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PubMed2004

Characterisation of a thermoalkali-stable cyclodextrin glycosyltransferase from the anaerobic thermoalkaliphilic bacterium Anaerobranca gottschalkii.

The thermoalkaliphilic anaerobic bacterium Anaerobranca gottschalkii produces an extracellular CGTase when grown on starch at 55 degrees C and pH 9.0. The gene encoding this CGTase was cloned and successfully expressed in Escherichia coli. It encodes a protein consisting of 721 amino acids with a signal sequence of 34 amino acids. On SDS-polyacrylamide gels, the purified CGTase from A. gottschalkii displayed the expected molecular mass of 78 kDa. The recombinant enzyme was purified with a yield of 13.5% and displayed a specific activity of 210 units/mg. This CGTase, which represents the first report of a CGTase from an anaerobic thermoalkaliphile, was active at a broad range of temperature and pH, namely 55-70 degrees C and pH 5-10. It completely converted amylose, amylopectin and native starch to cyclodextrins, preferentially alpha-cyclodextrin. With a longer incubation period, the alpha-cyclodextrin to beta-cyclodextrin ratio declined. Variations in substrate type and concentration influenced the product pattern. Increasing the substrate concentration (0.5-20.0%) and glucans containing branching points (alpha-1,6 glycosidic linkages) shifted the product pattern to: beta-cyclodextin > alpha-cyclodextrin > gamma-cyclodextrin. In addition to these cyclodextrins, larger cyclodextrins (>8 glucose units) were formed in the initial reaction period. The CGTase was stabilised against thermal inactivation by calcium ions and high substrate concentrations; and 5 mM of CaCl(2) shifted the apparent melting point of the enzyme from 60 degrees C to 69 degrees C.

Amino Acid Sequence↗

PubMed2001

Combined hydroxypropyl-beta-cyclodextrin and poly(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir.

The aim of this study was to prepare and characterize an hydroxypropyl-beta-cyclodextrin-saquinavir inclusion complex with the purpose of incorporating this complex into poly(alkylcyanoacrylate) nanoparticles in order to increase the drug loading. Hydroxypropyl-beta-cyclodextrin-saquinavir complex was characterized by thermal (differential scanning calorimetry), crystallographic (X-ray diffractography) and spectroscopic methods (circular dichroism, H1-NMR). Nanoparticles were prepared by polymerization of alkylcyanoacrylate monomers (isobutyl- and isohexylcyanoacrylate) in a water solution of the complex and further characterized. The apparent solubility of saquinavir was increased 400-fold at pH 7.0 in presence of hydroxypropyl-beta-cyclodextrin owing to the formation of a drug-cyclodextrin complex as demonstrated mainly by 1H NMR and confirmed by other techniques. Saquinavir-loaded nanoparticles could be easily prepared in the presence of a drug-cyclodextrin complex. It was found that large amounts of cyclodextrins remained associated with the particles, resulting in a 20-fold increase in saquinavir loading compared to nanoparticles prepared in the absence of cyclodextrins. This study has shown that the loading in saquinavir of poly(alkylcyanoacrylate) nanospheres could be dramatically improved by simultaneously increasing the apparent solubility of the drug in the preparation medium and the amount of cyclodextrin associated with the particles, making these nanospheres a promising system for oral application.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1998

Interactions of griseofulvin with cyclodextrins in solid binary systems.

