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PubMed2001

Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats.

The enhancing effects of cyclodextrins (CyDs) on the solubility, the dissolution rate, and the bioavailability of tacrolimus after oral administration to rats were examined and compared with those after administration of a PROGRAF capsule containing the solid dispersion formulation of tacrolimus. Here we used natural CyDs and the hydrophilic beta-CyD derivatives; that is, randomly methylated-beta-cyclodextrin (RM-beta-CyD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and sulfobutyl ether beta-cyclodextrins (SBE-beta-CyDs). Of the natural CyDs, the solubility of tacrolimus increased in the addition of beta-CyD, indicating that the cavity of beta-CyD comfortably fits the drug. Of the beta-CyD derivatives, DM-beta-CyD had the greatest solubilizing activity and gave the A(p) type phase solubility curve as defined by Higuchi and Connors, suggesting the formation of higher-order complexes. The result of van't Hoff plot suggests that the enthalpy is dominant for the complexation of tacrolimus with DM-beta-CyD. The dissolution rate of tacrolimus was markedly augmented by the complexation with DM-beta-CyD, reflecting its solubilizing activity. An in vivo study revealed that DM-beta-CyD increased the bioavailability of tacrolimus with low variability in the absorption after oral administration of the tacrolimus suspension to rats. The present results suggest that DM-beta-CyD is particularly useful in designing oral preparations of tacrolimus with an enhanced bioavailability and a reduced variability in absorption.

Administration, Oral↗
PubMed2004

Nuclear magnetic resonance and molecular modeling analysis of the interaction of the antimalarial drugs artelinic acid and artesunic acid with beta-cyclodextrin.

The artemisinin derivatives artelinic acid and artesunic acid are members of a class of compounds that have shown promise for the treatment of multidrug resistant strains of Plasmodium falciparum. Unfortunately, these compounds exhibit poor solubility and stability in aqueous solution. The research presented herein was conducted to determine whether complexation of artelinic acid or artesunic acid with beta-cyclodextrin would result in complexes with increased aqueous solubility while retaining the potent antimalarial activity of these compounds. Preliminary complexation studies with natural beta-cyclodextrins were conducted as a proof of concept, with a primary focus on understanding the electrostatic interactions that stabilize the resulting complexes. Complex formation was monitored using UV spectroscopy. The structures of the resulting complexes were determined using multidimensional nuclear magnetic resonance spectroscopy (NMR) and molecular modeling. NMR results are most consistent for artelinic acid and beta-cyclodextrin forming complexes in a ratio of 2:1; however, the presence of 1:1, 2:2, and 3:1 complexes in solution cannot be excluded based on the experimental data collected. The NMR data also indicate selective insertion of artelinic acid into the hydrophobic cavity of the beta-cyclodextrin via the primary face. NMR results indicate artesunic acid forms a similar complex with beta-cyclodextrin in a ratio of 1:1; again however, the presence of 1:1, 2:2, and 3:1 complexes in solution cannot be ruled out.

Animals↗
PubMed1991

Development of aqueous parenteral formulations for carbamazepine through the use of modified cyclodextrins.

The poor aqueous solubility of carbamazepine was dramatically increased via complexation with various chemically modified beta-cyclodextrins and gamma-cyclodextrins. A preparation of carbamazepine and 2-hydroxypropyl-beta-cyclodextrin was found to be stable to steam sterilization and to storage under a variety of conditions. Carbamazepine, when solubilized in this manner, was found to exert potent anticonvulsant effects in various seizure models and the formulation was tolerated in animals at high doses (100 mg/kg carbamazepine and 1200 mg/kg of the cyclodextrin excipient). The onset of anticonvulsant action was rapid and consistent with almost instantaneous in vivo complex dissociation. The low toxicity of 2-hydroxypropyl-beta-cyclodextrin, when administered via the parenteral route, and its ability to enhance the aqueous solubility of carbamazipine highly favor the use of this excipient.

Animals↗
PubMed1995

Modification of rectal absorption of morphine from hollow-type suppositories with a combination of alpha-cyclodextrin and viscosity-enhancing polysaccharide.

