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PubMedDate not supplied

Inclusion complexes of nifedipine and other 1.4-dihydropyridine derivatives with cyclodextrins. IV. The UV study on photochemical stability of the inclusion complexes of nisoldipine, nimodipine, nitrendipine and nicardipine with beta-cyclodextrin in the solution.

The results of measurements of photochemical stability of the inclusion complexes formed by nimodipine (NM), nisoldipine (NS), nitrendipine (NR) and nicardipine (NC) with beta-cyclodextrin (beta-CD) are reported. The inclusion complexes were obtained in solution. The formation of inclusion complexes in the liquid phase was estimated from a phase solubility diagram. The analysis of solubility curves in the phase diagram permitted calculation of stability constants of the inclusion complexes formed. Photochemical stability of 1.4-dihydropyridine derivatives obeyed the 1 order kinetic equation. The photodegradation of NM, NR and NC was found to be a single stage reaction. The photodegradation of NS occurred in two stages. In the inclusion complexes the photosensitivity of all studied DHP derivatives decreases. The complexation with beta-CD improved their photostability by 5-10 times. The greatest decrease in the photodegradation rate was observed for the most photosensitive compound NS whose photostability increased 100 times when in inclusion complex with beta-CD.

Calcium Channel Blockers↗
PubMed2001

Influence of the amino acid sequence and nature of the cyclodextrin on the separation of small peptide enantiomers by capillary electrophoresis using randomly substituted and single isomer sulfated and sulfonated cyclodextrins.

The separation of dipeptide and tripeptide enantiomers using negatively charged single isomers as well as randomly sulfated and sulfonated cyclodextrins (CDs) was investigated with respect to the amino acid sequence of the peptides and the nature of the CDs. Standardized conditions concerning buffer pH and molarity, CD concentration, and separation voltage were applied. Compared to suffobutylether-beta-CD and heptakis-(2,3-dimethyl-6-sulfato)-beta-CD, randomly sulfated beta-CD as well as the single isomer derivatives heptakis-6-sulfato-beta-CD and heptakis-(2,3-diacetyl-6-sulfato)-beta-CD were the more universal CDs for enantioseparations. The enantiomer migration order depended to a greater extent on the CD than on the amino acid sequence of the peptide although small structural differences such as formation of a peptide amide or ester affected the chiral recognition by the randomly substituted CD derivatives. Using sulfobutylether-beta-CD or heptakis-(2,3-diacetyl-6-sulfato)-beta-CD the DD enantiomers migrated before the LL enantiomers for most peptides while the opposite migration order, i.e. LL before DD, was observed when heptakis-6-sulfato-beta-CD was applied as chiral selector.

Amino Acids↗
PubMed2004

Enantioseparations of hydrobenzoin and structurally related compounds in capillary zone electrophoresis using heptakis(2,3-dihydroxy-6-O-sulfo)-beta-cyclodextrin as chiral selector and enantiomer migration reversal of hydrobenzoin with a dual cyclodextrin system in the presence of borate complexation.

We investigated the enantioseparations of racemic hydrobenzoin, together with benzoin and benzoin methyl ether, in capillary electrophoresis (CE) using the single-isomer heptakis(2,3-dihydroxy-6-O-sulfo)-beta-cyclodextrin (SI-S-beta-CD) as a chiral selector in the presence and absence of borate complexation and enantiomer migration reversal of hydrobenzoin with a dual CD system consisting of SI-S-beta-CD and beta-CD in the presence of borate complexation at pH 9.0 in a borate buffer. The enantioselectivity of hydrobenzoin increased remarkably with increasing SI-S-beta-CD concentration and the enantioseparation depended on CD complexation between hydrobenzoin-borate and SI-S-beta-CD. The (S,S)-enantiomer of hydrobenzoin-borate complexes interacted more strongly than the (R,R)-enantiomer with SI-S-beta-CD. The enantiomers of hydrobenzoin could be baseline-resolved in the presence of SI-S-beta-CD at a concentration as low as 0.1% w/v, whereas the three test analytes were simultaneously enantioseparated with addition of 0.3% w/v SI-S-beta-CD or at concentrations >2.0% w/v in a borate buffer and 0.5% w/v in a phosphate background electrolyte at pH 9.0. Compared with the results obtained previously using randomly sulfated beta-CD (MI-S-beta-CD) in a borate buffer, enantioseparation of these three benzoin compounds is more advantageously aided by SI-S-beta-CD as the chiral selector. The enantioselectivity of hydrobenzoin depended greatly on the degree of substitution of sulfated beta-CD. Moreover, binding constants of the enantiomers of benzoin compounds to SI-S-beta-CD and those of hydrobenzoin-borate complexes to SI-S-beta-CD were evaluated for a better understanding of the role of CD complexation in the enantioseparation and chiral recognition. Enantiomer migration reversal of hydrobenzoin could be observed by varying the concentration of beta-CD, while keeping SI-S-beta-CD at a relatively low concentration. SI-S-beta-CD and beta-CD showed the same chiral recognition pattern but they exhibited opposite effects on the mobility of the enantiomers.

