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PubMed2005

Simultaneous quantification of different cyclodextrins and Gantrez by HPLC with evaporative light scattering detection.

A rapid and simple HPLC method with evaporative scattering detection (ELSD) has been developed for the separation and quantitation of beta-cyclodextrin (beta-CD), 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD) and poly(methyl vinyl ether-co-maleic anhydride) (Gantrez). Separation was carried out on a Zorbax Eclipse XDB-Phenyl narrow bore column, with water-acetonitrile in gradient elution as mobile phase at a flow-rate of 0.25 ml/min. Polyethylenglycol 6000 was used as internal standard. The limit of quantification was of about 0.2 mg/ml for cyclodextrins and 0.05 mg/ml for Gantrez. The precision did not exceed 7%. This method was successfully applied to the rapid analysis of CD-Gantrez nanoparticle conjugates without interference from other components of the formulation.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2005

Preparation and characterization of inclusion complexes of pefloxacin mesylate with three kinds of cyclodextrins.

The ability of alpha-cyclodextrin, beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin (alpha-CD, beta-CD and HP-beta-CD) to break pefloxacin mesylate (PM) aggregates by forming inclusion complexes has been studied using 1H NMR (nuclear magnetic resonance spectroscopy), 13C NMR and fluorescence spectra. The inclusion constants are determined to compare the corresponding inclusion capacity. Solid-inclusion complexes of PM with CDs are synthesized by coprecipitation method, and all the inclusion ratios are found to be 1:1. Additionally, spatial characterization of complexes has been proposed based on two-dimensional nuclear magnetic resonance technique (2D NMR) and spatial conformation is also investigated to propose two possible models between PM and CDs.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2006

Study on the supramolecular systems of 5-(2-hydroxy phenyl)-10,15,20-tris (4-methoxy phenyl) porphyrin with cyclodextrins.

In neutral phosphate buffer solutions of pH 7.4, the inclusive complexation of 5-(2-hydroxy phenyl)-10,15,20-tris(4-methoxy phenyl) porphyrin (o-HTPP) with alpha-cyclodextrin (alpha-CD), beta-CD, heptakis (2,3,6-tri-O-methyl)-beta-CD (TM-beta-CD), SBE-beta-CD, HP-beta-CD and gamma-CD has been examined by means of UV-vis and fluorescence spectroscopy. The formation of inclusion complexes has been confirmed on the base of changes of spectroscopy properties. The o-HTPP forms 1:2 inclusion complexes with TM-beta-CD and 1:1 inclusion complexes with the other five cyclodextrins. The formation constants (K) of o-HTPP for the formation of the inclusion complexes have been estimated from the absorbance and fluorescence intensity changes in neutral phosphate buffer solutions. The K value (2.89x10(7)), which is the formation constant for the formation of the 1:2 inclusion supramolecular, is nearly 10(4) times than those of the 1:1 inclusion complexes. Compared to the other five cyclodextrins, the strongest inclusion ability of TM-beta-CD can be explained that the hydrogen bond plays significant role in the inclusion process. UV-vis experiments also showed that the cavity of TM-beta-CD causes the transform of the state of o-HTPP. In addition (1)H NMR data and 2D-ROSEY NMR spectra support the inclusion conformation of the o-HTPP-CD supramolecular system, indicating the interaction mechanism of inclusion processes.

Cyclodextrins↗
PubMed1997

Effects of sphingomyelin and phosphatidylcholine degradation on cyclodextrin-mediated cholesterol efflux in cultured fibroblasts.

The hydrolysis of plasma membrane sphingomyelin is known to dramatically alter cellular cholesterol homeostasis in different ways, whereas the degradation of plasma membrane phosphatidylcholine has much less or no effects on cell cholesterol homeostasis [Pörn, Ares, Slotte, J. Lipid Res. 34 (1993) 1385-1392]. In this study, we used an efficient extracellular cholesterol acceptor (cyclodextrin) and determined the extent of cholesterol efflux from cultured fibroblasts in which plasma membrane sphingomyelin or phosphatidylcholine was degraded. Treatment of cells with sphingomyelinase reduced the cell sphingomyelin content by about 76% (about 13 nmol SM degraded), and dramatically increased the desorption of [3H]cholesterol from the plasma membrane to 2-hydroxypropyl-beta-cyclodextrin. The corresponding hydrolysis of cell surface phosphatidylcholine (about 12% reduction of the cellular phosphatidylcholine content, corresponding to about 12 nmol degraded PC) had almost no effect on cell [3H]cholesterol efflux. The stimulatory effect of sphingomyelin degradation on cell [3H]cholesterol efflux was reversible, since rates of [3H]cholesterol efflux dropped back to control levels when cells (in this case baby hamster kidney cells) were allowed to restore their sphingomyelin content by re-synthesis in the absence of sphingomyelinase. The findings of this study clearly demonstrate that plasma membrane sphingomyelin markedly affected the rate of cholesterol transfer between cells and an extracellular acceptor (i.e., cyclodextrin), whereas the effect of phosphatidylcholine on cholesterol efflux was much smaller.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

Hydroxypropyl-beta-cyclodextrin and its combination with hydroxypropyl-methylcellulose increases aqueous solubility of delta9-tetrahydrocannabinol.

