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The electrospun nanofiber-based orally dissolving webs are promising candidates for rapid drug release, which is due to the high surface area to volume ratio of the fibers and the high amorphization efficacy of the fiber formation process. Although the latter is responsible for the physical and/or chemical instability of these systems. The primary aim of the present study was to elucidate how the addition of polysorbate 80 (PS80) and hydroxypropyl-β-cyclodextrin (HP-β-CD) influenced the electrospinning process, the properties, and the behavior of the obtained nanofibers. In order to reveal any subtle changes attributable to the applied excipients, the prepared samples were subjected to several state of the art imaging and solid state characterization techniques at both macroscopic and microscopic levels. Atomic force microscopy (AFM) revealed the viscoelastic nature of the fibrous samples. At relatively low forces mostly elastic deformation was observed, while at higher loads plasticity predominated. The use of polysorbate led to about two times stiffer, less plastic fibers than the addition of cyclodextrin. The 1H–13C nuclear magnetic resonance (NMR) cross-polarization build-up curves pointed out that cyclodextrin acts as an inner, while polysorbate acts as an outer plasticizer and, due to its “liquid-like” behavior, can migrate in the polymer-matrix, which results in the less plastic behavior of this formulation. Positron annihilation lifetime spectroscopy (PALS) measurements also confirmed the enhanced mobility of the polysorbate and the molecular packing enhancer properties of the cyclodextrin. Solid-state methods suggested amorphous precipitation of the active ingredient in the course of the electrospinning process; furthermore, the nature of the amorphous systems was verified by NMR spectroscopy, which revealed that the use of the examined additives enabled the development of a molecularly dispersed systems of different homogeneities. An accelerated stability study was carried out to track physical state related changes of the incorporated drug and the polymeric carrier. Recrystallization of the active ingredient could not be observed, which indicated a large stress tolerance capacity, but time-dependent microstructural changes were seen in the presence of polysorbate. Raman mapping verified homogeneous drug distribution in the nanofibrous orally dissolving webs. The performed dissolution study indicated that the drug dissolution from the fibers was rapid and complete, but the formed stronger interaction in the case of the PVA-CD-MH system resulted in a little bit slower drug release, compared to the PS80 containing formulation. The results obviously show that the complex physicochemical characterization of the polymer-based fibrous delivery systems is of great impact since it enables the better understanding of material properties including the supramolecular interactions of multicomponent systems and consequently the rational design of drug-loaded nanocarriers of required stability.

The efflux transporter responsible for the canalicular elimination of bile salts from the hepatocytes is the bile salt export pump (BSEP, ABCB11). Absence or inhibition of this transporter leads to bile salt retention in the hepatocyte and in turn can lead to cholestatic liver disease. We expressed the BSEP/Bsep protein from three species (human, rat, and mouse) in a baculovirus-infected Sf9 system. Vesicles prepared from these cells were used to evaluate bile salt transport of four conjugated bile salts. Because the Sf9 system contains less membrane cholesterol than the liver canalicular membrane, the effect of added cholesterol on the kinetics of BSEP/Bsep-mediated bile salt transport was also investigated. Cholesterol treatment increased the Vmaxvalues in all the species, with the most pronounced effect observed in the rat transporter. In contrast, Kmvalues, with the exception of glycochenodeoxycholate, remained largely unchanged. The species-specific bile salt transport inhibition potential of three compounds known to cause clinical cholestasis was investigated in vesicles containing BSEP/Bsep. Troglitazone and glibenclamide inhibited the BSEP/Bsep-mediated transport of different bile salts with similar affinities, whereas the potential of cyclosporine A to inhibit bile salt transport showed species- and bile salt-specific variations. In conclusion, the cholesterol-loaded Sf9 vesicles overexpressing BSEP/Bsep seem to be a useful system for the identification of potential cholestatic compounds and can also be used for the investigation of species specificity. We observed greater differences in IC50values for inhibitors than in Kmvalues for substrates between species.