An attempt was made to optimize the rectal delivery of morphine, using cyclodextrins as an absorption enhancer and polysaccharides as a swelling hydrogel in Witepsol H-15 hollow-type suppositories, and this was tested in rabbits. alpha- and beta-cyclodextrins enhanced the rate and extent of bioavailability, the former being more effective; gamma-cyclodextrin decreased the absorption of morphine. The in-vitro membrane permeation studies using excised rectal sacs revealed that alpha-cyclodextrin enhanced the permeation of morphine through the rectal membranes. In contrast, viscous polysaccharides such as xanthan gum retarded the plasma morphine levels after the rectal administration, reflecting in-vitro slow release characteristics. A combination of alpha-cyclodextrin and xanthan gum produced sustained plasma profiles of morphine along with an increased rectal bioavailability (more than 4 times). From the observation of the distribution behavior of suppositories in rabbit rectum and colon after the rectal administration, xanthan gum was found to prevent the upward spread of the drug. Gross and microscopic observations suggested that this preparation was less irritating to the rectal mucosa.

Animals↗
PubMed1995

Preliminary safety evaluation of parenterally administered sulfoalkyl ether beta-cyclodextrin derivatives.

Parenteral administration of beta-cyclodextrin (beta-CD) results in renal and/or local toxicity dependent on the mode of administration. In an attempt to alleviate these properties, a series of anionically charged sulfoalkyl ether cyclodextrin (SAE-beta-CD) derivatives have been developed. The parenteral safety of these derivatives was determined by survival of male mice after intraperitoneal (ip) injection, kidney histopathology, plasma urea nitrogen levels of mice determined 24 h after injection, relative in vitro hemolytic potential and activated partial thromboplastin times (APTT). In addition, the 24-h renal excretion behavior of the derivatives was measured. Where appropriate, the results obtained with these cyclodextrin derivatives were compared with results obtained for beta-CD and (hydroxypropyl)-beta-cyclodextrin (HP-beta-CD). The SAE-beta-CD derivatives did not produce mortality in mice following ip injection at doses exceeding 5.45 mmol/kg. No significant histological lesions were observed in the kidney tissue of mice receiving the cyclodextrin derivatives. The SAE-beta-CD derivatives were excreted faster and to a greater extent than beta-CD and at rates comparable to HP-beta-CD. The hemolytic potential of these derivatives was less than that of beta-CD and comparable to or better than that of HP-beta-CD. The SAE-beta-CD derivatives did not increase APTT clotting times indicating that these derivatives have no significant anticoagulant activity. The toxicological profile of these derivatives suggests that these molecules may have application as biologically safe beta-CD derivatives.

Animals↗
PubMed1995

Improvement of nasal bioavailability of luteinizing hormone-releasing hormone agonist, buserelin, by cyclodextrin derivatives in rats.

The effects of chemically modified cyclodextrins on the nasal absorption of buserelin, an agonist of luteinizing hormone-releasing hormone, were investigated in anesthetized rats. Of the cyclodextrins tested, dimethyl-beta-cyclodextrin (DM-beta-CyD) was the most effective in improving the rate and extent of the nasal bioavailability of buserelin. Fluorescence spectroscopic studies indicated that the cyclodextrins formed inclusion complexes with buserelin, which may reduce the diffusibility of buserelin across the nasal epithelium and may participate in the protection of the peptide against enzymatic degradation in the nasal mucosa. Additionally, the cyclodextrins increased the permeability of the nasal mucosa, which was the primary determinant based on the multiple regression analysis of the nasal absorption enhancement of buserelin. Scanning electron microscopic observations revealed that DM-beta-CyD induced no remarkable changes in the surface morphology of the nasal mucosa at a minimal concentration necessary to achieve substantial absorption enhancement. The present results suggest that DM-beta-CyD could improve the nasal bioavailability of buserelin and is well-tolerated by the nasal mucosa of the rat.

Absorption↗
PubMed2002

Direct investigation of the vectorization properties of amphiphilic cyclodextrins in phospholipid films.

Recently, new cyclodextrin derivatives were synthesized and shown to exhibit strong amphiphilic properties. In this paper, we study the action of these new amphiphilic cyclodextrins on phospholipids. Mixed phospholipid/cyclodextrin derivative films were prepared and studied using X-ray reflectivity for various phospholipid/cyclodextrin ratios. A molar ratio of 3 provides a highly stable film the molecular structure of which has been investigated in detail. The cholesterol tail of the cyclodextrin molecule was found to be anchored into the phospholipid film. The cyclodextrin moieties exposed to the aqueous medium are prone to the addition of the guest molecule Dosulepin, making them of high interest for drug delivery. For this purpose and as an example of a potential application, this cyclodextrin molecular carrier property is also addressed to this complex film architecture.

Cyclodextrins↗
PubMed2003

Monolithic silica columns with chemically bonded beta-cyclodextrin as a stationary phase for enantiomer separations of chiral pharmaceuticals.

