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Thorsteinn Loftsson - One of the best experts on this subject based on the ideXlab platform.
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Formulation of Drug-Cyclodextrin Complexes
Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement, 2015Co-Authors: Thorsteinn LoftssonAbstract:Cyclodextrins are water-soluble oligosaccharides that form hydrophilic complexes with many lipophilic poorly soluble drugs. Cyclodextrins and cyclodextrin complexes do not permeate intact skin, and, thus, hydrophilic Cyclodextrins do not affect the skin barrier, stratum corneum. Studies have shown that, in general, Cyclodextrins only enhance drug permeation into and through the skin from aqueous vehicles and only if an aqueous diffusion barrier at the skin exterior contributes to the overall skin permeation barrier. Cyclodextrins do not enhance drug penetration from lipophilic vehicles or when the skin barrier itself is the main permeation barrier. Cyclodextrins are able to prevent drug partition from an aqueous exterior into the skin. Thus, it is of uttermost importance to optimize composition of cyclodextrin-containing drug vehicles with regard to drug release and permeation. In this chapter, the effects of Cyclodextrins on percutaneous drug permeation are described. Simple mathematical models are used to explain how and when Cyclodextrins act as penetration enhancers and then how these models can be applied to optimize drug delivery from a topical formulation.
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pharmaceutical applications of Cyclodextrins effects on drug permeation through biological membranes
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Thorsteinn Loftsson, Marcus E BrewsterAbstract:Objectives Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context Cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories. Key findings Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that Cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in Cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation ‘push’ and may reduce the bioavailability of the system. Conclusions A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates.
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Drug/cyclodextrin: beyond inclusion complexation
Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2011Co-Authors: Sergey V. Kurkov, Elena V. Ukhatskaya, Thorsteinn LoftssonAbstract:Development of Cyclodextrins as enabling excipients began decades ago and during this time a conventional view of the substrate–cyclodextrin interaction was formed that has persisted in spite of numerous contradicting observations. Here the shortcomings of the phase-solubility method are elucidated. The limited permeability of drug/cyclodextrin complexes through semi-permeable membrane, as well as osmometric data and images from transition electronic microscopy (TEM) are used as convincing evidences of aggregation of Cyclodextrins and their complexes. The necessity of updating the existing notions of cyclodextrin complexation is discussed.
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effects of Cyclodextrins on drug delivery through biological membranes
Journal of Pharmaceutical Sciences, 2007Co-Authors: Thorsteinn Loftsson, Marcus E Brewster, Stine B Vogensen, Fifa KonraðsdottirAbstract:Cyclodextrins have proven themselves to be useful functional excipients. Cyclodextrin derivatives can be hydrophilic or relatively lipophilic based on their substitution and these properties can give insight into their ability to act as permeability enhancers. Lipophilic Cyclodextrins such as the methylated derivatives are thought to increase drug flux by altering barrier properties of the membrane through component extraction or fluidization. The hydrophilic cyclodextrin family also modulate drug flux through membranes but via different mechanisms. The current effort seeks to provide various explanations for these observations based on interactions of hydrophilic Cyclodextrins with the unstirred water layer that separates the bulk media from biological membranes such as the gastric mucosa, cornea and reproductive tract. Theories on the serial nature of resistances to drug flux are used to explain why hydrophilic Cyclodextrins can enhance drug uptake in some situation (i.e., for lipophilic material) but not in others. In addition, the nature of secondary equilibria and competition between Cyclodextrins and rheologically important biopolymers such as mucin are assessed to give a complete picture of the effect of these starch derivatives. This information can be useful not only in understanding the actions of cyclodextrin but also in expanding their application and uses.
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Cyclodextrins and their pharmaceutical applications.
International Journal of Pharmaceutics, 2007Co-Authors: Thorsteinn Loftsson, Dominique DuchêneAbstract:Cyclodextrins were first described by Villiers in 1891. Schardinger laid the foundation of the cyclodextrin chemistry in 1903–1911 and identified both α- and β-cyclodextrin. In the 1930s, Freudenberg identified γ-cyclodextrin and suggested that larger Cyclodextrins could exist. Freudenberg and co-workers showed that Cyclodextrins were cyclic oligosaccharides formed by glucose units and somewhat later Cramer and co-workers described their ability to form inclusion complexes. By the early 1950s the basic physicochemical characteristics of Cyclodextrins had been discovered, including their ability to solubilize and stabilize drugs. The first cyclodextrin-related patent was issued in 1953 to Freudenberg, Cramer and Plieninger. However, pure Cyclodextrins that were suitable for pharmaceutical applications did not come available until about 25 years later and at the same time the first cyclodextrin-containing pharmaceutical product was marketed in Japan. Later cyclodextrin-containing products appeared on the European market and in 1997 also in the US. New cyclodextrin-based technologies are constantly being developed and, thus, 100 years after their discovery Cyclodextrins are still regarded as novel excipients of unexplored potential.
