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PubMed1995

Solvent effects on chemical processes. 10. Solubility of alpha-cyclodextrin in binary aqueous-organic solvents: relationship to solid phase composition.

The equilibrium solubility at 25 degrees C of alpha-cyclodextrin was measured in several binary aqueous-organic solvent mixtures, the organic cosolvents being methanol, 2-propanol, ethylene glycol, and acetone. Solubility maxima were observed as the solvent composition was varied from pure water to pure cosolvent. The maximum in methanol systems was hardly detectable, but it was very pronounced in 2-propanol and acetone, and two maxima were seen in the ethylene glycol system. Karl Fischer analysis of the solid phase isolated from 2-propanol/water equilibrium systems showed that alpha-cyclodextrin hexahydrate is the stable form in water, whereas a solid phase containing three water molecules per molecule of alpha-cyclodextrin is the stable form in the presence of 2-propanol. The appearance of a solubility maximum in this system, and by extension presumably in the other cosolvent systems, is attributed to the existence of more than one stable solid phase of alpha-cyclodextrin.

Crystallization↗
PubMed1991

Modeling and conformation analysis of beta-cyclodextrin complexes.

A series of beta-cyclodextrin complexes containing various guest molecules was studied using computer-aided molecular modeling and conformation analysis techniques. The geometry of each complex was studied using crystallographic data. The positions of the glycosidic O4 atoms indicate that the beta-cyclodextrin molecules are elliptically distorted. This distortion can be related to the van der Waals volume of the guest molecules. This correlation is different for aromatic and non-aromatic guest compounds. Rigid body docking experiments demonstrated that in crystal structures the guest molecule occupies a position in the cavity of nearly minimum interaction energy when there are no other molecules having interactions with the guest molecule. From the crystallographic data several rules could be deduced which seem to determine the conformation of beta-cyclodextrin molecules in complexes. A procedure was developed to construct beta-cyclodextrin molecules that are able to encompass guest molecules having a given van der Waals volume.

Carbohydrate Conformation↗
PubMed1996

Molecular dynamics study of an alpha-cyclodextrin-phosphatidylinositol inclusion complex.

Cyclodextrins are cyclic oligosaccharides known for their ability to include substrate molecules in their hydrophobic cavity. Moreover, cyclodextrins show a hemolytic activity when mM concentrations are added to blood. This hemolysis is commonly interpreted as a massive dissociation of phospholipids from the cell membrane due to the formation of complexes with the cyclodextrins. In the literature, a complexation between alpha-cyclodextrin (alpha CD) and phosphatidylinositol (PI) specific to the inositol headgroup has been proposed. But the need for the detailed interaction mechanism between the two molecules motivated the present work based on molecular dynamics simulations. Investigation of long range electrostatic interactions shows that a mutual approach of the molecules is only possible when the primary hydroxyl side of alpha CD faces the inositol headgroup of PI. This orientation is also the most favourable from adiabatic-and free-energy profiles calculated along a reaction coordinate that leads to an inclusion of PI into alpha CD. For free energy simulations, partial hydration of the model has been used. A study of glycosidic bond dihedral angles in alpha CD shows an increase in dihedral fluctuations before complexation and a dihedral "freezing" once the complex is formed.

Carbohydrate Sequence↗
PubMed1991

Improved bioavailability from a spironolactone beta-cyclodextrin complex.

The relative bioavailabilty of spironolactone from a complex with beta-cyclodextrin has been evaluated. Capsules containing 100 mg micronised spironolactone powder were compared with 100 mg spironolactone beta-cyclodextrin complex in 8 healthy volunteers by a single dose, double blind, crossover pharmacokinetic study. Subjects were randomly allocated to each preparation and crossed over after 2 weeks. Relative bioavailability was assessed by the measurement of serum canrenone concentrations. The mean relative bioavailability of the spironolactone cyclodextrin complex, compared to the micronised spironolactone powder, was 233%. Statistical analysis (Wilcoxon signed rank test) revealed that this difference was significant with a mean area under the serum concentration time curve of 3.90 and 1.88 mg.h.l-1 for the complex and micronised spironolactone powder, respectively. Four of the volunteer also received a 100 mg spironolactone tablet (Aldactone) under identical conditions. Pharmacokinetic analysis revealed that the mean relative bioavailability of the spironolactone beta cyclodextrin complex and micronised powder when compared with spironolactone tablets (Aldactone) was 252% and 124%, respectively. There was no change in the canrenone elimination half lives of each subject.