Griseofulvin/cyclodextrin interactions were investigated in aqueous environment and in solid state. Two cyclodextrin derivatives (beta-cyclodextrin and 2-hydroxypropyl beta-cyclodextrin) were used to prepare different physical mixtures and kneaded systems, and the drug/cyclodextrin ratios were 1:1 and 1:2 mol/mol. Scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetry (TG), and X-ray powder diffractometry were employed to characterize pure substances and their kneaded counterparts and all of the binary systems. The solubility of griseofulvin was increased in accord with the quantity of cyclodextrin added. HSM examination revealed that 2-hydroxypropyl-beta-cyclodextrin was dissolved in the droplets of melted griseofulvin, but did not show any interactions between melted griseofulvin and beta-cyclodextrin particles. The presence of griseofulvin endothermic peak in the DSC curves of all binary systems suggests the absence of any griseofulvin/cylcodextrin inclusion compound in the solid state. In TG, data of weight loss owing to the dehydration of cyclodextrins was similar for both kneaded systems and physical mixtures. X-ray diffraction patterns exhibited the amorphous nature of 2-hydroxypropyl-beta-cyclodextrin and the crystalline nature of griseofulvin and binary systems. Griseofulvin dissolution profiles from all binary systems showed an improvement in drug dissolution, which indicates that an "in situ" drug/cyclodextrin inclusion compound was formed in the aqueous dissolution medium.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1991

The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat.

Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-beta-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1999

A new specific enzyme immunoassay allowing an efficient pharmacokinetic evaluation of gamma-cyclodextrin after intravenous administration to rats.

PURPOSE: Because of its ability to form complexes with drugs, gamma-cyclodextrin is of great potential value in pharmaceutical formulations. The biological fate of y-cyclodextrin must therefore be considered in safety evaluation, using sensitive and specific methods applicable to biological fluids. METHODS: Antibodies were raised against gamma-cyclodextrin, allowing the development of a new enzyme immunoassay. The analytical characteristics of this assay were evaluated. Rats were given a single intravenous 25 mg/kg dose of gamma-cyclodextrin. Plasma and urine samples were collected and assayed. RESULTS: This new enzyme immunoassay was sensitive (limit of detection close to 94 pg/mL) and suitable for quantification of gamma-cyclodextrin in urine and plasma after methanol extraction. The use of different linear and cyclic compounds demonstrated the high specificity of the assay. After i.v. administration, the concentration of gamma-cyclodextrin rapidly decreased in the plasma while the molecule was probably distributed into the tissues. Although urinary elimination predominates, only 50% of the injected gamma-cyclodextrin was recovered in urine, suggesting enzymatic degradation and/or tissular storage. CONCLUSIONS: This assay may provide important information on the fate of gamma-cyclodextrin inclusion complexes dedicated to drug-delivery using various modes of administration (oral, parenteral, transmucosal or dermal).

Acetylcholinesterase↗

PubMed1996

Intracellular trafficking of cholesterol monitored with a cyclodextrin.

The sterol binding agent 2-hydroxypropyl-beta-cyclodextrin is shown to be a convenient and useful experimental tool to probe intracellular pathways of cholesterol transport. Biochemical and cytochemical studies reveal that cyclodextrin specifically removes plasma membrane cholesterol. Depletion of plasma membrane sphingomyelin greatly accelerated cyclodextrin-mediated cholesterol removal. Cholesterol arriving at the plasma membrane from lysosomes and the endoplasmic reticulum was also removed by cyclodextrin. Cellular cholesterol esterification linked to the mobilization of cholesterol from lysosomes was strongly attenuated by cyclodextrin, suggesting that the major portion of endocytosed cholesterol is delivered from lysosomes to the endoplasmic reticulum via the plasma membrane. Evidence for translocation of lysosomal cholesterol to the endoplasmic reticulum by a plasma membrane-independent pathway is provided by the finding that cyclodextrin loses its ability to suppress esterification when plasma membrane sphingomyelin is depleted. The Golgi apparatus appears to play an active role in directing the relocation of lysosomal cholesterol to the plasma membrane since brefeldin A also abrogated cyclodextrin-mediated suppression of cholesterol esterification. Using cyclodextrin we further show that attenuated esterification of lysosomal cholesterol in Niemann-Pick C cells reflects defective translocation of cholesterol to the plasma membrane that may be linked to abnormal Golgi trafficking.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1999

Cholesterol efflux-mediated signal transduction in mammalian sperm. beta-cyclodextrins initiate transmembrane signaling leading to an increase in protein tyrosine phosphorylation and capacitation.