Delta9-tetrahydrocannabinol (THC) is the main psychoactive constituent of Cannabis sativa L. and its therapeutic effects are currently under intensive study. However, THC has a very low aqueous solubility (1-2 microg/mL), which restricts its use as a pharmaceutical. The present study demonstrates that THC forms a drug-cyclodextrin complex in an aqueous solution of hydroxypropyl-beta-cyclodextrin (HP-beta-CD), resulting in a thousand-fold increase in THC solubility. This improvement in solubility can be further increased by adding 0.1% hydroxypropylmethylcellulose to the HP-beta-CD solution. The present results suggest that the use of cyclodextrins might be a simple and useful method to overcome the poor water solubility of THC.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2003

Determination of second-order association constants by global analysis of 1H and 13C NMR chemical shifts. Application to the complexation of sodium fusidate and potassium helvolate by beta- and gamma-cyclodextrin.

The host-guest interaction between the steroid antibiotics sodium fusidate and potassium helvolate as guests and the hosts beta- and gamma-cyclodextrin was studied by 13C and 1H NMR techniques. The analysis of chemical shifts of individual nuclei leads to inconsistent values of the association constants and fails generally in the case of mixtures of 1:1 and 1:2 stoichiometries. The problem of parameter correlation is identified and the global analysis of two or more nuclei is proposed as a very effective method for the detection of complexes of higher stoichiometries and for the precise determination of the involved association constants. A matrix formulation of global analysis and the determination of confidence intervals is described. An analytical solution of the cubic equation, necessary for the description of higher order complexes, is presented in detail and its use together with commercial fitting software is compared with dedicated implementations. gamma-Cyclodextrin forms with both studied steroids, sodium fusidate and potassium helvolate, 1:1 complexes with high values of the association constants, K(1)=(60+/-24)x10(3)lmol(-1), and K(2)=(22+/-9)x10(3)lmol(-1), respectively. To the contrary, beta-cyclodextrin forms 1:1 and 1:2 (guest:host) complexes with both steroids, with moderate K(1) and low K(2) values (K(1)=(0.74+/-0.13)x10(3)lmol(-1), K(2)=(0.210+/-0.075)x10(3)lmol(-1)), and (K(1)=(2.42+/-0.87)x10(3)lmol(-1), K(2)=(0.06+/-0.09)x10(3)lmol(-1)), respectively.

Anti-Bacterial Agents↗
PubMed2003

Mechanistic studies of the effect of hydroxypropyl-beta-cyclodextrin on in vitro transdermal permeation of corticosterone through hairless mouse skin.

Literature reports reveal that the issue of whether cyclodextrins may act as skin permeation enhancers has not been resolved. Accordingly, in vitro skin transport studies were conducted to address this question. Corticosterone (3H-CS and/or non-radiolabeled CS) was chosen as the model permeant for transport experiments with hairless mouse skin (HMS) and with a synthetic cellulose membrane of 500 molecular weight cut off (MWCO), the latter to help establish baseline behavior. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) was selected as the representative cyclodextrin. The CS/HPbetaCD complexation constant was determined both from solubility data (saturation conditions) in phosphate buffered saline (PBS), pH 7.4 and with data obtained from PBS/silicone polymer partitioning experiments, the latter experiments permitting the determination of the complexation constant at low CS concentrations. These results were used in the calculations of the free CS concentrations in the donor chamber of the transport experiments. The CS transport experiments were conducted at CS solubility saturation and under supersaturation (resulting from autoclaving at 121 degrees C) conditions as well at very low (tracer level) concentrations. The effect of polyvinylpyrrolidone as a solution additive was also evaluated. The following were the key outcomes of this study. Contrary to literature reports, there was no evidence that HPbetaCD is an enhancer for CS transport through HMS. The CS permeability coefficient values obtained with HMS in all of the experiments were found to be the same within experimental error when calculated on the basis of the free CS concentration as the driving force for permeation. The constancy of the permeability coefficient in the presence and absence of HPbetaCD is interpreted to mean that, in these experiments, HPbetaCD did not alter the barrier properties of HMS stratum corneum to any significant extent nor did it enhance CS transport in any other manner such as by a carrier mechanism involving the aqueous boundary layer or by a carrier mechanism within the stratum corneum.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Solid lipid nanoparticles as carriers of hydrocortisone and progesterone complexes with beta-cyclodextrins.

