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PubMed2004

Photostability studies on nicardipine-cyclodextrin complexes by capillary electrophoresis.

Nicardipine (NC)-cyclodextrin solid systems were prepared in equimolar ratios and their photostability in aqueous solution under exposure to UV(A)-UV(B) radiations was evaluated. The photodegradation process was monitored by a capillary electrophoresis (CE) method able to provide the enantioresolution of the rac-nicardipine. Enantioresolution was achieved using the mixture 3.0% sulfate-beta-cyclodextrin (SbetaCD) and 2.0% heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD) as chiral selector in 20mM triethanolammonium phosphate solution (pH 3.0). The photostability studies were carried out on inclusion complexes of rac-nicardipine with alpha-cyclodextrin (alphaCD), beta-cyclodextrin (betaCD), gamma-cyclodextrin (gammaCD), hydroxypropyl-alpha-cyclodextrin (HPalphaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), hydroxypropyl-gamma-cyclodextrin (HPgammaCD), (2-hydroxyethyl)-beta-cyclodextrin (HEbetaCD) and methyl-beta-cyclodextrin (MbetaCD). A photoprotective effect was observed by betaCD, HPalphaCD, HEbetaCD, whereas gammaCD, MbetaCD, HPbetaCD and HPgammaCD did not affect the nicardipine photostability. Conversely, alphaCD was found to favour the drug photodegradation. Evidences for CDs-mediated stereoselective photodegradation of rac-nicardipine were observed only for the beta-CD complex. In this case, two distinct photodegradation profiles, with two different kinetic constants (k), were observed for the nicardipine enantiomers.

Biotransformation↗
PubMed2003

Functionalization of cyclodextrins via reactions of 2,3-anhydrocyclodextrins.

Three types of reactions of 2,3-anhydro-beta-cyclodextrins, namely nucleophilic ring-opening, reduction to 2-enopyranose, and reduction to 3-deoxypyranose, have been investigated to regio- and stereoselectively functionalize the secondary face of beta-cyclodextrin. Upon treatment with various nucleophiles, both 2,3-mannoepoxy and 2,3-alloepoxy-beta-cyclodextrins are found to undergo nucleophilic ring-opening reaction generating 3- and 2-modified cyclodextrin derivatives. In each case, the 3-position is more easily accessible than the 2-position. By using these ring-opening reactions, imidazolyl, iodo, azido, and benzylmercapto groups are selectively introduced to the secondary face of beta-cyclodextrin in place of the 2- or 3-hydroxyl groups. The functionalized cyclodextrins have either modified glucosidic subunits or modified altrosidic subunits that make the hydrophobic cavity slightly distorted from that of native beta-cyclodextrin. Thiourea also reacts with the cyclodextrin epoxides. In this case, thiirane and olefin species are generated instead of any ring-opening products. By ameliorating the reaction condition, cyclodextrin olefin, diene, and triene derivatives are prepared in moderate to good yields. Reduction of per[6-(tert-butyldimethyl)silyl]-beta-cyclodextrin permannoepoxide with lithium aluminum hydride produces the per(3-deoxy)-beta-cyclomannin. All these chemically modified cyclodextrins are structurally well characterized and most of them are expected to serve as versatile scaffolds for diverse purposes such as the construction of catalysts and development of synthetic receptors and molecular containers.

Binding, Competitive↗
PubMed2004

Polymer bilayer formation due to specific interactions between beta-cyclodextrin and adamantane: a surface force study.