Sperm capacitation in vitro is highly correlated with an increase in protein tyrosine phosphorylation that is regulated by cAMP through a unique mode of signal transduction cross-talk. The activation of this signaling pathway, as well as capacitation, requires bovine serum albumin (BSA) in the incubation medium. BSA is hypothesized to modulate capacitation through its ability to remove cholesterol from the sperm plasma membrane. Here we demonstrate that the cholesterol-binding heptasaccharides, methyl-beta-cyclodextrin and OH-propyl-beta-cyclodextrin, promote the release of cholesterol from the mouse sperm plasma membrane in media devoid of BSA. Both of these beta-cyclodextrins were also demonstrated to increase protein tyrosine phosphorylation in the absence of BSA in both mouse and bull sperm, and the patterns of phosphorylation were similar to those induced by media containing BSA. The potency of the different beta-cyclodextrins to increase protein tyrosine phosphorylation in sperm was correlated with their cholesterol binding efficiencies, and preincubation of the beta-cyclodextrins with cholesterol-SO4- to saturate their cholesterol-binding sites blocked the ability of these compounds to stimulate protein tyrosine phosphorylation. The beta-cyclodextrin effect on protein tyrosine phosphorylation was both NaHCO3 and protein kinase A-dependent. The beta-cyclodextrins were also able to capacitate mouse sperm in the absence of BSA, as measured by the ability of the zona pellucida to induce the acrosome reaction and by successful fertilization in vitro. In summary, beta-cyclodextrins can completely replace BSA in media to support signal transduction leading to capacitation. These data further support the coupling of cholesterol efflux to the activation of membrane and transmembrane signaling events leading to the activation of a unique signaling pathway involving the cross-talk between cAMP and tyrosine kinase second messenger systems, thus defining a new mode of cellular signal transduction initiated by cholesterol release.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1997

Use of cyclodextrins for manipulating cellular cholesterol content.

Previous studies from this laboratory have demonstrated that exposure of tissue culture cells to cyclodextrins results in rapid cholesterol depletion. In the present study, we have developed experimental systems for using solutions of cyclodextrins, either 2-hydroxypropyl beta-cyclodextrin or methylated beta-cyclodextrin, complexed with varying amounts of free cholesterol to manipulate cell cholesterol content. Cholesterol delivered via the cyclodextrin has been found to be metabolically active, as measured by the acyl-coenzyme A:cholesterol acyltransferase (ACAT)-mediated esterification of [3H]cholesterol in Fu5AH rat hepatoma cells and Chinese hamster ovary cells. The methylated beta-cyclodextrin was found to be a more efficient donor in all cell types studied, with an average cholesterol uptake of at least 100 microg cholesterol/mg protein within 6 h. By modifying the cyclodextrin:cholesterol molar ratio, it is possible to manipulate the cellular cholesterol content of cells, producing conditions ranging from net cholesterol enrichment to depletion. The use of cyclodextrins provides a convenient, precise and reproducible method for modulating the cholesterol content of tissue culture cells.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2000

Host-guest interactions at self-assembled monolayers of cyclodextrins on gold

We have developed synthesis routes for the introduction of short and long dialkylsulfides onto the primary side of alpha-, beta-, and gamma-cyclodextrins. Monolayers of these cyclodextrin adsorbates were characterized by electrochemistry, wettability studies, X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (TOF-SIMS), and atomic force microscopy (AFM). The differences in thickness and polarity of the outerface of the monolayers were measured by electro-chemistry and wettability studies. On average about 70% of the sulfide moieties were used for binding to the gold, as measured by XPS. Tof-SIMS measurements showed that the cyclodextrin adsorbates adsorb without any bond breakage. AFM measurements revealed for beta-cyclodextrin monolayers a quasi-hexagonal lattice with a lattice constant of 20.6 A, which matches the geometrical size of the adsorbate. The alpha-cyclodextrin and gamma-cyclodextrin monolayers are less ordered. Interactions of the anionic guests 1-anilinonaphthalene-8-sulfonic acid (1,8-ANS) and 2-(p-toluidinyl)naphthalene-6-sulfonic acid (2,6-TNS) and the highly ordered monolayers of heptapodant beta-cyclodextrin adsorbates were studied by surface plasmon resonance (SPR) and electrochemical impedance spectroscopy. The SPR measurements clearly showed interactions between a beta-cyclodextrin monolayer and 1,8-ANS. Electrochemical impedance spectroscopy measurements gave high responses even at low guest concentrations (< or = 5 microM). The association constant for the binding of 1,8-ANS (K = 289,000 +/- 13,000M-1) is considerably higher than the corresponding value in solution. (Partial) methylation of the secondary side of the beta-cyclodextrin strongly decreases the binding.

