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PubMed1993

Piroxicam-beta-cyclodextrin in the treatment of acute pain of rheumatic disease.

Analgesics continue to be the mainstay of therapy in osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role, particularly where there is a significant inflammatory component to the osteoarthritis. Piroxicam-beta-cyclodextrin (PBC) is a new formulation in which piroxicam has been complexed with beta-cyclodextrin, a cyclic oligosaccharide. This results in an increase in the rate of absorption of the active compound and, consequently, in an earlier onset of analgesic action. PBC, like piroxicam, is administered once daily. PBC has been used in the treatment of osteoarthritis. In comparison with piroxicam, PBC showed a more rapid analgesic-anti-inflammatory action after the first administration in patients with active osteoarthritis. Subsequent evaluations at the second, fifth and last day of treatment demonstrated a comparable efficacy of the two drugs. The efficacy and tolerability of PBC was compared with other NSAIDs given intramuscularly, such as diclofenac and ketoprofen. The three compounds provided marked pain relief within thirty minutes and this increased progressively until the third to fourth hour. The efficacy of oral PBC was comparable to that of intramuscular diclofenac or ketoprofen. In comparison with metamisole PBC achieved a more rapid and sustained reduction in pain intensity during the first twelve hours of treatment. This rapid and marked reduction in pain intensity with PBC was also observed in patients with low-back pain when compared with etodolac. In view of its efficacy, tolerability and rapid onset of action, piroxicam-beta-cyclodextrin appears to be an useful analgesic and a prominent progress in the treatment of acute rheumatic pain.

Acute Disease↗
PubMed1993

[Analgesic efficacy and the tolerance for piroxicam-beta-cyclodextrin compared to piroxicam, paracetamol and placebo in the treatment of postextraction dental pain].

INTRODUCTION: Acute postoperative pain is a common experience in oral surgery practice. Non-steroidal anti-inflammatory drugs (NSAIDs) are quite effective against mild to moderate pain and they are generally better suited in ambulatory outpatients than narcotic analgesics. The analgesic activity of piroxicam, a well known NSAID has been documented in many pain states. Piroxicam can be administered once daily because of its long half-life, but its absorption in the gastrointestinal tract is slow as it is its onset of action. Piroxicam-beta-cyclodextrin (PBCD) is a new formulation of piroxicam which is the product of supermolecular encapsulation of piroxicam with the cyclic oligosaccharide beta-cyclodextrin. PBCD is absorbed much faster than standard piroxicam, and its action as an analgesic is consequently more rapid. The purpose of this study was to assess the efficacy and the rapidity of action of piroxicam-beta-cyclodextrin in comparison with standard piroxicam, paracetamol and placebo following surgical extraction of impacted third molars. MATERIALS AND METHODS: The study population was composed of 32 patients of both sexes and in good health. To be included into the study, patients must have had third molar removal resulting in acute post-surgical pain of at least moderate intensity. The patients were then randomly assigned to one of four treatment groups. PBCD 20 mg tablets; piroxicam 20 mg capsules; paracetamol 500 mg tablets, or placebo. The study was conducted according to a double-blind, double-dummy design. Pain intensity and pain relief were recorded at 0.5, 1, 1.5, 2, 3, 4 hours after a single dose of the study drugs, by means of a Keele-type rating scale. Rescue analgesics were not allowed before one and a half hour after taking the study drugs. A global evaluation of study drugs was expressed by patients at the end of the observation period. RESULTS: Treatment groups were homogeneous for demographic characteristics of the patients and for pain intensity at the time of medication with study drugs. All patients who received placebo requested supplemental analgesics, while none of the patients treated with the active drugs needed rescue analgesics. PBCD and paracetamol were comparable for their analgesic effect, while the time lag before a significant reduction of pain intensity with piroxicam was longer. Piroxicam and PBCD were superior to paracetamol because they showed a substantial analgesic effect through the 4-hour study duration, while paracetamol did not induce a complete relief from pain. DISCUSSION: One of the most commonly utilized model for the evaluation of analgesics is the third molar extraction pain. Our study clearly differentiated between active drugs and placebo. Furthermore, while PBCD and paracetamol showed a rapid effect, piroxicam was slow in inducing pain relief. The analgesic and anti-inflammatory activity of PBCD and piroxicam brought about the resolution of pain and inflammation consequent to the dental extraction. Paracetamol, a pure analgesic, was not equally active and pain persisted, even if at a low grade, throughout the observation period; probably this was due to local inflammation and edema. The results of our study appear to confirm the pharmacokinetic data on PBCD, which showed that therapeutic blood levels are reached faster with PBCD than with the standard piroxicam formulation. This results should be confirmed in studies with an adequate number of patients.