Lajos Szente - One of the best experts on this subject based on the ideXlab platform.
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Applications of steroid drugs entrapped in Cyclodextrins
Environmental Chemistry Letters, 2019Co-Authors: Éva Fenyvesi, István Puskás, Lajos SzenteAbstract:Steroids are abundant in living organisms and are responsible for various biological functions. They are good candidates for inclusion complexes formation with Cyclodextrins; therefore, plenty of literature describes these complexes and their application in various fields. There are, however, hardly any reviews summarizing this tremendous amount of information. Here, we review steroid drugs in relation to their complexation with Cyclodextrins, highlighting the effect of cyclodextrin–steroid interaction on the solubility, stability and bioavailability of the entrapped steroid drugs. We have collected data on the changes in the pharmacokinetics of cyclodextrin-formulated steroid drugs designed for various routes of administration. We show some cyclodextrin-enabled steroid formulations introduced to the market. Sugammadex, the first cyclodextrin derivative approved as active pharmaceutical ingredient, which revolutionized anesthesia, is also discussed. Several examples demonstrate the catalysis and inhibition of various biotransformation reactions of steroids by cyclodextrin complexation used in biotechnology. The laboratory- and pilot-scale experiments for environmental application of cyclodextrin–steroid interaction are based on cyclodextrin-containing sorbents for capturing residual steroid drugs, such as contraceptives from purified wastewater.
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Novel stationary phases for high-performance liquid chromatography analysis of cyclodextrin derivatives.
Journal of Chromatography A, 2006Co-Authors: Julianna Szemán, Katalin Csabai, K. Kékesi, Lajos Szente, Gábor VargaAbstract:Novel stationary phases were prepared for separation of Cyclodextrins and cyclodextrin derivatives by bonding substituted aromatic groups (phenyl and naphthyl) to the silica gel matrix. Both the electron-withdrawing (nitro) and the hydrogen-donor/acceptor (amide or carbamide) substituents of the phenyl group play essential role in the separation of Cyclodextrins and cyclodextrin derivatives. On the basis of the comparison of experimental data obtained on different columns the N-(4-nitrophenyl)-carbamide group bonded silica gel stationary phase was selected as the most effective one for analysis of cyclodextrin derivatives. Improved separation potency was observed for hydroxypropylated, methylated and several other cyclodextrin derivatives compared with the previously and presently used stationary phases. Owing to the strong retention of Cyclodextrins and its derivatives on the selected column, detection of their decomposition products was easily achieved. Determination of unsubstituted, natural cyclodextrin as an impurity in the cyclodextrin derivatives was implemented. Identification and characterization of cyclodextrin derivatives in industrial products could also be performed.
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Cyclodextrins as food ingredients
Trends in Food Science and Technology, 2004Co-Authors: Lajos Szente, Jozsef SzejtliAbstract:The present paper deals with the practical aspects of the utilization of Cyclodextrins and cyclodextrin complexes in the food industry. The molecular encapsulation of lipophilic food ingredients with cyclodextrin improves the stability of flavours, vitamins, colourants and unsaturated fats, etc., both in physical and chemical sense leading to extended product shelf-life. Accelerated and long-term storage stability test results showed that the stability of cyclodextrin-entrapped food ingredients surpassed that of the traditionally formulated ones. Technological advantages of the use of Cyclodextrins in foods and food processing technologies are also manifested in improved sensory, nutritional and performance properties. Examples of marketed cyclodextrin-based food products for demonstration of the significance of cyclodextrin technology in the food industry are provided.
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Molecular Mechanics Studies on Cyclodextrin Complexes: Interaction of Crocetin with Cyclodextrins
Proceedings of the Eighth International Symposium on Cyclodextrins, 1996Co-Authors: Laszlo Jicsinszky, H. Hashimoto, K. Mikuni, Imre Bakó, Lajos SzenteAbstract:Crocetin is a light sensitive natural colorant. The aqueous crocetin/cyclodextrin solutions showed increased stability under stressed irradiation conditions. Molecular mechanics geometry optimizations are used to for modeling the interactions between crocetin and Cyclodextrins. The energies of obtained geometries suggest that the α-cyclodextrin has the strongest interaction to crocetin among the studied Cyclodextrins. These results corresponds to the experimentally observed enhanced photoresistance of crocetin/α-cyclodextrin solutions.
