)was taken to evaluate formation of pellets. The repetition ofrelease property in vitro was inspected throμgh the dissolutiontest of three batch gliclazide EPC prepared according to theoptimization of prescription and technique. The data of releasepercentage was modeled with three kinetic equations: Higuchiequation, zero order equation and first order equation. The effectof extended-release in vitro of EPC was inspected comparinggliclazide tablet. The factors involving high temperature, highhumidity and radiancy was investigated which influence thestability of EPC. The stability in accelerating condition wasinspected by estimating the character, content and releasepercentage of samples deposited 1 month, 2 month, 3month,6month at temperature 40℃±2℃and relative humidity 75%±5%.After oral administration of gliclazide EPC(80mg) andgliclazide tablet(80mg) to rabbits respectively, theconcerntration of gliclazide in rabbits plasma at certainsampling times were determined with high performance liquidchromatograph (HPLC). The pharmacokinetics parameters werecalculated by processing the data of concerntration-time with3P97 program based on the character of pharmacokineticsdefinited according to AIC technique.The effect of extended-release in vivo of gliclazide EPCwas evaluated by comparison of pharmacokinetics parametersincluding AUC,T1/2(Ke),Cmax,Tmax and MRT with pairing tcheck. The Absorption percentages in vivo of gliclazide EPCwere calculated according to Wagner-Nelson formula. Thecorrelation between absorption in vivo and release in vitro wasinvestigated through linear regression equation and correlationcoefficient calculated with the data of absorption percentages invivo and release percentage in vitro in 12 hours.Results: By analysis range of the orthogonal experimentresult, the optimization of prescription and technique weredefinited: gliclazide 15g; MCC 25g; EC 3g; Stearic Acid 6g;distilled water as adhesive, 35%; the pellets were prepared byextrusion/spheronization: speed of extrusion 30r/min;speed ofspheronization 50r/min, time of spheronization 1min; 30r/min,time of spheronization 4min.The pellets prepared had goodspheronization, the critical angle of plan was 12.1ã‚œ, therecovery was 94.8%. The data of release percentage in vitro ofthree batch gliclazide EPC prepared according to theoptimization of prescription and technique had not significantdiscrepancy (p>0.05). The repetition of release property invitro was good.Gliclazide EPC had good effect of extended-release invitro , released drμg slowly to last more than 12 hours,accumulative release percentage was more than 75%. The dataof release percentage was modeled with three kinetic equations:Higuchi equation, zero order equation and first order equation:F_t=6.892_t+12.03 r=0.9725F_t =30.17t^1/2-12.15 r=0.9936Log(F_∞-F_t)= -0.1134t+2.165 r=0.9717The result interpretated that the release behavior of gliclazideEPC coincidented with Higuchi equation well and the characterof extended-release was transparent.The increased weight owing to absorbing humidity ofgliclazide EPC was 3.16% which were deposited 10days atrelative humidity 95%. The result that the character, content andrelease percentage of EPC had not significant discrepancy at thecondition of high temperature, high humidity and radiancyproved that gliclazide EPC were stable at high temperature, highhumidity and radiancy condition. The result that the character,content and release percentage of samples had not significantdiscrepancy which were deposited 6month at acceleratingcondition proved the term of validity could be two years withroutine package.The pharmacokinetics study of rabbits in vivo proved thatgliclazide EPC had significant character of extended-release invivo. The pharmacokinetics parameters of gliclazide EPC andgliclazide tablet :...