Per(2,3,6-tri-O-benzyl)-γ-cyclodextrin was debenzylated by DIBAL-H to produce a mixture of C6(I),C6(IV) and C6(I),C6(V) isomeric diols, which were separated and isolated. The C2-symmetrical C6(I),C6(V) diol was transformed into dithiol and dimerized to produce a γ-cyclodextrin duplex structure. A crystal structure revealed tubular cavity whose peripheries are slightly elliptically distorted. The solvent accessible volume of the cavity of the γ-CD duplex is about 740 Å(3). Due to this large inner space the duplex forms very stable inclusion complexes with steroids; bile acids examined in this study show binding affinities to the γ-cyclodextrin duplex in the range of 5.3 × 10(7) M(-1)-1.9 × 10(8) M(-1).
- MeSH
- Dimerization MeSH
- Disulfides chemistry MeSH
- Chemistry, Pharmaceutical methods MeSH
- gamma-Cyclodextrins chemical synthesis chemistry MeSH
- Imatinib Mesylate chemistry MeSH
- Calorimetry MeSH
- Kinetics MeSH
- Hydrogen-Ion Concentration MeSH
- Crystallography, X-Ray MeSH
- Lithocholic Acid chemistry MeSH
- Oxygen chemistry MeSH
- Magnetic Resonance Spectroscopy MeSH
- Molecular Conformation MeSH
- Solvents chemistry MeSH
- Steroids chemistry MeSH
- Sulfhydryl Compounds chemistry MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Herein we report on the synthesis, characterization and the novel capillary electrophoretic use of octakis-(2,3-di-O-methyl-6-O-carboxymethyl)-γ-cyclodextrin sodium salt (ODMCM). ODMCM is the first single-isomer carboxymethyl-γ-cyclodextrin that is fully methylated on its secondary side and carries ionizable carboxymethyl functions on its primary side. ODMCM was prepared with high isomeric purity through a four-step synthetic procedure. The purity of each intermediate was characterized by appropriate chromatographic methods, while the isomeric purity of the carboxymethylated product was determined by an HPLC method using a CD-Screen-IEC column and by a capillary electrophoretic method using indirect UV detection, as well. The structural identification of the ODMCM was carried out by 1D, 2D NMR spectroscopy and ESI-MS. The acid-base characterization of the chiral selector was carried out by (1)H NMR-pH titration. The chiral separation ability of the synthesized selector was studied by chiral capillary electrophoresis. ODMCM was used as a background electrolyte additive to separate enantiomers of representative pharmacologically significant model molecules such as propranolol, citalopram, ketamine, tapentadol and dapoxetine. The effects of the selector concentration and the pH of the background electrolyte on the enantiorecognition properties were investigated. (1)H NMR spectroscopy was further applied to get deeper insight of the host-guest inclusion complex formation. The pH-dependent enantioselectivity of this new single-isomer chiral selector was demonstrated by chiral capillary electrophoresis and (1)H NMR spectroscopy.
- MeSH
- Electrophoresis, Capillary * MeSH
- gamma-Cyclodextrins chemistry MeSH
- Spectrometry, Mass, Electrospray Ionization * MeSH
- Indicators and Reagents MeSH
- Hydrogen-Ion Concentration MeSH
- Magnetic Resonance Spectroscopy MeSH
- Spectrophotometry, Ultraviolet * MeSH
- Stereoisomerism MeSH
- Chromatography, High Pressure Liquid MeSH
- Publication type
- Journal Article MeSH
The present study describes a rapid and effective capillary electrophoresis (CE) method for the enantioseparation of pindolol using single-isomer octa(6-O-sulfo)-γ-cyclodextrin. The complexation parameters were determined under neutral and high pH conditions to identify optimal separation conditions using a theoretical model. Baseline separation of pindolol enantiomers was achieved within 6 min in a sodium/MOPS buffer, pH 7.2, with a selector concentration of 6 mM. The method was validated according to the ICH guidelines using imidazole as an internal standard. Low limits of detection and quantification were found, specifically 1.2 μg/mL and 4 μg/mL (0.6 μg/mL and 2 μg/mL per enantiomer), respectively. The calibration curves showed good linearity, with a coefficient of determination R2 ≥ 0.999 over a 5 - 55 μg/mL concentration range and over a 50 - 300 μg/mL concentration range of the racemic mixture. The relative standard deviations (%RSD) of intra-day and inter-day precision were lower than 8% at LOQ level, lower than 3% at 50 μg/mL level and lower than 1.5% at 300 μg/mL level. Accuracy ranged from 95 to 103% (106% at LOQ level). The proposed method was successfully tested on a medical formulation of Visken® Sandoz intravenous solution and Visken® Teofarma pills for oral use.
