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PubMed2000

Hydroxypropyl-beta-cyclodextrin enhanced fluorimetric method for the determination of melatonin and 5-methoxytryptamine.

The effects of native cyclodextrins (alpha, beta or gamma), hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin solubilized in urea, soluble starch and glucose in water solution on the fluorescence behaviour of melatonin (N-acetyl-5-methoxytryptamine) (M) and 5-methoxytryptamine [5-methoxy-3-(2-aminoethyl)indole] (5M) were determined. In addition, the effect of methanol and propanol with and without beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin was assessed. From the fluorescence changes with pH, the values of the pKa for the ground (9.9 +/- 0.2) and the excited state (7.7 +/- 0.2) for 5M were determined. From the fluorescence changes with beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin, the association constants of M, 5MH [5-methoxy-3-(2-ammoniumethyl)indole] and 5M with the two hosts were determined. The values with beta-cyclodextrin were KAssoc5MH = (1.4 +/- 0.4) x 10(2) mol-1 dm3, KAssoc5M = (1.6 +/- 0.1) x 10(2) mol-1 dm3 and KAssocM = (1.1 +/- 0.2) x 10(2) mol-1 dm3, and with hydroxypropyl-beta-cyclodextrin KAssoc5MH = (1.1 +/- 0.3) x 10(2) mol-1 dm3, KAssoc5M = (2.5 +/- 0.1) x 10(2) mol-1 dm3 and KAssocM = (1.51 +/- 0.07) x 10(2) mol-1 dm3. The ratios of the fluorescence quantum yields for the bound and free substrate (phi b/phi f) were in the range 1.15-1.48. The detection limits under the optimum conditions were 0.381 +/- 0.001 ng cm-3 for the complex 5MH-hydroxypropyl-beta-cyclodextrin in water and 0.290 +/- 0.001 ng cm-3 for the complex M-hydroxypropyl-beta-cyclodextrin in water with 5% of methanol. The recovery of melatonin from pharmaceutical preparations was 98-103% with an RSD of 2%. The recovery from rat pineals was also good. The method is direct, simple and accurate.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2002

Dendritic galactosides based on a beta-cyclodextrin core for the construction of site-specific molecular delivery systems: synthesis and molecular recognition studies.

In order to evaluate the ability of multivalent glycosides based on a beta-cyclodextrin core as site-specific molecular carriers, a study on both the inclusion complexation behaviour and lectin binding affinity of branched and hyperbranched beta-cyclodextrins is presented. A series of cluster galactosides constructed on beta-cyclodextrin scaffolds containing seven 1-thio-beta-lactose or beta-lactosylamine bound to the macrocyclic core through different spacer arms were synthesised. In addition, the first synthesis of three first-order dendrimers based on a beta-cyclodextrin core containing fourteen 1-thio-beta-D-galactose, 1-thio-beta-lactose and 1-thio-beta-melibiose residues was performed. Calorimetric titrations performed at 25 degrees C in buffered aqueous solution (pH 7.4) gave the affinity constants and the thermodynamic parameters for the complex formation of these beta-cyclodextrin derivatives with guests sodium 8-anilino-1-naphthalenesulfonate (ANS) and 2-naphthalenesulfonate, and lectin from peanut (Arachis hypogaea) (PNA). The persubstitution of the primary face of the beta-cyclodextrin with saccharides led to a slight increase of the binding constant values for the inclusion complexation with ANS relative to the native beta-cyclodextrin. However, the increase of the steric congestion due to the presence of the saccharide residues on the narrow rim of the beta-cyclodextrin may cause a decrease of the binding ability as shown for sodium 2-naphthalenesulfonate. The spacer arms are not passive elements and influence the host binding ability according to their chemical nature. PNA forms soluble cross-linked complexes with cluster galactosides and lactosides scaffolded on beta-cyclodextrin but not with cluster galactopyranosylamines or melibiose. Both, perbranched and hyperbranched beta-cyclodextrins, form stronger complexes with PNA than the monomeric analogues. However, the use of hyperbranched CDs does not contribute to the improvement of the complex stability relative to heptakis-glycocyclodextrin derivatives. Finally, a titration experiment with PNA and a complex formed by a heptakis lactose beta-cyclodextrin derivative with sodium 2-naphthalenesulfonate showed the formation of a soluble cross-linked complex with stronger affinity constant and higher stoichiometry than those observed for the complex formation of PNA with the same heptakis-lactose beta-cyclodextrin derivative, suggesting the formation of a three component complex.