Adult↗
PubMed1997

beta-Cyclodextrin derivatives as carriers to enhance the antiviral activity of an antisense oligonucleotide directed toward a coronavirus intergenic consensus sequence.

The ability of cyclodextrins to enhance the antiviral activity of a phosphodiester oligodeoxynucleotide has been investigated. A 18-mer oligodeoxynucleotide complementary to the initiation region of the mRNA coding for the spike protein and containing the intergenic consensus sequence of an enteric coronavirus has been tested for antiviral action against virus growth in human adenocarcinoma cells. The phosphodiester oligodeoxynucleotide only showed a limited effect on virus growth rate (from 12 to 34% viral inhibition in cells treated with 7.5 to 25 microM oligodeoxynucleotide, respectively, at a multiplicity of infection of 0.1 infectious particle per cell). In the same conditions, the phosphorothioate analogue exhibited stronger antiviral activity, the inhibition increased from 56 to 90%. The inhibitory effect of this analogue was antisense and sequence-specific. Northern blot analysis showed that the sequence-dependent mechanism of action appears to be the inhibition of mRNA transcription. We conclude that the coronavirus intergenic consensus sequence is a good target for an antisense oligonucleotide antiviral action. The properties of the phosphodiester oligonucleotide was improved after its complexation with cyclodextrins. The most important increase of the antiviral activity (90% inhibition) was obtained with only 7.5 microM oligonucleotide complexed to a cyclodextrin derivative, 6-deoxy-6-S-beta-D-galactopyranosyl-6-thio-cyclomalto-heptaose+ ++ in a molar ratio of 1:100. These studies suggest that the use of cyclodextrin derivatives as carrier for phosphodiester oligonucleotides delivery may be an effective method for increasing the therapeutic potential of these compounds in viral infections.

Cells, Cultured↗
PubMed1989

A spectrophotometric assay for the cyclization activity of cyclomaltohexaose (alpha-cyclodextrin) glucanotransferase.

A cyclomaltohexaose (alpha-cyclodextrin) determination method which is both highly reproducible and selective is described. It involves the formation of an inclusion complex between the cyclodextrin and methyl orange under conditions of low pH (1.2) and low temperature (16 degrees C) and is useful for the assay of cyclodextrin glucanotransferase activity. The formation of the inclusion complex causes a decrease in absorbance of the methyl orange solution and this is monitored at a wavelength of 505 nm. The decrease in absorbance is linearly correlated with the cyclomaltohexaose concentration in the range of 0.25 optical density unit and 0.30 mM cyclomaltohexaose. The specificity of the test for cyclomaltohexaose is high, with only limited interference by linear oligosaccharides and other cyclodextrins: cyclomaltoheptaose and cyclomaltooctaose cause absorbance variations of 16 and 5%, respectively, of the response of maltohexaose. The formation of the complex is instantaneous and the complex is stable in time, provided the temperature is constant. The presence of methyl orange does not hinder enzymatic activity determination. The reaction is stopped by acidification and absorbance is measured at the fixed temperature of 16 degrees C. Possible interferences inherent to the composition of the sample itself can be suppressed by running appropriate controls and calculating a corrected optical density. This colorimetric method is simple and should be versatile in assaying diverse cyclomaltohexaose glucanotransferase enzymes.

Azo Compounds↗
PubMed1995

Extending the scope of chiral separation of basic compounds by cyclodextrin-mediated capillary zone electrophoresis.

In a previous paper on cyclodextrin-mediated capillary zone electrophoresis, it was shown that the use of short-chain tetraalkylammonium cations leads to a reversal in the direction of the electroosmotic flow without an adverse effect on enantioselectivity. As a result, enantiomeric resolution of basic (cationic) compounds can be improved as the electroosmotic flow counteracts the migration of solute enantiomers. It is demonstrated in this report that the scope of chiral separation of basic compounds can be further extended by a combination of reversing the electroosmotic flow and enhancing enantioselectivity through the chemical modifications of beta-cyclodextrin. Therefore, beta-cyclodextrin and its derivatives were evaluated as chiral recognition agents for the chiral separations of 22 basic compounds with rather complex molecular structures. The differences in enantioselectivity displayed by beta-cyclodextrin and derivatives are discussed in order to achieve a better understanding of the chiral interactions involved in the discrimination of solute enantiomers.

