Development of a mafedine lyophilizate for parenteral use

Abstract

Introduction. Cerebrovascular disease (CVD) is the most important medical and social problem of modern neurology because they have the highest rates of morbidity, mortality and disablement in the population. The growing incidence of CVD as a result of an aging population worldwide requires the emergent development of therapeutics, diagnostic and preventive tools. However, the development of drugs for the treatment of brain diseases has limitations due to the presence of the blood-brain barrier, which protects the brain against most molecules from the bloodstream entering the central nervous system. At the St. Petersburg State Chemical Pharmaceutical University of the Ministry of Health of Russia the alpha-2 adrenergic agonist mafedine was synthesized, which has mild psychostimulant and anxiogenic effects and which may be used in the treatment of traumatic brain injury as a neuroprotective agent.Aim. The development of a dosage form of mafedine in order to improve its penetration into the central nervous system.Materials and methods. Mafedine (pharmaceutical substance) [6-oxo-1-phenyl-2-(phenylamino)-1,6-dihydropyrimidin-4-olate sodium] (St. Petersburg State Chemical-Pharmaceutical University of the Ministry of Health of Russia); lecithin, span-60, Tween-80, Poloxamer 188, mannitol, vitamin E, ascorbic acid, methylene chloride, dimethyl sulfoxide, acetonitrile, trifluoroacetic acid. The fine emulsion of mafedine was obtained by ultrasound. The dosage form of mafedine was obtained by freeze drying. Residual solvents were determined by gas chromatography. Quantitative analysis of mafedine was performed by high-performance liquid chromatography. Particle size and zeta potential of emulsion were determined on a Zetasizer Nano ZS.Results and discussion. Lyophilizate of mafedine was obtained and presenting as a light yellow porous, odorless tablet. The average mass of dry tablet was (0,17 ± 0,01) g with mafedine content is (26 ± 1) mg. The water content in the lyophilizate was 3,85 %. The quantity of methylene chloride in the lyophilizate correspond to the requirements for residual solvent content. The reconstitution time of lyophilizate into a primary emulsion was 3–5 seconds. The reconstituted dispersion was yellow, odorless, and did not break within 2 days during storage. The pH of the reconstituted emulsion was 7,34. The average particle size was (164,7 ± 6,4) nm, the zeta potential was –32 mV.Conclusion. The developed dosage form is stable according to its physicochemical and pharmaceutical characteristics and is suitable for experimental study on models as a neuroprotective and neurorehabilitation agent.

Keywords

• mafedine
• lyophilizate
• dosage form
• cryoprotectant
• mannitol
• neuroprotection