Anilino Naphthalenesulfonates↗
PubMed1993

Fate of beta-cyclodextrin in the human intestine.

We assessed the fate of beta-cyclodextrin, which is composed of seven alpha(1-->4)-linked glucose units in ring structure, in the human gastrointestinal tract. In four healthy ileostomists, ileal effluent was collected after oral administration of beta-cyclodextrin during fasting (10 g of beta-cyclodextrin) and postprandially (10 g of beta-cyclodextrin three times daily with meals). In 10 healthy volunteers, the amount of beta-cyclodextrin passing into the colon was determined by means of the breath hydrogen technique using lactulose as a standard, and stools were collected after oral administration of beta-cyclodextrin during fasting (10 g of beta-cyclodextrin) and postprandially (10 g of beta-cyclodextrin three times daily with meals). In ileostomists, we recovered from the small intestine 91 +/- 5% and 97 +/- 10% (mean +/- SD) of beta-cyclodextrin ingested during fasting and with meals, respectively. In healthy volunteers, H2 excretion in breath after beta-cyclodextrin ingestion was low compared with excretion after lactulose, but only traces of beta-cyclodextrin were recovered in stools. We conclude that beta-cyclodextrin is poorly hydrolyzed in the human small intestine but that it is fermented by the colonic flora with apparent minimal H2 production.

Administration, Oral↗
PubMed2000

The role of arginine 47 in the cyclization and coupling reactions of cyclodextrin glycosyltransferase from Bacillus circulans strain 251 implications for product inhibition and product specificity.

Cyclodextrin glycosyltransferase (CGTase) (EC 2.4.1.19) is used for the industrial production of cyclodextrins. Its application, however, is hampered by the limited cyclodextrin product specificity and the strong inhibitory effect of cyclodextrins on CGTase activity. Recent structural studies have identified Arg47 in the Bacillus circulans strain 251 CGTase as an active-site residue interacting with cyclodextrins, but not with linear oligosaccharides. Arg47 thus may specifically affect CGTase reactions with cyclic substrates or products. Here we show that mutations in Arg47 (to Leu or Gln) indeed have a negative effect on the cyclization and coupling activities; Arg47 specifically stabilizes the oligosaccharide chain in the transition state for these reactions. As a result, the mutant proteins display a shift in product specificity towards formation of larger cyclodextrins. As expected, both mutants also showed lower affinities for cyclodextrins in the coupling reaction, and a reduced competitive (product) inhibition of the disproportionation reaction by cyclodextrins. Both mutants also provide valuable information about the processes taking place during cyclodextrin production assays. Mutant Arg47-->Leu displayed an increased hydrolyzing activity, causing accumulation of increasing amounts of short oligosaccharides in the reaction mixture, which resulted in lower final amounts of cyclodextrins produced from starch. Interestingly, mutant Arg47-->Gln displayed an increased ratio of cyclization/coupling and a decreased hydrolyzing activity. Due to the decreased coupling activity, which especially affects the production of larger cyclodextrins, this CGTase variant produced the various cyclodextrins in a stable ratio in time. This feature is very promising for the industrial application of CGTase enzymes with improved product specificity.

Amino Acid Substitution↗
PubMed2004

Role of cyclodextrins in ophthalmics.

