Γ-cyclodextrin Complexes Research Articles

Size controlled fullerene nanoparticles prepared by guest exchange of γ-cyclodextrin complexes in water

Fullerene nanoparticles (nCx; x = 60 or 70) with a monodisperse size and morphology are obtained through guest exchange of a γ-cyclodextrin (γ-CD) complex.

γ-Cyclodextrin complexes with histidine: Theoretical study of the structure and energy

γ-Cyclodextrin (CD), histidine (His), and the CD—His complexes have been calculated by the DFT method. All calculations with full geometry optimization and normal mode calculations have been performed with GAUSSIAN-09 for LINUX. It has been shown that L-His is more strongly bound to γ-CD as compared with D-His, which is caused by specific features of hydrogen bonding. In the complex with L-His, the guest molecule is in the zwitterionic state, which is not inherent in the free histidine molecule. The calculated rovibrational and vibrational spectra of the complexes have been characterized.

Preparation and characterization of β-cyclodextrin inclusion complexes as a tool of a controlled antimicrobial release in whey protein edible films

Control release of eugenol and carvacrol is difficult to obtain even when WPI is used as a carrier. Active compounds cyclodextrin inclusion complexes may encourage molecular interaction intervening in their release. α-, β-, and γ-cyclodextrin (α-, β-, and γ-CD) complexes were prepared and added to WPI edible films. Inclusion/spray-drying process yield was low (<50%, weigh basis). β-CD was selected because it showed a higher retention for eugenol (50.4%, molar basis) and carvacrol (79.6%, molar basis). Protons that lie inside the β-CD cavity and aromatic rings protons from active compounds are involved in host–guest interaction. The initial molar ratio using during complex preparation was not maintained. The final stoichiometric ratio of β-CD:eugenol and β-CD:carvacrol was 1:0.5 and 1:0.7, respectively, showing a β-CD cavity preference for carvacrol. The study suggests that adding β-CD to the WPI matrix resulted in a decreased release rate in a food simulant medium (ethanol: water, 1:1, v/v) when there is an effective interaction between β-CD and active compound. This fact shows significance for delivery of antimicrobial compounds that must release gradually in time.

Rescuing compound bioactivity in a secondary cell-based screening by using γ-cyclodextrin as a molecular carrier.

In vitro primary screening for identifying bioactive compounds (inhibitors, activators or pharmacological chaperones) against a protein target results in the discovery of lead compounds that must be tested in cell-based efficacy secondary screenings. Very often lead compounds do not succeed because of an apparent low potency in cell assays, despite an excellent performance in primary screening. Primary and secondary screenings differ significantly according to the conditions and challenges the compounds must overcome in order to interact with their intended target. Cellular internalization and intracellular metabolism are some of the difficulties the compounds must confront and different strategies can be envisaged for minimizing that problem. Using a novel screening procedure we have identified 15 compounds inhibiting the hepatitis C NS3 protease in an allosteric fashion. After characterizing biophysically the interaction with the target, some of the compounds were not able to inhibit viral replication in cell assays. In order to overcome this obstacle and potentially improve cellular internalization three of these compounds were complexed with γ-cyclodextrin. Two of them showed a five- and 16-fold activity increase, compared to their activity when delivered as free compounds in solution (while γ-cyclodextrin did not show antiviral activity by itself). The most remarkable result came from a third compound that showed no antiviral activity in cell assays when delivered free in solution, but its γ-cyclodextrin complex exhibited a 50% effective concentration of 5 μM. Thus, the antiviral activity of these compounds can be significantly improved, even completely rescued, using γ-cyclodextrin as carrier molecule.

Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: Influence of pH and excipients

In effort to prepare an eye drop formulation of irbesartan, the effect of γ-cyclodextrin complexation on irbesartan solubilization in aqueous solutions was investigated. The optimum cyclodextrin concentration for formation of irbesartan/cyclodextrin inclusion complex was found to be 10% (w/v) and the solubility of ionized irbesartan/γ-cyclodextrin complex (at pH 7.2) was shown to be three fold greater than that of the unionized complex (at pH 4.3). The irbesartan flux through semipermeable membranes increased with increasing γ-cyclodextrin concentration at both pH values. However, the ionized complex displayed decrease in the drug permeation coefficient with increasing cyclodextrin concentration. The effect of four pharmaceutical excipients on the cyclodextrin solubilization was investigated. EDTA, hydroxypropyl methylcellulose, and tyloxapol increased complexation efficiency of γ-cyclodextrin while benzalkonium chloride had negligible effect. The largest solubilization was observed in the eye drop vehicle that contained all four excipients in addition to γ-cyclodextrin. Dynamic light scattering measurements disclosed that excipients had impact on size of complex aggregates and consequently on the drug flux through the semipermeable membranes. Complex of irbesartan/γ-cyclodextrin was characterized by FT-IR, 1H NMR, XRPD, and TEM techniques.

