The Research Of Compound Tramadol Sustained-release Pellets

The research was aiming at the preparation of compound tramadol 12h sustained-release pellets and validation in vivo,consisting of preparation methods for pellets, the sustained-release system of coated pellets, stability, pharmacokinetics. The results show: the sustained-release pellets exhibited a marked sustained-release property and principal drugs were released in vivo over 12h.A reversed-phase HPLC method was established for determination of drug content and accumulative release quantity. Preformulation studies illustrated that principal drugs can affect alternately, which implies they should be prepared separately. Inclusion complex of promethazine with p-cyclodextrin was made to improve the stability of promethazine.A single-factor design was employed to isolate critical parameters that influenced the yield of pellets by extrusion-spheronization method. The result of this study found that amount of water, spheronization speed and spheronization time had greater influences on the yield of pellets. Then, 23 full factorical design had been used to investigate the main effects and their interactive of amount of water, spheronization speed and spheronization time on the yield, sphericity and friability. Pellets with good sphericity, high yield and appropriate hardness was produced.Pellets were coated with aqueous dispersion(Eudragit NE30D)using mini-fluidized bed spray coater. The effects of process variables and formulation variables on coating pellets preparation were investigated. The results showed: the coated pellets had a marked sustained release property.The process variables were optimized as followed: 21~24癈 coating temperature, middle pressure of atomization air and l.0ml/min spray rate. The coating level, amount of pore-forming agent could alter the release rate of the drug. The stability of the preparation was investigated under 4500Lx light condition, 40癈, 60癈, 92.5% RH, 75% RH, 40癈 and 75% RH. The results showed that the preparation was stable.Using HPLC to determine the plasma drug concentration and using compound conventional capsule as the reference, the relative bioavailability and pharmacokinetics study of compound tramadol slow release capsule was perfomed in three healthy dogs. The AUC of compound conventional capsule and compound sustained-release capsule were tramadol 1168.52 ?163.14ng.mL-1.h , 1279.85 ?132.76ng.mL-1.h, promethazine 588.88 ?102.96ng.mL-1.h 606.52?5.90ng.mL-1.h, The Cmax and Tmax of compound conventional capsule were tramadol 136.67 ?7.42ngTnL'\ 2.02?.22h, promethazine 35.00 ?.30ng.mL-12.31?.34h, The Cmax and Tmax of compound slow release capsule were tramadol 97.01 ?3.16ng-mL-1 , 6.48 ?.34h, promethazine 20.67 + 1.45ng.mL-1A 6.02?.22h. The relative bioavailability of compound slow release capsule was 109.53% compared with tramadol and 103.00% compared with promethazine in compound conventional capsule. It was very significant between in vivo absorption and dissolution in vitro using Wagner-Nelson equation to calculate the in vivo absorption fraction. Consequently, sustained-release capsule dosed 2 times a day was expected to show a more efficiency than its reference dosed 3-4 times a day.