An enantioselective silica rod type chiral stationary phase (CSP) is presented; a novel combination of the well known enantiomer separation properties of beta-cyclodextrin and the unique properties concerning the flow behavior of silica monoliths. Two different synthesis routes are described, and it was found that the in situ modification of a plain silica rod column turned out to be the best. The chromatographic behaviour of the beta-cyclodextrin silica rod was studied and compared with a very similar commercially available beta-cyclodextrin bonded particulate material (ChiraDex). Even if the amount of beta-cyclodextrin bound to the silica rod was only about half of the amount of beta-cyclodextrin bound to ChiraDex) particles, good resolutions were achieved for a set of chiral test components like Chromakalin, Prominal, Oxazepam, Methadone and some other drugs. By taking advantage of the unique features of the silica rods relating to their flat H/u (Van Deemter) curves, fast enantiomer separations could be demonstrated.

Chromatography↗
PubMed2005

Use of the three-phase model and headspace analysis for the facile determination of all partition/association constants for highly volatile solute-cyclodextrin-water systems.

A versatile method for measuring the partition coefficients of volatile analytes with an aqueous pseudophase using headspace gas chromatography is reported. A "three-phase" model accounts for all equilibria present in the system, including the partitioning of the analyte in the gas and aqueous phases to the pseudophase. This method is applicable to a wide variety of volatile analytes and aqueous pseudophases, providing that sufficient pseudophase may be used to reduce the analyte partial pressure. Generally, the method offers good reproducibility and high sensitivity. The associations of five volatile analytes (hydrogen sulfide, methanethiol, dimethyl sulfide, dichloromethane, and ethyl ether) with various cyclodextrins were examined. All analytes were found to partition preferentially to the cyclodextrin pseudophase compared to the aqueous phase. In addition, several analyte-cyclodextrin combinations formed insoluble complexes in solution that enhanced the extraction of the analyte from the gas and aqueous phases. Derivatization of the cyclodextrins generally decreased the extent of analyte-cyclodextrin interaction.

Cyclodextrins↗
PubMed1991

Soybean lipoxygenase catalysed oxygenation of unsaturated fatty acid encapsulated in cyclodextrin.

The linoleic or arachidonic acid entrapped in cyclodextrin (alpha, beta or gamma) serves as an excellent substrate for soybean lipoxygenase-1 catalysis. At pH 9.0 the Km values for the beta-cyclodextrin encapsulated arachidonic acid, referred herein as encapsulated substrate, and the Tween-20 dispersed substrate were 7.7 microM and 7.5 microM, respectively. However, the Vmax values for alpha- and beta-cyclodextrin solubilized substrates were lower in comparison with the Tween-20 dispersed substrate. Interestingly, the pH-activity profile for the enzyme towards cyclodextrin encapsulated arachidonic acid showed optimum around 7.5, while that towards Tween-20 dispersion showed the expected broad optimum in the alkaline range (8.5-10.0). The activity with encapsulated substrate at pH 7.5 was at least 5-fold higher than that obtained with Tween-20 dispersed substrate at the corresponding pH. Similar results were obtained using linoleic acid. The second order rate constant, Kcat/Km, for the encapsulated substrate was an order of magnitude higher when compared to the Tween-20 dispersed substrate. The plot of v obtained at pH 9.0, against S gave hyperbolic curves for both the encapsulated as well as the Tween-20 dispersed substrates, whereas at pH 7.5, the curve for cyclodextrin encapsulated arachidonic acid appeared initially concave and then at higher concentrations of the substrate sigmoidal. The positional specificity of soybean lipoxygenase remained unaltered, however.

Arachidonic Acid↗
PubMed1991

Effect of cyclodextrins on the chemical stability of mitomycins in alkaline solution.

The effects of cyclodextrins on the chemical stability of several mitomycin antibiotics in an alkaline medium have been investigated. A stability-indicating high-performance liquid chromatographic method was used to determine the overall degradation rate constants. The influence of various parameters such as structural variations of the cyclodextrins and mitomycins, temperature and pH was studied. It appears that complexation is most favourable with gamma-cyclodextrin. All mitomycin-gamma-cyclodextrin complexes degrade at lower rates than those of the free drugs. Moreover, it was shown that gamma-cyclodextrin influences the equilibrium between mitomycin C and its zwitterion mesomer.

Alkalies↗
PubMed1995

Enantiomeric separation of denopamine by capillary electrophoresis and high-performance liquid chromatography using cyclodextrins.

