Studying of membranes affinity for auxiliary substances and pharmacologically active ingredients by methods of fluorescent and spin probes

Abstract

The aim of the study was a comparative research of the phosphatidylcholine liposomes affinity for some hydrophilic non­aqueous solvents: propylene glycol (PG), polyethylene glycol (PEG) with mol. m. 400 and 1500 (PEG­400 and PEG­1500), which are used to create soft dosage forms as excipients. The dissociation constant (Cd) of non­aqueous solvents of PG and PEG: PEG­400 and PEG­1500 with phosphatidylcholine liposome membranes was graphically analyzed in the inverse coordinates based on results of fluorescent probes method. It was found that Cd is 2,5 M for propylene glycol and Cd = 4 • 10­1 M for PEG­400. An analysis of the electron­paramagnetic resonance spectra parameters in reverse coordinates showed that the Cd for PEG­1500 is 10­1 M. The effect of propylene glycol and PEG­400 in liposome membranes was studied. Propylene glycol and PEG­400 bind efficiently to the liposome membrane, displacing the fluorescent probe from the membrane into water. This may be one of the mechanisms of the influence of PG and PEG­400 on bioavailability, when pharmacologically active ingredients (FAI) can be displaced into water by excipient molecules, slowing down the absorption process of FAI. The introduction of PEG­400 into a suspension of liposomes leads to a decrease in the packing density of phospholipids in the membranes, which can resulf to change in the permeability of cell membranes and increase the bioavailability of FAI. The action of PG on membranes is milder than PEG­400. Obviously, in the absorption zone of the FAI on the membrane, the process of absorption of low molecular weight auxiliary substances, for example, nonaqueous solvents, takes place in parallel. In this case, the absorption of lipophilic FAI can occur surrounded by solvents (excipients), which leads to an increase in the bioavailability of FAI. When competing for binding sites on biological membranes of cell surfaces between FAI and non­aqueous solvents, the affinity of solvents lower by several orders of magnitude is compensated by a large number of solvents in a soft dosage form compared with FAI. It has been shown that the mechanism of biocompatibility increasing by PEG is the ability of their molecules (due to compaction (spiralization) or the expansion of molecules) to take the optimal conformation of the structure, providing their hydrophobic or polar groups for optimal binding to nanoparticles, medicinal substances, and biological objects. These results, together with data on Cd for various medicinal substances, will help to assess and predict the degree of competition between FAI and excipients on membranes in dosage forms and predict changes in the bioavailability of drugs.