Synthesis of methotrexate-betulonic acid hybrids and evaluation of their effect on artificial and Caco-2 cell membranes.

An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids with a (tert-butoxycarbonylamino)-3,6-dioxa-8-octanamine (Boc-DOOA) linkage has been developed. Reaction of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-betulonamide with methotrexate resulted in a mixture of isomeric conjugates which were separated by column chromatography. Their structures and composition have been fully established by 1H NMR, 13C spectra, FAB mass spectrometry and elemental analysis. The identity of conjugates was confirmed by LC-MS data. Membranotropic properties of the new hybrids were assessed on the basis of their interactions with artificial lipid membranes by differential scanning calorimetry (DSC) method. The ability of the conjugates to penetrate Caco-2 cells is inferior to methotrexate. Probably, this is due to the increasing lipophilicity, the affinity of these hybrid molecules for the lipid bilayer increases, which is confirmed by experiments with artificial membranes.

Thermoresponsive cholesteric liquid-crystal systems doped with terpenoids as drug delivery systems for skin applications.

Stimuli-responsive and tunable soft-matter systems are an advanced class of materials applicable for drug delivery. Liquid crystals (LCs) are promising candidates as multifunctional materials that can respond to temperature, light or magnetic field. Particularly, ordering and physical properties of thermoresponsive LCs depend predominantly on temperature as external trigger. The current work addresses an elegant strategy to implement the anisotropic properties of thermoresponsive LCs with a view to extending their application for drug delivery. We firstly fabricated novel compositions with a thermotropic core based on natural products - cholesteryl esters and mono-/bicyclic terpenoids. The distinctive feature of aforementioned systems is their temperature-induced switchability of drug release by transition to the LC state, depending on the skin temperature. Their mesomorphic and optical behavior was characterized via differential scanning calorimetry and polarizing optical microscopy. Furthermore, we describe the dependence of helical pitch on LC formulation for various ternary cholesteric systems doped with terpenoids, suggesting that these stimuli-responsive chiral dopants are nominally untwisting. Data from fluorescence probe technique indicate that cholesteryl esters and terpenoids as essential components of those LC systems jointly disrupt the tight structure of phospholipid bilayer packing enabling the facilitated penetration of drugs. The potential of LC formulations was explored for several model drugs with diverse physicochemical properties by in vitro and ex vivo penetration tests using artificial membranes and full human skin. Our findings confirm the potential of LC systems for various applications in skin drug delivery.

Investigation of thioctic acid, magnesium stearate and pyridoxine hydrochloride compatibility.

To identify possible interactions of components in dosage forms, studies are usually carried out at the stage of pharmaceutical development. Such studies can predict compatibility of active pharmaceutical ingredients and excipients in order to optimize drug formulation and certain parameters of technological process. Compatibility of some components of a newly developed neuroprotective medicinal product Neuronucleos, namely, thioctic acid, pyridoxine hydrochloride, magnesium stearate and magnesium lactate, was studied by means of differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). No interactions were observed between thioctic acid and pyridoxine hydrochloride. Formation of an intermolecular complex between thioctic acid and magnesium stearate was established, in which this acid substitutes the crystalline water of magnesium stearate. No significant interactions were found for magnesium lactate with thioctic acid or magnesium stearate. Thus, pharmaceutical compatibility of the most of the tested Neuronucleos components was studied and established, with the only exception (thioctic acid with magnesium stearate). Moreover, the present study provides valuable information about thermal effects in a certain temperature range, which is important for setting the technological process parameters.

Suppressed ionic effect and low-frequency texture transitions in a cholesteric liquid crystal doped with graphene nanoplatelets.

We focus on investigating the dielectric behaviors and the low-frequency texture transitions in a cholesteric liquid crystal (CLC) doped with graphene nanoplatelets (GNPs) by means of dielectric spectroscopy and measurements of electro-optical responses. The experimental results indicate that incorporating GNPs at a content of 0.5 wt% into the CLC leads to significant suppression of ionic behaviors, as manifested by the reduction in ionic density, diffusivity, and relaxation frequency. In addition, the electro-optical properties of the GNP-doped CLC cell show the lowered operation voltage for the switching from the planar to focal conic state and the absence of the low-frequency focal-conic-to-uniform-lying-helix texture transition. Such results are attributable to the effects of GNPs as nuclei in the CLC medium, giving rise to the repression of the ionic and electrohydrodynamic effects.