Acetaminophen↗
PubMed1998

Homogeneous assay for measuring low-density lipoprotein cholesterol in serum with triblock copolymer and alpha-cyclodextrin sulfate.

We have developed a fully automated method for measuring LDL-cholesterol (LDL-C) in human serum without the need for prior separation, using a nonionic surfactant, polyoxyethylene-polyoxypropylene block copolyether (POE-POP), and a sodium salt of sulfated cyclic maltohexaose, alpha-cyclodextrin sulfate. Of the surfactants tested, POE-POP with a higher molecular mass of the POP block and a greater hydrophobicity reduced the reactivity of cholesterol in lipoprotein fractions; the reactivity in descending order was LDL >> VLDL > chylomicron approximately HDL. Gel filtration chromatographic studies revealed that POE-POP removed lipids selectively from the LDL fraction and allowed them to participate in the cholesterol esterase-cholesterol oxidase coupling reaction system. By contrast, alpha-cyclodextrin sulfate reduced the reactivity of cholesterol, especially in chylomicrons and VLDL. A combination of POE-POP with alpha-cyclodextrin sulfate provided the required selectivity for the determination of LDL-C in serum in the presence of magnesium ions and a small amount of dextran sulfate without precipitating lipoprotein aggregates. There was a good correlation between the results of LDL-C assayed by the proposed method and the beta-quantification reference method involving 161 sera with triglyceride concentrations ranging from 0.3 to 22.6 mmol/L.

Automation↗
PubMed2003

Enhancement of solubility and bioavailability of beta-lapachone using cyclodextrin inclusion complexes.

PURPOSE: To explore the use of cyclodextrins (CD) to form inclusion complexes with beta-lapachone (beta-lap) to overcome solubility and bioavailability problems previously noted with this drug. METHODS: Inclusion complexes between beta-lap and four cyclodextrins (alpha-, beta-, gamma-, and HPbeta-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and 1H-NMR spectroscopy. Biologic activity and bioavailability of beta-lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). RESULTS: Phase solubility studies showed that beta-lap solubility increased in a linear fashion as a function of alpha-, beta-, or HPbeta-CD concentrations but not gamma-CD. Maximum solubility of beta-lap was achieved at 16.0 mg/ml or 66.0 mM with HPbeta-CD. Fluorescence and 1H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between beta-CD and HPbeta-CD with beta-lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of beta-lap in beta-CD or HPbeta-CD inclusion complexes (TD50 = 2.1 microM). Animal studies in mice showed that the LD50 value of beta-lap in an HPbeta-CD inclusion complex is between 50 and 60 mg/kg. CONCLUSIONS: Complexation of beta-lap with HPbeta-CD offers a major improvement in drug solubility and bioavailability.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMedDate not supplied

Reversed-phase chromatographic study of the binding of polychlorinated biphenyls to cyclodextrins and sodium dodecylsulphate.

The binding of polychlorinated biphenyls (PCBs) to hydroxypropyl-beta-cyclodextrin (HP-beta-CD), tau-cyclodextrin (tau-CD) and sodium dodecylsulphate (SDS) was studied by reversed-phase thin-layer chromatography and the relative strength of interaction was calculated. HP-beta-CD and SDS did not bind to PCBs making it unlikely that these compounds modify the adsorption capacity or decomposition rate of PCBs. Each PCB formed inclusion complexes with tau-cyclodextrin. The inclusion-forming capacity of PCBs increased with an increase in the number of chloro substitutions in the molecule, indicating that tau-CD can be successfully used for the modification of the physicochemical and biochemical characteristics of PCBs. The linear correlation between the hydrophobicity and specific hydrophobic area of PCBs indicated that they can be considered as a homologous series of compounds.

Chemical Phenomena↗
PubMedDate not supplied

Chiral separations of enantiomeric pharmaceuticals by capillary electrophoresis using sulphobutyl ether beta-cyclodextrin as isomer selector.

