Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе

Introduction. Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs.

Aim. Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form – a dispersible tablet for preparation of oral solution.

Materials and methods. Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated.

Results. The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) – from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) – from 16.8 to 29 mg/l.

It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.5¥10^-6 cm/s in the forward direction from the apical to basolateral cell membrane, and 1.5¥10^-6 cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented.

Discussion. The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented.

Conclusion. In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.