Thermodynamic Stability of [60]Fullerene and γ-Cyclodextrin Complex in Aqueous Solution: Free Energy Simulation

Using a supramolecular approach, water-soluble fullerenes were developed to increase the applicability of fullerenes in aqueous environments. γ-Cyclodextrin bicapped fullerene (C60·γ-CD) complex was proposed as one of the strong candidates to show high solubility and stability in aqueous solution. In this work, a series of free energy simulations of C60·γ-CD complex in both water and aqueous DMSO solution has been carried out to understand the effect of solvents on the thermodynamic stability of the complex. A high stability of the complex was observed in these solvents, although the stability was slightly reduced by the addition of DMSO to aqueous solution. The reduced stability in DMSO was illuminated by the change of complex structure, as well as solvation structure. The two-dimensional free energy map for the dissociation of the C60·γ-CD complex elucidated a possible pathway for a dissociation of single γ-CD from the C60·γ-CD complex. The information obtained on the molecular viewpoint might be useful to design a new stable water-soluble complex based on fullerene derivatives.

Development of eye drops containing antihypertensive drugs: formulation of aqueous irbesartan/γCD eye drops

Aqueous nanoparticulated eye drop formulations based on γ-cyclodextrin (γCD) complexes were developed and tested in vitro. Three antihypertensive drugs, i.e. enalapril maleate, irbesartan and verapamil HCl, that have been shown to possess IOP-lowering activity were selected for this study. All three drugs displayed Bs-type phase-solubility diagrams in aqueous γCD solutions and had relatively low affinity for γCD. Irbesartan was selected for further formulation development. The drug was relatively stable at pH 4.5 but somewhat less stable at physiologic pH. However, presence of γCD in the aqueous media enhanced the chemical stability of irbesartan. Aqueous γCD-based eye drop formulations containing 1% and 2% (w/v) irbesartan were prepared and the effect of pH on the particles size distribution and drug release investigated. Only ∼2% of the drug was in solution in the pH 4.5 formulations but up to 45% in the pH 7 formulations. The pH 7 formulations, where larger fraction of the drug was in solution, displayed somewhat greater drug permeation flux but much lower drug permeation coefficients than the pH 4.5 formulations. Dynamic light scattering studies indicated the faster permeation was due to formation of smaller particles in presence tyloxapol.

Antidiabetic effect of the α-lipoic acid γ-cyclodextrin complex.

In recent years, the number of patients suffering from diabetes mellitus has been increasing worldwide. In particular, type 2 diabetes mellitus, a lifestyle-related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and α-lipoic acid has been recognized for many years. In this study, we found that the α-lipoic acid γ-cyclodextrin complex exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, in this study, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKAy mice by using α-lipoic acid and the α-lipoic acid γ-cyclodextrin complex. Our results show that the α-lipoic acid γ-cyclodextrin complex strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we concluded that intake of the α-lipoic acid γ-cyclodextrin complex exerted an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise.

R-α lipoic acid γ-cyclodextrin complex increases energy expenditure: A 4-month feeding study in mice

ObjectiveA high-fat diet (HFD) affects energy expenditure in laboratory rodents. R-α lipoic acid cyclodextrin (RALA-CD) complex is a stable form of lipoic acid (LA) and may improve energy expenditure. The aim of this study was to determine the effect of RALA-CD on energy expenditure and underlying molecular targets in female laboratory mice. MethodsFemale C57BL/6J mice were fed a HFD containing 0.1% LA for about 16 wk. The effects on energy expenditure, gene and protein expression were assessed using indirect calorimetry, real-time reverse transcriptase polymerase chain reaction, and Western blot, respectively. ResultsSupplementing mice with RALA-CD resulted in a significant increase in energy expenditure. However, both RALA per se (without γ-cyclodextrin) and S-α lipoic acid cyclodextrin did not significantly alter energy expenditure. Furthermore RALA-CD changed expression of genes encoding proteins centrally involved in energy metabolism. Transcriptional key regulators sirtuin 3 and peroxisome proliferator-activated receptor-γ, coactivator 1 alpha, as well as thyroid related enzyme type 2 iodothyronine deiodinase were up-regulated in brown adipose tissue (BAT) of RALA-CD–fed mice. Importantly, mRNA and/or protein expression of downstream effectors uncoupling protein (Ucp) 1 and 3 also were elevated in BAT from RALA-CD-supplemented mice. ConclusionOverall, present data suggest that RALA-CD is a regulator of energy expenditure in laboratory mice.

