Studies On Rifampicin And Isoniazid Enteric-coated Tablets

Rifampicin（RIF）, isoniazid（INH）, pyraziamide（PYZ） and ethambutol hydrochloride （ETB） are the most effective drugs of choice for the treatment of tuberculosis at present. In recent years, to increase patient compliance, the World Health Organization（WHO） and the intemational Union Against Tuberculosis and Lung Disease（IUATLD） encourage the use of fixed-dose combination formulations （FDCs） that ensures ingestion of all the components of the therapy. By preventing monotherapy and by facilitating the delivery of correct drug doses, FDCs are expected to reduce the risk of emergence of drug resistant TB. However, R/F is often reported to have bioavailability problem in FDCs that raise the question of therapeutic failure of the current treatment. The probable reason for the poor bioavailability of RIF from FDCs may be that RIF degrades faster in the presence of INH trader acid conditions, which results from an interaction of INH with 3-formylrifamycin, an acid degradation product of RIF by the first-order reaction. Therefore, RIF and INH enteric-coated tablets were systematic designed and prepared.In the systematic preformulation study, the physicochemical properties of RIF and INH were investigated. The results showed that the apparent solubility and o/w partition coefficient of RIF and INH under the physiological pH range of 1.0～8.0 at 37℃are both somewhat pH dependent. INH was almost stable during 24 h under each physiological pH, while RIF had a great decomposition under stomach acid conditions and was rapidly lost in the presence of INH. There was also somewhat decomposition for INH due to interaction with RIF. The results of stress testing showed that light, humidity and high temperature had little effect on the appearance and content of RIF and INH. Furthermore, UV spectrophotometry was developed and validated for the vitro release determination of RIK Different HPLC-UV methods were applied to detect the dissolution of INH and the content of RIF and INH, as well as the plasma concentration of RIF in dogs respectively. A specific LC-ESI-MS method has been developed for quantification of INH in dog plasma. The methods mentioned above are accurate, liable, convenient and rapid, which all fit the requirements of analysis.Based on the results of single-factor tests about RIF and INH core tablets, the amounts of different excipients were set. The core formulation was optimized on the basis of three factors and three levels orthogonal design by evaluating the cumulative dissolution percent of RIF in pH 6.8 PBS in 15 min. RIF and INH core tablets were prepared according to the best components and preparing condition. Comparing the dissolution rate of RIF and INH in different media between self-made core tablets and several commercial formulations containing RIF and INH separately （as reference tablets）, the dissolution rates of RIF and INH from the former were both faster than those from the latter. Different kinds of enteric-coated material such as Eudragit（?） L30D-55, Kollicoat（?） MAE 30 DP and ACRYL-EZE（?） and various coating levels were investigated during the experiment. At last, we chose the ACRYL-EZE（?） as enteric-coated material and the coating level of core tablets was 8%（w/w）. The stability of accelerated testing showed that RIF and INH enteric-coated tablets were stable, well quality-controlled and met the purpose and requirement of dosage form design.With two-crossover design, the pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied comparing with the reference tablets. The t_1/2, T_max, C_max and AUC_0-48 of RIF in both reference and test tablets were （7.58±1.65） h and （8.22±2.29） h, （3.17±1.40） and （7.33±4.80） h, （21.19±4.54）μg·mL^-1 and （18.97±1.47）μg·mL^-1, （304.77±42.27）μg·h·mL^-1 and （353.79±31.63）μg·h·mL^-1 respectively. The t_1/2, T_max, C_max and AUC_0-48 of INH in both reference and test tablets were （2.88±0.96） h and （4.45±3.56） h, （1.33±0.52） and （3.17±1.60） h, （3901.29±1706.67） ng·mL^-1 and （3113.03±1892.89） ng·mL^-1, （17137.46±8587.41） ng·h·mL^-1 and （19618.61±10568.02） ng·h·mL^-1 respectively. The relative bioavailability of RIF and INH were （117.32±13.25） % and （113.26±9.77） %. The results of analysis of variance and two one-sided t-test demonstrated that the two dosage forms were not bioequivalent.