MAINTENANCE OF THERAPEUTICALLY ACTIVE LEVELS OF ISONIAZID FOR PROLONGED PERIODS IN RABBITS AFTER A SINGLE IMPLANT OF BIODEGRADABLE POLYMER

Setting: Poor patient compliance is the serious limiting factor in the chemotherapy of tuberculosis. Objective: To solve this problem we have been developing depot-drug delivery of antimycobacterial drugs. Earlier studies with mice using isoniazid in polylactic-co-glycolic acid (PLGA) co-polymer have shown that a single implant of the polymer could ensure sustained levels of free isoniazid for up to 8 weeks. Similar studies were now undertaken in rabbits. Design: The biodegradable PLGA polymer rods containing isoniazid were implanted on the back of the rabbits under anesthesia in an isoniazid dose of 90 mg/kg. Concentrations of isoniazid and acetylisoniazid in serum and urine were determined by the high-performance liquid chromatography (HPLC) method at close intervals up to 96 h to study the burst-size, and later at weekly intervals up to 9 weeks to study the sustained levels. Results and conclusions: There was no abnormal release of isoniazid in the earlier periods. Concentrations of isoniazid greater-than-or-equal-to 0.2 mug/ml were found both in serum and urine up to 63 days after implant. Urine specimen obtained at 6 weeks after giving the implant inhibited the growth of Mycobacterium tuberculosis in vitro as measured by the radiometric (Bactec) method. These findings in non-rodent animal species confirm the usefulness of the depot-drug delivery method of drug administration and warrant hopes for the successful treatment of tuberculosis avoiding the problem of non-compliance.