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PubMed2004

Effect of beta-cyclodextrin on aroma release and flavor perception.

Binding and release of volatile compounds to and from beta-cyclodextrin were measured in model aqueous systems using static equilibrium headspace and dynamic headspace dilution. Beta-cyclodextrin decreased the static equilibrium headspace for some volatiles (e.g., ethyl octanoate and decanone) due to binding, but dilution studies demonstrated that binding was readily reversible. Dynamic release of hydrophobic volatile compounds was similar to that observed from emulsions. When beta-cyclodextrin was added to fat free yogurt, the release of a commercial lemon flavoring was modified and was similar to release from a regular fat yogurt. Sensory difference testing confirmed the release results. The data demonstrate that beta-cyclodextrin can be used to modify flavor delivery in both model and real systems; the effects in the latter are sensorially significant.

Cyclodextrins↗
PubMed1999

Thermodynamic analysis of the binding of a hepatoprotectant drug, thioctic acid, by beta-cyclodextrin.

Spectroscopic and thermodynamic studies of the binding of a hepatoprotectant drug, thioctic acid, by beta-cyclodextrin (beta-CD) have been carried out using UV-vis and pH potentiometric measurements. The UV-vis spectra and the pH of the aqueous solutions of the drug were measured (i) as a function of total drug concentration in the absence of cyclodextrin, and (ii) as a function of cyclodextrin concentration at constant drug concentration. The spectroscopic study was done at pH = 7 and 25 degrees C, while the potentiometric study was performed at several temperatures ranging from 15 to 40 degrees C. From the spectroscopic data, the molar absorption coefficient, epsilon, for the pure drug in aqueous media and the stoichiometry of the inclusion complex with beta-CD were determined. The dissociation constant, Ka, of the pure drug (which is a weak acid), and the association constants of the complexes formed by beta-cyclodextrin and both the nonionized (HTIO) and ionized (TIO-) forms of the drug, have been simultaneously determined at several temperatures from the pH data, without the necessity of working with buffered solutions. The nonionic forms are complexed by the beta-CD with higher affinity than their ionic counterparts. From the dependency of the association constants on temperature (van't Hoff analysis), the inclusion complexes formed by HTIO or TIO- and the beta-CD were found to be enthalpy driven, with a favorable enthalpic term dominant over an unfavorable entropic term. Both contributions were found to show a possible dependence with temperature (DeltaCpo not equal 0). This pattern may reveal the contribution of van der Waals interactions, hydrophobic effect, and solvent reorganization as the main driving forces promoting the complexation.

Cyclodextrins↗
PubMed1999

Application of supercritical carbon dioxide for the preparation of a piroxicam-beta-cyclodextrin inclusion compound.

PURPOSE: Piroxicam is a poorly soluble NSAID, whose solubility is enhanced when included into beta-cyclodextrin. The preparation of a piroxicam-beta-cyclodextrin inclusion compound using supercritical CO2 was investigated. METHODS: The solubility and the stability of piroxicam in supercritical CO2 were determined. Then, the influence of the temperature, the pressure and the time of exposure on the inclusion rate was studied. RESULTS: The solubility of piroxicam varied over a wide range depending on the temperature and pressure (from 0.006 to 1.500 mg/g of CO2). The temperature and the time of exposure had a great influence on the inclusion yield, while pressure did not and a complete inclusion was achieved by keeping a physical mixture of piroxicam and beta-cyclodextrin (1:2.5 mol/mol) for 6 hours at 150 degrees C and 15 MPa of CO2. This complex was characterized by Differential Scanning Calorimetry, differential solubility and Fourier Transform Infrared Spectrometry. CONCLUSIONS: Supercritical carbon dioxide may prove to be a novel useful complexation method of drugs into beta-cyclodextrin.

Calorimetry, Differential Scanning↗
PubMed2000

Continuous free flow electrophoresis for preparative chiral separations of piperoxan using sulfated beta-cyclodextrin.

Continuous free flow electrophoresis was investigated as a tool for the preparative chiral separation of piperoxan using a sulfated cyclodextrin chiral additive. In the absence of chiral additive, the sample stream was deflected cathodically. However, the presence of sulfated cyclodextrin in the run buffer caused anodic deflection and splitting of the sample stream into two streams, each enriched in one enantiomer. Although the sulfated cyclodextrin used was comprised of a mixture of homologues and isomers, this polydispersity did not seem to significantly impact band dispersion. Sample introduction rates ranged from approximately 0.9-7.2 mg h-1. Maximum resolution was 0.53, using an applied voltage of 220 V, buffer composition of 0.075% sulfated cyclodextrin, 7.6 mM citrate (pH 3), 4.5 degrees C.

