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Fenyvesi E.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Szeman J.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Csabai K.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Malanga M.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Szente L.,CycloLab Cyclodextrin Research and Development Laboratory Ltd.
Journal of Pharmaceutical Sciences | Year: 2014

Methylated cyclodextrins (CDs) are effective solubilizers of poorly soluble organic compounds. In this work, we compared various methylated β-CDs concerning their structure characterized by nuclear magnetic resonance spectroscopy, composition analyzed by HPLC and solubilizing capability by using model compounds such as cholesterol, fatty acids, furosemide, tamoxifen, and amiodarone. All the commercially available methylated β-CDs are mixtures of various isomers and homologues except trimethyl β-CD. The effects of the degree of methylation, the composition, as well as the influence of further derivatization with ionic groups were studied. The number of methyl groups in a CD ring should be around 14 to get the highest solubility for the included guest molecules. Although the distribution of isomers and related compounds has hardly any effect at constant degree of substitution, the introduction of amino and succinyl moieties on the CD ring adds ionic interactions to the hydrophobic interactions of the inclusion complex formation, which might result in synergic effect in solubilization. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.


Plazzo A.P.,Humboldt University of Berlin | Plazzo A.P.,Venetian Institute of Molecular Medicine | Hofer C.T.,Humboldt University of Berlin | Jicsinszky L.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | And 6 more authors.
Chemistry and Physics of Lipids | Year: 2012

Cyclodextrins (CDs) are widely used both in pharmaceutical applications to improve drug bioavailability and in cell biology as cholesterol-depleting and -delivering agents. Recently, it was shown that β-CD covalently coupled to fluorescent dextran polymers accumulates in cholesterol-enriched lysosomal storage organelles of human fibroblasts (Rosenbaum et al., 2010). By employing a methyl-βCD tagged with fluorescein (FMβCD), we have characterized the cellular trafficking of the CD in mammalian cell lines and its distribution into the endocytic compartments within the first minutes following addition to cells. FMβCD enters mammalian cells via endocytosis. The colocalization of FMβCD with transferrin-containing endosomes and the inhibition of FMβCD internalization by chlorpromazine or by an antisense RNA against clathrin heavy chain indicate that FMβCD is taken up via receptor-mediated, clathrin-dependent endocytosis. These results not only highlight the possibility of using CDs to target drugs intracellularly, but also warn about potential unwanted effects on cell physiology other than cholesterol extraction/loading at high concentrations, high temperatures and prolonged incubation times. © 2012 Elsevier Ireland Ltd.


Vecsernyes M.,Debrecen University | Fenyvesi F.,Debrecen University | Bacskay I.,Debrecen University | Deli M.A.,Hungarian Academy of Sciences | And 2 more authors.
Archives of Medical Research | Year: 2014

Biological barriers are the main defense systems of the homeostasis of the organism and protected organs. The blood-brain barrier (BBB), formed by the endothelial cells of brain capillaries, not only provides nutrients and protection to the central nervous system but also restricts the entry of drugs, emphasizing its importance in the treatment of neurological diseases. Cyclodextrins are increasingly used in human pharmacotherapy. Due to their favorable profile to form hydrophilic inclusion complexes with poorly soluble active pharmaceutical ingredients, they are present as excipients in many marketed drugs. Application of cyclodextrins is widespread in formulations for oral, parenteral, nasal, pulmonary, and skin delivery of drugs. Experimental and clinical data suggest that cyclodextrins can be used not only as excipients for centrally acting marketed drugs like antiepileptics, but also as active pharmaceutical ingredients to treat neurological diseases. Hydroxypropyl-β-cyclodextrin received orphan drug designation for the treatment of Niemann-Pick type C disease. In addition to this rare lysosomal storage disease with neurological symptoms, experimental research revealed the potential therapeutic use of cyclodextrins and cyclodextrin nanoparticles in neurodegenerative diseases, stroke, neuroinfections and brain tumors. In this context, the biological effects of cyclodextrins, their interaction with plasma membranes and extraction of different lipids are highly relevant at the level of the BBB. © 2015 IMSS.