Cyclodextrins are oligosaccharides having outer hydrophilic surface and central hydrophobic cavity. These agents form inclusion complexes with poorly water-soluble drugs; hence they show an important implication for use in ophthalmics because of their applications in solubilising and stabilising the ocular drugs. Most of the drugs being used in ophthalmics were not tailor-made for the eye and considering the poor bioavailability of <1% from the corneal surface, presentation of the drug in a soluble form and at high concentration is important. Provision of a high drug concentration at the corneal surface increases the percent drug permeation indicating the usefulness of cyclodextrins as penetration enhancers. A decrease in irritation potential of some drugs upon incorporation of cyclodextrins is also reported. Polymer-cyclodextrin multicomponent systems further extend the role of cyclodextrins in improving the solubility and bioavilability of ocular drugs. Large hydrophilic cyclodextrins like hydroxypropyl-beta-cyclodextrin and sulphobutylether-beta-cyclodextrin are safe for the use in aqueous eye drop solutions especially since they do not cross the lipophilic cornea. Various aspects about the applications of cyclodextrins in ophthalmics, the formulation considerations and expected toxicity of cyclodextrins (especially if high concentration is used) is discussed in this review. Strategies like use of polymers to reduce the effective concentration of cyclodextrin required without compromising solubility are also included. Further the concept of incorporating the drug-cyclodextrin complexes into liposomes or niosomes for a better targeting of the drug at appropriate tissue destination is discussed as a possible future option.

Chemistry, Pharmaceutical↗
PubMed1998

Cyclodextrin solubilization of ETH-615, a zwitterionic drug.

Therapeutic usefulness of many zwitterionic drugs is hampered by their very low aqueous solubility. The purpose of this work was to investigate the effects of cyclodextrins on the solubility of the zwitterionic drug ETH-615, the role that charge might play in the cyclodextrin complexation, and the influence of polymers and ion-pairing agents on the cyclodextrin solubilization. The effects of five different beta-cyclodextrin derivatives were evaluated, i.e., the anionic beta-cyclodextrin sulfobutyl ether sodium salt and carboxymethyl-beta-cyclodextrin sodium salt, the uncharged 2-hydroxypropyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, and the cationic 2-hydroxy-3-trimethyl-ammoniopropyl-beta-cyclodextrin. The uncharged cyclodextrins had much larger solubilizing effect on ETH-615 than the charged ones. However, due to the highly polar zwitterionic structure of ETH-615 the stability constants of its cyclodextrin complexes were several orders of magnitude smaller than those commonly observed for uncharged lipophilic compounds. Cyclodextrin solubilization of ETH-615 was enhanced by water-soluble polymers and ion-pairing agents.

Choline↗
PubMed1998

Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs.

Cyclodextrins are used in nasal drug delivery as absorption enhancing compounds to increase the intranasal bioavailability of peptide and protein drugs. The most effective cyclodextrins in animal experiments are the methylated derivatives, dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, which are active at low concentrations ranging between 2% and 5%. However, large species differences between rats, rabbits and humans exist for the nasal absorption enhancement by cyclodextrins. Based on toxicological studies of the local effects of cyclodextrins on the nasal mucosa dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin are considered safe nasal absorption enhancers. Their effects were quite similar to controls (physiological saline), but smaller than those of the preservative benzalkonium chloride in histological and ciliary beat frequency studies. In these studies, and in a study of the release of marker compounds after nasal administration, methylated beta-cyclodextrins were less toxic than sodium glycocholate, sodium taurodihydrofusidate, laureth-9 and L-alpha-phosphatidylcholine. Systemic toxicity after nasal cyclodextrin administration is not expected, because very low doses of cyclodextrins are administered and only very small amounts are absorbed. The mechanism of action of cyclodextrins may be explained by their interaction with the nasal epithelial membranes and their ability to transiently open tight junctions.

Absorption↗
PubMed1998

Comparison of chiral recognition capabilities of cyclodextrins for the separation of basic drugs in capillary zone electrophoresis.

The enantiomeric separation of some racemic anti-histamines and anti-malarials, namely (+/-)-pheniramine, (+/-)-brompheniramine, (+/-)-chlorpheniramine, (+/-)-doxylamine, and (+/-)-chloroquine, was investigated by capillary zone electrophoresis. The enantiomeric separation of five compounds was obtained by addition of approximately 7 mM (1%, w/v) sulfated-beta-cyclodextrin into the buffer as a chiral selector. The effects of sulfated-beta-cyclodextrin concentration and buffer pH on migration and resolution are discussed. Two other cyclodextrins, carboxyethylated-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin were also investigated. Four of the racemic compounds were resolved using 14 mM (2%, w/v) carboxyethylated-beta-cyclodextrin while 28 mM (4%, w/v) hydroxypropyl-beta-cyclodextrin resolved only two of them. It was found that the type of substituent and the degree of substitution on the rim of the CD structure played an important role in enhancing the chiral recognition. Cyclodextrins with negatively charged substituents and higher degree of substitution on the rim of the structure proved to give better resolution to the cationic racemic compounds compared with cyclodextrin with neutral substituents. This is due to the countercurrent mobility of the negatively charged cyclodextrin relative to the cationic analytes thus allowing for a smaller difference in interaction constants to achieve a successful resolution of enantiomers. Furthermore, lower concentrations of negatively charged cyclodextrins were necessary to achieve the equivalent resolutions as compared with the neutral ones.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Cyclodextrin inclusion complexes of antimycotics intended to act in the oral cavity--drug supersaturation, toxicity on TR146 cells and release from a delivery system.