Adrenergic alpha-Antagonists↗
PubMed1995

Catalyzed thermal isomerization between previtamin D3 and vitamin D3 via beta-cyclodextrin complexation.

To examine the effect of microenvironments on previtamin D3<==>vitamin D3 isomerization, we have conducted kinetic studies of the reaction in an aqueous solution of beta-cyclodextrin. Our results showed that at 5 degrees C, the forward (k1) and reverse (k2) rate constants for previtamin D3<==>vitamin D3 isomerization were increased by more than 40 and 600 times, respectively, compared with those in n-hexane (k1, 8.65 x 10(-6) versus 1.76 x 10(-7) s-1; k2, 8.48 x 10(-6) versus 1.40 x 10(-8) s-1), the fastest rate of this isomerization ever reported at this temperature. Thermodynamic studies revealed that the equilibrium constant of the reaction was significantly reduced by more than 12-fold when compared to that in n-hexane at 5 degrees C, and the percentage of vitamin D3 at equilibrium was increased as the temperature was increased in beta-cyclodextrin. When complexed with beta-cyclodextrin, the previtamin D3<==>vitamin D3 isomerization became endothermic (delta H zero = 13.05 kJ mol-1) in contrast to being exothermic in other media. We propose that thermodynamically unfavorable cZc conformers of previtamin D3 are stabilized by beta-cyclodextrin, and thus the rate of the isomerization is increased. This conformation-controlled process may play an important role in the modulation of previtamin D3<==>vitamin D3 endocrine system in vivo such as in the sea urchin.

Animals↗
PubMed1999

Properties of a cyclodextrin-specific, unusual porin from Klebsiella oxytoca.

The function of CymA, 1 of the 10 gene products involved in cyclodextrin uptake and metabolism by Klebsiella oxytoca, was characterized. CymA is essential for growth on cyclodextrins, but it can also complement the deficiency of a lamB (maltoporin) mutant of Escherichia coli for growth on linear maltodextrins, indicating that both cyclic and linear oligosaccharides are accepted as substrates. CymA was overproduced in E. coli and purified to apparent homogeneity. CymA is a component of the outer membrane, is processed from a signal peptide-containing precursor, and possesses a high content of antiparallel beta-sheet. Incorporation of CymA into lipid bilayers and conductance measurements revealed that it forms ion-permeable channels, which exhibit a substantial current noise. CymA-induced membrane conductance decreased considerably upon addition of alpha-cyclodextrin. Titration experiments allowed the calculation of a half-saturation constant, K(S), of 28 microM for its binding to CymA. CymA assembled in vitro to two-dimensionally crystalline tubular membranes, which, on electron microscopy, are characterized by a p1-related two-sided plane group. The crystallographic unit cell contains four monomeric CymA molecules showing a central pore. The lattice parameters are a = 16.1 nm, b = 3.8 nm, gamma = 93 degrees. CymA does not form trimeric complexes in lipid membranes and shows no tendency to trimerize in solution. CymA thus is an atypical porin with novel properties specialized to transfer cyclodextrins across the outer membrane.

Amino Acid Sequence↗
PubMed2004

Bioavailability and anticataract effects of a topical ocular drug delivery system containing disulfiram and hydroxypropyl-beta-cyclodextrin on selenite-treated rats.