Direct separation of enantiomers of denopamine was investigated by two separation methods. One is capillary zone electrophoresis (CZE) using cyclodextrins (CDs) (CD-CZE) and the other is high-performance liquid chromatography (HPLC) using CD immobilized chiral stationary phases (CD-CSPs). Enantiomers of denopamine were successfully resolved by employing heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CD) and acetyl-beta-cyclodextrin (AC-beta-CD), and partially resolved with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TM-beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and beta-CD polymer under acidic conditions. Separation of enantiomers of denopamine by HPLC was also successful with one of the CD-CSPs, where perphenylated beta-CD (Ph beta-CD) was immobilized. In CD-CZE, some polymeric additives, such as hydroxy-propylmethylcellulose (HPMC) and polyvinylalcohol (PVA), and a coated capillary were used to improve the enantioseparation of denopamine. Method validations such as linearity, recovery and repeatability, etc., were investigated for HPLC, and the method was applied to the optical purity testing of the drug substances and in tablet form.

Adrenergic beta-Antagonists↗
PubMed2006

Sulfated cyclodextrins inhibit the entry of Plasmodium into red blood cells. Implications for malarial therapy.

The effect of sulfated cyclodextrins on Plasmodium falciparum cultures was determined. alpha-, beta-, and gamma-Cyclodextrins having equal degrees of sulfation inhibited parasite viability to a similar degree, a result suggesting that the ring size of the cyclodextrin is not a critical factor for inhibitory activity. beta-Cyclodextrins containing fewer than two sulfate groups had no inhibitory activity, however, compounds containing 7-17 sulfates were found to be active in the microM range. Examination of treated cultures indicated that intracellular forms of the parasite were unaffected; however, increased numbers of extracellular merozoites were present. Active compounds produced enhanced erythrocyte staining with cationic dyes that could be reduced by stilbene disulfonates, a result suggesting that sulfated cyclodextrins inhibit parasite growth by interacting with the anion transport protein, AE1. Compounds that were found to be active in P. falciparum cultures were also found to inhibit P. berghei merozoite entry and could reduce the parasitemia of P. berghei infection in a mouse model, results suggesting that these compounds inhibit a common step in the merozoite invasion process of at least two Plasmodium species.

Animals↗
PubMed2005

Association interaction and voltammetric determination of 1-aminopyrene and 1-hydroxypyrene at cyclodextrin and DNA based electrochemical sensors.

The aim of this work was voltammetric determination of 1-aminopyrene and 1-hydroxypyrene using carbon paste electrodes modified with cyclodextrin derivatives and double stranded deoxyribonucleic acid (dsDNA). The detection schemes based on a preconcentration and differential pulse voltammetric (DPV) determination at beta-cyclodextrin and gamma-cyclodextrin modified carbon paste electrode (beta-CD/CPE, gamma-CD/CPE), neutral beta-cyclodextrin polymer and carboxymethyl-beta-cyclodextrin polymer modified screen-printed electrode (beta-CDP/SPE, beta-CDPA/SPE) and dsDNA modified screen-printed electrode (DNA/SPE) are proposed for the trace determination of studied analytes within the concentration range from 2 x 10(-8) to 4 x 10(-7) mol dm(-3) and from 2 x 10(-7) to 4 x 10(-6) mol dm(-3) with the limits of quantification down to 10(-8) mol dm(-3). Depending on pH, 1-aminopyrene interacts with both surface attached CD and DNA by electrostatic bonds and supramolecular complexation while 1-hydroxypyrene associates with the CD hosts via complexation. The 1-aminopyrene interaction with dsDNA was confirmed by fluorimetric measurements in the solution phase using a competing DNA-TO-PRO-3 dye complex. In addition, the effect of temperature on this association was investigated using an electrically heated DNA-modified carbon paste electrode (DNA/CPE).

Biosensing Techniques↗
PubMed2006

Methylated beta-cyclodextrin as P-gp modulators for deliverance of doxorubicin across an in vitro model of blood-brain barrier.

Co-incubations of various beta-cyclodextrins and doxorubicin have been evaluated on an in vitro model of blood-brain barrier in order to increase the delivery of this P-gp substrate to the brain. Among these cyclodextrins used, the Rame-beta-cyclodextrin and Crysme-beta-cyclodextrin increased the transport by a factor of 2 and 3.7, respectively. This increase was attributed to the cholesterol extraction property of these cyclodextrins from brain capillary endothelial cells leading to a modulation of the P-gp activity.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Enhanced degradation of fluorene in soil slurry by Absidia cylindrospora and maltosyl-cyclodextrin.