The dissolution rate, the toxicity and the release from chewing gum of miconazole and econazole cyclodextrin products and complexes were investigated. The dissolution rate studies showed that an amorphous miconazole hydroxypropyl-beta-cyclodextrin product gave drug supersaturation, whereas drug supersaturation was not present during dissolution rate testing of an econazole hydroxypropyl-beta-cyclodextrin product. The miconazole hydroxypropyl-beta-cyclodextrin product and genuine cyclodextrin inclusion complexes of miconazole, econazole and clotrimazole were toxic on a human TR146 buccal cell culture model. The toxicity was probably due to drug supersaturation, thereby increasing the bioavailability of the antimycotics. The econazole hydroxypropyl-beta-cyclodextrin product and physical mixtures of miconazole or econazole and beta-cyclodextrin did not give supersaturation and were not as toxic as the above-mentioned compounds. Neat econazole and miconazole, a genuine econazole beta-cyclodextrin complex and the miconazole hydroxypropyl-beta-cyclodextrin product were incorporated in chewing gum. The miconazole hydroxypropyl-beta-cyclodextrin gum had a much higher drug release in vitro than the neat miconazole gum. The genuine econazole beta-cyclodextrin complex only increased the drug release moderately when compared with the release from the neat econazole gum. The release studies were performed on a mastication device.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2000

Review: cyclodextrins and their interaction with amylolytic enzymes.

This review is concerned with inhibition of amylases by cyclodextrins (cyclic maltooligosaccharides), the interaction that occurs between amylases and cyclodextrins and the application of cyclodextrin affinity chromatography in the purification of amylases. In many cases, amylases that are competitively inhibited by cyclodextrins can be purified by cyclodextrin affinity chromatography with the cyclodextrins interacting with the active site on such enzymes. Interestingly amylases that are not competitively inhibited by cyclodextrins may also be purified by cyclodextrin affinity chromatography. Therefore, cyclodextrin affinity chromatography can function in the purification of such amylolytic enzymes with the interaction occurring at a site removed from the active site. In such cases it appears that the cyclodextrin is interacting with an affinity site or binding site that is present on some amylolytic enzymes. It seems that certain similarities occur among the binding sites of such enzymes. Literature concerning amylases, and their subsequent purification using cyclodextrin affinity chromatography is reviewed and the fundamental basis of the interaction of the cyclodextrin with amylolytic enzymes is discussed here.

Journal Article↗
PubMed1976

Interaction of cyclodextrins with fluorescent probes and its application to kinetic studies of amylase.

It was found that 6-p-toluidinylnaphthalene-2-sulfonate (TNS) showed pronounced fluorescence enhancement when it was added to alpha-, beta-, and gamma-cyclodextrin solutions. 2. The following results were obtained by quantitative study of the interactions of three kinds of cyclodextrins with TNS by following TNS fluorescence at pH5.3. and 25 degrees. i) alpha-Cyclodextrin forms a l : l complex with TNS. ii) beta- and gamma-Cyclodextrins form 1 : 1 and also 2 : 1 complexes; in the latter two cyclodextrin molecules bind to one TNS molecule. iii) The dissociation constants of cyclodextrin-TNS complexes were determined to be 54.9 mM for alpha-cyclodextrin, 0.65 mM for beta-cyclodextrin and 0.66 mM for gamma-cyclodextrin in the 1 : 1 complex, and the secondary dissociation constants in the 2 : 1 complex were 71.4 mM for beta-cyclodextrin in the 1 : 1 complex, and the secondary dissociation constants in the 2 : 1 complex were 71.4 mM for beta-cyclodextrin and 32.6 mM for gamma-cyclodextrin. iv)...