Journal Article↗

PubMed2003

Enhanced Fenton degradation of hydrophobic organics by simultaneous iron and pollutant complexation with cyclodextrins.

The effectiveness and selectivity of Fenton degradation of hydrophobic organic compounds (HOCs) can be improved by simultaneous complexation of Fe(2+) and the organic compound with a cyclodextrin or derivatized cyclodextrin. Such selective complexation of a target substrate and a catalytic metal is a crude mimic of enzyme systems. Both beta-cyclodextrin and carboxymethyl-beta-cyclodextrin (CMCD) were able to simultaneously complex Fe(2+) and an aromatic hydrocarbon, such as phenol, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls (PCBs). Degradation of compounds included in cyclodextrins was unaffected by hydroxyl radical scavengers, indicating that the radical was formed at the ternary complex (HOC-cyclodextrin-iron) and in close proximity to the included molecule. Without cyclodextrins, humic acid (HA) decreased degradation efficiency. However, in the presence of CMCD, HA did not inhibit degradation of the target compound. CMCD is capable of removing HOCs from HA binding sites while at the same time complexing Fe(2+). PCBs sorbed to glass were resistant to Fenton degradation, but were significantly degraded using a cyclodextrin modified Fenton system. In all of these systems, the ternary HOC-cyclodextrin-iron complexes effectively direct hydroxyl radical reaction toward the HOC, increasing the efficiency of Fenton degradation. One potential application of such targeted degradation systems is the in situ remediation of hydrophobic organic pollutants in contaminated soil and groundwater or in industrial waste streams.

Journal Article↗

PubMed2000

Addition of polar organic solvents can improve the product selectivity of cyclodextrin glycosyltransferase. Solvent effects on cgtase.

Cyclodextrin glycosyltransferase (EC 2.4.1.19, CGTase) is an enzyme that produces cyclodextrins from starch via an intramolecular transglycosylation reaction. Addition of small amounts (10% v/v) of polar organic solvents can affect both the overall production yield and the type of cyclodextrin produced from a maltodextrin substrate under simulated industrial process conditions. Using CGTase from Thermoanaerobacter sp. all solvents produced an increase in cyclodextrin yield when compared with a control, the greatest increase being obtained with addition of ethanol (26%). In addition product selectivity was affected by the nature of the organic solvent used: beta-cyclodextrin was favoured in the absence of any solvent and on the addition of dimethylsulphoxide, t-butanol and dimethylformanide while alpha-cyclodextrin was favoured by addition of acetonitrile, ethanol and tetrahydrofuran. With CGTase from Bacillus circulans strain 251 relatively smaller increases in overall cyclodextrin production were achieved (between 5-10%). Addition of t-butanol to a B. circulans catalysed reaction however did produce the largest selectivity for beta-cyclodextrin of any solvent-enzyme combination (82%). The effect of solvent addition was shown not to be related to the product inhibition of CGTase, but may be related to reduced competition from the intermolecular transglycosylation reaction that causes degradation of cyclodextrin products. This rate of this reaction was shown to be dependent on the nature of the organic solvent used.

Journal Article↗

PubMed1999

Inclusion complexation of the sunscreen agent 2-ethylhexyl-p-dimethylaminobenzoate with hydroxypropyl-beta-cyclodextrin: effect on photostability.