Benzoin↗
PubMed1993

Synthesis of cyclodextrin glucosyl transferase by Bacillus cereus for the production of cyclodextrins.

A potent indigenous bacillus isolate identified as Bacillus cereus (RJ-30) was found to produce Cyclodextrin Glucosyl Transferase (CGTase) extracellularly. Process optimization of various fermentation parameters has been established for optimal growth of bacillus and the maximum enzyme synthesis. The organism had the highest specific growth rate (0.7 mu) with a generation time of 1 h in glucose containing medium at the conditions of pH 7.0, 37 degrees C at 300 rpm, 1.5 vvm of agitation, and aeration. At these conditions, it exhibited the maximum activity of 54 U/mL at the synthesis rate of 2.7 U/L/h. CGTase was produced from the early exponential growth and peaked during the midsporulating stage of about 16 h thereafter maintained at the same level of 50 U/mL. Saccharides containing media were better inducers than starch, and the influence of carbohydrate substrates has shown that enzyme synthesis is promoted by xylose (65 U/mL) and, more remarkably, by the supplementation of wheat bran extract in glucose medium (106 U/mL). This organism produced CGTase stably in a chemostat culturing over a period of 400 h with a maximum productivity of 5.4 kU/L/h (threefold higher than obtained in batch culturing [1.75 kU/L/h]). Comparatively, CGTase was produced by immobilized cells in a continuous fluidized bed reactor for over approx 360 h, at a relatively high dilution rate of 0.88 h-1 resulting in the productivity of 23.0 kU/L/h.

Bacillus cereus↗
PubMed1998

Production of cyclomaltononaose (delta-cyclodextrin) by cyclodextrin glycosyltransferases from Bacillus spp. and bacterial isolates.

The conversion of soluble starch to cyclomaltohexaose (alpha-CD), cyclomaltoheptaose (beta-CD), cyclomaltooctaose (gamma-CD) and cyclomaltononaose (delta-CD) by cyclodextrin glycosyltransferases (E.C. 2.4.1.19) from Bacillus spp. and bacterial isolates was studied. The results show that delta-CD was formed by all the enzymes investigated in the range of 5%-11.5% of the total amount of alpha-, beta-, gamma-, and delta-CD produced.

Bacillus↗
PubMed1989

Determination of cyclodextrins and branched cyclodextrins by reversed-phase chromatography with pulsed amperometric detection and a membrane reactor.

A high-performance liquid chromatographic method has been developed for the determination of cyclodextrins (CDs) and branched CDs. The method involves their separation on a reversed-phase column using a mixture of water and acetonitrile as an eluant, eluant pH modification with a cation-exchange membrane reactor surrounded by 1.5 M sodium hydroxide solutions, and pulsed amperometric detection with a gold working electrode. The calibration graphs constructed by peak height versus injected amount were linear over the ranges 50-1000 pmol. The detection limits for CDs and branched CDs were about 1-5 pmol at a signal-to-noise ratio of 3. The method was successfully applied to the assay of beta-CD in serum samples.

Chromatography, High Pressure Liquid↗
PubMed2003

Pullulan-cyclodextrin microspheres. A chromatographic approach for the evaluation of the drug-cyclodextrin interactions and the determination of the drug release profiles.

Pullulan microspheres containing cyclodextrin (CyD) were obtained by chemical crosslinking with epichlorohydrin of an alkaline solution of pullulan (Pul) and alpha-, beta- or gamma-CyD. The amount of alpha-, beta- and gamma-CyD in microspheres was 120, 156, and 138 micromol/g, respectively, as determined from the percentage of iodine incorporated in the hydrophobic cavity of CyD's. Microspheres were packed in a glass column and the liquid chromatographic behaviour by isocratic elution of different drugs or typical organic compounds (TOC), taken as model drugs, was investigated. The increase of the retention volume (V(R)) of each compound, depending on the interaction(s) between CyD's cavity and the considered molecule, is characterized by a broadening of the peaks. The interaction coefficient K, corresponding to the ratio between the V(R) value of each tested molecule on Pul-alpha-, Pul-beta- and Pul-gamma-CyD active stationary phase and the V(R) value of benzoic acid on St/maltodextrin neutral stationary phase, was determined. According to K values, the accurate prediction can be done on the potential drugs to be conditioned in suitable CyD cavity. Values of K allow to anticipate the release profiles of drugs considered.