Amylases↗
PubMed1999

Impact of beta-cyclodextrin and resistant starch on bile acid metabolism and fecal steroid excretion in regard to their hypolipidemic action in hamsters.

To examine the impact on bile acid metabolism and fecal steroid excretion as a mechanism involved in the lipid-lowering action of beta-cyclodextrin and resistant starch in comparison to cholestyramine, male golden Syrian hamsters were fed 0% (control), 8% or 12% of beta-cyclodextrin or resistant starch or 1% cholestyramine. Resistant starch, beta-cyclodextrin and cholestyramine significantly lowered plasma total cholesterol and triacylglycerol concentrations compared to control. Distinct changes in the bile acid profile of gallbladder bile were caused by resistant starch, beta-cyclodextrin and cholestyramine. While cholestyramine significantly reduced chenodeoxycholate independently of its taurine-glycine conjugation, beta-cyclodextrin and resistant starch decreased especially the percentage of taurochenodeoxycholate by -75% and -44%, respectively. As a result, the cholate:chenodeoxycholate ratio was significantly increased by 100% with beta-cyclodextrin and by 550% with cholestyramine while resistant starch revealed no effect on this ratio. beta-Cyclodextrin and resistant starch, not cholestyramine, significantly increased the glycine:taurine conjugation ratio demonstrating the predominance of glycine conjugated bile acids. Daily fecal excretion of bile acids was 4-times higher with 8% beta-cyclodextrin and 19-times with 1% cholestyramine compared to control. beta-Cyclodextrin and cholestyramine also induced a 2-fold increase in fecal neutral sterol excretion, demonstrating the sterol binding capacity of these two compounds. Resistant starch had only a modest effect on fecal bile acid excretion (80% increase) and no effect on excretion of neutral sterols, suggesting a weak interaction with intestinal steroid absorption. These data demonstrate the lipid-lowering potential of beta-cyclodextrin and resistant starch. An impaired reabsorption of circulating bile acids and intestinal cholesterol absorption leading to an increase in fecal bile acid and neutral sterol excretion is most likely the primary mechanism responsible for the lipid-lowering action of beta-cyclodextrin. In contrast, other mechanisms involving the alterations in the biliary bile acid profile or repressed hepatic lipogenesis, e.g., VLDL production, appear to be involved in the hypolipidemic effect of resistant starch.

Animals↗
PubMed2003

Separate and combined effects of local and continuous intravenous administration of beta-cyclodextrin tetradecasulfate on intimal hyperplasia after angioplasty in porcine coronary arteries.

BACKGROUND: Beta-Cyclodextrin tetradecasulfate binds fibroblast growth factors and possesses anticoagulant properties. This study was designed to assess the separate and combined effects of local intramural delivery and intravenous administration of beta-cyclodextrin tetrade-casulfate on neointimal formation and arterial damage following angioplasty. METHODS AND RESULTS: Fifty-two pigs randomized into four groups underwent coronary artery angioplasty: 1) control, 2) continuous intravenous infusion of 100 mg/kg/d of beta-cyclodextrin tetradecasulfate, 3) intramural delivery of 1250 mg beta-cyclodextrin tetradecasulfate, 4) intramural delivery of 1250 mg beta-cyclodextrin tetradecasulfate followed by continuous intravenous infusion of 100 mg/kg/d. Fourteen days after injury, morphometric analysis revealed that arteries randomized to the intravenous beta-cyclodextrin tetradecasulfate groups had a decreased normalized neointima area: control, 3.03 +/- 0.75 mm(2); intravenous, 1.67 +/- 0.73 mm(2) (40% decrease; P < 10(-7)); intravenous plus local, 1.95 +/- 0.76 mm(2) (30% decrease; P < 10(-5)). There was no difference in neointimal response following local beta-cyclodextrin tetradecasulfate delivery only (2.82 +/- 1.14 mm(2)). Coronary arterial damage, defined as aneurysm, dissection, adventitial rupture, and retromedial hematoma was similar in all groups (12% in control and local groups, 10% in the intravenous group, 14% in the intravenous plus local; NS). Bleeding complications were more frequent in the intravenous and intravenous plus local groups compared to the local and control groups (23%vs 7.6% and 0%, respectively; P < 0.05). CONCLUSIONS: Continuous intravenous administration of beta-cyclodextrin tetradecasulfate substantially reduced intimal hyperplasia, while intramural delivery had no effect, indicating that a single bolus of beta-cyclodextrin tetradecasulfate did not reduce intimal hyperplasia. There was no additive effect of local intramural delivery of beta-cyclodextrin tetradecasulfate. However, local delivery of beta-cyclodextrin tetradecasulfate induced less bleeding complications and did not lead to additional arterial injury, indicating that local delivery of an anticoagulant does not cause additional arterial injury.