Capillary electrophoresis has developed into an extremely useful technique for the separation of optical isomers. High efficiencies and the availability of many types of isomer selectors allowing rapid and inexpensive methods development make capillary electrophoresis (CE) an attractive alternative to gas chromatography (GC) and high-pressure liquid chromatography (HPLC) for the determination of chiral purity. In this research the separation of the enantiomers of some chiral pharmaceuticals was investigated using anionic sulphobutyl ether-beta-cyclodextrins as isomer selectors. These chiral selectors have a large countercurrent mobility, making them inherently advantageous as selectors as compared to neutral cyclodextrins. The effects of pH, buffer composition and selector concentration on the chiral separation of these compounds was investigated. All of the compounds studied were successfully resolved by the sulphobutyl ether beta-cyclodextrins (SBE-beta-CDs) typically with run times of less than 20 min using low concentrations of the SBE selector (1-5 mM).

Atenolol↗
PubMedDate not supplied

Separation of chiral amino acids by micellular electrokinetic chromatography with derivatized cyclodextrins.

The chiral separation of several amino acid (AA) enantiomers derivatized with naphthalene-2,3-dialdehyde (NDA) was achieved by use of cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC). Both neutral hydroxypropyl beta-cyclodextrin (HP-beta-CD) and charged carboxymethyl beta-cyclodextrin (CM-beta-CD) were used as buffer additives for optical resolution of derivatized amino acids. The order of elution and the mechanism of separation for different CDs were explained by considering important chemical equilibria in the sodium dodecyl suphate, CD and amino acid system. Furthermore, the importance of SDS for the separation of a mixture of AAs, and the effect of CD and analyte concentration on the resolution will be discussed.

Amino Acids↗
PubMedDate not supplied

Direct enantiomeric separations by high performance liquid chromatography using cyclodextrins.

Due to their identical chemical and physical properties, the separation of enantiomers has been considered one of the most difficult challenges in chemistry from both an analytical or a preparative viewpoint. With the development and commercialization of many new or improved chiral stationary phases and chiral additives, interest in enantiomeric separation by HPLC has grown tremendously in the last two decades. Cyclodextrins and modified cyclodextrins are widely used chiral selectors. They are used as either the chiral stationary phases, as chiral mobile phase additives, or as chiral counter-ions. This review describes the historical development of derivatized and underivatized cyclodextrins in HPLC and their various applications.

Chemical Phenomena↗
PubMed1999

Chiral discrimination of the analgesic cizolirtine by using cyclodextrins: A (1)H NMR study on the solution structures of their host-guest complexes.

The use of four cyclodextrins (three native and one beta-CD derivative) as NMR chiral solvating agents to resolve the enantiomers of (+/-)-cizolirtine, 1, and its chemical precursor (the carbinol, (+/-)-2), was investigated. The best enantiodiscrimination occurred when beta-cyclodextrin was used. ROESY experiments were performed to qualitatively ascertain the most probable host-guest structures in D(2)O solution, and the binding features found were explained in terms of spatial fitting of the guest molecules into the macrocyclic cavities. No geometrical differences were noted between the two diastereomeric complexes formed by a cyclodextrin and a racemic substrate, so the magnetic nonequivalence induced on guest protons by the enantioselective binding had to be explained as a result of subtle disparities in the orientation and/or the conformational state of the complexed enantiomers.

Analgesics, Non-Narcotic↗
PubMed1999

Comparison of sulfobutylether- and sulfated-beta-cyclodextrins as additives for the chiral separation of basic spirobenzopyrans by capillary electrophoresis.