Cyclodextrins↗
PubMed1997

6A-O-[(4-biphenylyl)acetyl]-alpha-, -beta-, and -gamma-cyclodextrins and 6A-deoxy-6A-[[(4-biphenylyl)acetyl]amino]-alpha-, -beta-, and -gamma-cyclodextrins: potential prodrugs for colon-specific delivery.

Cyclodextrins (CyDs) are known to be fermented to small saccharides by colonic microflora, whereas they are only slightly hydrolyzable and thus are not easily absorbed in the stomach and small intestine. This property of CyDs is particularly useful for colon-specific delivery of drugs. In this study, an antiinflammatory 4-biphenylylacetic acid (BPAA) was selectively conjugated onto one of the primary hydroxyl groups of alpha-, beta-, and gamma-CyDs through an ester or amide linkage, 6A-O-[(4-biphenylyl)acetyl[-alpha-, -beta-, and -gamma-CyDs (1-3) and 6A-deoxy-6A-[[(4-biphenylyl)acetyl]amino]-alpha-, -beta-, and -gamma-CyDs (4-6). In rat cecal and colonic contents (10%, w/v), 1 and 3 released more than 95% of BPAA within 1-2 h, and 2 released about 50% of the drug within 12 h. The amide prodrugs, 4-6, did not release BPAA in the cecal contents, but gave BPAA/maltose or BPAA/triose conjugates linked through an amide bond. On the other hand, these prodrugs were found to be stable in the contents of rat stomachs and small intestines, in intestinal or liver homogenates, and in rat blood. The serum levels of BPAA increased about 3 h after oral administration of 1 and 3 to rats, accompanying a marked increase in the serum levels, whereas 2 and 4-6 resulted in little increase of the serum levels. These facts suggest that BPAA is released after the ring opening of CyDs followed by the ester hydrolysis, and the BPAA activation takes place site-specifically in the cecum and colon. Therefore, the present CyD prodrug approach provides a versatile means of constructing a novel colon-specific drug delivery system.

Animals↗
PubMed2005

Molecular recognition thermodynamics of bile salts by beta-cyclodextrin dimers: Factors governing the cooperative binding of cyclodextrin dimers.

The complex stability constants (K(S)), standard molar enthalpy (DeltaH degrees), and entropy changes (DeltaS degrees) for the inclusion complexation of two families of beta-cyclodextrin (beta-CD) dimers, i.e. beta-CD dimers Se1-Se4 bearing 2,2'-diselenobis(benzoyl) tether (Se-dimers) and beta-CD dimers Py1-Py4 bearing 2,2'-bipyridine-4,4'-dicarboxy tether (Py-dimers), with four bile salt guests, i.e. sodium cholate (CA), sodium deoxycholate (DCA), sodium glycocholate (GCA), and sodium taurocholate (TCA), were determined at 25 degrees C in Tris buffer solution (pH 7.4) at 298.15 K by means of isothermal titration microcalorimetry. The thermodynamic parameters obtained, together with the ROESY spectra of interactions between beta-CD dimers and bile salts, consistently suggest that the length, flexibility, and structure of spacers linking the two beta-CD cavities not only determine the binding modes but also significantly alter the molecular selectivity of beta-CD dimers.

Calorimetry↗
PubMed1998

Colon-specific drug delivery based on a cyclodextrin prodrug: release behavior of biphenylylacetic acid from its cyclodextrin conjugates in rat intestinal tracts after oral administration.

An antiinflammatory drug biphenylylacetic acid (BPAA) as a model drug was selectively conjugated onto one of the primary hydroxyl groups of alpha-, beta-, and gamma-cyclodextrins (CyDs) through an ester or amide linkage, and the in vivo drug release behavior of these prodrugs in rat gastrointestinal tracts after oral administration was investigated. The CyD prodrugs were stable in rat stomach and small intestine and negligibly absorbed from these tracts. Three to six hours after the oral administration, most of the prodrugs had moved to the cecum and colon. The alpha- and gamma-CyD amide prodrugs were hydrolyzed to the maltose conjugate in the cecum and colon, and these prodrugs and the conjugate were negligibly absorbed. On the other hand, the alpha- and gamma-CyD ester prodrugs produced BPAA in the cecum and colon, and BPAA appeared in the blood after 3-6 h. Both beta-CyD amide and ester prodrugs released only small or negligible amounts of the maltose conjugate or BPAA in the cecum and colon, within 24 h, probably due to the low solubility in the biological media. Further, the antiinflammatory effect of the gamma-CyD ester prodrug was evaluated using the model of carageenan-induced acute edema in rat paw and compared with those of BPAA alone and the BPAA/beta-CyD complex prepared by the kneading method in a molar ratio of 1:1. In the case of the beta-CyD complex, a rapid antiinflammatory response was observed, compared to BPAA alone, because the drug is mainly absorbed from the small intestine after a fast dissolution of the complex. In sharp contrast, the gamma-CyD ester prodrug needed a fairly long lag time to exhibit the drug activity, because BPAA is produced after the prodrug had reached the cecum and colon. The present results clearly suggest that the CyD prodrug approach can provide a versatile means for constructions of not only colon-specific delivery systems but also delayed-release system of certain drugs.