Cyclodextrins are well known in supramolecular chemistry as host molecules capable of engulfing molecules in their hydrophobic cavity via noncovalent interactions. Although cyclodextrins are frequently used for chiral separation of racemates, the mechanism of chiral recognition has not yet been fully characterised. The current investigation was aimed at examining chiral recognition mechanism in order to construct an in silico method for prediction of chiral recognition. Amino acids were selected as model guest, whereas αCD was used as model host. The results of molecular docking and molecular dynamic calculations were compared to results of stability constant determination and capillary electrophoresis measurements of enantioseparations. Positive correlation between binding strength and chiral separation ability was found. However, the small energy differences between interaction energy of each enantiomer with αCD fell into the range of standard error of molecular docking calculations limiting its applicability for in silico prediction. Examining the stability of complex geometry during molecular dynamics simulation revealed that stable complex geometry is likely to be a prerequisite for chiral recognition. This hypothesis was tested on methylderivatized tryptophan. Indeed, chiral separation of β-methyl-tryptophans by αCD could be successfully predicted by examining the complex geometries during molecular dynamic simulation.

The objective of this mini-review is to summarize the findings concerning the physicochemical properties and the pharmaceutical applications of acidic drugs whose performances have been modified by simultaneous complexation with cyclodextrins and salt formation. Particular attention is paid to the approaches undertaken for increasing the solubility of the drugs by proper choice of the type of counterion analogously to what has been reported for complexes of basic drugs in the presence of hydroxy acids. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:979–986, 2001

The objective of this mini-review is to summarize the findings concerning the physicochemical properties and the pharmaceutical applications of acidic drugs whose performances have been modified by simultaneous complexation with cyclodextrins and salt formation. Particular attention is paid to the approaches undertaken for increasing the solubility of the drugs by proper choice of the type of counterion analogously to what has been reported for complexes of basic drugs in the presence of hydroxy acids. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:979–986, 2001

The objective of this mini-review is to summarize the findings concerning the properties and the pharmaceutical applications of multicomponent complexes made of a sparingly water-soluble amino-type drug, a cyclodextrin, and a hydroxy carboxylic acid. Simultaneous complexation and salt formation with these acids significantly increase the solubilizing power, allowing us to reduce the amount of cyclodextrin necessary for making the targeted formulation. In many cases, the aqueous solubility of the hydrophobic drug can be enhanced by several orders of magnitude, while that of CD can be enhanced more than 10-fold. The mechanism through which these complexes elicit their synergetic effects on the drug solubility is also discussed. Finally, some general observations are made concerning the structural requirements of the drug necessary for exploiting the aforementioned effect. © 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1–8, 2000

The objective of this mini‐review is to summarize the findings concerning the properties and the pharmaceutical applications of multicomponent complexes made of a sparingly water‐soluble amino‐type drug, a cyclodextrin, and a hydroxy carboxylic acid. Simultaneous complexation and salt formation with these acids significantly increase the solubilizing power, allowing us to reduce the amount of cyclodextrin necessary for making the targeted formulation. In many cases, the aqueous solubility of the hydrophobic drug can be enhanced by several orders of magnitude, while that of CD can be enhanced more than 10‐fold. The mechanism through which these complexes elicit their synergetic effects on the drug solubility is also discussed. Finally, some general observations are made concerning the structural requirements of the drug necessary for exploiting the aforementioned effect. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1–8, 2000

Digitoxin was modified by condensation with propylene oxide or with 1,4‐butanediol diglycidyl ether in aqueous alkali, yielding products in which some of the CH2H groups of digitonin were converted to CH2OCH2CHOHCH3or to CH2OCH2CHOHCH2O(CH2)4O‐CH2CHOHCH2OH groups, respectively. These modified digitonins were very soluble in water and chloroform and effectively solubilized lipophilic compounds into aqueous solutions; e.g., 2mg of vitamin A or 0.6mg of cholecalciferol could be dissolved per 1mL of 5% aqueous solutions of modified digitonins. Compared with the toxicity of digitonin (LD504 mg/kg iv), the toxicity of modified digitonin was greatly reduced: doses of 500 mg/kg by intravenous infusion were not lethal for mice.

