Study On Sustained Release Tablets And Controlled Release Tablets Of Sirolimus

Sirolimus（SRL） is a novel antirejection drug with potent immunosuppressive activity, which has been used as a widespread drug for organ transplantatan patients and some autoimmune diseases such as rheumatoid arthritis, lupus erythematosus and psoriasis vulgaris. It was reported that hyperlipidemia caused by the narrow therapeutic window (4～8ng·ml^-1) was the main adverse effect of SRL, and the incidence was about 44%. Meanwhile, the incidence increased with the blood drug level increased. Thus, the thesis aimed at preparing a sustained-release tablet to decrease the C_max, the risk of hyperlipidemia, the exposure of drug, and to keep the blood drug level smooth.High-performance liquid chromatography method （HPLC） was developed for the determination of SRL physicochemical properties, content and drug release in vitro.The absorption kinetics of sirolimus at different intestine segments in rats were investigated. The absorption rate constants （K_a） at duodenum, jejunum, ileum and colon were 0.1967, 0.1577, 0.1220 and 0.0827h^-1 respectively, and they decreased in order. The K_a values at different drug concentrations (2.0, 5.0, 10 and 20μg·ml^-1) were 0.2461, 0.1866, 0.2145 and 0.2316 h^-1, respectively. The K_a values at different pH （5.4, 6.8, 7.4） were 0.2792, 0.2974 and 0.2852h^-1, respectively. The absorption kinetics was not influenced by the concentration and pH of the drug solution, and the absorption kinetic of sirolimus at rat intestine was a first-order process with the passive diffusion mechanism.The influence of different kinds of carriers and proportions of drug-carrier on the dissolution of SRL was examined. Finally, F68 was chose as the optimal carrier. When the ratio of drug and carrier was 1:10, the solubility of SRL was improved from 0.3μg·ml^-1 to 27.29μg·ml^-1. The cumulative dissolution was 100% in 60 minutes. X-ray powder diffraction analysis exhibited that the solid dispersion of SRL-F68 was in an amorphous form. And the DSC curves proved that the thermal characteristic of SRL was sheltered after forming the solid dispersion with F68.SRL matrix sustained-release tablets （MST） were prepared based on the solid dispersion using power direct compression method, and the hydroxypropyl methycelluse （HPMC） was used to make the tablets. The effects of many factors including formulation and technique on the release behavior of tablets were investigated. Based on the results of single factor tests, an optimal self-prepared MST which contained 30% HPMC K4M, 2% lactose and MCC was definite. The result showed that self-prepared MST had good release behavior in vitro. The mechanism of drug release included matrix erosion and drug diffusion.In the study of mono-layer macromolecular polymers osmotic pump controlled-release tablets （MOPT）, Polyephylene oxide（PEO） and NaCl were selected as the main materials to make the tablet core, cellulose acetate（CA） and polyethylene glycol 400（PEG400） were selected as the coating materials and acetone was employed as the coating medium. The factors such as composition of tablet core, coating membrane, technology of preparing tablet and the condition of drug release on the in vitro release behavior of MOPT were also investigated. Based on the single-factor, amount of NaCl, weight of coating film and amount of PEG 400 were selected as the causal factors. The orthogonal design test was carried out to optimize the formulation. The optimal self-prepared MOPT contained that PEO （Mw20000） 30mg, NaCl 70mg, the weight of coating film 12mg, and PEG400 12%. The result showed that self-prepared MOPT had good release behavior in vitro and was accorded with zero order equation（r=0.9954）.With the commercial tablet as the reference, the pharmacokinetic study of self-prepared MST was performed in six Beagle dogs. With crossover design, microparticle enzyme immuno assay（MEIA） was applied to determine the drug concentrations in whole blood of dogs that had been administered with single dose （1mg per tablet） . The pharmacokinetic parameters of the test and reference tablets were as follows: AUC (ng·h·ml^-1) were 83.8±9.9 and 82.1±13.8; C_max(ng·ml^-1) were 4.74±0.585 and 14.0±2.37; T_max（h） were 4.00±0.00 and 0.833±0.118 separately. The relative bioavailability was 102.1%. Bioequivalent judgment indicated that these two dosage forms were bioequivalent. The results of judgment indicated that the in vitro release of self-prepared MST was well correlative with absorption fraction in vivo （r=0.9836）.