The purposes of this study are to utilize the interactions between an adamantane end-capped poly(ethylene oxide) (PEO) and a cationic polymer of beta-cyclodextrin to build polymer bilayers on negatively charged surfaces, and to investigate the interactions between such layers. The association of this system in solution has been studied by rheology, light scattering, and fluorescence measurements. It was found that the adamantane-terminated PEO (PEO-Ad) mixed with the beta-cyclodextrin polymer gives complexes where the interpolymer links are formed by specific inclusion of the adamantane groups in the beta-cyclodextrin cavities. This results in a higher viscosity of the solution and growth of intermolecular clusters. The interactions between surfaces coated with a cationized beta-cyclodextrin polymer across a water solution containing PEO-Ad polymers were studied by employing the interferometric surface force apparatus (SFA). In the first step, the interaction between mica surfaces coated with the cationized beta-cyclodextrin polymer in pure water was investigated. It was found that the beta-cyclodextrin polymer adsorbs onto mica and almost neutralizes the surface charge. The adsorbed layers of the beta-cyclodextrin polymer are rather compact, with a layer thickness of about 60 A (30 A per surface). Upon separation, a very weak attractive force is observed. The beta-cyclodextrin solution was then diluted by pure water by a factor of 3000 and a PEO-Ad polymer was introduced into the solution. Two different architectures of the PEO-Ad polymer were investigated: a four-arm structure and a linear structure. After the adsorption of the PEO polymer onto the beta-cyclodextrin layer reached equilibrium, the forces were measured again. It was found that the weak repulsive long-range force had disappeared and an attractive force caused the surfaces to jump into contact, and that the compressed layer thickness had increased. The attractive force is interpreted as being due to a specific recognition between the hydrophobic adamantane groups on the PEO-Ad polymer and the hydrophobic cavity in the beta-cyclodextrin molecules. Furthermore, the attractive force observed on separation has increased significantly, which is a further indication of a specific interaction between the beta-cyclodextrin polymer and the adamantane groups.

Adamantane↗
PubMed1992

Cyclodextrins as nasal absorption promoters of insulin: mechanistic evaluations.

The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl-beta-cyclodextrin (DM beta CD) greater than alpha-cyclodextrin (alpha-CD) greater than beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) greater than gamma-cyclodextrin (gamma-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5'-nucleotidase (5'-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HP beta CD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5'-ND and total absence of LDH activity. On the other hand, 5% DM beta CD caused extensive removal of the membrane-bound 5'-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption.

5'-Nucleotidase↗
PubMed1991

The effect of parenterally administered cyclodextrins on cholesterol levels in the rat.

The inclusion complex formation of intravenously administered hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol-cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000-8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol-cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol-beta-cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered beta-cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl-beta-cyclodextrin after intravenous administration.

Animals↗
PubMed2002

Estimation of cyclodextrin affinity to steroids.

A nonlinear spectrometric method for determination of the stability constant (Ks) for cyclodextrin complex with steroid was developed. The method is based on calculation of the parameters of competitive cyclodextrin complexation by simultaneous fitting of two types of curves. Those of the first type are the dependencies of absorbance of methyl orange solution on the cyclodextrin concentration, the second type being the absorption curves of displacement of the dye, by steroid, from the cyclodextrin complex. With the method proposed, Ks values were calculated with standard deviation less than 10%. This method is validated by determination of Ks values using the phase-solubility technique. For neutral steroid molecules, the effect of pH on Ks was found to be insignificant. Ks values for the cyclodextrin-dye complex were determined for randomly methylated beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin. More hydrophobic steroids were characterised by higher Ks values. Anionic beta-cyclodextrins showed high affinity for the steroids studied. Simple equipment and sufficient computing allowed recommendation of the method for express estimation of cyclodextrin's affinity for hydrophobic substrates.

Cyclodextrins↗
PubMed1994

Parenteral hydroxypropyl cyclodextrins: intravenous and intracerebral administration of lipophiles.

Hydroxypropyl cyclodextrins are nontoxic carbohydrate derivatives of moderate molecular weight (1030-1750 Da) which form water-soluble complexes with many lipophiles. The fate of hydroxypropyl beta-cyclodextrin alone and in complex with testosterone or cholesterol injected intravenously or intracerebrally into rats was followed. More than 90% of intravenously administered hydroxypropyl beta-cyclodextrin was cleared into urine in 4 h, as previously described (Monbaliu, J.; Van Beijsterveld, L.; Meuldermans, W.; Szathmary, S.; Haykants, J. Abstracts, 5th International Symposium on Cyclodextrins, Paris, 1990; Abstract 65). After the injection of steroids in complex with hydroxypropyl beta-cyclodextrin into the tail vein of rats, the steroid component was released from the complex, before it reached the kidneys; the release occurred mainly into the proteins and lipoproteins of serum. Hydroxypropyl beta-cyclodextrins injected alone into the brain were cleared within less than 24 h, presumably via the flow of interstitial and cerebrospinal fluids, and eventually were excreted in urine. Testosterone, incorporated in a hydroxypropyl beta-cyclodextrin complex, after intracerebral injection was cleared from the brain even more rapidly than hydroxypropyl beta-cyclodextrin, presumably by crossing the blood-brain barrier and later removal to the liver by the specific carrier proteins in serum. Complexed cholesterol, in a similar experiment, was largely retained in the brain and its distribution there was uneven and remained that way for at least 3 days. It is clear that lipophilic agents, after their incorporation into hydroxypropyl beta-cyclodextrin complexes and subsequent in vivo administration, are rapidly released and exchanged into the plasma. In absence of plasma they enter tissues surrounding the injection site and thus are also promptly transferred into the organism's lipid systems. The manner in which different lipophilic agents are transported in vivo appears not to be greatly affected by their previous complexation; rather hydroxypropyl cyclodextrins just enable their entry in a larger amount and in an exchangeable, nonaggregated form.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2006