Three charged substituted beta-cyclodextrins (beta-CDs), sulfobutylether-beta-(SBE-beta-CD), degree of substitution (DS) 4 and 7), and sulfated-beta-(S-beta-CD) cyclodextrins, were compared as chiral additives in capillary electrophoresis for the enantiomeric separation of basic spirobenzopyran derivatives (pKa 9.9) which differ from each other by an N-alkyl group. The number of sulfobutylether groups attached to the cyclodextrin moiety significantly influences the enantioseparation of the basic drugs. SBE-beta-CD (DS 7) which is more strongly bound to cationic analyte than SBE-beta-CD (DS 4.6), requires smaller concentrations to achieve the same resolution. Besides, better enantioresolutions were obtained with S-beta-CD rather than with SBE-beta-CDs though higher concentrations are required, which led to high current values. However, both pairs of enantiomers cannot be resolved using S-beta-CD while SBE-beta-CDs make it possible to resolve simultaneous enantioseparation of such solutes slightly differing in hydrophobicity. This supports the hypothesis that hydrophobic interactions (outside of the CD cavity) between the butyl group attached to SBE-beta-CD and the N-alkyl group of spirobenzopyran play a role in the enantioseparation. On the other hand, the sulfate group of S-beta-CD was directly attached to the CD moiety which means that the S-beta-CD-drug complexation mechanism arises through the combination of electrostatic and hydrophobic (inside the CD cavity) interactions. Finally, enantiomers of spirobenzopyran drugs were satisfactorily resolved by CE using a 20 mg/mL S-beta-CD concentration (resolution 4.0), 7 mg/mL SBE-beta-CD DS 4 (resolution 1.3), or 5 mg/mL SBE-beta-CD DS 7 (resolution 3.3) added to the phosphate buffer (pH 2.6, 50 mM ionic strength).

Anions↗
PubMed1999

Enantioseparation of derivatized amino acids by capillary isoelectric focusing using cyclodextrin complexation.

Enantioseparation of dansylated as well as 6-aminoquinolyl-N-hydroxysuccinimidylcarbamate (AQC)-derivatized amino acids by means of capillary isoelectric focusing using various cyclodextrin derivatives is demonstrated. Separation is based on the enantioselective shift of the isoelectric points upon complexation with the chiral selectors. The zwitterionic, diastereomeric analyte-cyclodextrin complexes exhibited differences in the pI values up to more than 0.25 pI units. Enantioresolution was achieved for a number of derivatized amino acids and various selectors added to the carrier ampholyte solution. The hydroxypropyl-beta-cyclodextrin proved to be the best selector for this purpose. Enantioseparation as dependent on the selector concentration was evaluated in a range between 5 and 30 mM. Separation could be attained down to selector concentrations corresponding to a degree of complexation as low as 30%. The peaks appear according to the degree of complexation between the positions adopted without and with full complexation. The kinetics of complex formation and dissociation was fast enough in most instances to produce single peaks, even with complexation degrees near 0.5 and significant pI shifts. Peak widths were slightly enlarged in these instances. The method offers excellent perspectives for preparative applications.

Amino Acids↗
PubMed2000

Cyclodextrin dimers as receptor molecules for steroid sensors.

The dansyl-modified dimer 9 complexes strongly with the steroidal bile salts. Relative to native beta-cyclodextrin, the binding of cholate (1a) and deoxycholate (1b) salts is especially enhanced. These steroids bind exclusively in a 1:1 fashion. For other bile salts (1c-1e) both 1:1 and 1:2 complexes were observed with stabilities similar to those of native beta-cyclodextrin. This indicates that only one cavity is used, with a small contribution from the second. The difference is attributed to the absence of a 12-hydroxy group in the second group of steroids. Comparison with a dimer that lacks the dansyl moiety (6) shows that this group especially hinders the cooperative binding of la and 1b. The smaller interference in the binding of the other steroids indicates that self-inclusion of the dansyl moiety hardly occurs. This weak self-inclusion is supported by fluorescence studies. The dansyl fluorescence of dimer 9 is less blue-shifted than that of other known dansyl-appended cyclodextrin derivatives; this is indicative of a more polar micro-environment. Addition of guests causes a change in fluorescence intensity.

Bile Acids and Salts↗
PubMed2000

Fast enantiomeric separation of uniconazole and diniconazole by electrokinetic chromatography using an anionic cyclodextrin: application to the determination of analyte-selector apparent binding constants for enantiomers.

The enantiomeric resolution of the fungicides uniconazole and diniconazole was performed using electrokinetic chromatography with cyclodextrins as pseudostationary phase (CD-EKC). A systematic evaluation of several chiral selectors was made. The anionic derivative carboxymethylated-gamma-cyclodextrin (CM-gamma-CD) was found to be the most appropriate for the enantioseparation of fungicides among all cyclodextrins tested. The influence of some experimental conditions such as nature and buffer pH, chiral selector concentration, and temperature on the enantiomeric separation of the compounds studied was also investigated. The use of a 50 mM phosphate buffer (pH 6.5) containing 5 mM CM-gamma-CD and a temperature of 50 degrees C enabled the baseline enantioresolution of mixtures of uniconazole and diniconazole in less than 5 min. In addition, apparent binding constants for each enantiomer-CM-gamma-CD pair at several temperatures, as well as thermodynamic parameters for binding were calculated.