- MeSH
- Time Factors MeSH
- Electrophoresis, Capillary methods MeSH
- gamma-Cyclodextrins chemistry MeSH
- Calibration MeSH
- Hydrogen-Ion Concentration MeSH
- Limit of Detection MeSH
- Pindolol isolation & purification MeSH
- Buffers MeSH
- Reproducibility of Results MeSH
- Software * MeSH
- Stereoisomerism MeSH
- Publication type
- Journal Article MeSH
- Validation Study MeSH
The health benefits of resveratrol have been proven to inhibit the development of numerous diseases. A frequent limitation in its use is a low bioavailability stemming from a poor solubility and fast enterohepatic metabolism. Thus, the aim of the research was to investigate the possibility to formulate mucoadhesive cyclodextrin- and xanthan gum-based buccal tablets in order to increase the solubility of resveratrol and to eliminate bypass enterohepatic metabolism. Systems of resveratrol with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) prepared by the dry mixing method (ratio 1:1) were selected for the of tablets where xanthan gum was used as a mucoadhesive agent. They were identified on the basis of PXRD, FT-IR analysis. Tablets F1 (with α-CD), F2 (with β-CD) and F3 (with γ-CD) were characterized by the highest compactibility as well as by favorable mucoadhesive properties. Resveratrol release from these tablets was delayed and controlled by diffusion. The tablets prepared in the course of this study appear to constitute promising resveratrol delivery systems and are recommended to increase the effectiveness of the treatment in many diseases, particularly periodontitis.
- Publication type
- Journal Article MeSH
Práce podává souborné výsledky studia rozpouštění kalciového antagonisty nimodipinu ve vodnýchroztocích devíti cyklodextrinů, nativního β-cyklodextrinu (β-CD) a jeho derivátů hydroxyethyl-β-CD(HE-β-CD), tří hydroxypropyl-β-CD (HP-β-CD) s navzájem různým stupněm substituce, methyl-β--CD (M-β-CD), nativního α-cyklodextrinu (α-CD), hydroxypropyl-α-CD (HP-α-CD) a hydroxypropyl--γ-CD (HP-γ-CD). Rozpouštění nimodipinu bylo sledováno v závislosti na čase (až 14 dní) a koncentracicyklodextrinu zhruba do 0,07 mol/l, s výjimkouméně rozpustného β-CD.Ve sledovanémrozmezíbyly pozorovány vesměs lineární fázové diagramy rozpustnosti nimodipinu v roztocích studovanýchcyklodextrinů, z nichž byly vyhodnoceny konstanty stability inkluzních komplexů nimodipin –cyklodextrin (1:1) a odvozeny lineární empirické rovnice pro výpočet koncentrace solubilizovanéhonimodipinu při dané koncentraci cyklodextrinu.Nejúčinnějším solubilizérem nimodipinu je M-β-CD,dobrou solubilizační účinnost mají též HE-β-CD a HP-β-CD s nízkým stupněm substituce, kterémohou být přijatelné i pro přípravu parenterálních roztoků nimodipinu.
The results of a comprehensive study of the dissolution of the calcium antagonist nimodipine inaqueous solutions of nine cyclodextrins are reported. The used cyclodextrins were native β-cyclodextrin(β-CD), its derivatives hydroxyethyl-β-CD (HE-β-CD), three hydroxypropyl-β-CD (HP-β-CD)with various degree of substitution and methyl-β-CD (M-β-CD), native α-cyclodextrin (α-CD),hydroxypropyl-α-CD (HP-α-CD) and hydroxypropyl-γ-CD (HP-γ-CD). The nimodipine dissolutionwas studied as a function of time (up to 14 days) and cyclodextrin concentration up to 0.07 mol/l,excepting the less soluble β-CD. In this range of cyclodextrin concentration, linear phase diagramsof nimodipine solubility in the cyclodextrin solutions were observed. From them we derived thestability constants of the inclusions complexes nimodipine – cyclodextrin (1:1) as well as theempirical linear equations for the calculation of the saturated nimodipine concentration at a givencyclodextrin concentration. The most efficient solubiliser of nimodipine was M-β-CD, a good solubilizingefficiency was also shown by HE-β-CD and HP-β-CDs (with a low degree of substitution),which may be acceptable for the preparation of parenteral nimodipine solutions.
A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity and of impurities of the chiral drug ambrisentan has been developed following the Quality by Design principles. The selected separation system consisted of a micellar pseudostationary phase made by sodium dodecyl sulphate with the addition of γ-cyclodextrin. The effects of critical process parameters (capillary length, temperature, voltage, borate concentration, pH, sodium dodecyl sulphate concentration, γ-cyclodextrin concentration) on enantioresolution of ambrisentan and analysis time were extensively investigated by multivariate strategies involving a screening phase and Response Surface Methodology. The Design Space was defined with a desired probability level π≥90%, and the working conditions, with the limits of the Design Space, corresponded to the following: capillary length, 64.5cm; temperature, 22°C; voltage, 30kV (26-30kV); background electrolyte, 100mM borate buffer pH 9.20 (8.80-9.60), 100mM sodium dodecyl sulphate, 50mM (43-50mM) γ-cyclodextrin. A Plackett-Burman design was applied for robustness testing, and a method control strategy was established. The method was fully validated according to the International Conference on Harmonisation guidelines and was applied to ambrisentan coated tablets.