Estradiol sustained release from high affinity cyclodextrin hydrogels.

Hydrogels for loading estradiol and controlling its release were prepared cross-linking various cyclodextrins with ethyleneglycol diglycidylether. To select the more adequate cyclodextrins, estradiol solubility diagrams in water with beta-cyclodextrin (betaCD), methyl-beta-cyclodextrin (MbetaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), and sulfobutyl-beta-cyclodextrin (SBbetaCD) were made in absence and presence of hydroxypropyl methylcellulose (HPMC) applying or not autoclaving. Although all cyclodextrins showed enough complexation capability, the low solubility of betaCD and the high anionic character of SBbetaCD hindered the cross-linking process, and these cyclodextrins were discarded for preparing hydrogels. Hydrogels prepared with MbetaCD (20%, 25%) or HPbetaCD (20%, 25%, and 30%), with or without HPMC 0.25%, absorbed 4-10 times their weight in water and loaded up to 24 mg estradiol per gram, which is 500 times greater than the amount of drug that can be dissolved in their aqueous phase. Positive linear correlation was found between the stability constant and the network/water partition coefficients of drug. The hydrogels sustained the release up to one week; the affinity of estradiol for the cyclodextrin units controlling the process, as shown by the negative correlation with the release rate constants. These results highlight the potential of cyclodextrin complexation for the development of hydrogels useful in loading hydrophobic drugs and controlling their release.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

Combined poly(isobutylcyanoacrylate) and cyclodextrins nanoparticles for enhancing the encapsulation of lipophilic drugs.

PURPOSE: The aim of this study was to prepare and characterize nanoparticulate systems constituted of poly(isobutylcyanoacrylate) and cyclodextrins and intended for increasing the loading of the particles with lipophilic substances. Progesterone was used as a model substance. METHODS: Nanoparticles were prepared by polymerization of isobutylcyanoacrylate in presence of cyclodextrins or progesterone/ hydroxypropyl-beta-cyclodextrin complex. Particle size, zeta potential, cyclodextrin and progesterone loading of the particles were determined. RESULTS: Nanoparticles could be easily prepared in presence of cyclodextrins. An increase in hydroxypropyl-beta-cyclodextrin concentration resulted in small nanoparticles (less than 50 nm). It was found that large amounts of cyclodextrins remained associated to the particles, resulting in a 50 fold increase in progesterone loading compared to nanoparticles prepared in absence of cyclodextrins. CONCLUSIONS: The poly(isobutylcyanoacrylate)cyclodextrin nanoparticles were characterized by the presence of many lipophilic sites belonging to the cyclodextrins which were firmly anchored to the structure of the particles. Therefore, this new type of nanoparticles offers probably an opportunity for increasing the loading of nanoparticles with various lipophilic drugs.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1993

Beta-cyclodextrins enhance bioavailability of pilocarpine.

