THE SAFETY ASSESSMENT OF RIFABUTIN NANOFORMULATIONS

Introduction. One of the ways to reduce the toxicity of antibiotics is to deliver the latter primarily to infected organs and tissues, which can be achieved by different drug delivery systems. Of particular interest are polymer nanoparticles that combine the properties of importance for carriers, such as stability and high capacity for a wide range of drugs. Objective: to determine the toxic, maximum tolerated, and lethal doses of rifabutin nanoformulations. Material and methods. Water-compatible injectable formulations were obtained by incorporation of rifabutin in polylactide nanoparticles (Rb-PLGA) or by its solubilization with human serum albumin (Rb-HSA). Experiments were carried out on male and female sexually mature outbred rats and mice, which were kept under standard vivarium conditions. Results. The rifabutin nanoformulations Rb-HSA and Rb-PLGA are suitable for the intravenous injection of colloidal nanosuspensions wherein the concentration of rifabutin is about 5 mg/ml, which is 25 times more than the solubility of the substance. According to the level of acute toxicity, rifabutin nanoformulations can be assigned to GOST 12.1.007-76, Class 3 (moderately toxic substances) and to Class 4 (lowly toxic substances) as classified by K.K. Sidorov. The major target organs of toxicity for drugs are the central nervous system, liver, and lung. After intravenous injection of high-dose Rb-PLGA in rats there was an increase in locomotor activity, which may be associated with a pseudoallergic reaction to the administration of a colloidal formulation. Conclusion. The application of a nanotechnological approach could obtain suitable intravenous nanoformulations of the insoluble antibiotic rifabutin. The results of a comprehensive study of acute toxicity parameters refer rifabutin nanoformulations to as moderately toxic substances (Class 3 according to GOST 12.1.007-76).