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PubMed2004

Inclusion complexes of paclitaxel and oligo(ethylenediamino) bridged bis(beta-cyclodextrin)s: solubilization and antitumor activity.

The inclusion complexation behavior of paclitaxel with a series of oligo(ethylenediamino) bridged bis(beta-cyclodextrin)s possessing bridge chains in different length (1-4) has been investigated in order to improve the water solubility of paclitaxel. It is found that only the long-tethered bis(beta-cyclodextrin)s 1 and 2 can form the inclusion complexes with paclitaxel, which are characterized by NMR, SEM, XRD, FT-IR, TG-DTA, DSC, and microcalorimetry technology. The results obtained show that bis(beta-cyclodextrin)s 1 and 2 are able to solubilize paclitaxel to high levels up to 2 and 0.9 mg/mL, respectively. The high complex stability of bis(beta-cyclodextrin) 1 and paclitaxel is discussed from thermodynamic viewpoint. Furthermore, the cytotoxicity of these complexes assessed using a human erythroleukemia K562 cell line indicates that the IC(50) value of 1/paclitaxel complex is 6.0 x 10(-10) mol/dm(3) (calculated as paclitaxel molar concentration), which means that the antitumor activity of 1/paclitaxel complex is better than that of parent paclitaxel (IC(50) value 9.8 x 10(-10) mol/dm(3)). This high antitumor activity, along with the satisfactory water solubility and high thermal stability of the 1/paclitaxel complex, will be potentially useful for its clinical application as a highly effective antitumor drug.

Antineoplastic Agents↗
PubMed2005

Synthesis of mono-glucose-branched cyclodextrins with a high inclusion ability for doxorubicin and their efficient glycosylation using Mucor hiemalis endo-beta-N-acetylglucosaminidase.

The mono-glucose-branched cyclodextrins having an appropriate spacer between the beta-cyclodextrin and a glucose moiety were synthesized from beta-cyclodextrin and arbutin. They had the significantly high association constants for doxorubicin, the anticancer agent, in the range of 10(5)-10(6)M(-1), and worked as highly reactive glycosyl acceptors for the transglycosylation reaction by endo-beta-N-acetylglucosaminidase of Mucor hiemalis to produce sialo-complex type oligosaccharide-branched cyclodextrins in the high yields of 65-67%.

Acetylglucosaminidase↗
PubMed2005

Removal and pre-concentration of phenolic species onto beta-cyclodextrin modified poly(hydroxyethylmethacrylate-ethyleneglycoldimethacrylate) microbeads.

Poly(Hydroxyethylmethacrylate-Ethyleneglycoldimethacrylate), poly(HEMA-EGDMA), microbeads with 150-200 microm in size, was prepared by suspension polymerization. Beta-cyclodextrin was modified onto the polymeric microbeads using glutaraldahyde activation in an acidic medium at pH=2.5. FT-IR and TGA were used for the characterization of modified polymers and the determination of the nature of the interaction between phenolic compounds and the modified polymeric microbeads. Plain and beta-cyclodextrin modified microbeads were used in adsorption-desorption studies of phenolic species in single solution. Adsorption capacities of the phenolic species onto the plain microbeads were found to be 28.2, 17.0, 14.3, 9.8, and 1.92 mg/g polymer for o-chloro phenol, p-nitro phenol, p-chloro phenol, o-nitro phenol, and phenol, respectively. However, for beta-cyclodextrin modified microbeads, adsorption capacity of phenolic species was determined as 274, 365, 128, 182, and 87 mg/g for phenol, o-nitro phenol, p-nitro phenol, o-chloro phenol, and p-chloro phenol, respectively. Desorption ratio for the phenolic species was more than 90%, except for o-nitro phenol. Detection limits of the phenolic species were improved at least 500-fold for UV-Vis spectrophotometric detection, after the pre-concentration of all phenolic species used in this study. Adsorption time for the phenolic species onto beta-cyclodextrin-modified poly(HEMA-EGDMA) microbeads was found to be reasonable short (10-60 min) and suitable for the applications. Also, synthesized microbeads were useful for the repeated use for the removal and pre-concentration of phenolic species.

Adsorption↗
PubMed2005

Photo-Fenton treatment of TNT contaminated soil extract solutions obtained by soil flushing with cyclodextrin.