The paper provides data on the practical utilization of the benefits of the molecular encapsulation of natural colorants by cyclodextrins. Experimental results on the stability of cyclodextrin complexed curcumin, curcuma oleoresin, β-carotene and carotenoid oleoresins against light-, heat- and oxygen prove the benefits of molecular encapsulation of colorants. The parent β-cyclodextrin stabilized most effectively the curcumines, while the stability of carotenoids was most effectively achieved by α-cyclodextrin complexation. Methylated β-cyclodextrin was found to be the most potent solubilizing agent for both carotenoids and curcuminoids.

A survey on the non-chromatographic analytical uses of cyclodextrins is presented. Aspects covered extend from substrate/analyte solubilization and stabilization to the development of cyclodextrin based sensors and detectors. Examples are given of the use of cyclodextrins for the elimination of interfering components in analytical systems. The improvement in sensitivity of traditional analytical methods by using cyclodextrins is illustrated on practically relevant cases with special emphasis on biopharmaceutical and clinical analysis.

Poly-l-methionine sulfoxide is a water-soluble polymer containing the sulfoxide moiety. The preparation and radiolabeling of this polymer is described and its bioeffects are compared with those of dimethyl sulfoxide. Poly-l-methionine sulfoxide is similar to dimethyl sulfoxide in that it is a potent solubilizer of lipophilic compounds in water. Although the partition coefficient of poly-l-methionine sulfoxide in 1-octanol-water is only 20 times lower than that of dimethyl sulfoxide, it was found not to penetrate into intracellular spaces. In contrast to dimethyl sulfoxide, poly-l-methionine sulfoxide and L-methionine sulfoxide were found to be ineffective in inducing differentiation in murineerythroleukemia cells and inhibiting differentiation of avian neural crest cells, suggesting that compounds effective in these processes must have the ability to penetrate into cells or membrane proteins. Overall lack of bioactivity of poly-l-methionine sulfoxide, combined with low toxicity (2g/kg, iv, in the mouse with no effect), makes this compound a suitable inert solubilizer and carrier for lipophilic drugs.

A new, simple method has been developed for the methylation of cyclodextrins. The reaction proceeds in the heterogeneous phase with dimethyl sulphate, using a solvent in which the original cyclodextrins and the bases used are poorly soluble or insoluble. However, in the presence of phase transfer catalysts, methylation proceeds with good yields. The products are mixtures of randomly methylated cyclodextrins (RAMEB), containing 60–70% of heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DIMEB), 10–15% of heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin (TRIMEB) and some monomethylated isomers. These methylated products have proved to be excellent detergents; e.g., they are able to significantly increase the water solubility of hydrocortisone, methyltesterone, etc. On repeating methylation twice, the amount of TRIMEB increases, and a pure product (28% yield) can be obtained by crystallisation.

The complexation of fatty acids (both saturated and unsaturated) with various cyclodextrins and cyclodextrin derivatives greatly modifies their properties. Inclusion complex formation — depending upon the type of host cyclodextrin — may result in protection against the environment, in improved water solubility and bioavailability. Thus lipid complexation enables the preparation of more reliable diagnostic reagents, better chromatographic separations and higher yields in biotechnological processes. The relevant literature is reviewed with particular emphasis on the practical utility of the molecular encapsulation of fatty acids with cyclodextrins.

Heptakis-(2,6-di-O-methyl)-ß-cyclodextrin (DIMEB), a compound having a great water-solubility enhancing effect on lipids via inclusion complex formation was investigated as a potential bile-substituting agentin vivo in rats. The normal fat digestion was inhibited by ligating the bile duct. 3-H-Stearic acid or edible oil were administered orally to rats and the effect of simultaneously administered DIMEB on the lipid absorption was studied by measuring the blood radioactivity level or plasma triglyceride and free fatty acid concentrations. The lipid absorption was significantly improved by DIMEB. Accordingly, it seems to be a new fat digestion and absorption enhancing drug, i.e. a possible bile-substituting agent.