In vitro toxic evaluation of two gliptins and their main impurities of synthesis.

BACKGROUND: The presence of impurities in some drugs may compromise the safety and efficacy of the patient's treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively). METHODS: MTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated. RESULTS: Cytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 µM of sitagliptin and 10 µM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations. CONCLUSIONS: This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.

Diphenyl diselenide-loaded nanocapsules: preparation and biological distribution.

Over the past years, organoselenium compounds have been aimed as targets of interest in organic synthesis. Diphenyl diselenide [(PhSe)2] is an important example of this class showing several pharmacological properties. However, the poor water-solubility and its low oral bioavailability may be considered an obstruction for the clinical utility of this compound. For this reason, the use of nanocapsules is a prominent approach to increase the bioavailability of lipophylic molecules. This study aims to prepare diphenyl diselenide-loaded nanocapsules with two different concentrations, by interfacial deposition of the preformed polymer in order to develop a system to improve its oral bioavailability. The drug-loaded nanocapsules with 1.56 and 5 mg ml−1 and unloaded nanocapsule suspensions presented macroscopic homogeneous aspect, as well as submicronic sizes, low polydispersity, negative zeta potentials and slightly acid or neutral pH values. The biological tests of selenium distribution in different tissues of mice show a higher bioavailability of the (PhSe)2 nanocapsules when compared with the free (PhSe)2, both administered by per oral route at the dose of 50 mg/kg, showing a prominent influence of the nanocarries systems for biological properties of this organochalcogenium compound.