Marcus E Brewster - One of the best experts on this subject based on the ideXlab platform.
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pharmaceutical applications of Cyclodextrins effects on drug permeation through biological membranes
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Thorsteinn Loftsson, Marcus E BrewsterAbstract:Objectives Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context Cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories. Key findings Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that Cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in Cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation ‘push’ and may reduce the bioavailability of the system. Conclusions A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates.
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effects of Cyclodextrins on drug delivery through biological membranes
Journal of Pharmaceutical Sciences, 2007Co-Authors: Thorsteinn Loftsson, Marcus E Brewster, Stine B Vogensen, Fifa KonraðsdottirAbstract:Cyclodextrins have proven themselves to be useful functional excipients. Cyclodextrin derivatives can be hydrophilic or relatively lipophilic based on their substitution and these properties can give insight into their ability to act as permeability enhancers. Lipophilic Cyclodextrins such as the methylated derivatives are thought to increase drug flux by altering barrier properties of the membrane through component extraction or fluidization. The hydrophilic cyclodextrin family also modulate drug flux through membranes but via different mechanisms. The current effort seeks to provide various explanations for these observations based on interactions of hydrophilic Cyclodextrins with the unstirred water layer that separates the bulk media from biological membranes such as the gastric mucosa, cornea and reproductive tract. Theories on the serial nature of resistances to drug flux are used to explain why hydrophilic Cyclodextrins can enhance drug uptake in some situation (i.e., for lipophilic material) but not in others. In addition, the nature of secondary equilibria and competition between Cyclodextrins and rheologically important biopolymers such as mucin are assessed to give a complete picture of the effect of these starch derivatives. This information can be useful not only in understanding the actions of cyclodextrin but also in expanding their application and uses.
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cyclodextrin based pharmaceutics past present and future
Nature Reviews Drug Discovery, 2004Co-Authors: Mark E. Davis, Marcus E BrewsterAbstract:Cyclodextrins are cyclic oligomers of glucose that can form water-soluble inclusion complexes with small molecules and portions of large compounds. These biocompatible, cyclic oligosaccharides do not elicit immune responses and have low toxicities in animals and humans. Cyclodextrins are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current cyclodextrin-based therapeutics are described and possible future applications discussed. Cyclodextrin-containing polymers are reviewed and their use in drug delivery presented. Of specific interest is the use of cyclodextrin-containing polymers to provide unique capabilities for the delivery of nucleic acids.
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pharmaceutical applications of Cyclodextrins 1 drug solubilization and stabilization
Journal of Pharmaceutical Sciences, 1996Co-Authors: Thorsteinn Loftsson, Marcus E BrewsterAbstract:Cyclodextrins are cyclic oligosaccharides which have recently been recognized as useful pharmaceutical excipients. The molecular structure of these glucose derivatives, which approximates a truncated cone or torus, generates a hydrophilic exterior surface and a nonpolar cavity interior. As such, Cyclodextrins can interact with appropriately sized molecules to result in the formation of inclusion complexes. These noncovalent complexes offer a variety of physicochemical advantages over the unmanipulated drugs including the possibility for increased water solubility and solution stability. Further, chemical modification to the parent cyclodextrin can result in an increase in the extent of drug complexation and interaction. In this short review, the effects of substitution on various cyclodextrin properties and the forces involved in the drug–cyclodextrin complex formation are discussed. Some general observations are made predicting drug solubilization by Cyclodextrins. In addition, methods which are useful in the optimization of complexation efficacy are reviewed. Finally, the stabilizing/destabilizing effects of Cyclodextrins on chemically labile drugs are evaluated.
R. G. Kooser - One of the best experts on this subject based on the ideXlab platform.
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Solute-solvated cyclodextrin-bonded phase interactions as studied by the spin probe technique
The Journal of Physical Chemistry, 1992Co-Authors: A. J. Hooper, J. Heindl, P. Wright, M. P. Eastman, R. G. KooserAbstract:Using spin probes with {alpha} and {beta} Cyclodextrins, the spin probe-{alpha} cyclodextrin surface interaction is due to polar/nonpolar interactions, but the {beta} cyclodextrin interaction has a bimodal behavior depending upon the solute polarity. For nonpolar probes there is partial insertion into the cyclodextrin cavity, but polar probes involve interactions between the solute and the hydroxyl region surrounding the rims of the bound cyclodextrin. This evidence show that surface immobilized Cyclodextrins do not interact in the same way as free Cyclodextrins. 66 refs., 2 figs., 8 tabs.
