Solubilities of the cyclodextrins in the presence of transition metal salts

The solubilities of -, -, and -cyclodextrin have been measured in the presence of the first row transition metals: Cr³⁺, Mn²⁺, Fe³⁺, Co²⁺, Ni²⁺, Cu²⁺ and Zn²⁺; chlorides, nitrates and sulphates (in this case Fe²⁺), and, for companson, with CaCl₂, the corresponding Group IIa salt. Where possible the measurements are reported as a function of the activity of the salts. In general, for the transition metals the sulphates all show a linear decrease in solubility with increasing salt activity: for the nitrates the solubility increases and then reaches a limiting value; and for the chlorides a small decrease in solubility is observed at low activity followed by an increase in solubility at higher salt activity. Circular dichroism measurements confirm that there is no direct complexation at non-basic pH.Presented at the Sixth International Seminar on Inclusion Compounds, Istanbul, Turkey, 27–31 August 1995.     

Conformation of permethylated cyclodextrins and the host-guest geometry of their inclusion complexes

Macrocylic conformation of permethylated cyclodextrins and the geometry of their inclusion complexes were examined on the basis of the X-ray data of three permethylated -cyclodextrin complexes and two permethylated -cyclodextrin complexes. The host macrocyclic ring is remarkably distorted owing to steric hindrance involving the methyl groups and the inability to form intramolecular hydrogen bonds. The guest molecules are included within the host cavity, but their position and orientation are quite different from those found in the corresponding cyclodextrin complexes.     

The effect of cyclodextrins on the hydrolysis of carboxylic acid esters

Cyclodextrins and their derivatives act as inverse phase-transfer catalysts in the hydrolysis of carboxylic acid esters. The reaction is affected by temperature, choice of cyclodextrin and also by the stirring rate. Lipophilic esters are better hydrolyzed under inverse phase-transfer catalysis conditions than under classic phase-transfer catalysis (PTC) conditions. Some typical features of the reaction are emphasized and compared with classical PTC reactions.     

相溶解度法研究芦荟大黄素和环糊精及其衍生物的包结作用

本文用相溶解度法研究了芦荟大黄素与β－环糊精（ＣＤ）衍生物的包结作用,测定了包结物的包结常数,表明β－ＣＤ衍生物对芦蔡大黄素有较好的增溶作用,有应用价值。     

Development of a Total Organic Carbon method for the quantitative determination of solubility enhancement by cyclodextrins: Application to essential oils

Formation of inclusion complexes with cyclodextrins (CDs) is known to enhance guest solubility in aqueous medium. Different techniques allow determining the evolution in solubility of individual guest compounds. However, examination of mixtures solubility encapsulated in CDs is still a challenge. This is mainly related to the difference in the response of mixture components to the applied technique or to the fact that most of the conventional methods examine the signal of an individual constituent of the mixture. Thus, applying current techniques may not reflect the behavior of the whole mixture. Here, we used for the first time Total Organic Carbon (TOC) analysis to explore and assess the efficiency of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to enhance the solubility of natural complex mixtures such as essential oils (EOs). Phase solubility studies were performed for eleven EOs with HP-β-CD. The TOC method has provided good validation parameters for linearity, precision and accuracy. For further validation of the method, phase solubility studies were performed with HP-β-CD for eugenol, as a model EO component. The eugenol solubility was determined by UV–Visible and TOC analyses in order to compare the results. Data obtained from both methods were similar (p < 0.05), thereby proving the effectiveness of the developed TOC method. Finally, the phase solubility diagrams of EOs showed that the solubilizing potential of CD increased proportionally with the decrease in EO intrinsic solubility. Results proved that TOC could be successfully applied to investigate CD/guest inclusion complexes and is expected to have a broad range of applications in the field of mixtures encapsulation.     

Effect of cyclodextrins on biological membrane. II. Mechanism of enhancement on the intestinal absorption of non-absorbable drug by cyclodextrins.