PURPOSE: To test the effect of aqueous eye drops containing a high concentration of disulfiram (DSF) in a cyclodextrin- based drug delivery system. This system increases both the drug solubility in aqueous eye drops and the permeability of drug into the rabbit eye, by the formation of a drug-cyclodextrin inclusion complex, and so enhances the ocular bioavailability and anti-cataract effect of DSF. METHODS: The DSF and hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion (DSF/HPbetaCD) was studied using solubility methods, IR spectra and X-ray diffraction patterns. Suitable formulations for DSF eye drops were first identified by a trans-corneal penetration experiment in vitro. Finding a new p-bromophenacyl bromide (p-BPB) derivative reagent for diethyldithiocarbamic acid (DDC), which was a metabolite of DSF, allowed precise determination of the contents of DSF in aqueous humor. The ocular bioavailability was calculated by a transcorneal experiment of DSF in vivo. The lens opacity of a selenite-induced cataract in rat pups was monitored using a slit lamp with an anterior eye segment analysis system. RESULTS: The formation of DSF/HPbetaCD inclusion and the addition of hydroxypropylmethylcellulose (HPMC), as a penetration enhancer, played very important roles in increasing the ocular bioavailability of DSF. DSF eye drops, with a formulation of 1.26% (w/v) DSF/HPbetaCD inclusion, 0.01% (w/v) HPMC, 0.005% (w/v) benzalkonium chloride and 0.9% (w/v) sodium chloride, inhibited the onset of selenite-induced cataracts effectively. CONCLUSIONS: The cyclodextrin-based drug delivery system enhances both the solubility of DSF in aqueous eye drops and permeability of the drug into the rabbit eye. DSF ocular bioavailability in rabbit aqueous humor exceeded those reported for the DSF ophthalmic preparation. DSF eye drops effectively prevent the development of selenite-induced cataracts.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1990

Liquid chromatographic retention behavior and separation of chlorophenols on a beta-cyclodextrin bonded-phase column, Part I. Monoaromatic chlorophenols: retention behavior.

The liquid chromatographic retention behavior of nineteen monoaromatic chlorophenols on a beta-cyclodextrin bonded-phase column is investigated with respect to mobile phase composition, pH, temperature, and ionic strength. The mechanistic aspects of retention of these compounds on the beta-cyclodextrin column are studied and compared to other reversed-phase columns. Most of the evidence suggests that the unique selectivity of this column is due to inclusion complex formation, which provides the physical basis for the resolution of positional isomers. Under certain chromatographic conditions, however, the more highly chlorinated congeners appear to be excluded from the cyclodextrin cavity; in such cases a normal-phase chromatographic mechanism is postulated, based on the interaction of the substrates with the secondary hydroxyls on the periphery of the cyclodextrin moieties.

Chlorophenols↗
PubMed1994

Evidence for a polysaccharide-binding domain in Hormoconis resinae glucoamylase P: effects of its proteolytic removal on substrate specificity and inhibition by beta-cyclodextrin.

The hydrolysis of soluble starch, raw starch and pullulan with recombinant glucoamylase P from Hormoconis resinae was competitively inhibited by beta-cyclodextrin with apparent Ki values of 190 microM, 13 microM and 1.4 microM, respectively. Inhibition of dextran hydrolysis was partial: a maximum inhibition of 22% was achieved with a dextran concentration of 0.3 x Km and up to 4 mM beta-cyclodextrin. Hydrolysis of short oligosaccharides was not inhibited by beta-cyclodextrin at levels up to 20 mM. The enzyme bound to raw starch at pH 4.3 and 4 degrees C with an association constant of 3.4 x 10(5) M-1. Sequence alignment studies showed raw-starch-binding consensus amino acids in the C-terminal part of glucoamylase P. Partial hydrolysis with papain resulted in degradation of deglycosylated glucoamylase P into three fragments of 53, 51 and 14 kDa, respectively, as estimated by SDS-PAGE. The amino-terminal sequences of the 51 and 53 kDa fragments were identical with that of native glucoamylase P. The amino terminus of the 14 kDa fragment (Ser-Ser-X-Gln-Val-Ser-), corresponded to the sequence starting at residue 474 of intact glucoamylase P. Kinetic measurements of truncated glucoamylase P showed changes in the Km values of larger polysaccharides, but no changes in kcat values compared to the intact enzyme. It was concluded that glucoamylase P contains a catalytic core domain and a raw-starch-binding domain involved in inhibition of polysaccharide hydrolysis by beta-cyclodextrin.

Amino Acid Sequence↗
PubMed1984

The production of alpha-cyclodextrin by enzymatic degradation of starch.