Angioplasty, Balloon, Coronary↗
PubMed1985

Absorption, distribution, excretion and metabolism of orally administered 14C-beta-cyclodextrin in rat.

The absorption, distribution, excretion and metabolism of orally administered universally labelled 14C-beta-cyclodextrin and 14C-glucose were compared in rat. The maximum radioactivity of the blood derived from 14C-beta-cyclodextrin was observed between 4th and 11th h and the value of the maximum in different experiments ranged between 5 and 17 0/00 of the total administered radioactivity. Following 14C-glucose treatment radioactivity reached the maximum within half-an-hour, with values of 15 to 82 0/00. In the 8th h after a high dose (313.5 mg/kg) of beta-cyclodextrin no more than 3-50 ppm beta-cyclodextrin was detectable in the blood by HPLC. After 14C-beta-cyclodextrin treatment 4.2-4.8% of the administered total radioactivity was excreted by the urine and about the same quantity (2-3.6%) in case of 14C-glucose. No specific accumulation was observed after 14C-beta-cyclodextrin treatment in the different organs. The large intestine contained 10-15% of the cyclodextrin radioactivity while this value was only 2% in case of 14C-glucose. Following p.o. administration of different doses of 14C-beta-cyclodextrin the radioactivity peak was detected in the exhaled air between the 4-6th and 6-8th h, respectively, depending on the administered doses, while in case of 14C-glucose treatment it was observed within 2 h. The total radioactivity exhaled by 14C-beta-cyclodextrin treated animals in 24 h was 55 to 64% of the administered radioactivity and 58% in case of 14C-glucose. It is assumed that beta-cyclodextrin is metabolized in rats slower but similarly to glucose, therefore p.o. administered beta-cyclodextrin cannot induce toxic symptoms.

Administration, Oral↗
PubMed1989

Differential effects of alpha-, beta- and gamma-cyclodextrins on human erythrocytes.

Alpha-, beta- and gamma-cyclodextrins are cyclic hexamers, heptamers, and octamers of glucose, respectively, and thus are hydrophilic; nevertheless, they have the ability to solubilize lipids through the formation of molecular inclusion complexes. The volume of lipophilic space involved in the solubilization process increases with the number of glucose units in the cyclodextrin molecule and, consequently, cyclodextrins were found to have different effects on human erythrocytes: (a) in the induction of shape change from discocyte to spherocyte the potency was observed to be alpha greater than gamma, but with beta-cyclodextrin hemolysis occurred before the change was complete; (b) in the increase of fluorescence intensity of 1-anilinonaphthalene-8-sulfonate in cyclodextrin-pretreated membranes, the observed potency was beta much greater than gamma greater than alpha; (c) in the release of potassium and hemoglobin, the potency was beta greater than alpha greater than gamma. The potencies of cyclodextrin for solubilizing various components of erythrocytes were alpha greater than beta much greater than gamma for phospholipids, beta much greater than gamma greater than alpha for cholesterol and beta much greater than gamma greater than alpha for proteins. The solubilization potencies were derived from concentration/final-effect curves. The above processes occurred without entry of solubilizer into the membrane, since (a) beta-[14C]cyclodextrin did not bind to erythrocytes and (b) cyclodextrins did not enter the cholesterol monolayer. A study of the [3H]cholesterol in erythrocytes indicated that beta-cyclodextrin extracted this lipid from membrane into a new compartment located in the aqueous phase which could equilibrate rapidly with additional erythrocytes. Therefore, the effects of cyclodextrins differ from those of detergents which first incorporate themselves into membranes then extract membrane components into supramolecular micelles.