The effects of two kinds of cyclodextrins (CyDs), alpha- and beta-CyD, on biological membranes were investigated by measuring changes in the absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine, using in situ and in vitro experiments. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), only beta-CyD increased the absorption of SA significantly compared to the absorption without pretreatment. The mechanism of the enhancing effect of CyDs on the absorption of SA was discussed. Almost no morphological change in the small intestine was observed by pretreatment with N-Ac alone, N-Ac or alpha- or beta-CyD combinations. The liberation of membrane components differed among the CyDs, e.g., alpha-CyD selectively released phospholipid while beta-CyD released mainly cholesterol from the intestinal membrane. It is suggested that the interaction of membrane components with CyDs may be at least partly responsible for the enhanced absorption of SA. Moreover it was found from in vitro electrophysiological experiment, that the alteration in enhanced permeability caused by beta-CyD occurred primarily in the transcellular pathways, rather than in the paracellular pathways of the small intestine. These results suggest that the enhancement of intestinal absorption by beta-CyD, after removal of the mucin layer from the intestinal surface, is due to the interaction between the membrane components and CyD. This interaction would induce disorder in cell membrane lipid, resulting in the increased permeability of the transcellular route.     

Relationships between the stability,circular dichroism spectrum and type of substitution in inclusion complexes formed between phenophthalein and different cyclodextrins

The perturbation of the three-site interaction of phenolphthalein on complexation with different cyclodextrins (CDs) has been investigated as a function of the type and degree of substitution of the CD. The UV visible spectra are practically identical, while the circular dichroism spectra change dramatically both in intensities and signs. Parallel to this, the stability constants are influenced not only by the size of the cavity but also by the substitution of its rims, particularly by that of the primary hydroxyls. The two phenomena can be related to allow conclusions concerning the mode of inclusion.     

Spectroscopic study and antioxidant properties of the inclusion complexes of rosmarinic acid with natural and derivative cyclodextrins

Measurement of total antioxidant activity/capacity of polyphenols in various solvent media necessitates the use of cyclodextrins to solubilize lipophilic antioxidants of poor aqueous solubility. The inclusion complexes of the slightly water soluble antioxidant, rosmarinic acid (RA), with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), 2-hydroxyethyl-β-cyclodextrin (HE-β-CD), and methyl-β-cyclodextrin (M-β-CD) were investigated for the first time. The effect of cyclodextrins (CDs) on the spectral features of RA was measured in aqueous medium using UV-vis and steady-state fluorescence techniques by varying the concentrations of CDs. The molar stoichiometry of RA-CD inclusion complexes was verified as 1:1, and the formation constants of the complexes were determined from Benesi-Hildebrand equation using fluorescence spectroscopic data. Among the CDs, maximum inclusion ability was measured in the case of M-β-CD followed by HP-β-CD, HE-β-CD, β-CD and α-CD. Solid inclusion complexes were prepared by freeze drying, and their functional groups were analyzed by IR spectroscopy. Antioxidant capacity of CD-complexed rosmarinic acid was measured to be higher than that of the lone hydroxycinnamic acid by the CUPric Reducing Antioxidant Capacity (CUPRAC) method. The mechanism of the TAC increase was interpreted as the stabilization of the 1-e oxidized o-catechol moiety of RA by enhanced intramolecular H-bonding in a hydrophobic environment provided by CDs, mostly by M-β-CD.     

ESR-spin trapping in the presence of cyclodextrins. Detection of PBN-superoxide spin adduct

In phosphate buffer solution the half-life of the PBN-superoxide spin adduct is very short. However, as a result of the formation of inclusion complexes, its ESR signal was easily detected for up to 25 min when the trapping of superoxide anion with PBN was carried out in the presence of different cyclodextrins. Furthermore, the formation of these inclusion complexes results in a significant protection of the PBN-superoxide adduct against l-ascorbate monoanion reduction.     