Cyclodextrins↗
PubMed1987

Colorimetric determination of beta-cyclodextrin: two assay modifications based on molecular complexation of phenolphtalein.

The decolorization of phenolphtalein upon complexation to cyclodextrins was studied to measure beta-cyclodextrin concentrations. Several factors possibly affecting the self-life of the dye were tested. By making the assays in 0.1 M NaCO3 solution beta-cyclodextrin concentrations down to 6 microM (SNR = 2) could be determined while the practical assay range reached up to 0.06 mM. In this form the method was unaffected by acyclic oligosaccharides and directly applicable to cyclodextrin assays in complex starch hydrolyzates. The method was further modified to be used in a flow-injection analyzator and the results were comparable to those obtained by HPLC analyses after prepurification of the samples.

Autoanalysis↗
PubMed1991

Interaction of beta-cyclodextrin with the granular starch binding domain of glucoamylase.

The granular starch binding domain of glucoamylase 1 (EC 3.2.1.3 1,4-alpha-D-glucan glucohydrolase) binds two molecules of beta-cyclodextrin, with a dissociation constant (Kd) for the second ligand of 1.68 microM. The catalytic domain showed no interaction with beta-cyclodextrin. Beta-cyclodextrin competitively inhibited the adsorption of the binding domain onto granular starch with an inhibition constant (Ki) of 11.0 +/- 1.9 microM. The results show that beta-cyclodextrin binds to the binding domain of glucoamylase at the same site(s) as granular starch.

Aspergillus niger↗
PubMed1994

Analysis and modelling of the structures of beta-cyclodextrin complexes.

A systematic computer graphics study of all available beta-cyclodextrin crystal structures has been carried out specifically to aid in the modelling and design of beta-cyclodextrin-drug complexes. The analyses show that the basic conformation of the molecule remains constant among natural, mono-substituted and partially permethylated beta-cyclodextrins, with major changes observed only in the case of full permethylation. In all the structures, however, there are no significant perturbations caused by guest molecule inclusion. On the basis of these observations models are proposed for the structures of beta-cyclodextrin-indomethacin complexes, the principal features of which are shown to be consistent with the data obtained in 1H-NMR studies.

Carbohydrate Sequence↗
PubMed1991

HPLC and 1H-NMR study of chiral recognition in some thromboxane antagonists induced by beta-cyclodextrin.

The interaction of beta-cyclodextrin with a series of structurally related chiral thromboxane antagonists was investigated using NMR and RP-HPLC. HPLC studies used both a cyclodextrin bonded phase (Cyclobond I), and beta-cyclodextrin as a mobile phase additive with an achiral C8 column. Many of the compounds exhibited chiral recognition with beta-cyclodextrin in each technique, but only partial correlations between the three data sets were observed. HPLC and ROESY NMR data suggested the possibility of bimodal inclusion.

Chromatography, High Pressure Liquid↗
PubMed1988

Relative affinity of 5-methoxypsoralen and 8-methoxypsoralen towards beta-cyclodextrin: a fluorescence, circular dichroism and chromatographic study.

The relative affinity of 5-methoxypsoralen (5-MOP) and 8-methoxypsoralen (8-MOP) towards beta-cyclodextrin, a good model for the study of lipophilic interactions in biological systems and a potential drug carrier, has been investigated using spectroscopic and chromatographic methods. The fluorescence emission of 5-MOP in aqueous solution containing beta-cyclodextrin (10(-2) M) is found to be markedly blue shifted and enhanced by a factor of 6 whereas no significant changes are observed for 8-MOP. The existence of an induced circular dichroism is evidence for the formation of a 1:1 inclusion complex (association constant K = 400 +/- 50 M-1). Moreover, chromatographic results obtained with a beta-cyclodextrin linked stationary phase are consistent with our spectroscopic results and might have interesting analytical implications. These results clearly demonstrate that, in contrast to 8-MOP, 5-MOP exhibits a strong affinity for hydrophobic medium. Interesting pharmacological and analytical applications may result from the possible inclusion of psoralen derivatives into beta-cyclodextrin.

