pH-Sensitive Glycyrrhizin Based Vesicles for Nifedipine Delivery

Abstract

Glycyrrhizic acid, or glycyrrhizin (GA), a major active component of licorice root, has been widely used in traditional Chinese and Japanese medicine since ancient times. However, only in the last decades has a novel and unusual property of the GA been discovered to form water-soluble, supramolecular complexes with a variety of lipophilic drugs. These complexes show significant advantages over other known delivery systems, in particular, due to strong pH sensitivity, the properties of GA self-associates. In the present study, a supramolecular complex formation of the hypotensive and antiarrhythmic drug nifedipine with GA has been studied at different pH values, corresponding to the different degrees of GA dissociation, including a fully dissociated state of GA. Both NMR experiments and molecular dynamics simulations demonstrate the existence of the nifedipine complex with GA at all dissociation states of GA. However, optical absorption experiments show the decrease of complex stability and solubility at pH > 6 when the GA molecule is fully deprotonated. It means the higher release rate of the drug in a neutral and basic environment compared with acid media. These results could form the basis of follow-up studies of GA self-associates as pH-controlled drug delivery systems.

Mechanism of the enhancing effect of glycyrrhizin on nifedipine penetration through a lipid membrane

“…Note that all measurements were performed for a fully protonated form of GA at pH = 3.5. However, recent results show that GA/NF complex exists over a wide range of solution pH [33] . The enlargement of GA/NF concentration from 0.64 g/l (corresponds to 0.5 mM GA) to 6.4 g/l (corresponds to 5 mM GA) results in permeation enhancement from 27 mg (free NF) up to 85 μg respectively during 2.5 hours.…”

“…Recent results obtained by O. Yu. Selyutina with coauthors show that the GA/NF complex exists over a wide range of solution pH [33] . In the present study, the solubility measurement was performed for a full protonated form of GA, the formation of stable associates of NF with the GA dimer was confirmed by MD simulation (see the next section “Unconstrained simulation of GA/NF complex”).…”

“…The membrane modifying ability of GA has been described recently [28] , [29] , [30] , [31] , [32] , [33] . Thus, an additional mechanism of GA’s influence on the drug bioavailability was suggested, namely, an increase in membrane permeability.…”

Photostabilization of ketoprofen by inclusion in glycyrrhizin micelles and gel nanoparticles

“…At pH value 46 GA micelles become unstable due to Coulomb repulsion; however, recent studies show that the supramolecular associates of some drugs with GA exists even at pH 6-7.4. [55][56][57] First, in this study, we attempted to incorporate KP molecules into GA micelles and gel nanoparticles in acidic (pH o 4) solution using NMR spectroscopy to monitor KP solubilization. Inclusion of KP in the GA micelles and gel nanoparticles results in the broadening of its NMR lines (Fig.…”

New Aspects of the Antioxidant Activity of Glycyrrhizin Revealed by the CIDNP Technique

“…Glycyrrhizin complexes significantly enhance drug solubility and bioavailability, so they are considered perspective drug delivery systems [ 19 ]. Furthermore, the membrane-modifying ability of glycyrrhizin has been demonstrated [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. In particular, molecular dynamics simulation shows a significant decrease in the energy barrier of drug penetration through the lipid bilayer in the presence of glycyrrhizin in model lipid membranes [ 31 , 32 ].…”