Inclusion complexes of hydrocortisone and progesterone were formed with beta-cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin. The formation of the complexes was confirmed by differential scanning calorimetry (DSC). The inclusion complexes were incorporated in two types of solid lipid nanoparticles (SLN). In the presence of the complexes the sizes of SLN remained below 100 nm. DSC analysis showed that hydrocortisone and progesterone are dispersed in SLN in an amorphous state. Using the beta-cyclodextrin complexes the incorporation of the more hydrophilic drug, hydrocortisone, was higher than that of progesterone. Release of hydrocortisone and progesterone from SLN was lower when they were incorporated as inclusion complexes than as free molecules.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2002

Study on the inclusion complexes of bromazepam with beta- and beta-hydroxypropyl-cyclodextrins.

Solubility enhancement of the water insoluble bromazepam was studied during the formation of its inclusion complexes with beta-cyclodextrin (beta-CD) and beta-hydroxypropyl-cyclodextrin (beta-HP-CD). The phase solubility technique established by Higuchi and Connors and UV-spectrophotometric methods (zero- and second-order derivative approaches) were used to measure the changes introduced in this chemical system. The amount of time, which was necessary to reach equilibrium between inclusion complexes and their free components, was estimated and found equal to 24 h. The study was carried out at (i) pH 7.0 and 25 degrees C and (ii) pH 7.4 and 37 degrees C. The solubility of bromazepam increased linearly as a function of concentration for both beta-and beta-hydroxypropyl-cyclodextrins. Thus, the phase solubility diagrams were classified as of A(L) type in all cases. Under the above-mentioned conditions, the formation constants of the inclusion complexes were calculated and their stoichiometry was evaluated, found in the range of 69-85 M(-1) and 1:1, respectively.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2002

Chromatographic determination of the association constants between nimesulide and native and modified beta-cyclodextrins.

The retention of a non-steroidal anti-inflammatory drug (NSAID), i.e. nimesulide, in high performance liquid chromatography (HPLC) was investigated using a phenyl bond silica column and beta-cyclodextrin (beta-CD) or hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as mobile phase additive (0-10 mM). Such a study was carried out in order to determine the most efficient cyclodextrin as a potential drug complexing agent for a future application in pharmaceutical formulation. Assuming a 1:1 stoichiometry, the association constants (K) were calculated from the chromatographic data. At a column temperature of 25 degrees C and in a highly aqueous medium (98% phosphate buffer-2% methanol (v/v)), K was equal to 523 and 1285 M(-1) for the nimesulide-beta-CD and nimesulide HP-beta-CD complexes, respectively. These results were consistent with the data reported previously using phase solubility studies and UV spectrophotometry. As well, the thermodynamic parameters of the inclusion complexes were determined from linear van't Hoff plots for the two inclusion complexes. From the enthalpy and entropy changes, it appeared that nimesulide interact more strongly with HP-beta-CD due to a significant hydrophobic effect between the compound and the flexible hydroxypropyl groups.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

Molecular modeling study of beta- and gamma-cyclodextrin complexes with miconazole.

Different authors have demonstrated the inclusion of miconazole in cyclodextrins (CD). Miconazole can be included in the CD cavity both in the neutral and in the ionized form. The present study tries to understand which fragment of the miconazole molecule is involved in the inclusion. Austin Model 1 approximate molecular orbital calculations have been performed on several complexes between beta-cyclodextrin (betaCD) or gamma-cyclodextrin (gammaCD) and miconazole in the ionized and the non-ionized forms of the two R and S enantiomers in three different orientations. We observed that betaCD is a good vehicle to transport miconazole which can be very easily released. The complexation energy between miconazole and betaCD is not very high but the entropic factor has a great incidence on the stability of the formed complex. The inclusion of the dichlorobenzene-CH(2)-O- and of the imidazole part of the S isomer gives rise to the most probable complex in acidic conditions (ionized miconazole). Nevertheless, the inclusion should be considered as a dynamic process in which different parts of the molecule could be alternatively included in betaCD. The present work demonstrates the high capability of deformation of betaCD which could easily accommodate several types of ligand. By opposite, the cycle extension in gammaCD leads to a more rigid vehicle with regards to miconazole.

