Study On The Compatibility Of Anti-tuberculosis Drugs And Quality Control Of Its Enteric Tablets

Rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ) and ethambutol hydrochloride (ETB) comprise one kind of Fixed dose combination formulations (FDCs) recommended by WHO and IUATLD for the treatment of tuberculosis (TB).The clinical practice proved their effect on the drug-resistant strains, and they also improve the patients’ Compliance for less tablets taken. However, the bioavailability of RIF decreased significantly for the enhancement of INH on the degradation of RIF in acid and the unstability of the FDCs. A series researches on the causes of the unstability of FDCs were done, including the test of imputrities content of raw materials from different manufacturers for less impurities in the tablets, the incompatibility of four drugs, the compatibility between drugs and excipients and the influence of the processes of the tablets for more stable products. FDC enteric tablets were prepared to avoid the degradation in the acid in the stomach.The HPLC method was validated for the simultaneous analysis of three drugs, RIF, INH, PYZ, and five relative substances, Isonicotinic acid,1,2-isoicotinyl hydrazine(1,2-INH), 25-desacetyl rifampin(25-DR),3-formyl rifamycin SV(3-FR) and Rifampin qinone(RQ). Ethambutol copper (II) complex was applied for the quantitative analysis of ehtambutol hydrochloride with HPLC.Thermo-analysis was employed for the primary studies of the compatibility of four drugs and excipients. Granulation process was selected to avoid interaction of drugs.After being exposed to light, moisture, heat and buffers at different pH values, the stability of drugs and their preparations was researched by determining the amount of impurities.Applying the amount of impurity in raw materials, crystal forms and particle distribution as indexes, the raw materials from differents manufacturers were tested to minimize the initial impurities in tablets. The thermalanalysis, influence factors test and the stability in solutions with different pH were employed in the studies of compatibility of four drugs. There was incompatibility not only between RIF and INH, but also among four drugs, which showed clearly under wet or hot or acidic conditions.RIF was granulated separately to minimize the chance of interaction between drugs, with hydroscopic property and dissolution as indexes, the whole process of granulation was confirmed as:dry granulation of RIF, wet granulation of INH and PYZ, and wet granulation of ETB.The results of the compatibility between drugs and exicipients using thermoanalysis and heat accelerated test were that there was incompatibility with magnesium stearate and the red lake. Therefore, sodium stearyl fumarate was used as the lubricant and the coating color was white. Acryl-EZE(?)930 water system, Eudragit(?)L100-55 and AQOAT(?)AS-LG acetone solution were used for coating, which would investigate the influence of the coating materials and coating process on the stability of the tablets. The stability of the tablets in the blister package in both the accelerated condition and long-term condition were compared with the commercial tablets.Acryl-EZE(?)930 coated tablts were as stable as Eudragit(?)L100-55 coated tablets, which demonstrated that there was no negative affects on the stabililty of the tablets using water coating system.But AQOAT(?)AS-LG coated tablets was unstable under accelerated conditions, which indicated that AQOAT(?)AS-LG was not suitable to improve the stability of tablets.Kept under dry light-resistant condition at room tmeprature for four months, the stability of Acryl-EZE(?)930 coated tablets were more stable than the commercial ones, which indicated that the compatibility study and optimization of granulation process, coating system study above helped to improve the stability of FDC tablets.The studies of pharmacokinetics of RIF were performed after single oral administration of Acryl-EZE(?)930 coated enteric tablets and the commercial filmed tablets. The pharmacokinetic parameters of enteric tablets and commercial tablets were as below:t1/3 were 9.65±3.20h and 10.00±0.041 h, respectively. Tmax were 3.50±0.84h and 7.83±2.04h, respectively. Cmax were 34.51±6.19ng-mL-1and 32.84±6.92μg-mL-1,respectively. AUC0-t were 556.43±61.62 h·μg·mL-1 and 526.72±88.26 h·μg·mL-1,respectively. The relative bioavailability of the enteric tablets was 94.5±10.46% compared with commercial tablets.