The technical feasibility and performances of coupling flushing abilities of cyclodextrin solutions for 2,4,6-trinitrotoluene (TNT) removal from contaminated soil and the ability of Photo-Fenton treatment for final disposal of soil extract solutions containing high TNT loads have been investigated at laboratory scale. Methylated-beta-cyclodextrin (MCD) has shown better ability than hydroxypropyl-beta-cyclodextrin (HPCD) to complex TNT. The MCD solution increased the aqueous concentration of TNT in soil extract effluents as much as 2.1 times the concentrations obtained during the water flush of the soil. TNT in soil extract solution has been treated by Photo-Fenton. Our results indicate that MCD has a beneficial effect on the degradation rates of TNT. This relative improvement of TNT degradation rate (1.3 time) in presence of high amounts of hydroxyl radical scavengers can be ascribed to the formation of a ternary complex (TNT-cyclodextrin-iron) which can direct hydroxyl radical reaction toward TNT. Complete mineralization of soil extraction solutions was not achieved and TNT degradation pathway has been elucidated in order to ensure that no potential toxic intermediate is left at the end of the treatment time. After successive TNT hydroxylations, oxidative opening of the TNT aromatic ring quickly occurred, leading to the accumulation of short chain carboxylic acids such as oxalic acid and formic acid.

Cyclodextrins↗
PubMed2005

Study of structural features and thermodynamic parameters, determining the chromatographic behaviour of drug-cyclodextrin complexes.

The chromatographic behaviour of host-guest inclusion complexes was studied, in order to predict the optimal conditions for their accurate analysis and overcome the significant analytical errors generated by the presence of cyclodextrins. Complexes of tolfenamic acid and ketoprofen with beta-cyclodextrtin (betaCD), 2-hydroxypropyl-betaCD (HPbetaCD) and methyl-betaCD (MebetaCD) prepared in different molar ratios, were studied. Since the drug release from cyclodextrins' complexes is a prerequisite for its accurate quantitation, several parameters affecting the dissociation during the analysis were evaluated. In an attempt to explain the drug release mechanism from cyclodextrins, during HPLC analysis, the possible correlation of the NMR structural findings with the binding constants and the thermodynamic quantities of complexation were examined, in relation to their chromatographic behaviour. Finally, the presence of the solvation spheres around the supramolecules, which affect the complex stability, is suggested to be crucial for our chromatographic findings. Particularly, entropy change in the system is considered the most critical factor, determining the time required for dissociation of drug-cyclodextrin complexes, during drug quantitation.

Chromatography, High Pressure Liquid↗
PubMed2006

Influence of substituents on selectivity and efficiency of chiral separations of anions containing single nido-7,8-dicarbaundecaborane cluster with alpha-cyclodextrin.

In background electrolyte (BGE) with the optimal methanol concentration of 30% (v/v), the ion with -NCS group bonded to a cluster boron atom exhibits the strongest interaction with alpha-cyclodextrin and the highest separation selectivity. Interaction of ions with alkyl or thioalkyl group weakens with the increasing substituent size. The ion with phenyl group exhibits the weakest interaction. Bonding of a group to boron atom weakens the ion interaction with alpha-cyclodextrin. Second substituent further weakens the interaction with alpha-cyclodextrin. Separation efficiency is lower at the presence of alpha-cyclodextrin than at its absence. This separation efficiency loss, amounts up to 90%.

Anions↗
PubMed2005

Cyclodextrin complexes of valdecoxib: properties and anti-inflammatory activity in rat.

The influence of natural beta-cyclodextrin and its hydrophilic derivatives (HPbetaCd and SBE7betaCd) on the in vitro dissolution rate, in vivo absorption and oral bioavailability of a poorly water soluble anti-inflammatory agent, valdecoxib (VALD) was studied. Equimolar drug-cyclodextrin solid complexes were prepared by kneading and coevaporation methods and characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffraction. In the liquid state, the cyclodextrin complexes were studied using phase solubility analysis, (1)H nuclear magnetic resonance and circular dichroism spectroscopy. Drug solubility and dissolution rate in distilled water were notably improved by employing the betaCds. The DP(15) (i.e. percent of dissolved VALD at 15 min) was 10.5% for the pure drug and 50, 91 and 93% for VALD-betaCd, VALD-HPbetaCd and VALD-SBE7betaCd complexes, respectively. Moreover, it was found that in the, the cyclodextrin complexes of drug showed significant improvement in the anti-inflammatory activity.

Animals↗
PubMed2005

Synthesis and characterisation of novel nanospheres made from amphiphilic perfluoroalkylthio-beta-cyclodextrins.