Antifungal Agents↗
PubMed2000

Considerations in the use of hydroxypropyl-beta-cyclodextrin in the formulation of aqueous ophthalmic solutions of hydrocortisone.

The in vivo ocular bioavailability of hydrocortisone (HC) in the NZW rabbit was determined following topical administration of solutions containing HC (1%) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) alone, or containing the mucoadhesive, viscosity enhancing polymers sodium hyaluronate (0.2 and 0.5% w/v) or Carbopol 934P (0.1% w/v). A 1% HC suspension was used as control. Formulation of HC as a solution with HP-beta-CD in the absence of polymer increased the bioavailability of HC in the aqueous humour by approximately 55% and cornea by 75% when compared to suspension. Inclusion of either polymer did not result in any further increase in ocular bioavailability over that noted for the polymer-free solution. The in vitro corneal permeability of HC was also evaluated. A linear relationship (r(2)=0.999) was noted between corneal permeability and the concentration of free (uncomplexed) HC in solution. Permeability was greatest when formulated either as a suspension, or as an HP-beta-CD solution in which the concentration of free (uncomplexed) HC is equivalent to that of a saturated solution. Thus, when using cyclodextrins in the reformulation of ophthalmic suspensions as solutions, consideration must be given to the concentration of cyclodextrin used and to the benefits of including viscosity enhancing polymers.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

Study on the supramolecular system of meso-tetrakis (4-sulfonatophenyl) porphyrin and cyclodextrins by spectroscopy.

The ability of beta-cyclodextrin (beta-CD), sulfurbutylether-beta-CD (SBE-beta-CD) and hydroxypropyl-beta-CD (HP-beta-CD) to break the aggregate of the meso-Tetrakis (4-sulfonatophenyl) porphyrin (TPPS4) and to form 2:1 inclusion complexes has been studied by adsorption and fluorescence spectroscopy. The formation constants are calculated, respectively by fluoremetry, from which the inclusion capacity of different CDs is compared and the inclusion mechanism of charged-beta-CD (SBE-beta-CD) is quite different from that of parent beta-CD. At lower pH, the complexation between HP-beta-CD and H2TPPS(2+)4 (the form of the diprotonated TPPS4) hampers the continuous protonation of the pyrrole nitrogen of TPPS4 and the hydrophobic cavity may prefer to bind an apolar neutral porphyrin molecule. 1HNMR data support the inclusion conformation of the porphyrin-cyclodextrin supramolecular system, indicating the interaction of meso-phenyl groups of TPPS4 with the cavity of CDs. For this host-guest inclusion model, cyclodextrin, being regarded as the protein component, which acts as a carrier enveloping the active site of heme prosthetic group within its hydrophobic environment, provides a protective sheath for porphyrin, creating artificial analogues of heme-containing proteins. However, the TPPS4, encapsulated within this saccharide-coated barrier, its physico-chemical, photophysical and photochemical properties changed strongly.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2003

Formation of natamycin:cyclodextrin inclusion complexes and their characterization.

Natamycin is a broad spectrum antimycotic with very low water solubility, which is used to extend the shelf life of shredded cheese products. beta-Cyclodextrin (beta-CD), hydroxypropyl beta-cyclodextrin (HP beta-CD), and gamma-cyclodextrin (gamma-CD) were found to form inclusion complexes with natamycin in aqueous solution. The increase in solubility of natamycin with added beta-CD was observed to be linear (type A(L) phase solubility diagram). The 1:1 stability constant of natamycin:beta-CD complex was estimated from its phase solubility diagram to be 1010 M(-1). The phase solubility diagrams of both gamma-CD and HP beta-CD exhibited negative deviation from linearity (type A(N) diagram) and, therefore, did not allow the estimation of binding constants. The water solubility of natamycin was increased 16-fold, 73-fold, and 152-fold with beta-CD, gamma-CD, and HP beta-CD, respectively. The natamycin:CD inclusion complexes resulted in in vitro antifungal activity nearly equivalent to that of natamycin in its free state.

Antifungal Agents↗
PubMed2005

The effect of solvent interactions on alpha-, beta-, and gamma-cyclodextrin/flavor molecular inclusion complexes.

Three commonly used flavor industry solvents (propylene glycol, triacetin, and triethyl citrate) were tested for their capacity to interfere with the ability of alpha-, beta-, and gamma-cyclodextrin to form molecular inclusion complexes with flavors. Six flavor compounds (ethyl butyrate, ethyl heptanoate, l-menthol, methyl anthranilate, neral, and geranial) were measured by headspace gas chromatography above 2:1 water/ethanol containing appropriate additions of cyclodextrin and flavor solvent. The smallest and most polar solvent molecule represented by propylene glycol had the least effect on cyclodextrin/flavorant complex formation. In contrast, triacetin, intermediate in size among the three flavor diluents studied, had the greatest effect, even though, based on at least some computed molecular parameters, it appears to be more polar than triethyl citrate. The explanation for this apparent anomaly may lie in differences in the extent to which triacetin and triethyl citrate are able to interact with cyclodextrins by means of partial interaction with the hydrophobic cavities of the latter.

