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PubMed2001

Preparation of prednisolone-appended alpha-, beta- and gamma-cyclodextrins: substitution at secondary hydroxyl groups and in vitro hydrolysis behavior.

The carboxyl group of prednisolone 21-hemisuccinate was conjugated to one of the hydroxyl groups of alpha-, beta-, and gamma-cyclodextrins using a coupling agent, carbonyldiimidazole. The direct coupling produced prednisolone-appended cyclodextrin conjugates in which the drug is selectively introduced at one of the secondary hydroxyl groups of cyclodextrins through an ester linkage. The aqueous solubility (> 50% w/v at 25 degrees C) of these conjugates was much higher than those of prednisolone and its 21-hemisuccinate. Prednisolone was slowly released from the conjugate: the percents of prednisolone and its hemisuccinates released from the alpha-, beta-, and gamma-cyclodextrin conjugates were 49, 57, and 85%, respectively, for 24-h. The release pathway is proposed to be via two fast acyl migrations between the 2- and 3-hydroxyl groups of cyclodextrins and between the 21- and 17-hydroxyl groups of prednisolone. The slow release of prednisolone from the ester conjugates was in sharp contrast to the fast release of the prednisolone amide conjugate reported previously. Because of relatively slow and/or site-specific release properties, the present prednisolone-appended cyclodextrin conjugates may be of value as an orally administered delayed-release and/or colon-specific prodrug.

Cyclodextrins↗
PubMed2006

Cyclodextrins found in enzyme- and heat-processed starch-containing foods.

Native and branched-type (glucosylated and maltosylated) cyclodextrins have been isolated and identified in different enzyme- and heat-processed starch-containing food products. Amylolytic enzyme-processed foods such as different beer samples, corn syrup of different dextrose equivalents, and thermally-processed food such as bread, contained minute amounts of different types of cyclodextrins. HPLC/MS Analyses of appropriately preconcentrated and purified food samples indicated the presence of parent beta- and gamma-cyclodextrins and all the three, alpha-, beta-, and gamma-branched cyclodextrins with different degrees of glycosylation. The data presented in this account are thought to be of practical importance in terms of both the analysis methods used for the cyclodextrins and the approval status of different cyclodextrin-containing food, cosmetic, and pharmaceutical products.

Amylases↗
PubMed2003

Multiple lithium exchange under lithium cationization of cyclodextrins.

Multiple lithium exchange is observed during electrospray ionization of alpha-, beta- and gamma-cyclodextrins from aqueous methanolic solution containing LiOH. Apart from [M + Li](+) and [M + nLi - (n - 1)H](+) ions, abundant multiply lithiated doubly charged ions corresponding to [M + nLi - (n - 2)H](2+) ions were observed. At least six lithium exchanges in alpha-cyclodextrin, seven in beta-cyclodextrin and eight in gamma-cyclodextrin were noted. The propensity of multiply lithiated doubly charged ions is much less in the open-ended maltoheptaose. It appears that during droplet or cluster formation and subsequent desolvation, LiOH trapped in the cavity of cyclodextrin reacts to form multiply lithiated ions. The singly charged [M + Li](+) and doubly charged [M + 2Li](2+) ions fragment by glycosidic cleavages, giving B series of ions, whereas the multiply lithiated ions fragment by cross ring cleavages ((2, 4)A or (O, 2)X) followed by glycosidic cleavage. From the tandem mass spectra, it appears that a maximum of two lithium exchanges occur in one sugar unit in these cyclodextrins.

Carbohydrate Conformation↗
PubMed2002

Self-association and cyclodextrin solubilization of drugs.

Phase-solubility diagrams are frequently used to calculate stoichiometry of drug/cyclodextrin complexes. Linear diagrams (A(L)-type systems) are thought to indicate that the complexes are first order with respect to cyclodextrin and first or higher order with respect to the drug. Positive deviation from linearity (A(P)-type systems) are thought to indicate formation of complexes that are first order with respect to the drug but second or higher order with respect to cyclodextrin. The phase solubility of several different compounds, i.e., cholesterol, ibuprofen, diflunisal, alprazolam, 17beta-estradiol and diethylstilbestrol, and various charged and uncharged cyclodextrins was investigated. Phase-solubility diagrams of cholesterol in aqueous cyclodextrin solutions were all of A(P) type. However, the phase-solubility diagrams obtained with charged cyclodextrins could not be fitted to complexes of second or higher order with respect to cyclodextrin. The phase-solubility diagrams of ibuprofen and diflunisal were of A(L) type with slope greater than unity indicating formation of 2:1 drug/cyclodextrin complexes. However, Job's plots and space filling docking studies indicated that 1:1 complexes were formed. These and other observations show that stoichiometry of drug/cyclodextrin complexes cannot be derived from simple phase-solubility studies. Furthermore, the results indicate that drug/cyclodextrin complexes can self-associate to form water-soluble aggregates, which then can further solubilize the drug through non-inclusion complexation.