This work describes the synthesis of new amphiphilic perfluorohexyl- and perfluorooctyl-propanethio-beta-cyclodextrins and the comparison of the ability of these molecules and alkyl analogue, nonanethio-beta-cyclodextrin to form nanospheres. Nanospheres were prepared using nanoprecipitation method (perfluoroalkylthio-beta-cyclodextrin in THF [0.11 x 10(-3)M], stirring rate 700rpm, addition of aqueous phase at 64 degrees C into organic phase at 50 degrees C). They were characterised by Photon Correlation Spectroscopy (PCS) and by electron microscopy (SEM and cryo-TEM). The nanospheres prepared from these new beta-cyclodextrin derivatives have an average size of 260nm, and appear to be spherical in cryo-TEM images. Whereas alkyl analogue forms polydisperse aggregates with sizes in the range 60-350nm.

Alkylation↗
PubMed2005

Dehydrocrotonin and its beta-cyclodextrin complex: cytotoxicity in V79 fibroblasts and rat cultured hepatocytes.

Trans-dehydrocrotonin has antiulcerogenic and antitumor activities. A complex of beta-cyclodextrin with dehydrocrotonin was developed to improve the delivery of dehydrocrotonin. Complex in solid state was evaluated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and scanning electron microscopy (SEM). X-ray diffraction and scanning electron microscopy studies showed that dehydrocrotonin exists in a semicrystalline state in the complexed form with beta-cyclodextrin. Differential scanning calorimetry studies showed the existence of a complex of dehydrocrotonin with beta-cyclodextrin. The thermal gravimetric analysis studies confirmed the differential scanning calorimetry results of the complex. Free dehydrocrotonin and the dehydrocrotonin/beta-cyclodextrin inclusion complex were assayed in freshly isolated rat hepatocytes and in V79 cells. Cytotoxicity was determined using nucleic acid content, methylthiazoletetrazolium (MTT) reduction and neutral red uptake assays. In all assays, there was a large reduction (3.5-16.1-fold) in the cytotoxicity of dehydrocrotonin in hepatocytes when complexed with beta-cyclodextrin, whereas for V79 cells the decrease in cytotoxicity was 1.7- and 1.87-fold for MTT reduction and nucleic acid content assays, respectively. The lower cytotoxicity of the dehydrocrotonin/beta-cyclodextrin complex compared to free dehydrocrotonin in rat hepatocytes and V79 cells suggests that such a complex may be useful for the administration of dehydrocrotonin in vivo.

Animals↗
PubMed2004

NMR studies of the inclusion complex between beta-cyclodextrin and paroxetine.

A 1H and 13C NMR study on the inclusion complex of paroxetine with beta-cyclodextrin was carried out in order to define the stoichiometry of the association and its strength. Proton and carbon chemical shift measurements of paroxetine and beta-cyclodextrin were performed at several molar ratios and temperatures, allowing the determination of a 1:1 stoichiometry and an association constant value of the order of 2 x 10(3) for the paroxetine-beta-cyclodextrin complex. Overhauser effects in the rotating frame were also measured, and the experimental interproton distance constraints have been used for molecular model building of the complex. The obtained model indicates that the benzodioxolyl moiety of paroxetine is deeply inserted in the cavity of the cylindrical structure of beta-cyclodextrin, while the fluoro-phenyl ring lays above the wider rim.

Freezing↗
PubMed2005

Vascular PET prostheses surface modification with cyclodextrin coating: development of a new drug delivery system.

PURPOSE: Cyclodextrins (CDs) are torus shaped cyclic oligosaccharides with a hydrophobic internal cavity and a hydrophilic external surface. We performed and analysed an antibiotic binding on Dacron (polyethyleneterephtalate, PET) vascular grafts, previously coated with CDs based polymers. METHODS: The CDs coating process was based on the pad-dry-cure method patented in our laboratory. The Dacron prostheses were immersed into a solution containing a polycarboxylic acid, a cyclodextrin and a catalyst, and placed into a thermofixation oven before impregnation with an antibiotic solution (Vancomycin). Biocompatibility tests were performed with L132 human epithelial cells. The antibiotic release in an aqueous medium was assessed by batch type experiments using UV spectroscopy. RESULTS: Viability tests confirmed that the CDs polymers coating the Dacron fibers were not toxic towards L132 cell. Cell proliferation was similar on coated and uncoated grafts. A linear release of Vancomycin was observed over 50 days. CONCLUSION: Our results demonstrate the feasibility of coating CDs onto vascular Dacron grafts. Biological tests show no toxicity of the different cyclodextrins coated. A linear release of antibiotics was depicted over 50 days, demonstrating that cyclodextrin grafting was an efficient drug delivery system.