Cyclodextrins have been used to improve drug solubility, stability and absorption for oral and parenteral administration. However, their potential for improving ocular drug delivery has received little attention. To evaluate the ability of hydroxypropyl-beta-cyclodextrins to improve ophthalmic drug bioavailability following topical administration, the miotic effect of topical solutions of pilocarpine was studied in New Zealand White rabbits. Pilocarpine varying in dose from 5 to 500 micrograms in the presence or absence of 5% cyclodextrin was administered (50 microliters) topically and the change in pupil diameter determined. These results demonstrated that pilocarpine alone or in the presence of cyclodextrin produces a dose-related reduction in pupil diameter. The addition of cyclodextrins produced a significant left-shift in the dose response curve, with an ED50 of 64 micrograms and 19 micrograms for pilocarpine and pilocarpine/5% cyclodextrin solutions, respectively. Studies in which the concentration of cyclodextrin was varied revealed that a one-to-one molar ratio of pilocarpine to cyclodextrin was sufficient to provide maximum increase in pilocarpine bioavailability. Electrophysiology and scanning electron microscopic studies demonstrated that cyclodextrin does not disrupt the normal ion transport currents, barrier properties or surface features of the corneal epithelium. Viscosity measurements indicated that difference in the viscosity of pilocarpine and pilocarpine/cyclodextrin solutions cannot account for increased bioavailability of pilocarpine. These data support the idea that the addition of cyclodextrin significantly improves the ocular bioavailability of pilocarpine. This enhanced bioavailability of pilocarpine does not appear to be due to a mechanism destructive to the epithelium or to an increase in vehicle viscosity.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2002

Metallothionein mRNA levels are influenced by dietary cyclodextrins in rats.

The relationship between metallothionein mRNA levels and the amounts of copper and zinc in liver, kidney and small intestine by feeding dietary cyclodextrin was examined in growing Wistar rats. alpha-, beta- or gamma-cyclodextrin was fed at 50 g/kg of diet for a 7-days period (ad libitum). After feeding, the liver zinc of rats fed beta-cyclodextrin was greater than those of rats fed the other three diets. Copper accumulated in kidney of rats fed alpha- or beta-cyclodextrin. Copper content in the small intestine did not show any alterations among rats fed all kinds of diets. The cyclodextrin-supplemented diets were ineffective in zinc content in every organ. There was the greatest level of copper in serum of rats fed beta-cyclodextrin, whereas the highest level of serum zinc was observed in rats fed gamma-cyclodextrin diet. Northern blot analysis demonstrated that dietary beta- and gamma-cyclodextrins, but not alpha-cyclodextrin markedly increased the metallothionein mRNA in the liver, whereas small intestinal metallothionein mRNA levels were markedly decreased. Kidney metallothionien mRNA levels were raised appreciably by all dietary cyclodextrin intakes. Metallothionein gene expressions in liver, kidney and small intestine were not proportional to liver and serum copper or zinc levels in those tissues. These results suggest that regulation of the metallothionein mRNA levels may at least partly involved with the accumulation of metals as copper in liver and kidney of rats fed cyclodextrins.

Journal Article↗
PubMed1990

Slow-release characteristics of diltiazem from ethylated beta-cyclodextrin complexes.

Release characteristics of two ethylated beta-cyclodextrins [heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (diethyl-beta-cyclodextrin) and heptakis(2,3,6-tri-O-ethyl)-beta-cyclodextrin (triethyl-beta-cyclodextrin)] as sustained-release drug carriers were evaluated using diltiazem hydrochloride, a water-soluble calcium antagonist. The release rate of diltiazem from compressed tablets was significantly retarded by the complexation with ethylated beta-cyclodextrin. Various environmental effects (such as pH, rotating speed, and additive in the dissolution medium) on the release rate were investigated, together with a microscopic observation of the tablet surface. The water penetration rate into the tablet was measured in order to gain insight into the release mechanism. The results suggested that diltiazem is released slowly from the hydrophobic matrix consisting of diethyl-beta-cyclodextrin following water penetration. When a single dose of tablets containing diethyl-beta-cyclodextrin complex was orally administered to dogs, the sustained-release pattern of the drug, without decrease in area under the plasma concentration-time curve, was produced for a long period. The release rate of diltiazem can be controlled by combining the ethylated beta-cyclodextrin complexes with the parent beta-cyclodextrin complex in different mixing ratios.

Animals↗
PubMed2002

Effect of sulfated beta-cyclodextrin, a water soluble cycloamylose, on the promotion and/or inhibition of angiogenesis.

