Biopharmaceutical studies of a novel sedative sublingual lozenge based on glycine and tryptophan: A rationale for mucoadhesive agent selection.

Effective sedative drugs are in great demand due to increasing incidence of nervous disorders. The present work was aimed to develop a novel sublingual sedative drug based on glycine and L-tryptophan amino acids. Carbopol and different hydroxypropyl methylcellulose species were alternatively tested as mucoadhesive agents intended to prolong tryptophan sublingual release time. A model lipid medium of fully hydrated L-α-dimyristoylphosphatidylcholine was used for optimal mucoadhesive agents selection. Simultaneous processes of drug release and diffusion in lipid medium were first investigated involving both experimental and theoretical approaches. Individual substances, their selected combinations as well as different drug formulations were consecutively examined. Application of kinetic differential scanning calorimetry method allowed us to reveal a number of specific drug-excipient effects. Lactose was found to essentially facilitate tryptophan release and provide its ability to get into the bloodstream simultaneously with glycine, which is necessary to achieve glycine-tryptophan synergism. Introduction of a mucoadhesive agent into the formulation was shown to change kinetics of drug-membrane interactions variously depending on viscosity grade. Among the mucoadhesive agents, hydroxypropyl methylcellulose species K4M and E4M were shown to further accelerate drug release, therefore they were selected as optimal. Thus, effectiveness of the novel sedative drug was provided by including some excipients, such as lactose and the selected mucoadhesive agent species. A dynamic mathematical model was developed properly describing release and diffusion in lipid medium of various drug substances. Our study clearly showed applicability of a lipid medium to meet challenges such as drug-excipient interactions and optimization of drug formulations.

Preparation and in-vivo evaluation of cytochrome-C-containing liposomes.

This study investigates the development of a method for obtaining cytochrome C-containing liposomes (LS-Cyt), and evaluates their stability and specific activity. LS-Cyt were intended for the therapy of ophthalmic diseases. LS-Cyt were prepared by high pressure homogenization technique and lyophilized to obtain freeze-dried LS-Cyt. It was proposed to use anionic phospholipid- dipalmitoylphosphatidylglycerol (DPPG-Na) and phosphatidylcholine (PC) in a nanoparticulate composition. Were investigated various concentrations of lactose and trehalose as cryoprotectants. Samples with a lactose concentration of 6% showed the best results in terms of the emulsion formation time, encapsulation and preservation of nanosize. The main technological parameters for the obtained freeze-dried LS-Cyt were encapsulation of no less than 95% of cytochrome C (Cyt C), particle size of 140-170 nm, pH of 6.85±0.1, osmolarity of 330±3 mOsmol/kg, a lysophosphatidylcholine content (LPC) of 0.65±0.05 % of the total of lipids. Stability of the freeze-dried LS-Cyt during storage was established. The freeze-dried LS-Cyt was kept for 1 year in a light protected place at the temperature of -15 °C. No changes in the composition of LS-Cyt samples were detected over the observation period. Preclinical in-vivo research was conducted, namely the evaluation of specific activity on the model of the penetrating corneal injury. It was established that use of LS-Cyt contributes to a more rapid process of tissue regeneration and reduction of the inflammatory response in comparison with a non-liposomal dosage form.