Cyclodextrins↗
PubMed2006

The binding interaction of synthetic ozonide antimalarials with natural and modified beta-cyclodextrins.

The current studies were undertaken to explore the potential basis for a significant difference in the pharmacokinetic parameters after intravenous administration of a synthetic ozonide (OZ) antimalarial drug candidate (1) to rats when formulated in either Captisol (a sulfobutylether substituted beta-cyclodextrin derivative ((SBE)(7)-beta-CD)) or a buffered aqueous vehicle. It was suspected that the differences may have been due to failure of 1 to rapidly dissociate from the cyclodextrin complex in vivo, perhaps due to an unusually tight binding within the cyclodextrin cavity. To address this hypothesis, the binding of representative synthetic OZ antimalarial drug candidates (including 1) with beta-cyclodextrin and (SBE)(7)-beta-CD was investigated by isothermal titration calorimetry and phase solubility analysis. It was found that each of the OZ compounds exhibited an exceptionally high binding constant ( approximately 10(6)/M) with both Cyclodextrins (CD). The nature of the complexation was investigated by molecular dynamics simulations and NMR to explore the mechanisms, which generated such high binding constants. The data suggested that the most probable cause of the unusually high binding constants was a very close fit within the cyclodextrin cavity that resulted in more favourable changes in both the enthalpy and entropy of the binding interaction, compared to published data for other drugs.

Adamantane↗
PubMed2006

Phase solubility and inclusion complex of itraconazole with beta-cyclodextrin using supercritical carbon dioxide.

Phase-solubility techniques were used to assess the formation of inclusion complex between itraconazole and beta-cyclodextrin. The stability constant and free energies of transfer of itraconazole from aqueous solution to the cavity of beta-cyclodextrin were calculated. Itraconazole solubility in supercritical carbon dioxide (SC CO(2)) was measured at different temperatures and pressures. Drug formulations of itraconazole were prepared by complexation of the drug into beta-cyclodextrin using SC CO(2). Effects of temperature and pressure on inclusion yield of the prepared complexes were studied. The solvent-free inclusion complexes obtained from this method were characterized by UV spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy and compared to those obtained from physical mixing and coprecipitation methods. Results showed that beta-cyclodextrin significantly improved solubility of itraconazole in aqueous solutions. The free energies of transfer of itraconazole from aqueous solution to the cavity of beta-cyclodextrin increased negatively with increasing beta-cyclodextrin concentration. Higher inclusion yields were obtained in the SC CO(2) method compared to physical mixing and coprecipitation methods. Both temperature and pressure had significant effects on itraconazole solubility in SC CO(2) and the inclusion yield of the complex prepared by SC CO(2) method.

Calorimetry, Differential Scanning↗
PubMed1994

In vitro corneal permeability of diclofenac sodium in formulations containing cyclodextrins compared to the commercial product voltaren ophtha.

The influence of different cyclodextrin derivatives on the in vitro permeability of diclofenac sodium through pig cornea was investigated and compared to the commercial product Voltaren ophtha. (Hydroxypropyl)-beta-cyclodextrin (HP beta CD) and two amorphous methylated cyclodextrins with different degrees of substitution were used. In hemolysis studies on human erythrocytes, the hemolytic activity of the different cyclodextrins and the drug was assessed. It was shown that HP beta CD reveals the most favorable toxicological properties. A decrease in the hemolytic activity of diclofenac was yielded by adding HP beta CD. In the permeability experiments the dependency of the permeability coefficients and lag times on the type of cyclodextrin and pH of the solutions were examined. A solution containing HP beta CD buffered in the pH range 6.5 to 7 is proposed as a useful eye drop formulation. All cyclodextrin formulations showed advantages as compared to Voltaren ophtha.

Animals↗
PubMed1995

Theoretical studies on the structures of natural and alkylated cyclodextrins.