Cyclodextrin complexed [60]fullerene derivatives with high levels of photodynamic activity by long wavelength excitation.

We have evaluated the photodynamic activities of C60 derivative·γ-cyclodextrin (γ-CDx) complexes and demonstrated that they were significantly higher than those of the pristine C60 and C70·γ-CDx complexes under photoirradiation at long wavelengths (610-720 nm), which represent the optimal wavelengths for photodynamic therapy (PDT). In particular, the cationic C60 derivative·γ-CDx complex had the highest photodynamic ability because the complex possessed the ability to generate high levels of (1)O2 and provided a higher level of intracellular uptake. The photodynamic activity of this complex was greater than that of photofrin, which is the most widely used of the known clinical photosensitizers. These findings therefore provide a significant level of information toward the optimization of molecular design strategies for the synthesis of fullerene derivatives for PDT.

Effect of 18β-glycyrrhetinic acid and hydroxypropyl γcyclodextrin complex on indomethacin-induced small intestinal injury in mice

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury is a serious clinical event with recent advances of diagnostic technologies, but a successful therapeutic method to treat such injuries is still lacking. Licorice, a traditional herbal medicine, and its derivatives have been widely used for the treatment of a variety of diseases due to their extensive biological actions. However, it is unknown whether these derivatives have an effect on NSAIDs-induced small intestinal damage. Previously, the anti-inflammatory effects of three compounds extracted from the licorice root, glycyrrhizin, 18β-glycyrrhetinic acid, and dipotassium glycyrrhizinate, were compared in vitro cell culture. The most prominent inhibitory effect on the tumor necrosis factor-α (TNF-α) production was observed with the administration of 18β-glycyrrhetinic acid as an active metabolite of glycyrrhizin. In this study, a complex compound of 18β-glycyrrhetinic acid and hydroxypropyl γcyclodextrin was examined to improve the oral bioavailability. After administration of this complex to indomethacin treated mice, a significantly high plasma concentration of 18β-glycyrrhetinic acid was detected using the tandem mass spectrometry coupled with the HPLC. Furthermore, the complex form of 18β-glycyrrhetinic acid and hydroxypropyl γcyclodextrin reduced mRNA expressions of TNF-α, interleukin (IL)-1β, and IL-6, which was histologically confirmed in the improvement of indomethacin-induced small intestinal damage. These results suggest that the complex of 18β-glycyrrhetinic acid and hydroxypropyl γcyclodextrin has the potential therapeutic value for preventing the adverse effects of indomethacin-induced small intestinal injury.

Titanocene / cyclodextrin supramolecular systems: a theoretical approach

BackgroundRecently, various metallocenes were synthesized and analyzed by biological activity point of view (such as antiproliferative properties): ruthenocenes, cobaltoceniums, titanocenes, zirconocenes, vanadocenes, niobocenes, molibdocenes etc. Two main disadvantages of metallocenes are the poor hydrosolubility and the hydrolytic instability. These problems could be resolved in two ways: synthetically modifying the structure or finding new formulations with enhanced properties. The aqueous solubility of metallocenes with cytostatic activities could be enhanced by molecular encapsulation in cyclodextrins, as well as the hydrolytic instability of these compounds could be reduced.ResultsThis study presents a theoretical approach on the nanoencapsulation of a series of titanocenes with cytotoxic activity in α-, β-, and γ-cyclodextrin. The HyperChem 5.11 package was used for building and molecular modelling of titanocene and cyclodextrin structures, as well as for titanocene/cyclodextrin complex optimization. For titanocene/cyclodextrin complex optimization experiments, the titanocene and cyclodextrin structures in minimal energy conformations were set up at various distances and positions between molecules (molecular mechanics functionality, MM+). The best interaction between titanocene structures and cyclodextrins was obtained in the case of β- and γ-cyclodextrin, having the hydrophobic moieties oriented to the secondary face of cyclodextrin. The hydrophobicity of titanocenes (logP) correlate with the titanocene-cyclodextrin interaction parameters, especially with the titanocene-cyclodextrin interaction energy; the compatible geometry and the interaction energy denote that the titanocene/β- and γ-cyclodextrin complex can be achieved. Valuable quantitative structure-activity relationships (QSARs) were also obtained in the titanocene class by using the same logP as the main parameter for the in vitro cytotoxic activity against HeLa, K562, and Fem-x cell lines.ConclusionsAccording to our theoretical study, the titanocene/cyclodextrin inclusion compounds can be obtained (high interaction energy; the encapsulation is energetically favourable). Further, the most hydrophobic compounds are better encapsulated in β- and γ-cyclodextrin molecules and are more stable (from energetically point of view) in comparison with α-cyclodextrin case. This study suggests that the titanocene / β- and γ-cyclodextrin complexes (or synthetically modified cyclodextrins with higher water solubility) could be experimentally synthesized and could have enhanced cytotoxic activity and even lower toxicity.