This study investigates the fungal biodegradation of fluorene, a polycyclic aromatic hydrocarbon, in liquid medium and soil slurry. Fungal strains and cyclodextrins were used in order to degrade fluorene and optimize fluorene bioavailability and degradation in soil slurries. After a procedure of selection in solid and liquid media, maltosyl-cyclodextrin, a branched cyclodextrin was chosen. 47 fungal strains isolated from a contaminated site were tested for biodegradation. Results showed the greater efficiency of "adapted" fungi isolated from contaminated soil vs reference strains belonging to the collection of the laboratory. These assays allowed us to select the most efficient strain, Absidia cylindrospora, which was used in a bioaugmentation process. Bioaugmentation tests were performed in an artificially contaminated non-sterile soil. In the presence of A. cylindrospora, more than 90% of the fluorene was degraded within 288 h, while 576 h were necessary in the absence of fungal bioremediation. It also appeared that biodegradation was enhanced by amendment with previously selected maltosyl-cyclodextrin. The results of this study indicate that A. cylindrospora and maltosyl-cyclodextrin could be used successfully in fluorene bioremediation systems.

Absidia↗
PubMed2004

Enhanced solubilization of arsenic and 2,3,4,6 tetrachlorophenol from soils by a cyclodextrin derivative.

The application of extracting aqueous solutions with cyclodextrins in several soil remediation technologies has been increasingly studied but little is known about their removal capacities toward the inorganic species. Herein, the effectiveness of cyclodextrins (CDs) in extracting arsenic, copper, and iron from a mining soil is presented. In a preliminary test of four types of CD aqueous solutions, only the addition of carboxylmethyl-beta-cyclodextrin CMCD (a cyclodextrin derivative) led to a significant enhancement in arsenic removal. An increase in the concentration of copper and iron in the leachates was also observed with CMCD. Kinetic study of arsenic release was carried out at two temperatures (20 and 35 degrees C). The arsenic concentration in the leachates increases with increasing cyclodextrin concentration. At an 80 mM CMCD concentration, arsenic, copper, and iron released in filtrates were about 20-, 1,000-, and 4,000-fold greater, respectively, than that obtained using deionized water. In the soil system, the CMCD capacity removal was found to be higher for cations than for arsenic. Because the tetrachlorophenol can co-occur with arsenic and copper in several contaminated sites, its solubilization by CMCD was also investigated. Extraction experiments were performed to extract 2,3,4,6 tetrachlorophenol (TeCP) in spiked soil with CMCD. The results of batch experiments have shown that CMCD could significantly increase the TeCP extraction from soil. CD sorption on soils as quantified by a fluorescence technique was low, indicating no significant loss of CD during the leaching experiments. The use of CMCD as a flushing agent to enhance the removal of both inorganic and organic pollutants from mixed-contaminated soils appears as a promising remediation method.

Arsenic↗
PubMed2004

Capillary electrochromatography with polymeric continuous beds synthesized via free radical polymerization in aqueous media using derivatized cyclodextrins as solubilizing agents.

A novel synthetic route to amphiphilic acrylamide-based monolithic stationary phases for capillary electrochromatography (CEC) employing water-soluble cyclodextrins as solubilizing agents was explored. N,N'-Octamethylenebisacryamide and N,N'-dodecamethylenebisacryamide were synthesized and their solubilization in aqueous solution with derivatized and underivatized cyclodextrins of different cavity size was studied. Amphiphilic stationary phases were synthesized by free radical copolymerization of the bisacrylamide-cyclodextrin host-guest complexes with hydrophilic monomers and an additional hydrophilic cross-linker in aqueous solution. Complex formation in solution and removal of the complexed cyclodextrin from the polymer during synthesis was studied with 1H-NMR and solid state 13C-NMR spectroscopy and cyclodextrin-modified micellar electrokinetic chromatography. The impact of the incorporated alkylene groups in the acrylamide-based macroporous polymer on retention was studied with neutral solutes by CEC in the normal-phase elution mode and in the reversed-phase elution mode. Batch-to-batch reproducibility of the synthesis procedure and day-to-day repeatability of the separations achieved were investigated. With these capillaries, a sufficiently high electroosmotic flow velocity, a high reproducibility and repeatability of separation parameters and high plate numbers (up to 200,000 m(-1) were obtained.

Chromatography, Micellar Electrokinetic Capillary↗