Anti-Bacterial Agents↗
PubMed2006

Prediction of mono- and polycyclic aromatic hydrocarbon degradation in spiked soils using cyclodextrin extraction.

In this study, an aqueous-based hydroxypropyl-beta-cyclodextrin (HPCD) extraction technique was assessed for its capacity to determine the microbially degradable fraction of mono- and polycyclic aromatic hydrocarbons in four dissimilar soils. A linear relationship (slope=0.90; R2=0.89), approaching 1:1 between predicted and observed phenanthrene mineralization, was demonstrated for the cyclodextrin extraction; however, the water only extraction underestimated the microbially available fraction by a factor of three (slope=3.35; R2=0.64). With respect to determining the mineralizable fraction of p-cresol in soils, the cyclodextrin extraction (slope=0.94; R2=0.84) was more appropriate than the water extraction (slope=1.50; R2=0.36). Collectively, these results suggested that the cyclodextrin extraction technique was suitable for the prediction of the mineralizable fraction of representative PAHs and phenols present in dissimilar soils following increasing soil-contaminant contact times. The assessment of the microbial availability of contaminants in soils is important for a more representative evaluation of soil contamination.

Carbon Radioisotopes↗
PubMed2005

Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers.

The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2- to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins>bile salts congruent with medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.

Animals↗
PubMed2006

Effects of hydroxypropyl cyclodextrins on the reactivation of SDS-denatured aminoacylase.

Cyclodextrins are natural-occurring circular oligosaccharides with an internal hydrophobic cavity and external hydrophilic edges. Because cyclodextrins bind with protein aromatic residues, they can prevent protein aggregation, and their ability to bind with detergents enables them to act as stripping reagents to release proteins from protein-detergent complexes. In this research, we investigated the effects of three hydroxypropyl cyclodextrins (HPCDs) on the refolding of aminoacylase from SDS-denatured states. It was found that the three HPCDs could effectively assist aminoacylase reactivation though they have different abilities. HP-gamma-CD, which has the largest cavity among the three HPCDs, was the most efficient one. Spectroscopic results further indicated that the secondary structure recovery of aminoacylase could be completed with the help of low concentrations of HPCDs. However, the activity of the released protein could not fully recover even though high concentrations of HPCDs were used. The concentration-dependent effects of HPCDs also indicated that cyclodextrins could also act as folding assistants in addition to acting as stripping reagents during the refolding of detergent-denatured proteins.

Amidohydrolases↗
PubMed2006

Solubilization and quantification of lycopene in aqueous media in the form of cyclodextrin binary systems.

An optimized kneading method for the preparation of lycopene-cyclodextrin binary systems was developed leading to solubilization of lycopene in water and 5% (w/v) dextrose solution. Lycopene quantification in the prepared binary systems was performed by a developed spectrometric method that followed a successful single-step extraction with dichloromethane. Storage stability characteristics of the binary systems were studied at 4 degrees C in solution and at -20 degrees C in the lyophilized products. Lycopene content was monitored at lambda(max)=482 nm, the limit of detection was 0.41 microg/ml and relative standard deviation was less than 3.1%. The results obtained with the spectrometric method were confirmed by a HPLC method. In the presence of cyclodextrins, lycopene concentration in water was 8.0+/-1.0, 27.1+/-3.2 and 16.0+/-2.2 microg/ml for beta-CD, HP-beta-CD and Me-beta-CD, respectively. In 5% (w/v) aqueous dextrose solutions the corresponding values were 16.0+/-1.8, 48.0+/-5.1 and 4.0+/-0.5 microg/ml, respectively. At 4 degrees C, storage stability of lycopene-cyclodextrin binary systems in water or 5% (w/v) aqueous dextrose solutions, was limited (t(1/2)=1-4 days). Addition of the antioxidant sodium metabisulfite increased the stability of lycopene-HP-beta-CD binary system in water. At -20 degrees C, the lyophilized lycopene-cyclodextrin binary systems were stable for at least 2 weeks.

Antioxidants↗
PubMed2005

Lack of effect of beta-cyclodextrin and its water-soluble derivatives on in vitro drug transport across rat intestinal epithelium.