The interaction between the UV filter, 2-ethylhexyl-p-dimethylaminobenzoate, and unmodified and modified alpha-, beta- or gamma-cyclodextrins was studied in water by phase-solubility analysis. Of the cyclodextrins available, only hydroxypropyl-beta-cyclodextrin caused a marked increase in the aqueous solubility of 2-ethylhexyl-p-dimethylaminobenzoate. The data from the solubility study indicated the formation of a 1:1 (sunscreen-cyclodextrin) complex. The inclusion of the sunscreen agent into the hydroxypropyl-beta-cyclodextrin cavity was confirmed by thermal analysis and by nuclear magnetic resonance spectroscopy. Irradiation-induced degradation of 2-ethylhexyl-p-dimethylaminobenzoate was reduced by complexation with hydroxypropyl-beta-cyclodextrin, this effect being more pronounced in solution (the extent of degradation was 25.5% for the complex compared with 54.6% for free 2-ethylhexyl-p-dimethylaminobenzoate) than in the emulsion vehicle (the extent of degradation was 25.1% for the complex compared with 33.4% for free 2-ethylhexyl-p-dimethylaminobenzoate). Although photodegradation of the sunscreen agent is significantly reduced by formation of the inclusion complex it is important to design a suitable vehicle. Inclusion of 2-ethylhexyl-p-dimethylaminobenzoate-DMAB into the hydroxypropyl-beta-cyclodextrin cavity limits interaction of the UV filter with the skin reducing the side-effects of the formulation.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2003

Synthesis, analytical characterization and use of octakis(2,3-di-O-methyl-6-O-sulfo)-gamma-cyclodextrin, a novel, single-isomer, chiral resolving agent in low-pH background electrolytes.

The third member of the family of single-isomer, sulfated gamma-cyclodextrins, the sodium salt of octakis(2,3-di-O-methyl-6-O-sulfo)-gamma-cyclodextrin has been synthesized, analytically characterized and used for the capillary electrophoretic separation of the enantiomers of nonionic, weak acid and weak base analytes in low-pH aqueous background electrolytes. Though octakis(2,3-di-O-methyl-6-O-sulfo)-gamma-cyclodextrin complexes less strongly with many of the analytes tested than the other members of the single-isomer, 6-O-sulfo gamma-cyclodextrin family, such as octa(6-O-sulfo)-gamma-cyclodextrin and octakis(2,3-di-O-acetyl-6-O-sulfo)-gamma-cyclodextrin, it offers excellent separation selectivities, often complementary to those of both the single-isomer, 6-O-sulfo beta-cyclodextrins and 6-O-sulfo gamma-cyclodextrins. Rapid, efficient enantiomer separations were observed for a large number of structurally diverse analytes in acidic aqueous background electrolytes.

Cyclodextrins↗

PubMed2005

Solid-state characterization and dissolution properties of naproxen-arginine-hydroxypropyl-beta-cyclodextrin ternary system.

The effect of ternary complexation of naproxen, a poorly water soluble anti-inflammatory drug, with hydroxypropyl-beta-cyclodextrin and the basic aminoacid L-arginine on the drug dissolution properties has been investigated. Equimolar binary (drug-cyclodextrin or drug-arginine) and ternary (drug-cyclodextrin-arginine) systems were prepared by blending, cogrinding, coevaporation, and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry. The dissolution behavior of naproxen from the different products was evaluated by means of a continuous flow through method. The results of solid state studies indicated the presence of strong interactions between the components in ternary coevaporated and coground systems, which were both of totally amorphous nature. In contrast, the presence of either free drug or free arginine was detected when the third component (cyclodextrin or aminoacid) was physically mixed, respectively, to the drug-arginine binary system (as physical mixture, coevaporate, or coground product) or to the drug-cyclodextrin binary system (as physical mixture, coevaporate, or coground product). All ternary combinations were significantly (P<0.001) more effective than the corresponding binary drug-cyclodextrin and drug-arginine systems in improving the naproxen dissolution rate. The best performance in this respect was given by the ternary coevaporate, with about 15 times increase in terms of both drug relative dissolution rate and dissolution efficiency. The synergistic effect of the simultaneous use of arginine and cyclodextrin on the dissolution rate of naproxen was attributed to the combined effects of inclusion in cyclodextrin and salt formation, as well as to a specific role played by arginine in this interaction.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2002

