Drug-polyelectrolyte matrices as a strategy to increase gastric stability of rifampicin in fixed combination with isoniazid.

LUCCIANI GIACOBE LC; RAMIREZ RIGO MV; MANZO RH; OLIVERA ME

Rosario

Congreso; II Reunión Internacional de Ciencias Farmacéuticas (RICIFA); 2012

Universidad Nacional de Rosario

Introduction: Rifampicin (RIF) and Isoniazid (INH) are administered as fixed dose combination solid formulations to improve patient compliance in the treatment of tuberculosis1. In these formulations, RIF degrades in presence of INH under acidic conditions through a reaction involving formation of isonicotinyl hydrazine (IH), which results from an interaction of INH with 3-formylrifamycin (3FR), an acidic degradation product of RIF2. This shortcoming, added to the slow dissolution rate of RIF, is a major cause for substandard performance of RIF+INH fixed dose combinations. The goal of this study was to reduce IH formation by reducing co-exposition of RIF and INH in a fixed dose combination using drug-polyelectrolyte matrices. Materials and methods: Drug-polyelectrolyte matrixes of carboxymethylcellulose-RIF (CMC-RIF) and alginic acid-INH (AA-INH), containing 300 mg of RIF and 150 mg of INH, were prepared by compression of the particulate materials obtained by acid-base reaction. To obtain 3FR, RIF was subjected to hydrolysis in HCl 0.01N (pH=2) at room temperature. The precipitated solid was dissolved in ethyl acetate and washed with HCl. The organic phase was evaporated and the solid was characterized by a stability indicating HPLCUV technique3 and mass spectrometry. The same procedure was used to obtain IH but an excess of INH was added to RIF solution before hydrolysis. Calibration curves were constructed for RIF, INH, 3FR and IH. To assess release rate and stability CMC-RIF/AA-INH matrixes were subjected to dissolution (N=6) in 900 ml of buffer HCl/KCl pH=1.2 (37±0.5 °C) in apparatus 1 (100 rpm). At predetermined intervals 5 mL were withdrawn, diluted and stabilized with ascorbic acid and buffer solution to pH=7 before to be quantified. For comparison, RIFINAH® (immediate release capsules of RIF and INH in fixed dose combination) and RIFADIN® (immediate release capsules of RIF) +AA-INH were also studied. Results: HPLC-UV and mass spectrometry chromatograms accounted for 3FR and IH identity and purity. After immediate disintegration, RIF is rapidly released from CMC-RIF (101.41% in 10 min) while dissolution of INH from AA-INH is slow and controlled by a gel layer. As shown in table 1, dissolution efficiency of RIF and INH for CMC-RIF/AA-INH were respectively the highest and lowest of the series. As a result, IH levels were significantly lower when compared with RIFINAH®. In a similar way, the highest dissolution efficiency of INH in RIFINAH® conducted to twice the amount of IH. In RIFADIN®+AA-INH the IH levels are similar to CMC-RIF/ AA-INH but only a small percentage of RIF was released. The concentration of 3FR was low and similar in the three systems. Conclusions and discussion: These results underline the fact that minimization of contact between RIF and INH in acidic media results in less degradation of RIF to IH. Additionally, a higher bioavailability of RIF can also be expected due to the high dissolution efficiency from CMC-RIF. The systems CMC-RIF/AA-INH, in which RIF and INH are molecularly dispersed, are interesting to develop and improved bi-layer formulation for oral administration.