The present study aimed to investigate whether beta-cyclodetxrin (beta-CD) and its water-soluble derivatives, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD), exert any effects on the permeation of two drug transport markers (propranolol and lucifer yellow) across rat intestinal epithelium. Rat ileum was stripped of its serosa and mounted inside an Ussing Chamber. Apparent permeability coefficients (P(app)) of the markers from the mucosal to serosal side of the tissue were determined at 37 degrees C in the presence and absence of the beta-cyclodextrins on the mucosal side. Potential difference (PD) was constantly monitored during each experiment to ensure maintenance of the viability and integrity of the tissue. Pre-incubation with 1% beta-CD, 1% HP-beta-CD or 1.48% SBE-beta-CD on the mucosal side for 30 min did not significantly alter the PD and the propranolol permeability (p>0.05). Co-incubation with 1% beta-CD or 1% HP-beta-CD exerted no significant effect on the P(app) of both propranolol and lucifer yellow (p>0.05), but co-incubation with 1.48% SBE-beta-CD lowered the P(app) of propranolol from (1.71+/-0.44)x10(-5) to (0.19+/-0.04)x10(-5)cm/s, which may be ascribed to the molecular complexation of propranolol with SBE-beta-CD. All three beta-cyclodextrins exert no apparent impact on both (passive) transcellar and paracellular drug transports.

Adrenergic beta-Antagonists↗
PubMed2005

Formulation and biological evaluation of glimepiride-cyclodextrin-polymer systems.

Glimepiride is one of the third generation sulfonylureas used for treatment of type 2 diabetes. Poor aqueous solubility and slow dissolution rate of the drug lead to irreproducible clinical response or therapeutic failure in some cases due to subtherapeutic plasma drug levels. Consequently, the rationale of this study was to improve the biological performance of this drug through enhancing its solubility and dissolution rate. Inclusion complexes of glimepiride in beta-cyclodextrin (beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutylether-beta-cyclodextrin (SBE-beta-CyD), with or without water soluble polymers were prepared by the kneading method. Binary systems were characterized by thermogravimetric analysis, IR spectroscopy and X-ray diffractometry. Phase solubility diagrams revealed increase in solubility of the drug upon cyclodextrin addition, showing A(p) type plot indicating high order complexation. All the ternary systems containing beta-CyD or HP-beta-CyD showed higher dissolution efficiency compared to the corresponding binary systems. The hypoglycemic effect of the most rapidly dissolving ternary system of glimepiride-HP-beta-CyD-PEG 4000 was evaluated after oral administration in diabetic rats by measuring blood glucose levels. The results indicated that this ternary system improves significantly the therapeutic efficacy of the drug. In conclusion, the association of water soluble polymers with glimepiride-CyD systems leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug.

Administration, Oral↗
PubMed2006

Effects of pH and cyclodextrins on pentachlorophenol degradation (mineralization) by white-rot fungi.

White-rot fungi (WRF) such as Trametes hirsuta completely degrade (mineralize) pentachlorophenol (PCP) and many other organopollutants. This has led to them being used to decontaminate various substrates (e.g. soil) through biorememediation. However, because PCP is a biocide, it can inhibit fungal growth and thereby its own degradation. It was hypothesized that substrate pH might affect PCP degradation, because when the pH is lower than 4.7 (the pKa for PCP) the phenol predominates, while at higher pH the phenate does. These two PCP species differ markedly in physical and biological properties. The effect of cyclodextrins was also investigated since it is known that the inclusion complexes these form with PCP differ in bioavailability and toxicity from non-complexed PCP. Tests were first made in liquid and agar media (where conditions are relatively easy to control), and then in a sawdust, because it is a common target matrix for WRF bioremediation. Results with the liquid and agar media showed that growth in the presence of inhibitory PCP concentrations decreased as the pH decreased, consistent with the phenol being more toxic. Growth in sawdust was less affected by PCP regardless of the pH, presumably because the PCP sorbed to the wood which decreased its bioavailability. Some cyclodextrins markedly decreased the PCP's toxicity in liquid, agar and sawdust media. Rates of PCP mineralization (measured from production of (14)CO(2) from (14)C PCP) in liquid cultures containing 0.5 mgkg(-1) PCP (a sub-inhibitory concentration) were similar from pH 2.5-7.5, indicating that the phenol and the phenate were equally degradable. Degradation of a growth inhibiting concentration on sawdust (1,000 mgkg(-1)) could be increased slightly by lowering the pH below the pKa, this increasing sorption to the wood. Degradation increased more when the pH was raised well above the pKa, presumably due to the phenate being less toxic and more soluble, making it more available to the degradative system. Although some cyclodextrins decreased growth inhibition, they also interfered with degradation. If this interference could be overcome, cyclodextrins could be used to increase the maximal PCP concentration that could be treated by WRF bioremediation.

Agar↗