A series of semiempirical molecular orbital calculations using the AM1 method have been performed on isolated natural and alkylated alpha- and beta-cyclodextrins. For natural cyclodextrins, three geometries were considered: (i) molecular mechanics (MM2); (ii) AM1 fully optimized geometry; (iii) X-ray structures based on the experimental coordinates for heavy atoms with positions of hydrogen atoms optimized by AM1. Large differences between AM1 calculated properties of geometries i-iii were found. The differences between ii and iii are smaller and reflect the intermolecular, crystal packing forces. Comparisons are made between ii and iii and properties determined therefrom, such as cavity diameter, outer diameter, and height. In addition, AM1 semiempirical calculations were performed on the mixed (2,3,6) (hydroxyprophyl)-beta-cyclodextrin, 2,6-dimethyl-beta-cyclodextrin, and 2,6-bis(hydroxypropyl)-beta-cyclodextrin. The results were compared with the substituent effects on monoglucose. It was found that the alkylation and methyl and 2-(hydroxypropyl) functions on beta-cyclodextrin does not introduce significant steric hindrance.

Alkylation↗
PubMed2002

Interaction between a novel gemini surfactant and cyclodextrin: NMR and surface tension studies.

The interaction between cyclodextrins, hydroxypropyl-beta-cyclodextrin (HPbetaCD), and hydroxypropyl-gamma-cyclodextrin (HPgammaCD) and a novel type of nonionic surfactant synthesized from a fatty acid has been investigated. The so-called nonionic heterogemini surfactant (NIHG750) contains two hydrophobic groups and two hydrophilic groups, composed of one monomethyl ethylene glycol and one secondary OH group, CH(3)(CH(2))(7)-CH[OH]-CH[O(CH(2)CH(2)O)(16)CH(3)]-(CH(2))(7)CN. Surface tension studies indicate that micelles form in NIHG750 systems in both the presence and the absence of small quantities (molar ratio (HPbetaCD:NIHG750) approximately 2) of cyclodextrin (HPbetaCD or HPgammaCD). This gives NIHG surfactants an advantage compared to single-tailed nonionic surfactants, which generally lose their ability to micellize at much lower additions of cyclodextrins. However, the interaction between HPbetaCD and NIHG750 results in a disruption of the micellar aggregates at higher levels of cyclodextrin. In the dilute systems (C(NIHG750)<0.1% (w/w) approx) prolate-shaped mixed aggregates (HPbetaCD and NIHG750) form, with a short and a long axis of the order of 8-9 and 17-20 A, respectively. These gradually aggregate into micellar-like structures at higher concentrations. In the aqueous bulk phase HPbetaCD interacts mainly with the hydrophobic part of NIHG750, but both NMR and surface tension measurements indicate that an interaction with the hydrophilic part of NIHG750, as well, may exist. This interaction results in a better packing of NIHG750 at air-water interfaces. However, at elevated temperatures results from turbidity measurements indicate that NIHG750 and HPbetaCD interact mainly through the hydrophilic part of the surfactant; a decrease in the cloud point temperature is observed. The interaction of the larger cavity molecule, HPgammaCD, with NIHG750, on the other hand, seems to be relatively weak. The interaction, when present, most probably takes place through inclusion of the hydrophilic EO part of NIHG750. The results suggest that HPgammaCD in combination with NIHG750 is a better solubilizing system than with HPbetaCD.

Cyclodextrins↗
PubMed1994

Bacterial toxicity of cyclodextrins: luminuous Escherichia coli as a model.

The effect of various concentrations of natural and chemically modified cyclodextrins on the luminescence of an Escherichia coli suspension was investigated. All cyclodextrins were found to reduce, albeit to a varying degree, the luminescence level of the bacterial cells, thus suggesting a direct interaction between the cyclodextrins and cells. The inhibitory concentrations IC20 and IC50 of the various cyclodextrins were determined and taken to represent their toxicity effects upon the bacterial cells. Among the natural cyclodextrins, gamma- and alpha-CD interfered minimally with the bacterial luminescence and consequently were essentially non-toxic. The following descending order of toxicity was observed: beta-CD >> alpha-CD > gamma-CD. Among the chemically modified cyclodextrins, Dimeb was clearly toxic while Trimeb and the hydroxylated derivatives (hydroxypropyl-alpha-CD, HPACD; -beta-CD, HPBCD; -gamma-CD, HPGCD) were essentially non-toxic. The following descending order of toxicity was observed: Dimeb >> HPBCD > Trimeb > HPACD > HPGCD.

Cyclodextrins↗
PubMed1996

Energetics of cyclodextrin-induced dissociation of insulin.