Administration, Oral↗
PubMed2000

Absorption, distribution and excretion of galactosyl-beta-cyclodextrin and mannosyl-beta-cyclodextrin in rats.

Microanalytical methods were developed for measuring galactosyl-beta-cyclodextrin (Gal-betaCD) and mannosyl (Man)-betaCD in biological matrices of the rat by HPLC with pulsed amperometric detection. Then, using these methods, the absorption, distribution and excretion of intravenously and orally administered Gal-betaCD and Man-betaCD were determined in rats, and compared with those of glucosyl (Glc)-betaCD. The pharmacokinetic behavior of Gal-betaCD, Man-betaCD and Glc-betaCD after intravenous administration (50 mg/kg) was very similar. Within 6 h after intravenous administration, unchanged Gal-betaCD and Man-betaCD recovered in urine accounted for about 90% of each dose. After oral administration (500 mg/kg), 0.37% and 0.38% of Gal-betaCD and Man-betaCD, respectively, were excreted in urine. After intravenous and oral administration of Gal-betaCD and Man-betaCD, the decomposition of Gal-betaCD and Man-betaCD to betaCD in the urine, kidney and liver was greater than that of Glc-betaCD. The sum of the molar concentrations of branched CDs and their decomposition product, betaCD, in the liver at 4 h after intravenous administration of Gal-betaCD and Man-betaCD was greater than that of Glc-betaCD. Furthermore, the inclusion complexes of estriol and betamethasone with Gal-betaCD, Man-betaCD and Glc-betaCD were prepared and their absorption was evaluated after oral administration in rats. The plasma concentrations of the drugs after oral administration of drug-Gal-betaCD and drug-Man-betaCD complexes were the same as those after the administration of drug-Glc-betaCD complexes.

Administration, Oral↗
PubMed1990

Effect of cyclodextrins on biological membrane. I. Effect of cyclodextrins on the absorption of a non-absorbable drug from rat small intestine and rectum.

The effects of three kinds of cyclodextrins (CyDs), alpha-, beta- and gamma-CyD on biological membranes were investigated by changes in absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine and rectum using an in situ perfusion technique. The absorption of SA from the intestine was slight and was not affected by the addition of CyDs. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), the absorption of SA was increased compared with SA alone in the presence of only beta-CyD. Similar treatment with sodium deoxycholate (SDC) and sodium lauryl sulfate (SLS) to gastro-intestinal membrane showed the enhanced absorption of SA by the addition of beta-CyD. The mucin layer on the surface of the gastro-intestinal membrane may play an important role in the absorption of drugs. On the other hand, enhanced absorption of SA from the rat rectum was not induced by beta-CyD with or without pretreatment with N-Ac, SDC or SLS. Simultaneously, the release of neutral sugars in the perfusate after treatment with adjuvants was also observed with N-Ac, SDC and SLS. These results indicate that the mucin layer works as a barrier to the increased absorption of SA by beta-CyD.

Animals↗
PubMed1992

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.

Animals↗
PubMed1992

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.

Absorption↗
PubMed1994

Galactosylation of cyclodextrins and branched cyclodextrins by alpha-galactosidases.

Transgalactosylated derivatives of cyclodextrins (CDs) and glucosyl and maltosyl CDs (G1- and G2-CDs) were synthesized by alpha-galactosidases from coffee bean and Mortierella vinacea (M. vinacea). The structures of the transfer products were analyzed by FAB-mass, 13C-NMR and methylation. Coffee bean alpha-galactosidase transferred a galactosyl residue not only to side chains of G1-CDs and G2-CDs, but also directly to CD rings. M. vinacea alpha-galactosidase transferred a galactosyl residue only to side chains of G2-CDs.

Carbohydrate Sequence↗
PubMed2001

A polyrotaxane series containing alpha-cyclodextrin and naphthalene-modified alpha-cyclodextrin as a light-harvesting antenna system.

Supramolecular light-harvesting antenna systems were constructed by using polyrotaxanes, in which cyclodextrin (CD) rings of alpha-CD and naphthalene (energy donor)-appended alpha-CD are threaded by a poly(ethylene glycol) chain with anthracene (energy acceptor) units at both ends (5-8). The effects of the component ratio of the polyrotaxanes on the efficiencies of energy migration and energy transfer were examined by fluorescence emission and excitation spectra and anisotropy and by fluorescence decay measurements. The observed results were explained by using the Forster mechanism.

Journal Article↗