The maximum concentration of alpha-cyclodextrin for the enzymatic degradation of starch is limited to about 13.5 g X 1(-1). By addition of decanol, the equilibrium of the reaction system can be shifted towards an alpha-cyclodextrin yield of 50% even at high substrate concentrations. The main variables of the decanol process--pH, temperature, substrate quality, substrate, and enzyme concentration--have been studied. The cyclodextrin-glycosyltransferase from Klebsiella pneumoniae M5 al can preferentially be employed at pH 6 to 8, temperatures of 40 to 50 degrees C and a decanol concentration of 0.1 kg-1 starch. The dextrose equivalent of starch is important with respect to the maximum achievable starch concentration, but not with respect to the reaction. Under process conditions, the rate of alpha-cyclodextrin evolution is limited by the enzymatic reaction and not by mass transfer of decanol into the aqueous phase.

Cyclodextrins↗
PubMed1996

In-vitro evaluation of biphenylyl acetic acid-beta-cyclodextrin conjugates as colon-targeting prodrugs: drug release behaviour in rat biological media.

Biphenylyl acetic acid was selectively conjugated to one of the primary hydroxyl groups of beta-cyclodextrin through an ester- or amide-linkage, and the physicochemical properties (aqueous solubility and hydrolysis) were investigated. Aqueous solubility of the conjugates was lower than those of either drug or parent beta-cyclodextrin. The amide conjugate was stable in aqueous solution and in rat biological fluids and gastrointestinal contents. The ester conjugate was hydrolysed to beta-cyclodextrin and biphenylyl acetic acid at moderate rates resulting in a V-shaped rate-pH profile in aqueous solution. The ester conjugate released the drug preferentially when incubated with the contents of caecum or colon, whereas no appreciable drug release was observed on incubation with contents of stomach or intestine, nor on incubation with intestinal or liver homogenates, nor on incubation with rat blood. The present results suggest that the ester-type drug conjugate of beta-cyclodextrin may serve as a colon-targeting prodrug.

Animals↗
PubMed1997

Intestinal safety of water-soluble beta-cyclodextrins in paediatric oral solutions of spironolactone: effects on human intestinal epithelial Caco-2 cells.

Effects of water-soluble beta-cyclodextrins (beta CDs) on intestinal epithelial integrity were investigated, to establish the safe use of these beta CDs as solubilizers of spironolactone in paediatric enteral solutions. Mannitol permeability and transepithelial resistance (TER) of human intestinal epithelial Caco-2 cell monolayers during exposure to dimethyl-beta-cyclodextrin (DM beta CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) and sulphobutyl ether beta-cyclodextrin (SBE beta CD) were followed. Staining methods were used to discern cells with damaged membranes and to study the integrity of cytoskeletal actin and tight junctions. Cytotoxicity of the beta CDs was tested by effects on intracellular dehydrogenase activity. Exposure to HP beta CD and SBE beta CD solutions had only minor effects on the integrity of Caco-2 cell monolayers. In contrast, DM beta CD clearly increased the epithelial permeability for the hydrophilic marker [14C]mannitol across Caco-2 monolayers, decreased TER and showed a dose-dependent cytotoxicity. According to staining, DM beta CD increased the permeability of the apical cell membrane without discernable effects on cytoskeletal actin. HP beta CD and SBE beta CD appear to be safe additives for use in enteral spironolactone preparations with respect to their acute local effects on epithelial integrity.

Administration, Oral↗
PubMed1997

Fluorimetric studies of the formation of riboflavin-beta-cyclodextrin inclusion complex: determination of the stability constant by use of a non-linear least-squares model.

The non-linear least-squares model for calculation of the stability constant (Kst) of a drug-cyclodextrin complex has been used in fluorimetry studies. Complexation of riboflavin with beta-cyclodextrin (beta-CyD) was monitored fluorimetrically by measuring changes in the fluorescence intensity of the vitamin in the presence of various amounts of beta-CyD. Formation of an inclusion complex was confirmed in the solid state by differential scanning calorimetry (DSC) and in aqueous solution by proton nuclear magnetic resonance spectroscopy (1H NMR). The experimental Kst value (2112 M-1) derived from the fluorimetry studies appeared to fit well to a 1:1 drug-to-cyclodextrin molar ratio according to the non-linear mathematical model. The model is particularly suitable for fluorescent compounds of which fluorescence intensity is influenced by the presence of cyclodextrins.

Calorimetry, Differential Scanning↗
PubMed1983

Heptakis(2,6-O-dimethyl)beta-cyclodextrin: a novel growth stimulant for Bordetella pertussis phase I.

