Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins.

The bitter taste of drugs, food components, and any other substances which get in the mouth as dissolved in an aqueous solution, or in the saliva, can be strongly reduced or fully eliminated, if the bitter component forms an inclusion complex with an appropriate cyclodextrin (CD). The value of the complex association constant (determined by the structure of the bitter 'guest' molecule and the size and eventual substitution of the 'host' CD molecule), the temperature and the host/guest ratio determine the extent of complexation of the guest molecule (percentage of complexation) at the equilibrium. The K(ass) for most drug/CD complexes at 36 degrees C buccal cavity temperature is between 10(2) and 10(4) mol-1. If the unit dose (of a sublingual or chewing tablet, chewing gum) with a bitter drug (molecular weight of about 150, forming a 1:1 complex with betaCD) is approximately 10mg then the betaCD can be taken in a 5- or even 10-fold molar excess. Under such conditions more than 99% of the bitter drug is complexed, and because complexed molecules cannot react with the taste buds in the buccal cavity no bitter taste is perceived. Frequently, preparation of the drug/CD complex is not necessary, because the betaCD is present in a large excess, dissolved very quickly in the saliva and results in a saturated CD solution. Therefore, the complexation of the bitter drug is completed very rapidly. Only dissolved substances have taste and only CD complexable drug molecules can become debittered by CDs. Bitter, astringent components of foods (e.g. soya), beverages (e.g. naringin in citrus fruit juice, or chlorogenic acid and polyphenols in coffee) cigarette smoke (nicotine) also can be complexed and their taste reduced or fully eliminated.

The inclusion of fluoxetine into gamma-cyclodextrin increases its bioavailability: behavioral, electrophysiological and pharmacokinetic studies.

The inclusion of a drug into cyclodextrin generally results in the modification of its physical and chemical properties and sometimes can increase its oral bioavailability. The aim of this study was to compare the effects of the fluoxetine HCl/gamma-cyclodextrin complex to that of traditional fluoxetine HCl. In the forced swimming test in mice, fluoxetine HCl/gamma-cyclodextrin was more effective than fluoxetine HCl, the ED30s being, respectively, 9.5 and 16.9 mg/kg PO. Both compounds (10 mg/kg PO) were able to reduce the firing rate of dorsal raphe neurons in the rat. However, between-groups comparisons showed no significant differences between fluoxetine HCl treated animals and the vehicle group, while fluoxetine HCl/gamma-cyclodextrin appeared significantly more effective than vehicle from minute 25 of the measurement period. In healthy volunteers, the relative oral bioavailability, calculated as the ratio AUC 0-infinity fluoxetine HCl/gamma-cyclodextrin on AUC 0-infinity fluoxetine HCl (20 mg PO), was equal to 249.9%. The three experiments taken together suggest that the complexation of fluoxetine HCl into gamma-cyclodextrin increases its pharmacological efficacy in animals, this effect being related to an enhancement of its oral bioavailability as demonstrated in human healthy subjects.

The effect of glypondin on glycogen and protein accumulation in rat organs.

Rats were treated for 21 days with 20, 30 and 40 mg/kg Glypondin dissolved in the drinking water. The weight-increasing effect of Glypondin was studied in rat organs. In the liver a significant rise in the concentration of TCA-soluble glycogen was demonstrated. In the myocardium and m. gastrocnemius the concentration of both the labile and glycogen was unchanged. In the m. gastrocnemius of rats treated with Glypondin a significant rise in the concentration of noncollagenous protein was demonstrated.

Effect of the degree of substitution of cyclodextrin derivatives on chiral separations by high-performance liquid chromatography and capillary electrophoresis.

Optical isomers of some basic racemic drugs (oxprenolol, AMEBD, ephedrine) were separated by high-performance liquid chromatography (HPLC) and/or capillary electrophoresis (CE) using carboxymethyl-beta-cyclodextrin (CMBCD) with various degree of substitution (DS). The effects of the separation conditions (pH, concentration and DS of CMBCD) were studied and compared using CE and HPLC. The degree of substitution had a significant effect on the resolution of the optical isomers and the ionic strength of the separation media, hence the use of well characterized CD derivatives is crucial. Different optimum DS values for the same test samples were obtained when HPLC or CE was used.

Cyclodextrin complexes of salts of acidic drugs. Thermodynamic properties, structural features, and pharmaceutical applications.

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.

Drug/cyclodextrin/hydroxy acid multicomponent systems. Properties and pharmaceutical applications.

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.

Quantitative structure-stability relationships among inclusion complexes of cyclodextrins. I: Barbituric acid derivatives.