Previous studies have reported that sulfated b b-cyclodextrin, a naturally occurring cycloamylose built up from six to eight glucopyranose units, when administered alone promotes angiogenesis, but administered with an angiostatic steroid inhibits angiogenesis in the cick embryo bioassay. In our experiments sulfated b b-cyclodextrin has been shown to possess many properties unrelated to its classical functions in the promotion and inhibition of angiogenesis that were not previously described. We studied the angiogenic and angiostatic properties of b b-cyclodextrin in a subcutaneous plastic sponge model in mice. We realized two set of experiments. In each set mice were randomized into five groups (n= 5 mice). The first group was treated with sulfated b b-cyclodextrin (200 ng), the second group was treated with sulfated b b-cyclodextrin (2000 ng), the third group received unsubstituted b b-cyclodextrin (2000 ng), the fourth group was treated with sulfated b b-cyclodextrin (20000 ng) and the last group was used as a control group. In all groups compounds were administered intraperitoneally 4 days after subcutaneous implantation of a sterile polyvinyl sponge on day 0, controls were not treated. Cyclodextrin administered alone at low drug concentration (200 ng) promoted angiogenesis and increased the development of venules in the sponge matrix. However, cyclodextrin administered at high drug concentration (2000 and 20 000 ng) reduced the vessel index in the sponge and areas of microhemorrhages were observed. From our results we propose that b b-cyclodextrin contains both a promoter and an inhibitor of angiogenesis and that the activation of both is drug concentration dependent.

Analysis of Variance↗
PubMed2005

Interactions between n-octyl and n-nonyl beta-D-glucosides and alpha- and beta-cyclodextrins as seen by self-diffusion NMR.

In this work (1)H NMR self-diffusion experiments have been performed to determine the self-diffusion coefficients of n-octyl beta-d-glucoside and n-nonyl beta-d-glucoside in alpha-cyclodextrin and beta-cyclodextrin solutions at 25 degrees C. Two questions are addressed. The first concerns the general influence on nonionic surfactant transport properties when cyclodextrins are present in solution. The second question concerns the influence of surfactant-chain length and cyclodextrin cavity volume on the association constant. The self-diffusion coefficients of the alkyl glucosides, in cyclodextrin-containing solutions, depend on the cyclodextrin concentration on account of the formation of complexes. The cyclodextrin diffusion is only mildly influenced, since the complex has similar diffusion coefficients as the free cyclodextrin. There are some obstruction effects at the highest surfactant concentrations which decrease the cyclodextrin diffusion. A set of equations to model the self-diffusion coefficients of the surfactant and cyclodextrin was developed and is presented. On the basis of such equations, properties such as association constants, and micelle and complex diffusion coefficients can be estimated.

Diffusion↗
PubMed2001

Methyl-beta-cyclodextrin: an alternative carrier for intravenous infusion of palmitate during tracer studies in swine (Sus scrofa domestica).

Fatty acid-free albumin has been the standard carrier for intravenous infusion of fatty acids to study in vivo lipid metabolism. However, subjects can have adverse reactions to infusion of albumin. We sought an alternative to albumin as a carrier for intravenous infusion of fatty acids, using the pig as a model. Cyclodextrins are naturally occurring water-soluble molecules that can serve as carriers for lipid-soluble compounds. 13C-palmitate was complexed to either 20% methyl-beta-cyclodextrin, 20% 2-hydroxypropyl-beta-cyclodextrin, or 5% porcine albumin (isotopic purity of infusates: 99.22+/-0.06%). 13C-palmitate-albumin was infused under fed conditions and 13C-palmitate-methyl-beta-cyclodextrin was infused under fasted and fed conditions in 50-kg pigs. Palmitate remained in solution at 4 degrees C in methyl-beta-cyclodextrin, but precipitated at 25-30 degrees C in 2-hydroxypropyl-beta-cyclodextrin. Pigs infused with 13C-palmitate-methyl-beta-cyclodextrin maintained normal body temperature and appetite; those infused with 13C-palmitate-albumin became anorexic and exhibited other negative side effects to albumin. Palmitate oxidation rates under fed conditions were similar using either 13C-palmitate-methyl-beta-cyclodextrin or 13C-palmitate-albumin complexes. Fasting increased 13C-palmitate-methyl-beta-cyclodextrin oxidation by approximately eight-fold. These data suggest that methyl-beta-cyclodextrin may be a suitable substitute for albumin in fatty acid metabolism studies in swine.

Albumins↗
PubMed1986

Interaction of soman with beta-cyclodextrin.