A randomized, double-blind, multicenter trial of nimesulide-beta-cyclodextrin versus naproxen in patients with osteoarthritis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are the most widely used agents in the symptomatic treatment of osteoarthritis (OA). No data are presently available on the medium-term management of this disease with an on-demand treatment regimen, which nevertheless reflects medical practice. OBJECTIVES: The aim of this study was to compare nimesulide-beta-cyclodextrin and naproxen in terms of short-term (2 weeks) pain control with scheduled dosing and medium-term (5.5 months) pain control with on-demand dosing in patients with OA. METHODS: In this multicenter, randomized, double-blind, controlled study, we compared 2 weeks of scheduled treatment plus 5.5 months of on-demand treatment in patients with OA of the hip and/or knee and moderate to severe pain, with no important concomitant disorders. Treatment consisted of nimesulide-beta-cyclodextrin (400 mg BID, orally = 100 mg nimesulide BID) or naproxen (500 mg BID). The primary outcome measures for scheduled dosing were pain on movement (measured by visual analog scale), morning stiffness score, Lequesne index, and adverse events. For on-demand dosing, the measures were the same as for scheduled dosing, plus duration of treatment and global assessment of efficacy and tolerability by patient and physician. RESULTS: After 2 weeks, there was equivalent reduction from baseline in pain on movement in the 2 treatment groups (nimesulide-beta-cyclodextrin, -41.5%; naproxen, -40.5%); the reduction was significant after 1 week (P < 0.001). The findings were also similar for the morning stiffness score and Lequesne index. There were no significant differences in mean duration of on-demand treatment (nimesulide-beta-cyclodextrin, 163.03 days; naproxen, 166.3 days) or in mean consumption of study drug (nimesulide-beta-cyclodextrin, 0.85 +/- 0.61 sachets/d; naproxen, 0.74 +/- 0.42 sachets/d). Withdrawal due to intolerance occurred in 8 patients given nimesulide-beta-cyclodextrin and 13 patients given naproxen, with no significant difference between groups; 3 and 12 patients, respectively, withdrew due to gastrointestinal intolerance, a finding that was significantly different between groups (P < 0.01). Global assessment of efficacy by patient and physician was similar for both drugs. Assessment of tolerability significantly favored nimesulide-beta-cyclodextrin on the physician assessments (P < 0.05) but was similar for the 2 drugs on the patient assessments (physicians, 46.9% vs 30.9%; patients, 43.5% vs 33.3%). CONCLUSIONS: The results suggest that nimesulide-beta-cyclodextrin provides similar pain relief to naproxen in the management of OA of the hip and/or knee and is associated with fewer gastrointestinal adverse reactions. On-demand dosing may be an effective and well-tolerated low-dose regimen of nonsteroidal anti-inflammatory drugs for the maintenance of pain control in OA in the medium term.

Aged↗

PubMed1999

Influence of the preparation method on the physicochemical properties of binary systems of econazole with cyclodextrins.

Equimolar combinations of econazole, a very poorly water soluble antifungal agent, with beta-cyclodextrin and statistically substituted methyl-beta-cyclodextrin were investigated for both solid state characterization (differential scanning calorimetry, hot-stage microscopy, infrared spectroscopy, scanning electron microscopy) and dissolution properties (dispersed amount method). The influence of the preparation method (physical mixing, ball-milling, kneading, sealed-heating) on the physicochemical properties of the products was evaluated. Kneading and sealed-heating techniques led to amorphous products in the case of systems with methyl-beta-cyclodextrin, whereas crystalline drug was still clearly detectable in all products with beta-cyclodextrin. Independently of the preparation technique, all combinations with methyl-beta-cyclodextrin yielded better performance than the corresponding ones with beta-cyclodextrin. However, the influence of the preparation method was clearly more marked for products with methyl-beta-cyclodextrin and made to be possible to better display the different performance of the examined carriers. In fact, the sealed-heated with the beta-derivative showed an increase of drug dissolution efficiency of 130% with respect to the corresponding physical mixture, in comparison to the 70% increase obtained from that with beta-cyclodextrin. Moreover, whereas the difference in dissolution efficiency values between coground products was only about 8% in favor of the beta-derivative, it reached 80 and 90% between sealed-heated and kneaded products, respectively.