Csempesz F.,Eötvös Loránd University | Sule A.,Eötvös Loránd University | Puskas I.,Cyclolab Cyclodextrin Research and Development Laboratory Ltd.
Colloids and Surfaces A: Physicochemical and Engineering Aspects | Year: 2010

Complexation of active therapeutic agents with cyclodextrins (CDs) offers potential uses in pharmaceutical and biomedical applications for controlling drug delivery and targeting. This paper reports on possible enhancement of the aqueous solubility and bioavailability of sparingly soluble statins (simvastatin and lovastatin) by inclusion complexation with native β-cyclodextrin and a chemically modified β-cyclodextrin, respectively. Complexation-induced surface activity of the supramolecular associates and the effect of the pure CDs and the amphiphilic CD-statin complexes on the physical stability of colloidal liposomes of dipalmitoyl phosphatidyl choline (DPPC) are discussed. It was shown that complexation with either cyclodextrin may lead to considerable improvement of the aqueous solubilities of both statins. Randomly methylated β-cyclodextrin (RAMEB) showed particularly outstanding solubilizing effects. The cyclodextrin molecules dissolved in the medium of liposome dispersions strongly reduced the physical stability of the phospholipid membranes. Complexation of the hydrophobic DPPC chains with cyclodextrins may ultimately lead to disintegration of the vesicles. In ternary systems, where due to the complexation of the pharmacon with the cyclodextrin amphiphilic CD-statin associates could develop, an enhanced and prolonged physical stability of the vesicles could be ensured. © 2009 Elsevier B.V. All rights reserved.


Shityakov S.,University of Würzburg | Sohajda T.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Puskas I.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Roewer N.,University of Würzburg | And 2 more authors.
Molecules | Year: 2014

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-ß- cyclodextrin (trimethyl-ß-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ψGCR solv = -9.98 kcal.mol-1), which has a minimal (ψGOR solv of -67.01 kcal.mol-1. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding ((ψGbind) value of -5.57 ± 0.02 kcal.mol-1, an equilibrium binding constant (Kb) of 79.89 ± 2.706 μM, and a ligand efficiency index (LElig) of -0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-ß-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations. © 2014 by the authors.


Fenyvesi E.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Vikmon M.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Szente L.,CycloLab Cyclodextrin Research and Development Laboratory Ltd.
Critical Reviews in Food Science and Nutrition | Year: 2016

Cyclodextrins are tasteless, odorless, nondigestible, noncaloric, noncariogenic saccharides, which reduce the digestion of carbohydrates and lipids. They have low glycemic index and decrease the glycemic index of the food. They are either non- or only partly digestible by the enzymes of the human gastrointestinal (GI) tract and fermented by the gut microflora. Based on these properties, cyclodextrins are dietary fibers useful for controlling the body weight and blood lipid profile. They are prebiotics, improve the intestinal microflora by selective proliferation of bifidobacteria. These antiobesity and anti-diabetic effects make them bioactive food supplements and nutraceuticals. In this review, these features are evaluated for α-, β- and γ-cyclodextrins, which are the cyclodextrin variants approved by authorities for food applications. The mechanisms behind these effects are reviewed together with the applications as solubilizers, stabilizers of dietary lipids, such as unsaturated fatty acids, phytosterols, vitamins, flavonoids, carotenoids and other nutraceuticals. The recent applications of cyclodextrins for reducing unwanted components, such as trans-fats, allergens, mycotoxins, acrylamides, bitter compounds, as well as in smart active packaging of foods are also overviewed. © 2016, Copyright © Taylor and Francis Group, LLC.


Fejos I.,Semmelweis University | Urbancsok Z.,Semmelweis University | Zhou W.,Chinese Academy of Sciences | Sohajda T.,Cyclolab Cyclodextrin Research and Development Laboratory Ltd. | And 3 more authors.
Electrophoresis | Year: 2014

The single enantiomer drug, alogliptin (Alo, Nesina®) is a novel, orally available and selective dipeptidyl peptidase-4 inhibitor used for the treatment of type II diabetes. Following its pKa determination by CE-pH titration, a validated chiral CE method has been developed to separate Alo enantiomers. Preliminary screening of the native CDs and their ten derivatives revealed that sulfopropylated-γ-CD, sulfopropylated-β-CD and sulfopropylated-γ-CD, sulfobutyl-ether-β-CD (SBE-β-CD) and sulfobutyl-ether-γ-CD enabled enantioresolution. Furthermore, cavity size dependent enantiomer migration order reversal was observed between γ- and β-CD derivatives. To improve enantioseparation, buffer composition and pH, CD concentration, applied voltage, temperature, and injection parameters were optimized for the Alo/ SBE-β-CD system, yielding a resolution of 8.34. RSD percentage of the resolution value, migration times, and corrected peak areas were below 3 and 5% during testing repeatability and intermediate precision. LOD and LOQ values were found to be 2 and 6 μg/mL, respectively, for each enantiomer. Calibration lines ranging from 6 to 250 μg/mL were constructed with r2 > 0.9997. Robustness could be successfully verified by using the Plackett-Burman statistical experimental design. The optimized system containing 5 mM SBE-β-CD in a 25 mM acetate buffer at pH 4.75 was found promising to detect 0.1% distomer in the presence of the API. © 2014 WILEY-VCH Verlag GmbH & Co.