The effect of cyclodextrins on the growth of Bordetella pertussis Tohama phase I in synthetic medium was evaluated. The addition of cyclodextrins, especially heptakis(2,6-O-dimethyl)beta-cyclodextrin (Me beta CD), to a complete synthetic medium such as Stainer-Scholte medium gave the same number of individual colonies and growth rates as those on Bordet-Gengou medium. Furthermore, with the addition of Me beta CD, growth inhibition by fatty acids such as oleic or palmitic acid was overcome and normal cell growth was observed. This modified Stainer-Scholte medium, designated as cyclodextrin solid medium (CSM), supported excellent growth of 20 lyophilized clinical isolates. Serotypes of the organisms after 10 passages on this CSM plate were not changed. These results suggest that Me beta CD is a significant growth stimulant and CSM is one of the most suitable synthetic media for culture of B. pertussis phase I.

Antigens, Bacterial↗
PubMed2004

Triamterene-beta-cyclodextrin systems: preparation, characterization and in vivo evaluation.

The purpose of this research was to improve the solubility and therefore dissolution and bioavailability of triamterene, a poorly water soluble diuretic, by complexation with beta-cyclodextrin. Triamterene has been reported to show low bioavailability after oral administration, with wide intersubject variation. This study presents the formulation of solid dispersions of triamterene with beta-cyclodextrin--by cogrinding, kneading, and coevaporation, using low pH conditions--and their characterization, evaluation of improvement in dissolution profiles, and in vivo advantage. Phase solubility studies indicated complex with possible stoichiometry of 1:1 and a stability constant of 167.67 M(-1). The solid dispersions were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, x-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the phenyl ring of triamterene within the nonpolar cavity of beta-cyclodextrin in the coevaporate. Remarkable improvement in in vitro drug release profiles in 0.1N HCl and pH 6.8 phosphate buffer was observed with all dispersions, especially the coevaporate. The coevaporate, when administered orally in rats, also exhibited improved in vivo activity, as measured by net sodium ion excretion, as compared with triamterene powder. Thus, coevaporation of the drug and beta-cyclodextrin from acidified alcohol provide the optimum condition for inclusion complexation to give a binary system with remarkable improvement in in vitro drug release profile and in vivo performance.

Animals↗
PubMed2000

Improvement of subcutaneous bioavailability of insulin by sulphobutyl ether beta-cyclodextrin in rats.

The objective of this study was to examine and compare how hydrophilic beta-cyclodextrin derivatives (beta-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-beta-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substitution of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8 h. The bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-CyD may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.

Animals↗
PubMed1999

Stability of diclofenac sodium in the inclusion complex with beta-cyclodextrin in the solid state.

The aim of this study was to characterize the thermal stability of diclofenac sodium both alone and in the inclusion complex with beta-cyclodextrin in the solid state, by determination of the number of the products of its decomposition, which were identified by GC-MS. The molar ratio of diclofenac sodium in the inclusion complex with beta-cyclodextrin was 1:1. The decomposition of diclofenac sodium both alone and in inclusion complex with beta-cyclodextrin occurred according to the first-order reaction. The HPLC of the samples thermostated at 80 degrees C gave five products of decomposition, which were identified by GC-MS. Diclofenac sodium in the inclusion complex with beta-cyclodextrin was more thermally stable. Thermal decomposition of diclofenac sodium leads to formation of five products, of which 4-chloro-10H-9-acridinone had not been reported previously in the literature.

Calorimetry, Differential Scanning↗
PubMed1989

Effect of the interaction of drug-beta-cyclodextrin complex with bile salts on the drug absorption from rat small intestinal lumen.

This investigation was concerned with the change of the bioavailability of a drug owing to the interaction of the drug-beta-cyclodextrin complex with bile salts in rat intestinal lumen. The absorption of sulfamethizole (SMZ) from rat intestinal lumen after administration of SMZ-beta-cyclodextrin complex was determined by a closed-loop method in the presence or absence of bile. The blood level of SMZ after administration of SMZ-beta-cyclodextrin complex was significantly decreased in comparison with that after administration of SMZ alone in bile duct-ligated rats. On the other hand, the blood level of SMZ after SMZ-beta-cyclodextrin administration in intact rats (bile duct non-ligated) or on the addition of sodium cholate was similar to the level in the case of SMZ alone. Thus, bile salts were found to act as a competing agent in the gastrointestinal tract.

Animals↗