5-Methoxypsoralen↗
PubMed2005

Inclusion complexes of alpha- and gamma-cyclodextrins and the herbicide norflurazon: I. Preparation and characterisation. II. Enhanced solubilisation and removal from soils.

The interaction of norflurazon with alpha- and gamma-cyclodextrins (CDs) yielded the formation of inclusion complexes at a 1:1 stoichiometric ratio in solution and in the solid state. Apparent stability constants of 50.7+/-1.6 and 37+/-1.7 M(-1) and an increase in herbicide solubility by up to five and fourfold for alpha- and gamma-CD, respectively, were determined from the phase solubility diagrams at 25 degrees C in water. Three processing methods (kneading, spray-drying and vacuum evaporation) were used to prepare norflurazon-CD solid inclusion complexes, which were characterised by infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. A high increase in the norflurazon dissolution rate was obtained with all the solid complexes with gamma-CD, but when alpha-CD was used, only the solid system obtained after the vacuum evaporation process showed a higher dissolution rate. This finding is a first step in the development of new, environmentally sound formulations of norflurazon (NFL), due to the capacity for increasing its dissolution rate and hydrosolubility, and thus diminishing the use of organic solvents. On the other hand, the effect of alpha- and gamma-cyclodextrin on the solubility of norflurazon in solution was also considered as a way of modifying its behaviour in the soil environment. Desorption studies of NFL from soils in the presence of alpha- and gamma-cyclodextrin were carried out using a batch equilibration method. The results obtained showed that alpha- and gamma-cyclodextrin greatly increased the removal of norflurazon previously adsorbed, proving the potential use of these CDs for in situ remediation of pesticide-contaminated soils.

Adsorption↗
PubMed2006

Effect of preparation technique on the properties of liposomes encapsulating ketoprofen-cyclodextrin complexes aimed for transdermal delivery.

The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated in order to develop an effective topical formulation of ketoprofen. Equimolar complex of drug and hydroxypropyl-beta-cyclodextrin (HPbetaCyd) was added at different concentrations to the aqueous phase of liposomes consisting of phosphatidylcholine and cholesterol (60%/40%, w/w). Liposomes were prepared with different techniques, such as thin layer evaporation, freezing and thawing, extrusion through microporous membrane, and reverse phase evaporation method, obtaining, respectively, multi-lamellar vesicles (MLV), frozen and thawed MLV (FATMLV), small uni-lamellar vesicles (SUV) and large uni-lamellar vesicles (LUV). Size and morphology of the different types of liposomes were investigated by light scattering analysis, transmission electron microscopy, and confocal laser scanning microscopy, whereas drug entrapment efficiency was determined by dialysis experiments. Cyclodextrin complexation improved drug solubilization and allowed a strong improvement of its entrapment into the aqueous liposomal phase. Liposome preparation method and operating conditions clearly affected both liposome size and drug loading capacity. Encapsulation efficiency increased with increasing the complex concentration up to 10 mM, and was in the order MLV>LUV>SUV. An opposite behaviour was observed for FATMLV, probably due to the freezing phase required by such a preparation method, which reduced the complex solubility. Moreover, it was not possible to use higher complex concentrations, due to the destabilizing effect of cyclodextrins toward the liposomal membrane. Permeability studies of drug-HPbetaCyd complexes, directly in solution or incorporated in liposomes, performed across artificial membranes simulating the skin behaviour, highlighted, as expected, a prolonged release effect of liposomal formulations. Furthermore, the drug permeation rate depended on the vesicle characteristics and varied in the order: SUV>MLV=FATMLV>LUV. Therefore, the most suitable liposome preparation method can be suitably selected on the basis of drug encapsulation efficiency and/or desired drug release rate.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2005

How cyclodextrin incorporation affects the properties of protein-loaded PLGA-based microspheres: the case of insulin/hydroxypropyl-beta-cyclodextrin system.