Cyclodextrins↗
PubMed2001

Enantioseparation of ofloxacin in urine by capillary electrokinetic chromatography using charged cyclodextrins as chiral selectors and assessment of enantioconversion.

A method was developed for the enantioseparation of ofloxacin, a member of the fluoroquinolones, using an anionic cyclodextrin-derivative with or without combination with a neutral cyclodextrin-derivative, as the chiral selector (s) in an electrokinetic chromatography system. The best results were obtained with 0.35 mM sulfated beta-cyclodextrin dissolved in a 50 mM phosphate buffer, pH 2.5, and at 15 degrees C. Under these conditions, a resolution of 2 was readily achieved. Furthermore, under adequate separation conditions, studies were performed in order to assess possible in vitro and in vivo enantioconversion of levofloxacin. The current method allows detection of 2 microg R-(+)-ofloxacine/mL diluted urine without the necessity of sample cleanup.

Chromatography↗
PubMed2002

Chiral recognition of functionalized cyclodextrins in capillary electrophoresis.

The chiral recognition of hydroxypropylated, dimethylated, and sulfated cyclodextrins was evaluated by utilizing them as chiral additives in capillary electrophoresis. Although each selector yielded enantiomeric separations of most of the target analytes, differences were observed in the electrophoretic results for the different derivatized cyclodextrins and for additives having varying degrees of substitution. The results for the sulfated cyclodextrins also highlighted the importance of knowing the degree of substitution as well as the location of the substituents when comparing chiral selectors.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed1991

Release of ketoprofen from dermal bases in presence of cyclodextrins: effect of the affinity constant determined in semisolid vehicles.

We describe a method to determine the affinity constant values between Ketoprofen and beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in semisolid vehicles. The method is based on the diffusion of the drug, released from semisolid vehicles, through a lipidic non porous membrane. The affinity constants of Ketoprofen towards cyclodextrins as determined in semisolid media better represent the release of the drug from dermal bases than the corresponding values in aqueous systems.

Chemical Phenomena↗
PubMed2006

Cyclodextrins micrometric powders obtained by supercritical fluid processing.

Supercritical fluid technology offers the possibility to produce dry powder formulations of biocompatible materials, overcoming the drawbacks of classical micronization processes. In this work, Supercritical Assisted Atomization (SAA) has been used to micronize alpha-cyclodextrin (alpha-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Some process parameters, such as precipitation temperature and solute concentration in the liquid solution, have been studied to evaluate their influence on morphology and size of precipitated particles. Cyclodextrins (CDs) micronization has been successful: well-defined spherical microparticles of alpha-CD and HP-beta-CD have been produced. Particle size analysis revealed that sharp distributions have been obtained: 95% of particles have diameters ranging between 0.1 and 5 microm for both CDs. X-ray and DSC analyses have been also performed to investigate CDs modifications induced by SAA processing: amorphous particles have been obtained in both cases, whereas raw alpha-CD was crystalline and raw HP-beta-CD was amorphous.

Automation↗
PubMed2004

Diastereoisomer-selective inclusion complexation of Cinchona alkaloids with a modified beta-cyclodextrin: fluorescent behavior enhanced by chiral-tether binding. Short communication.

The molecular 1:1 complexation of cinchona alkaloids by mono(6-deoxy-6-{[(R)-1-(hydroxymethyl)propyl]amino})-beta-cyclodextrin (1) in aqueous solution has been investigated by 2D-NMR, fluorescence titration, and fluorescence-lifetime experiments. Generally, with 1 as the host, in contrast to beta-cyclodextrin proper, strong binding of quinine (2; Ka = 84,200 M(-1)) and quinidine (3; Ka = 27,300 M(-1)) at pH 6.8 was observed, as monitored by an increase in fluorescence intensity, with a fair degree of diastereoisomer discrimination (ca. 3:1). To rationalize these results, two possible cooperative complexation modes, including specific H-bonding interactions to the chiral tether of the cyclodextrin portion, are proposed.

Binding Sites↗