Enhancement of Diastereoselectivity in Photodimerization of Alkyl 2-Naphthoates with Chiral Auxiliaries via Inclusion within γ-Cyclodextrin Cavities

Irradiations of alkyl 2-naphthoates are known to result in four isomeric "cubane-like" photodimers: anti(HH)-2, syn(HH)-2, anti(HT)-2, and syn(HT)-2 where the anti(HH)-2, anti(HT)-2, and syn(HT)-2 consist of pairs of diastereomers. Here, chiral auxiliary and chiral microreactor strategies have been combined to achieve high diastereoselectivity in photodimerizations of an enantiomeric pair of 2-naphthoates with (R)- and (S)-1-methoxycarbonylethyl esters as chiral auxiliaries (1R and 1S). Thus, irradiations of their γ-cyclodextrin (γ-CD) complexes have been conducted. Fluorescence, IR, and NMR spectra of both enantiomers of 1 demonstrate that their γ-CD complexes are mainly 2:2 with the molecules of 1 in head-to-head orientations. Irradiation of the complexes in the solid state mainly resulted in anti(HH)-2. The absolute configuration of each diastereomer of anti(HH)-2 has been established for the first time here. The diastereomeric excesses (de's) of anti(HH)-2 from 1R and 1S were 94% and 86%, respectively. These de's are much higher than those found from irradiations in solution (55% for 1R and 1S), where the opposite diastereomeric form is in excess! Calculations of the energies of various conformations of the head-to-head 2:2 inclusion complexes were performed using the PM3 approach. The predicted major diastereomers based on the calculation are consistent with those found experimentally.

Glucose Recognition by a Supramolecular Complex of Boronic Acid Fluorophore with Boronic Acid-Modified Cyclodextrin in Water

A boronic acid fluorophore (C1-APB)/boronic acid-modified γ-cyclodextrin (3-PB-γ-CyD) complex as a supramolecular sensor has been designed for selective glucose recognition in water. The fluorescent response behavior of the C1-APB/3-PB-γ-CyD complex under various pH conditions revealed that a C1-APB/3-PB-γ-CyD complex solution containing glucose showed a large increase in the fluorescence intensity under alkaline pH conditions. In contrast, only small increases in the fluorescence intensity were noted for fructose and without sugar solutions. The observed response selectivity for the C1-APB/3-PB-γ-CyD complex was on the order of glucose >> galactose, mannose > fructose. The evidence on a large value of the inclusion constant (K(L·CyD) = 6.5 × 10(3) M(-1)), a marked broadening of the (1)H NMR spectra, and an enhancement of induced circular dichloism (ICD) intensity for the C1-APB/3-PB-γ-CyD complex by glucose binding supported the multi-point interaction of the C1-APB/3-PB-γ-CyD complex with glucose. These results demonstrated that the C1-APB/3-PB-γ-CyD complex functioned as an efficient supramolecular sensor for selective glucose recognition in water.

Pseudorotaxane structure of a fullerene derivative—cyclodextrin 1 : 2 complex

X-Ray crystallography revealed that the C(60) derivative·γ-cyclodextrin (γ-CDx) complex has a pseudorotaxane structure and the structure of the crystal clarified the importance of multi-point hydrogen bonds between two γ-CDxs for stabilising the 3·γ-CDx complex.

Formation of CoQ10 reduced form by mixing CoQ10 oxidized form γCD complex and vitamin C in powder

We have already reported the enhancement of the stability and bioavailability of coenzyme Q10 (CoQ10) oxidized form by γ-cyclodextrin (γCD) complexation. In a series of the studies, we investigated an easy and economical conversion of CoQ10 oxidized form to its reduced form in complex powder, using inexpensive vitamin C (VC) as the reductant. CoQ10 oxidized form or its γCD complex and VC were physically mixed at the molar ratio of 1:0 to 1:50. The mixtures were stored at 60 °C and 75% RH. The sampling was made at certain interval, and both CoQ10 oxidized and reduced form contents were measured by high performance liquid chromatography (HPLC). The result shows that the conversion ratio to CoQ10 reduced form in γCD complex was significantly higher than that of non-inclusion compound (ca. 80% versus ca. 30% at the maximum). It was also confirmed that CoQ10 reduced form in γCD complex remains as stable as its oxidized form in γCD complex. Free radical scavenging potential of partially reduced CoQ10–γCD complex was assayed with 1,1-diphenyl-2-picrylhydrazyl (DPPH).