- MeSH
- Borates chemistry MeSH
- Chromatography, Micellar Electrokinetic Capillary * methods MeSH
- Cyclodextrins MeSH
- Sodium Dodecyl Sulfate MeSH
- Phenylpropionates analysis chemistry MeSH
- Calibration MeSH
- Hydrogen-Ion Concentration MeSH
- Drug Contamination MeSH
- Buffers MeSH
- Pyridazines analysis chemistry MeSH
- Reproducibility of Results MeSH
- Quality Control MeSH
- Stereoisomerism MeSH
- Tablets analysis MeSH
- Publication type
- Journal Article MeSH
Enantiomers of helical N-heteroaromatic dications, helquats, were separated by CE. An acidic 22/35 mM sodium/phosphate background electrolyte, pH 2.4, with addition of randomly sulfated α-, β- and γ- cyclodextrins allowed enantioresolution of a series of helquats, which comprised 5, 6 and 7 fused rings participating in the helical backbone. In general, at least one of the chiral selectors was found to provide baseline separation for 22 out of 24 helquats and partial separation for the remaining two. Individually, the sulfated γ-cyclodextrin turned out to separate 79% of the helquats, followed by the β- and α-congeners with 54 and 42% of the resolved compounds, respectively. Migration order of enantiomers was inspected for selected helquats and a relation of molecular size of the analytes to a cavity of the cyclodextrin selectors is discussed.
A method for the separation of enantiomers of leucine and phenylalanine benzothiazole derivatives as potential antimicrobial agents was developed using capillary zone electrophoresis with a dual cyclodextrin (CD) system. The best resolution of enantiomers was achieved in 100 mmol/L phosphate background electrolyte (pH 3.5) with the dual CD system consisting of 10 mmol/L of β-CD with 10 mmol/L of 2-hydroxypropyl-β-cyclodextrin for leucine derivative and 10 mmol/L of 2-hydroxypropyl-γ-cyclodextrin for phenylalanine derivative, respectively. Under the optimal conditions, the highest enantioresolution of 1.25 was achieved in a noncoated-fused silica capillary at 17°C and 24 kV applied voltage.
Sugammadex je modifikovaný g-cyklodextrin, jehož efekt spočívá v tvorbě pevných komplexů se steroidními svalovými relaxancii. Terapeutickou indikací je zrušení neuromuskulární blokády způsobené rokuroniem nebo vekuroniem. Sugammadex je biologicky inaktivní a ukázal se jako bezpečné a dobře tolerované léčivo.
A modified γ -cyclodextrin, sugammadex exerts its effect by forming tight complexes with steroidal neuromuscular blocking drugs. Sugammadex is indicated in reversal of neuromuscular blockade induced by rocuronium or vecuronium. Sugammadex is biologically inactive and appears to be safe and well tolerated.
- MeSH
- Anesthesiology methods trends MeSH
- Pharmacokinetics MeSH
- Financing, Organized MeSH
- gamma-Cyclodextrins administration & dosage adverse effects therapeutic use MeSH
- Humans MeSH
- Evidence-Based Medicine trends MeSH
- Neuromuscular Blockade adverse effects trends utilization MeSH
- Neuromuscular Agents pharmacokinetics pharmacology therapeutic use MeSH
- Drug-Related Side Effects and Adverse Reactions MeSH
- Vecuronium Bromide antagonists & inhibitors therapeutic use MeSH
- Check Tag
- Humans MeSH
Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe2O3) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe2O3 provides a relatively stable colloid product containing 48μmol of MCDg(-1). MCD-modified γ-Fe2O3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[(14)C]glutamate and increase the extracellular l-[(14)C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol.
- MeSH
- beta-Cyclodextrins chemistry pharmacology MeSH
- Biological Transport drug effects MeSH
- Cell Membrane drug effects metabolism MeSH
- Cholesterol isolation & purification metabolism pharmacology MeSH
- Kinetics MeSH
- Rats MeSH
- Glutamic Acid metabolism MeSH
- Magnetite Nanoparticles chemistry MeSH
- Membrane Potentials drug effects MeSH
- Brain drug effects metabolism MeSH
- Rats, Wistar MeSH
- Presynaptic Terminals drug effects metabolism MeSH
- Carbon Radioisotopes MeSH
- Silanes chemistry MeSH
- Synaptosomes drug effects metabolism MeSH
- Ferric Compounds chemistry MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