The aim of this work was to study the influence of cyclodextrin (CD) incorporation on the properties of protein-loaded poly(lactide-co-glycolide) (PLGA) microspheres, with particular regards to protein release kinetics. To this purpose, insulin-loaded microspheres were prepared by spray-drying emulsion or solution formulations, with or without hydroxypropyl-beta-cyclodextrin (HPbetaCD), and fully characterized for encapsulation efficiency and release kinetics of both insulin and cyclodextrin. Homogeneous populations of spherical microparticles entrapping both insulin and HPbetaCD were obtained. In order to get an insight into insulin/HPbetaCD interactions occurring inside microspheres, Fourier transform infrared (FTIR) analysis in the Amide I region was performed. FTIR spectra of dried microspheres containing HPbetaCD showed a change in insulin secondary structure, attributed to the presence of insulin/HPbetaCD complexes within microspheres. Insulin release was affected by the presence of HPbetaCD depending on the initial formulation conditions. In the case of microspheres prepared from emulsion, cyclodextrin reduced only insulin burst, whereas in the case of microspheres obtained from solution, the overall insulin release rate was slowed down. Combining the release kinetics of HPbetaCD with the FTIR results on hydrated microspheres, it was concluded that the formation of insulin/HPbetaCD complexes inside microspheres is critical to decrease protein diffusivity in the polymer matrix and achieve an effective modulation of protein release rate.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2005

Comparative study on the inclusion behavior between meso-tetrakis(4-N-ethylpyridiniurmyl)porphyrin and beta-cyclodextrin derivatives.

5,10,15,20-Tetrakis(4-N-ethylpyridiniurmyl)porphyrin (TEPyP) formed 1:1 stoichiometry inclusion complexes with beta-cyclodextrin (beta-CD) and its derivatives including hydroxypropyl-beta-cyclodextrin (HP-beta-CD), sulfobutylether-beta-cyclodextrin (SBE-beta-CD) in basic aqueous solution. The supramolecular system was investigated by the methods of fluorescence, UV-vis absorption spectroscopy, nuclear magnetic resonance (NMR) technique. The inclusion ability of cyclodextrins exhibited remarkable difference for beta-CD, HP-beta-CD and SBE-beta-CD. Association constants as high as K=1.1 x 10(4) M(-1) in the case of HP-beta-CD/TEPyP and 2.0 x 10(5) M(-1) in the case of SBE-beta-CD/TEPyP complexes were determined, whereas a lower value (K=550 M(-1)) was given in the case of beta-CD/TEPyP. The results showed that hydrogen bonding and charge attraction play important roles in the processes of host-guest interaction. The interaction mechanism of inclusion processes could be explained by the analysis of NMR spectroscopy. The supramolecular assembly was formed. beta-CD and HP-beta-CD approached from the primary face of cavities of CDs.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

Synthesis of branched cyclomaltooligosaccharide carboxylic acids (cyclodextrin carboxylic acids) by microbial oxidation.

Novel branched cyclomaltooligosaccharide carboxylic acid (cyclodextrin carboxylic acid) derivatives were synthesized by microbial oxidation using Pseudogluconobacter saccharoketogenes to oxidize five types of branched cyclodextrins, including maltosyl beta-cyclodextrin (maltosyl-beta-CyD). For each novel cyclodextrin carboxylic acid derivative synthesized, the hydroxymethyl group of the terminal glucose residue in the branched part of the molecule was regiospecifically oxidized to a carboxyl group to give the corresponding uronic acid. In addition, the physicochemical properties of cyclomaltoheptaosyl-(6-->1)-alpha-D-glucopyranosyl-(4-->1)-alpha-D-glucopyranosiduronic acid (GUG-beta-CyD) (1) and its sodium salt were studied more extensively, as these compounds are most likely to have a practical application.

Alcohol Dehydrogenase↗
PubMed2001

The crystal structure of the 1:1 inclusion complex of beta-cyclodextrin with squaric acid.

The crystal and molecular structure of the 1:1 inclusion complex of beta-cyclodextrin (cyclomaltoheptaose) with squaric acid (3,4-dihydroxycyclobutene-1,2-dione) was determined by X-ray diffraction. The complex crystallizes in the monoclinic P2(1) space group and belongs to the monomeric cage-type, characterized by a herringbone-like packing motif. Co-crystallized water molecules are present on seven sites, of which six are fully occupied. The guest molecule is placed inside the beta-cyclodextrin cavity, perpendicular to the plane defined by the glycosidic O-4n atoms, and held in place by direct and water-mediated hydrogen bonds mainly involving symmetry-related beta-cyclodextrin molecules. The accommodation of the planar guest molecule into the beta-cyclodextrin cavity determines a significant distortion of the latter from the sevenfold symmetry.

Carbohydrate Conformation↗