Citrates↗
PubMed1997

Influence of hydroxypropyl beta-cyclodextrin on the stability of benzylpenicillin in chloroacetate buffer.

Hydroxypropyl beta-cyclodextrin (HP beta CyD) has been shown to stabilize a wide variety of chemically distinct pharmaceutical entities through inclusion-complex formation between drug and cyclodextrin. The effect of HP beta CyD on the acid-catalysed hydrolysis of benzylpenicillin (penicillin G) was evaluated in chloroacetate buffer at pH 2.20. At penicillin G: cyclodextrin molar concentration ratios from 1:1 to 1:10, HP beta CyD effected stabilization of penicillin G by 1.56- to 5.21-fold. At all temperatures, the observed first-order rate constant (kobs) values assumed a non-linear, Michaelis-Menten type decrease as a function of increasing HP beta CyD concentration. Degradation of penicillin G complexed with HP beta CyD (penicillin G-HP beta CyD), was approximately ninefold slower than uncomplexed penicillin G. The proportion of penicillin G degrading in either of these forms was, in turn, determined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HP beta CyD have also been evaluated. The negative standard enthalpy change (delta H degrees) for the complexation implied that the penicillin G-HP beta CyD complex would be predisposed towards enhanced stability, and thus the kobs value for the hydrolysis of penicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (delta H ++) for the hydrolysis of uncomplexed and complexed penicillin G seemed to be compensated by the significant difference between the entropies of activation (delta S ++) for these hydrolytic reactions. The results indicate that HP beta CyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1994

The effect of a modified beta-cyclodextrin, SBE4-beta-CD, on the aqueous stability and ocular absorption of pilocarpine.

In the present study, the effects of a novel, modified beta-cyclodextrin derivative (SBE4-beta-CD; a variably substituted sulfobutyl ether of beta-cyclodextrin with an average degree of substitution of four) on the aqueous stability of pilocarpine and on its ocular absorption in albino rabbits were studied. For stability reasons, commercial pilocarpine eyedrops are formulated at pH 4-5, a pH range where pilocarpine (pKa approximately 7) is almost completely ionized. As shown in the present and past studies, increasing the pH of the pilocarpine solution from 4.5 to 7.0 increases the ocular absorption of pilocarpine. SBE4-beta-CD increased the aqueous stability of pilocarpine (0.36 mM) at pH 7.0 (4 degrees C, projected values from Arrhenius data at 25 degrees C, 37 degrees C and 50 degrees C); in the absence of SBE4-beta CD, t90% was 236 days. In the presence of 1 mM and 25 mM of SBE4-beta-CD, t90% was 382 days and 2054 days, respectively suggesting that indeed, pilocarpine does interact with SBE4-beta-CD. SBE4-beta-CD did not damage the corneal epithelium in vitro and was well-tolerated by the rabbit eye in vivo. Coadministered SBE4-beta-CD did not significantly affect the miotic response of pilocarpine solutions at pH values of 4.5 or 7.0 when the molar ratio of SBE4-beta-CD to pilocarpine was between 0.2:1-7:1. The effect of the coadministered SBE4-beta-CD on the miotic response of pilocarpine solutions was also compared to that of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) which has recently been suggested to increase ocular bioavailability of pilocarpine in rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2000

Effect of hydroxypropyl-beta-cyclodextrin on hydrocortisone dissolution from films intended for ocular drug delivery.

The formation of an inclusion complex between hydrocortisone and hydroxypropyl-beta-cyclodextrin can affect the in vitro transfer rate of hydrocortisone from the aqueous to the organic phase. The observed first order transfer rate constants showed that the complexation of hydrocortisone with hydroxypropyl-beta-cyclodextrin decreased significantly the transport of the drug depending on the partition coefficient of the drug, and the relative magnitude of the stability constant of the inclusion complex. To optimize the ocular drug delivery, high molecular weight cellulosis and PVA polymeric films were prepared. No unified mathematical model can predict the release profile of drug and complex from films. The drug and complex-polymer interactions in each system could be responsible for the solubility of the drug, and different release behaviours of hydrocortisone and cyclodextrin inclusion complex from the films prepared.

2-Hydroxypropyl-beta-cyclodextrin↗