Cyclodextrins↗
PubMed2004

Bupivacaine hydrochloride complexation with some alpha- and beta-cyclodextrins studied by potentiometry with membrane electrodes.

Membrane electrodes selective to bupivacaine cations were developed and those with PVC-dibutylphthalate membrane containing sparingly soluble bupivacaine phosphotungstate appeared to be the most suitable. Inclusion complexation of bupivacaine cations with cyclodextrins was studied by potentiometric measurements of the free bupivacaine cation concentration in aqueous solutions of bupivacaine hydrochloride with cyclodextrin using the prepared electrodes. Native alpha-cyclodextrin (alpha-CD) and beta-cyclodextrin (beta-CD), as well as their random-substituted derivatives hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and methyl-beta-cyclodextrin (M-beta-CD), were chosen for the study. The measured potentiometric data processed both by a linear and nonlinear regression corroborated the formation of weak 1:1 bupivacaine cation-cyclodextrin complexes and the corresponding complexation constants K(11) approximately 50-155 M(-1) were evaluated by the non-linear least-squares method. The mutual order of K(11) values, especially alpha-CD > beta-CD, suggested that the bupivacaine butyl group was mainly responsible for the inclusion complexation; the highest K(11) was exhibited by M-beta-CD followed by alpha-CD. The observed complexation may substantially modify properties of bupivacaine hydrochloride dosage forms with sufficient concentration of cyclodextrin but bupivacaine cations are readily released from the weak cyclodextrin complexes by dilution.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

Nutritional effects of cyclodextrins on liver and serum lipids and cecal organic acids in rats.

The effect of dietary cyclodextrins on liver and serum lipids and cecal organic acid production was investigated. Male Wistar rats were fed a basal diet and a diet containing 5% of alpha-, beta-, or gamma-cyclodextrin. The body weight gain in rats fed the alpha-cyclodextrin diet was not significantly different from rats fed the other three kinds of diets. The feeding of dietary alpha-cyclodextrin increased total lipid and phospholipids in the liver. Beta-cyclodextrin significantly lowered serum total cholesterol and phospholipid levels compared with the basal diet et al. A decrease in serum triacylglycerol levels was also observed in beta-cyclodextrin-fed rats. Dietary alpha-cyclodextrin significantly increased the weight of cecal tissues and contents, and an approximate fourfold increase in acetate, propionate, and total organic acids was noted, indicating the fermentibility of beta-cyclodextrin compared with the basal diet. It seems likely that the suppression of serum cholesterol levels by alpha- and beta-cyclodextrins might be due to the increasing acetate and propionate productions in the cecum. cecal organic acid, cyclodextrin, serum cholesterol, rats

Acetates↗
PubMed1999

Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing.

It is well known that cyclodextrins can enhance the permeation of poorly soluble drugs through biological membranes. However, the permeability will decrease if cyclodextrin is added in excess of the concentration needed to solvate the drug. The mechanism of cyclodextrin effect on drug permeability has not been fully explained. The effect of cyclodextrins can not be explained as solely due to increased solubility of the drug in the aqueous donor phase nor can it be explained by assuming that cyclodextrins act as classical permeation enhancers, i.e. by decreasing the barrier function of the lipophilic membrane. In the present work we have modeled the effect of cyclodextrins in terms of mixed barrier consisting of both diffusion and membrane controlled diffusion, where the diffusion of the drug in the aqueous diffusion layer is significantly slower than in the bulk of the donor. This diffusion model is described by simple mathematical equation where the properties of the system are expressed in terms of two constants P(M)/Kd and M1/2. Data for the permeation of hydrocortisone through hairless mouse skin in the presence of various cyclodextrins, and cyclodextrin polymer mixtures, were fitted to obtain values for these two constants. The rise in flux with increased cyclodextrin complex concentration and fall with excess cyclodextrin was accurately predicted. Data for the permeation of drugs through semi-permeable cellophane membrane could also be fitted to the equation. It was concluded that cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution towards the lipophilic surface of biological membranes, where the drug molecules partition from the complex into the lipophilic membrane.

Animals↗