Szente L.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Szeman J.,CycloLab Cyclodextrin Research and Development Laboratory Ltd. | Sohajda T.,CycloLab Cyclodextrin Research and Development Laboratory Ltd.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2016

The main goal of this review is to provide a comprehensive overview on the methods used for analysis of cyclodextrins (CDs) and CD-derivatives. The paper intends to act as a guide for the readers in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples.At present, in the European and United States Pharmacopoeias, the three parent CDs and two synthetic derivatives, namely the (2-hydroxypropyl)-beta-CD and sulfobutylether-beta-CD Na salt are official. Besides these modified CDs, two other derivatives are approved as excipients in human pharmaceutical products: the (2-hydroxypropyl)-gamma-CD and the randomly methylated-beta-CD.Although most of the official analysis methods in the pharmacopoeias have been well used for decades, new aspects of the functional excipient CD characterization suggest a need to revisit compendial methods.Comparison of strengths and weaknesses of current official methods with new improved techniques intends to help analysts to decide on changing traditional analytical methods with improved new ones. This review also deals with the analytical aspects of the first single isomer CD derivative approved as a drug active (Sugammadex/Bridion®) as well as analytical considerations of using CDs themselves as active pharmaceutical ingredients.Stability-indicating instrumental methods suitable to adequately follow chemical- and enzymatic degradation of CDs will also be discussed. Challenges in the determination of CDs in different biological matrices will be illustrated on real pharmaco- and toxicokinetic studies of CD-enabled drug formulations. © 2016 Elsevier B.V.


PubMed | CycloLab Cyclodextrin Research and Development Laboratory Ltd.
Type: | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2016

The main goal of this review is to provide a comprehensive overview on the methods used for analysis of cyclodextrins (CDs) and CD-derivatives. The paper intends to act as a guide for the readers in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples. At present, in the European and United States Pharmacopoeias, the three parent CDs and two synthetic derivatives, namely the (2-hydroxypropyl)-beta-CD and sulfobutylether-beta-CD Na salt are official. Besides these modified CDs, two other derivatives are approved as excipients in human pharmaceutical products: the (2-hydroxypropyl)-gamma-CD and the randomly methylated-beta-CD. Although most of the official analysis methods in the pharmacopoeias have been well used for decades, new aspects of the functional excipient CD characterization suggest a need to revisit compendial methods. Comparison of strengths and weaknesses of current official methods with new improved techniques intends to help analysts to decide on changing traditional analytical methods with improved new ones. This review also deals with the analytical aspects of the first single isomer CD derivative approved as a drug active (Sugammadex/Bridion


PubMed | CycloLab Cyclodextrin Research and Development Laboratory Ltd
Type: | Journal: Beilstein journal of organic chemistry | Year: 2015

The fluorescent tagging of cyclodextrin derivatives enlarges their spectroscopic properties thus generating chemosensors, biological tools for visualization and sophisticated photoresponsive devices. Cyclodextrin polymers, due to the cooperative interactions, exhibit additional properties compared to their monomeric counterpart. These macromolecules can be prepared either in well water-soluble form or as gels of high swelling. Two versatile synthetic strategies for introducing a fluorescent tag (rhodamine, fluorescein, nitrobenzofuran or coumarin) into the water-soluble epichlorohydrin branched cyclodextrin polymers were worked out and compared. The fluorescent labeling was realized in three steps: 1) building in azido moieties, 2) transforming the azido groups into amino groups and 3) coupling the proper fluorescent compound to the amino groups. The other strategy started by functionalization of the monomer prior to the branching. Either the fluorescent-labeled monomer or the intermediate azido derivative of the monomer was branched. Further tuning of the properties of the polymer was achieved via branching of the methylated cyclodextrin derivative. The key intermediates and the fluorescent final products were characterized by various spectroscopic techniques and capillary electrophoresis. The applied synthetic routes were evaluated based on the molecular weight, cyclodextrin content of the products and the efficiency of labeling.

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