Irina V Terekhova - One of the best experts on this subject based on the ideXlab platform.
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effect of cyclodextrin complexation on solubility of novel anti alzheimer 1 2 4 thiadiazole derivative
Journal of Thermal Analysis and Calorimetry, 2017Co-Authors: Maria Brusnikina, Oleg Silyukov, Alexey N. Proshin, A. S. Mazur, Mikhail Chislov, Tatyana V Volkova, Peter M Tolstoy, Irina V TerekhovaAbstract:New 1,2,4-thiadiazole derivative displaying neuroprotective potential and high activity in the treatment of Alzheimer’s disease has been synthesized. The objective of this study was to improve the aqueous solubility of this drug-like compound by means of complex formation with native and hydroxypropylated β-Cyclodextrins. To this end, aqueous solubility of 1,2,4-thiadiazole derivative was investigated in the presence of β-Cyclodextrins. It was shown that the phase solubility diagrams are of Bs type demonstrating the initial increase in thiadiazole solubility in solutions of Cyclodextrins (concentration up to 0.01 mol kg−1) followed by a solubility decrease due to the precipitation of the complexes formed. In comparison with β-cyclodextrin, hydroxypropyl-β-cyclodextrin displays more pronounced solubilizing action since it forms more stable complexes with thiadiazole. Solid complexes of 1,2,4-thiadiazole derivative with β-Cyclodextrins were prepared by grinding and freeze-drying methods. DSC, TG, hot-stage microscopy, solid-state 13C MAS CP/TOSS NMR, powder X-ray diffractometry and FTIR spectroscopy were used to prove the existence of complexes in the solid state. Solubility of the obtained formulations was also examined. It was found that complexes of thiadiazole with hydroxypropyl-β-cyclodextrin exhibited higher solubility in phosphate buffer (pH 7.4) compared with pure thiadiazole and its complexes with β-cyclodextrin.
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Thermodynamics of inclusion complex formation of hydroxypropylated α- and β-Cyclodextrins with aminobenzoic acids in water
Journal of Thermal Analysis and Calorimetry, 2010Co-Authors: Wojciech Zielenkiewicz, Irina V Terekhova, Małgorzata Wszelaka-rylik, Roman S. KumeevAbstract:Calorimetry, densimetry, 1H NMR and UV–vis spectroscopy were used to characterize inclusion complex formation of hydroxypropylated α- and β-Cyclodextrins with meta- and para-aminobenzoic acids in aqueous solutions at 298.15 K. Formation of more stable inclusion complexes between para-aminobenzoic acid and Cyclodextrins was observed. The binding of aminobenzoic acids with hydroxypropyl-α-cyclodextrin was found to be enthalpy-governed owing to the prevalence of van der Waals interactions and possible H-binding. Complex formation of hydroxypropyl-β-cyclodextrin with both acids is mainly entropy driven. The increased entropy contribution observed in this case is determined by dehydration of solutes occurring during the revealed deeper insertion of aminobenzoic acids into the cavity of hydroxypropyl-β-cyclodextrin. By comparing complex formation of aminobenzoic acids with native and substituted Cyclodextrins it was found that the availability of hydroxypropyl groups slightly influenced the thermodynamic parameters and did not change the binding mode or driving forces of interaction.
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Interactions of beta- and hydroxypropyl-beta-cyclodextrin with some purine alkaloids: thermodynamic study.
Current drug discovery technologies, 2008Co-Authors: Irina V TerekhovaAbstract:The effect of native and hydroxypropylated beta-cyclodextrin on the solubility and activity of some purine alkaloids was examined. For this purpose, the solubility of purine alkaloids in pure water and in aqueous solutions of mentioned beta-Cyclodextrins was determined at 298.15 K. Stability constants of inclusion complexes and their stoichiometry were obtained from solubility diagrams. Enthalpic characteristics of interactions occurring between beta-Cyclodextrins and purine alkaloids in aqueous solution were calculated from the direct calorimetric measurements. It was found, that beta-cyclodextrin forms with purine alkaloids weak complexes which are stabilized only by the entropy term. Due to very low complexing affinity of both beta-Cyclodextrins to studied purine alkaloids their solubilizing effect is insignificant. The influence of structure of purine alkaloids and beta-cyclodextrin on the thermodynamic parameters of interaction was discussed.