Microemulsion electrokinetic chromatography of corticosteroids. Effect of surfactants and cyclodextrins on the separation selectivity

The separation of neutral hydrophobic corticosteroids (cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, prednisolone and prednisolone acetate) by microemulsion electrokinetic chromatography (MEEKC) was studied. In the preparation of microemulsion, heptane was the solvent, n-butanol the co-surfactant and, as anionic surfactants, sodium dodecyl sulfate (SDS) or taurodeoxycholic acid sodium salt (STDC) were employed. Using an acidic running buffer, (phosphate pH 2.5) a strong suppression of the electroosmotic flow (EOF) was observed; this resulted in a fast anodic migration of the analytes partitioned into the negatively charged microemulsion droplets. Under these conditions, STDC showed better separation of corticosteroids than the conventional SDS; however, the use of a single anionic surfactant did not provide the required selectivity. The addition of the neutral surfactant polyoxyethylene glycol octadecyl ether (Brij 76) significantly altered the migration of each analytes allowing a better tuning of separation; however, in order to obtain adequate resolution between couples of adjacent critical peaks, the addition of neutral cyclodextrins (CDs) was found to be essential. This apparently complex system (CD-MEEKC), was optimized by studying the effect of the most important parameters affecting separation: STDC concentration, Brij 76 concentration, nature and concentration of cyclodextrins. Following a rational step-by-step approach, the optimised conditions providing the complete separation of the analytes were found to be: 4.0% STDC, 2.5% Brij 76, 6.6% n-butanol, 1.36% heptane and 85.54% of a solution 5 mM beta-CD in 50 mM phosphate buffer (pH 2.5). The optimized system was preliminary applied to the detection of corticosteroids related substances at impurity level and it could be considered a useful orthogonal alternative to HPLC methods.     

Effect of cyclodextrins on the viability of endothelial cells

Natural cyclodextrins (CD) and some of their derivatives have been tested in order to evaluate their cytotoxicity on LT2 endothelial cells. After 1 h of treatment with concentrations not higher than 10 mM, the number of cells was quantified by measuring DNA content. No significative decrease in the DNA amount was observed except for the dimethyl-β-CD at the highest tested concentration.     

Influence of cyclodextrins on the physical stability of DPPC-liposomes

This paper reports on the physical stability of DPPC-(dipalmitoyl phosphatidyl choline) liposomes in various aqueous dispersions and its control by uncharged polymers. The effect of natural (-, β-, γ-) cyclodextrins (CDs) on the stability of bare and polymer-bearing liposomes and also, the attachment of the CD molecules and the macromolecules, respectively, to the DPPC-bilayers of small unilamellar vesicles (SUV) were studied.

It was found that above a CD/DPPC ratio, each cyclodextrin caused a definite destruction in the phospholipid bilayers. The extent of membrane destabilization due to a cyclodextrin closely related to the amount of the CD molecules bound to the DPPC-bilayers.

The polymer-coated liposomes formulated by incorporating a dissolved homopolymer or copolymer into the phospholipid bilayer of the vesicles exhibited higher physical stability. Uncharged polymers effectively hindered the disintegration of the liposomal membranes brought about by the CD molecules. The polymer layers formed around the phospholipid bilayers ensured an enhanced steric stabilization for the DPPC-liposomes. Methylcellulose (MC) with high molecular mass and a polyvinyl alcohol-co-vinyl propional copolymer alike exhibited efficient stabilizing effect.     

Spectroscopic characterisation of the inclusion complexes between the antifungal drugs naftifine and terbinafine and cyclodextrins

The complexation of naftifine (NF) and terbinafine (TB) with cyclodextrins (CDs) has been investigated by UV/visible and ¹H NMR spectroscopy, ROESY techniques and also ESI-MS. Both drugs form 1:1 inclusion complexes with all the CDs tested except with α-CD, as deduced from the Benesi–Hildebrand plots and confirmed by ESI-MS and NMR spectroscopy (Job plot method). The K ₁₁ values for NF decrease in the order β-CD > methylated β-CD > 2-hydroxypropyl-β-CD >γ-CD. The determination of the enthalpy and entropy provides information about the main driving forces in the process. The stability constants of the complexes NF–β-CD, TB–β-CD and TB–γ-CD determined by ¹H NMR spectroscopy are in agreement with the values obtained by UV. For TB–β-CD, the value is higher, due to the fact that the length of the TB aliphatic chain allows a deeper inclusion of the naphthalene group inside the corresponding β-CD molecule, according to the 2D ROESY experiments.     