The energetics of dissociation of bovine insulin in aqueous solution have been investigated by sensitive dilution microcalorimetry. Cyclodextrins increase dissociation of insulin oligomers in a manner consistent with their interaction with protein side chains. For example, assuming monomer-dimer equilibrium, in the absence of cyclodextrins the calorimetric dilution data (25 degrees C, pH 2.5) indicate a dimer dissociation constant (K(diss)) of about 12 microM and an endothermic dissociation enthalpy (delta H(diss) of +41 kJ mol-1. Addition of methyl-beta-cyclodextrin (up to 200 mM) makes dissociation significantly more endothermic (delta H(diss) = 79 kJ mol-1) and reduces the apparent dimer dissociation constant by more than two orders of magnitude (K(diss) approximately 1.7 mM). Qualitatively similar results are observed with alpha-cyclodextrin and other beta-cyclodextrin derivatives. Cyclodextrin-induced insulin dissociation is also observed at pH 7.4.

Animals↗
PubMed1993

Effects of cyclodextrins on the hydrolysis of ganglioside GM1 by acid beta-galactosidases.

The hydrolysis of ganglioside GM1 by acid beta-galactosidases was greatly enhanced by the inclusion of heptakis(2,6-di-O-methyl)-beta-cyclodextrin or alpha-cyclodextrin in the assay mixture. The other cyclodextrins tested were not effective. The extent of stimulation by these cyclodextrins was relatively smaller than those by taurodeoxycholate and taurochenodeoxycholate. However, it is suggested that stimulation by bile salts may be partly a reflection of the detergent effects of bile salts on GM1 and partly a reflection of the interaction between bile salts and the enzyme itself. On the other hand, the stimulation by the cyclodextrins seems to correlate to the formation of an inclusion complex between GM1 and cyclodextrin without enzyme protein interaction.

Animals↗
PubMed1986

Inclusion complexation of warfarin with cyclodextrins to improve some pharmaceutical characteristics.

Inclusion complexation of warfarin and alpha- or beta-cyclodextrins in water and in the solid phase were studied by a solubility method, a membrane permeation study, thin-layer chromatography, a dissolution study, IR spectroscopy and differential scanning calorimetry. The solubility of warfarin increased with the addition of cyclodextrins. The apparent stability constants of the alpha- and beta-cyclodextrin complexes are 10.29 M-1 and 148.88 M-1, respectively. The greater the stability constant of the inclusion complex the lesser the permeability of warfarin. Solid complexes of warfarin and alpha- or beta-cyclodextrins were obtained by freeze-drying. Clear differences in IR absorption spectra and DSC thermograms were observed between the inclusion complexes and physical mixtures. The dissolution rate of the freeze-dried warfarin-cyclodextrin complexes was increased about 1200-fold and 550-fold for alpha- and beta-cyclodextrins, respectively. The dissolution rate of warfarin was significantly improved by complex formation.

Calorimetry, Differential Scanning↗
PubMed1993

Protection of erythrocytes against hemolytic agents by cyclodextrin polysulfate.

Cyclodextrins generally exhibit hemolytic activity, some at concentrations as low as 1-10 mg/mL or lower. However, we found previously that a highly polysulfated cyclodextrin has no demonstrable hemolytic activity (Macarak et al., Biochem Pharmacol 42: 1502-1503, 1991). In the present study, we determined that, in fact, cyclodextrin polysulfate (CDS) actively protected erythrocytes against hemolysis induced by a wide spectrum of hemolytically active substances, ranging from pharmaceuticals, such as chlorpromazine, to solid suspensions of siliceous particles. The protective action was also effective against the hemolytic action of non-sulfated cyclodextrins. The similar kinetic responses of the erythrocytes to CDS protection against such chemically and structurally diverse hemolytic agents suggest a common mechanism involving the cell. Addition of the sulfated cyclodextrins to other cyclodextrin compounds used to solubilize poorly soluble pharmaceutical agents can extend the allowable maximum dosage without deleterious hemolytic action.

Cells, Cultured↗
PubMed2006

Thermodynamics of inclusion complexes of natural and modified cyclodextrins with propranolol in aqueous solution at 298 K.

The association constant, standard Gibbs energy, enthalpy and entropy for formation of inclusion complexes of propranolol, a beta-blocker, with various natural and modified cyclodextrins have been determined by calorimetry at 298 K. Both natural and methyl-modified alpha-cyclodextrins do not form complexes, while beta- and gamma-cyclodextrins do. Complexing ability of 2-hydroxypropyl-beta-cyclodextrin depends on the average substitution degree. For gamma-cyclodextrin, hydrophobic interactions play the major role in binding the guest. The association of natural and modified beta-cyclodextrins is ruled by van der Waals interactions and hydrogen bonding because of the tighter fit of the guest into the cavity. Decreasing pH determines increasingly negative values of the association enthalpies.