Optimisation of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes

This study aims to develop and characterise a beclomethasone diproprionate:γ-cyclodextrin (BDP:γ-CYD) complex and to optimise the variables on the spray-drying process, in order to obtain a powder with the most suitable characteristics for lung delivery. The spray-dried powder – in a mass ratio of 2:5 (BDP:γ-CYD) – was physically mixed with three carriers of different particle sizes and in different ratios. Particle-size distribution, shape and morphology, moisture content, and uniformity in BDP content of formulations were studied. In vitro aerolisation behaviour of the formulations was evaluated using the Rotahaler, and the performance was characterised based on the uniformity of emitted dose and aerodynamic particle-size distribution (respirable fraction (RF), as a percentage of nominal dose (RFN) and emitted dose (RFE)). The most suitable conditions for the preparation of BDP:γ-CYD complexes were obtained with the solution flow of 5 ml/min, T in of 70 °C and T out of 50 °C. Statistically significant differences in the aerodynamic performances were obtained for formulations containing BDP:γ-CYD complexes prepared using different solution flows and different T in ( p < 0.05). RFN and RFE vary in direct proportion with T in, while an inverse relationship was observed for the solution flow. A direct correlation between the RFE and the T out was identified. Performance of the formulations was compared with an established commercial product (Beclotaide Rotacaps 100 μg) with improved performance of RF: formulations with respitose carrier attained RFN and RFE twofold greater, and formulations based on 63–90 μm fraction lactose and trehalose achieved a threefold improvement; also, all formulations showed that the percentage of dose of BDP deposited in the “oropharynx” compartment was reduced to half.

Direct and short-time uptake of [70]fullerene into the cell membrane using an exchange reaction from a [70]fullerene–γ-cyclodextrin complex and the resulting photodynamic activity

[70]Fullerene (C70) was directly incorporated into the cell membrane using an exchange reaction from a C70-gamma-cyclodextrin (gamma-CDx) complex within 10 min and the incorporated C70 acted as a photodynamic sensitiser for a cancer cell.

Cyclodextrin Controlled Release of Poorly Water-Soluble Drugs from Hydrogels

The effect of 2-hydroxypropyl-β-cyclodextrin and γ-cyclodextrin on the release of ibuprofen, ketoprofen and prednisolone was studied. Stability constants calculated for inclusion complexes show size dependence for complexes with both cyclodextrins. Hydrogels were prepared by ultraviolet irradiation and release of each model drug was studied. For drugs formulated using cyclodextrins an increase in the achievable concentration and in the release from hydrogels was obtained due to increased solubility, although the solubility of all γ-cyclodextrin complexes was limited. The Load also was increased by adjusting pH for the acidic drugs and this exceeds the increase obtained with γ-cyclodextrin addition.

Assessment of coenzyme Q10 absorption using an in vitro digestion-Caco-2 cell model

The feasibility of using a coupled in vitro digestion-Caco-2 cell uptake as a model for examining the digestive stability and absorption of coenzyme Q10 (CoQ10) from a variety of commercially available CoQ10 products was examined. The products were first subjected to simulated digestion to mimic their passage through the GI tract to generate micelles containing CoQ10, and the micelle fractions added to monolayers of Caco-2 cells to determine CoQ10 uptake. The data demonstrate enhanced uptake of CoQ10 from formulations containing solubilized forms of CoQ10 and also from a CoQ10–γ-cyclodextrin complex as compared with pure CoQ10 powder or tablets based on CoQ10 powder. The CoQ10 uptake by the cells was correlated with the extent of micellarization of CoQ10 during simulated digestion. Most of CoQ10 taken up by the cells was converted to ubiquinol either during or following uptake. The data also indicate a correlation between in vitro dissolution of CoQ10 products and uptake of CoQ10 by Caco-2 cells. Thus, this study demonstrates the utility of coupled in vitro digestion-Caco-2 cell model as a cost-effective screening tool that will provide useful information for the optimal design of human trials to assess the bioavailability of CoQ10 and also other bioactive compounds.