Enhancing effect of cyclodextrins on nasal absorption of insulin and its duration in rabbits.

The absorption of insulin (from porcine pancreas) in rabbits after the nasal administration of aqueous preparations containing insulin and five kinds of cyclodextrins (CyDs) in phosphate buffer solution at pH 7.0 was investigated. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a marked increase in the plasma levels of insulin and a decrease in glucose concentrations were observed following the simultaneous administration of insulin and CyD such as alpha- and heptakis (2,6-di-O-methyl)-beta-CyD (DM-beta-CyD). The largest enhancing effect on the nasal absorption of insulin was obtained by DM-beta-CyD. To evaluate the duration of the absorption-enhancing effect of CyDs, preadministration (administration of CyD 0.5, 6, 12 and 24 h before insulin administration) was performed. The area under plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration of DM-beta-CyD 6, 12 and 24 h before nasal administration. The absorption-enhancing effect disappeared 24h after the preadministration. These findings demonstrate that CyDs enhance the nasal absorption of insulin, and the recovery of the membrane transport barrier function in nasal mucosa is achieved, at the latest, 24 h after the administration of CyDs.     

Absorption enhancement of polypeptide drugs by cyclodextrins. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits.

The absorption of insulin (from porcine pancreas) from the rectum of rabbits after the administration of hollow-type suppositories containing insulin and five kinds of cyclodextrins (CyDs) was investigated. Three types of suppositories were employed: suppository I containing insulin (approximately 26 IU/mg) and various amounts of each CyD in citric buffer solution at pH 3.0 or powder in its cavity, suppository II containing CyD without insulin, and suppository III containing insulin without CyD. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a significant increase in the plasma insulin concentration and a marked decrease in the glucose levels were found following simultaneous administration of insulin and CyDs by suppository I. The enhancing effect of CyD on rectal insulin absorption (absorption-enhancing effect) by chemically modified CyDs (heptakis(2,6-di-O-methyl)-beta-CyD (DM-beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD)) was higher than those by natural CyDs (alpha-, beta-, and gamma-CyD). The area under the plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration (administration of CyD 6, 24 and 48 h before rectal insulin administration) of DM-beta-CyD. The absorption-enhancing effect disappeared 24 h after preadministration. These results suggest that CyDs enhance insulin absorption from the rectum, and that attenuation of the membrane transport barrier function in the rectum recovers at a maximum of 24 h after administration of CyDs.     

Effect of cyclodextrins on the electrochemical behaviour of ascorbic acid on platinum electrodes in acidic and neutral solutions

The effect of β-CD and α-CD on the electrochemical behaviour of H₂A and HA⁻ on platinum is studied. The adsorption of β-CD on this electrode is demonstrated and proved to be dependent on the base electrolyte composition. The maximum adsorption coverage was reached in phosphate solution at pH 6.95. The homogeneous H₂A---β-CD complex formation produced a decrease in the oxidation current and a positive shift in the oxidation peak potential. These effects are predominant in acid solutions. In neutral solutions the opposite behaviour is observed, i.e. an increase in the oxidation current at lower oxidation potentials. The presence of a parallel oxidation route for the vitamin involving strongly adsorbed CO residues is considered, and evidence for a decrease in CO_ad in the presence of β-CD was given by variations in hydrogen adsorption charges. This fact, more important in neutral solutions, must be responsible for the catalytic effect observed. α-CD was not adsorbed, neither did it modify the electro-oxidation behaviour of H₂A and HA⁻.