Development of a Gastro-retentive Dosage Form of a New Promising Anti-tuberculosis Drug Macozinone
Authors: Nesterenko V. G. , Bolgarin R. N. , Rudoy B. A. , Salakhetdinov D. K. , Kazaishvili Yu. G. , Scherbakova V. S. , Nikitina N. A. , Medvedev Yu. V. , Fisher E. N. , Malashenko E. A. , Shohin I. E. 
Published: August 2021

Introduction. Due to increase in the frequency of detecting cases of tuberculosis caused by strains of mycobacteria with resistance not only to traditional, but also recently introduced into clinical circulation anti-tuberculosis drugs, it is urgent to search for and develop new drugs that can be effective against multidrug-resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains. One of the most promising classes of such compounds are fluorine derivatives of benzothiazinones, and particularly compound PBTZ169 (INN macozinone). This antibiotic has a high specificity against mycobacteria tuberculosis (M. tuberculosis), inhibiting one of the key enzymes of cell wall synthesis. However, macozinone as an active pharmaceutical ingredient has significant features of physical and chemical properties that hinder the development of oral dosage forms based on it. It is classified as class IV by BCS and is characterized by a very low solubility and lipophilicity, a pronounced dependence of dissolution rate on the pH of the medium, and very low bioavailability when taken orally.

Aim. To substantiate the target profile, critical quality attributes and to develop a prototype of an oral dosage form with modified release of macozinone, allowing to maximize its pharmacological activity.

Materials and methods. Using pharmaceutical substance macozinone hydrochloride and various excipients, experimental tablets with a dosage of 500 mg macozinone were developed. The influence of the composition of the media and the added excipients on the solubility of macozinone in various biorelevant media, the degree of swelling in the liquid and the degree of mucoadhesion of the experimental tablets to the mucus of the pig stomach were evaluated. The HPLC method was used to evaluate the kinetics of the release of the active substance.

Results and discussion. In this work, the expediency of creating macozinone-containing gastro-retentive dosage forms with a slow release of the active substance, the delay mechanism of which is provided by swelling and increased adhesion to the gastric mucosa, has been substantiated. Various tablet samples were experimentally tested in which the modification of the release of the active substance and the degree of swelling and mucoadhesion were varied by introducing various excipients into the formulations, including known swelling and bioadhesive matrix agents.

Conclusion. According to the results of the experiments, samples of high-dose (500 mg) swellable and mucoadhesive tablets created by the technology of two-stage granulation with the inclusion of macozinone - hydroxypropyl-beta-cyclodextrin mixtures in the primary granules and introduction of combinations of soluble and insoluble hydrophilic matrix agents into the intergranular space were recognized as the most promising for subsequent pharmacokinetic studies.