Of the following neurotoxic agents, pinacolyl methylphosphonofluoridate (soman), isopropyl methylphosphonofluoridate (sarin) and ethyl N,N-dimethylphosphoramidocyanidate (tabun), only soman was inactivated appreciably at pH 7.40 by beta-cyclodextrin. The interaction of soman, a mixture of four stereoisomers designated as C(+)P(-), C(-)P(-), C(+)P(+), and C(-)P(+), with cyclodextrins was revealed by methods based on the irreversible inhibition of acetylcholinesterase (AChE) that is phosphonylated chiefly by P(-)-isomers of racemic soman and continuous titration of fluoride ions released by soman using a fluoride-specific electrode. Soman and beta-cyclodextrin form a 1:1 complex. At pH 7.40 and 25 degrees C the dissociation constant Kd of this complex and the rate constant k2 of cleavage of soman by beta-cyclodextrin are (0.53 +/- 0.05) mM and (5.9 +/- 0.6) X 10(-2) min-1, respectively. The rate constant k2 max for the cleavage of soman by monoionized beta-cyclodextrin has a value of 2.8 X 10(3) min-1 and the second order rate constant k2 max/kd is 5.3 X 10(6) M-1 min-1. Consequently, soman is hydrolyzed about 2500 times faster by the monoanion of beta-cyclodextrin, than by the hydroxide ion. The cleavage of P(-)-soman by beta-cyclodextrin as estimated by AChE inhibition proceeds apparently at the same rate for the C(-)P(-)-and C(+)P(-)-isomers. However, the release of fluoride ions indicated a stereospecific rate of reaction, the P(-)-isomers reacting faster than the P(+)-isomers. At pH 7.40, the inactivation rate of soman by beta-cyclodextrin was as fast in human plasma in vitro as in Tris buffer. This interaction between soman and beta-cyclodextrin, and other data from the literature, suggests that the introduction of catalytic or noncatalytic groups on beta-cyclodextrin might possibly make it a better catalyst for soman inactivation through improvement in the catalytic or in the binding process.

Acetylcholinesterase↗
PubMed2006

Novel stationary phases for high-performance liquid chromatography analysis of cyclodextrin derivatives.

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.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Synthesis and physicochemical characterization of folate-cyclodextrin bioconjugate for active drug delivery.

beta-Cyclodextrin-poly(ethylene glycol)-folic acid conjugate (CD-PEG-FA) was synthesized according to a two-step procedure: (1). synthesis of CD-PEG-NH(2) by reaction of monotosyl-activated beta-cyclodextrin with excess of 700 Da diamino-PEG; (2). synthesis of CD-PEG-FA by reaction of CD-PEG-NH(2) with succinimidyl ester-activated folic acid. The CD-PEG-NH(2) intermediate was purified by precipitation in acetone, and the CD-PEG-FA by gel permeation and C-18 reversed-phase chromatography. Both CD-PEG-NH(2) and CD-PEG-FA were analyzed by mass spectrometry, (1)H NMR, and UV-vis spectroscopy. All analytical methods confirmed the theoretical composition of the conjugates: the CD-PEG-NH(2) intermediate was composed of CD and PEG in the molar ratio of 1:1, and the CD-PEG-FA was composed of beta-cyclodextrin, PEG, and folic acid in the molar ratio of 1:1:1. The CD-PEG-FA conjugate was highly soluble in buffer (>42 mM) as compared to the unmodified beta-cyclodextrin (16.3 mM). Phase solubility diagrams of beta-estradiol revealed that drug solubility increases from 11 microM in buffer to 600 microM in the presence of beta-cyclodextrins and 5900 microM with CD-PEG-FA. However, the affinity of beta-estradiol for beta-cyclodextrins decreased about 4 times with PEG and folic acid conjugation. Stability studies carried out using chlorambucil confirmed that the conjugate partially prevents drug degradation in buffer, although this effect was considerably lower than that obtained with beta-cyclodextrin. Computer modeling studies showed that the folic acid linked to the beta-cyclodextrins through a PEG spacer could partially interact with the cyclodextrin cavity. Finally, CD-PEG-FA displayed reduced hemolytic effect as compared to unmodified beta-cyclodextrin.

Chemical Phenomena↗