Calorimetry↗
PubMed2005

Enantioselective separation of rivastigmine by capillary electrophoresis with cyclodextrines.

Different beta-cyclodextrines (beta-cyclodextrin, heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfated beta-cyclodextrin) were investigated as additives for the enantioselective separation of the R-form from rivastigmine ((S)-N-ethyl-3-[(1-dimethylamino) ethyl]-N-methyl-phenyl carbamate), contained as impurity in this drug, which is used for the treatment of Alzheimer's disease. Electrophoresis was performed in an acidic background electrolyte (triethanolammonium phosphate, 75 mM, pH 2.5) with various concentrations of the additives. The electrophoretic mobilities measured are typical functions of the additive concentrations, with complex constants (obtained by fitting the appropriate binding curve on the data) ranging between about 180 and 770 M(-1). Best separation was obtained with 7.5 mM beta-cyclodextrin, with the R-enantiomer as impurity migrating before the main S-compound. Intra- and interday reproducibility (n = 6 and 18, respectively) of migration time and peak area was in the low percentage range, linearity of the calibration line for the quantitation of the impurity in the range between 2.3 and 50 microg/ml, expressed by the linear correlation coefficient, was 0.9998. The limits of detection and quantitation, respectively, were 0.7 and 2.3 microg/ml, corresponding to 0.05 and 0.15%, m/m of the R- relative to the S-compound. Analysis can be carried out at 18 degrees C in less than 19 min.

Electrophoresis, Capillary↗
PubMed2004

Improvement of gliquidone hypoglycaemic effect in rats by cyclodextrin formulations.

This study was carried out with the aim to optimize the pharmacological profile of gliquidone (GLI)--a poorly bioavailable hypoglycaemic agent sparingly soluble in water--through complexation with cyclodextrins. In order to increase the apparent solubility of GLI, two cyclodextrins, namely beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), were tested. The effect of cyclodextrin addition on the aqueous solubility of GLI was evaluated by the phase solubility method at different pH values. The amount of GLI in solution increased upon CD addition according to A type plots. The aqueous solubility of GLI was enhanced more at higher pH values and using HPbetaCD. On the basis of its performance, HPbetaCD was selected as host to prepare GLI oral formulations. GLI/HPbetaCD solid systems were prepared at 1:2 molar ratio by co-grinding, spray-drying and freeze-drying and characterized by DSC, FTIR and X-ray powder diffractometry. Powders were amorphous and showed an improved dissolution rate in comparison with GLI. GLI/HPbetaCD co-ground and freeze-dried products were the most interesting systems, since they dissolved 62 and 94% of total drug after 15 min, respectively. The hypoglycaemic effect of the most rapidly dissolving binary systems was evaluated after oral administration in fasted rats by measuring plasma glucose level in the time interval 0.5-36 h and compared to free GLI. Our findings indicate that cyclodextrin-containing formulations not only provide an onset of hypoglycaemic effect faster than GLI, but also enhance significantly the pharmacological effect due to improved biopharmaceutics. The association GLI/HPbetaCD allows a reduction of the oral dose and is expected to provide a better control over drug side effects, contributing to improve safety and efficacy of GLI.

Algorithms↗
PubMed2005

Evaluation of cyclodextrin solubilization of drugs.

The most common stoichiometry of drug/cyclodextrin complexes is 1:1, i.e. one drug molecule forms a complex with one cyclodextrin molecule, and the most common method for stoichiometric determination during formulation studies is the phase-solubility method. However, in recent years it has becoming increasingly clear that solubilizing effects of cyclodextrins are frequently due to the formation of multiple inclusion and non-inclusion complexes. The aqueous solubility of 38 different drugs was determined in pure aqueous solution, aqueous buffer solutions and aqueous cyclodextrin solutions, and the apparent stability constant (K1:1) of the 1:1 drug/cyclodextrin complexes calculated by the phase-solubility method. For poorly soluble drugs (aqueous solubility <0.1mM) the intrinsic solubility (S0) is in general much larger than the intercept of the phase-solubility diagram (Sint) resulting in non-linearity of otherwise linear (AL-type) phase-solubility diagram. This can lead to erroneous K(1:1)-values. A more accurate method for determination of the solubilizing efficiency of cyclodextrins is to determine their complexation efficiency (CE), i.e. the concentration ratio between cyclodextrin in a complex and free cyclodextrin. CE is calculated from the slope of the phase-solubility diagrams, it is independent of both S0 and Sint, and more reliable when the influences of different pharmaceutical excipients on the solubilization are being investigated.

Algorithms↗