Antifungal Agents↗

PubMed2003

Medium effect (transfer activity coefficient) of methanol and acetonitrile on beta-cyclodextrin/benzoate complexation in capillary zone electrophoresis.

Association constants, Kc, were derived from the electrophoretic mobilities of the anionic solutes (seven benzoates with hydroxy or chloro substituents) by capillary zone electrophoresis in different solvent systems, consisting of binary mixtures of water with up to 20% (v/v) methanol or acetonitrile, respectively. The association constants expectedly are found to decrease with increasing organic solvent concentration. The effect of organic solvents on the Kc of the benzoates with beta-cyclodextrin was analyzed applying the concept of the transfer activity coefficient (or the medium effect). This concept enables the evaluation of the significance of the contributions of the individual species involved in the complexation equilibrium in the different solvents: the benzoate ion, beta-cyclodextrin, and the anionic benzoate-beta-cyclodextrin complex. The medium effect on benzoate was calculated from the change in acidity constant of benzoic acid in the different mixed solvents and the corresponding transfer activity coefficients of the proton and the molecular acid. The transfer activity coefficients for beta-cyclodextrin results from its solubility at saturation in the different solvents. In this way, an estimation of the standard free energy of transfer, deltaG(t)0, of each species involved in the complexation equilibrium was possible for the transfer from water into the respective mixed solvent. It was found that the organic solvents do not significantly affect deltaG(t)0 for the benzoate anion. However, the organic solvents play a different role concerning the stabilization of beta-cyclodextrin and the complex anion: whereas the addition of acetonitrile has nearly no influence on deltaG(t)0 of the anionic complex, the reduction in Kc is caused by the enhanced stabilization of beta-cyclodextrin (reflected by its better solubility). Addition of methanol, on the other hand, lowers the solubility of beta-cyclodextrin, thus giving positive values for deltaG(t)0. Thus, the overall effect on Kc in methanolic solutions must be related to the pronounced destabilization of the benzoate-beta-cyclodextrin complex.

Acetonitriles↗

PubMed2003

Effects of dietary beta-cyclodextrin in hypercholesterolaemic rats.

Beta-cyclodextrin is a compound that forms inclusion complexes with a variety of molecules, specially bile acids and sterols. This study examines the effects of beta-cyclodextrin on cholesterol and bile acid metabolism in hypercholesterolaemic rats. Male Wistar rats were divided into 4 groups that received during 7 weeks: control diet, 2% cholesterol diet (A), A+2.5% beta-cyclodextrin (B) and A+5% beta-cyclodextrin (C). The cholesterol-rich diet induced hepatomegaly and fatty liver and significantly reduced cholesterol, bile acid and phospholipid secretion. Addition of beta-cyclodextrin normalised biliary lipid secretion. Moreover, when compared to A, beta-cyclodextrin significantly lowered plasma phospholipid concentration (B: -21%; C: -29%) and the liver free/total cholesterol molar ratio (B: -40%; C: -38%), increased bile acid faecal output (B: +17%; C: +62%) and enhanced cholesterol 7alpha-hydroxylase activity (B:+50%; C : +100%)and mRNA levels (B: + 14%; C: +29%). 5% beta-cyclodextrin also reduced plasma triglycerides concentration (-38%). However, ALT and AST activities were significantly increased (B: +140% and +280%; C: +72% and +135%) and there was a high incidence of cell necrosis with portal inflammatory cell infiltration. Addition of beta-cyclodextrin to a cholesterol-rich diet results in a triglyceride-lowering action, enhancement of bile acid synthesis and excretion, and normalization of biliary lipid secretion, but produces a marked hepatotoxic effect.

Alanine Transaminase↗