Quantitative structure-stability relationships (QSSRs) are formulated for the inclusion complexation of 17 barbituric acid derivatives with alpha- and beta-cyclodextrin. The variation in the complex stability constants K alpha and K beta is found to be partly accounted for by the molar refractivity or the hydrophobicity of the substituent R1 at position 5 of the barbiturate ring. In addition, K alpha also depends upon whether or not R1 is branching or cyclic, and K beta also depends upon whether the guest molecule is a barbiturate or a thiobarbiturate. The results suggest that in alpha-cyclodextrin-barbiturate complexes the cyclodextrin cavity includes only R1, while in beta-cyclodextrin complexes both R1 and (part of) the barbiturate ring are included. This complexation model is compared with those proposed by other authors.

13C-N.M.R. spectra of cyclomalto-oligosaccharides (cyclodextrins), their derivatives, and complexes with azo dyes.

The nature of the inclusion complexes of several cyclomalto-oligosaccharides (cyclodextrins, CDs) with azo dyes has been studied on the basis of 13C-n.m.r. chemical shifts, relaxation times, correlation times, and broadening and doubling of the n.m.r. signals. All CDs show the azo dye-induced shifts at the narrow-rim side of the CD, indicating that the azo dyes protrude from the cavity. CD-induced shifts of azo dyes depend on the hydrophobic nature of the cavity, van der Waals forces, as well as ring-current and deformation effects, and suggest inclusion essentially from the hydrophobic site. The broadening and the doubling of the 13C-n.m.r. signals, the altered relaxation and correlation times, as well as the temperature dependence for these phenomena, also provide particular information about the characteristic host-guest interactions.

Interaction between indometacin and beta-cyclodextrin.

CHINOIN-137 consists of indometacin and beta-cyclodextrin in a 1 : 2 molar ratio. solid phase analytical techniques, as thermal analysis, mass spectrometry and X-ray powder diffraction do not support the existence of a well-defined crystalline complex. However this product dissolved in water more readily and results in a higher indometacin concentration than indometacin itself. The formation of an inclusion complex with a reasonable stability in aqueous solution was proved by diffusion tests and chiroptical properties. Following oral administration of CHINOIN-137 to rats, higher blood levels (by about 25%) of indometacin can be achieved than with the uncomplexed drug. A significant difference was observed in the absorption of 14C-labelled indometacin and its cyclodextrin complex by "in loco" techniques in the small intestines of anaesthetized rats: from indometacin 56%, from the complex 68% of the activity was resorbed within 10 min.

Improvement of the absorption of 3H-Cholecalciferol by formation of its cyclodextrin complex.

Following oral administration to rats of beta-cyclodextrin inclusion complex of 3H-labelled vitamin D3 (cholecalciferol) resulted in significantly higher blood radioactivity as with the non-complexed vitamin. Difference in the first 90 min was 2,3-2,8 fold, and it remained significantly higher up to the 6th h. After 24 h there was no difference between the blood radioactivity of animals treated with complexed and with non-complexed vitamin D3.

Suppositories containing beta-cyclodextrin complexes. Part 1: Stability studies.

Application of beta-cyclodextrin complexes of volatile substances in suppositories improves the mechanical properties and stability of suppositories. The incompatibility between the volatile components and suppository bases can be eliminated.

Simulation of pharmacokinetic behaviour of drug-cyclodextrin complexes.

Complexation with cyclodextrin decreases the hydrophobicity of poorly soluble drugs and results in enhanced dissolution rates and higher solubility. In vivo experiments showed that this "molecular encapsulation" of drugs leads to enhanced bioavailability, which is controlled by the solubilities, stability constants of the complexes, the molar ratio of drug: cyclodextrin, etc. This modification of the pharmacokinetic processes has been simulated by computing the theoretical blood level curves. These computer-simulated curves seem to be appropriate models of the experimental observations. Knowing the numerical values of the parameters utilized in these computer simulations, the modification of the pharmacokinetics can be predicted when using cyclodextrin complexes in oral dosage forms.

Suppositories containing cyclodextrin complexes. Part 2: Dissolution and absorption studies.

The dissolution and absorption of poorly water-soluble drugs from rectal suppositories can be enhanced by complexing these substances (e.g., essential oils, indomethacin) with beta-cyclodextrin. Preliminary in vivo studies showed, that the application of cyclodextrin complexes to suppositories, the same as to oral applications, resulted in an increased blood level.

Cyclodextrin polymer, a new tablet disintegrating agent.

Cyclodextrin (CD) polymer, a type of crosslinked cyclodextrin, has been evaluated as a new tablet disintegrating agent in comparison with four common disintegrants (crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl cellulose, formaldehyde casein and corn starch). Physical properties of the disintegrants have been studied. Tablets made by direct compression using microcrystalline cellulose as binder, magnesium stearate as lubricant and talc as antiadherent have been compared. The parameters evaluated were disintegration time, hardness and friability. CD polymer performs well as a tablet disintegrating agent with results paralleling those of crosslinked carboxymethyl cellulose (Ac-Di-Sol) and superior to the other three.

Influencing of resorption and side-effects of salicylic acid by complexing with beta-cyclodextrin.

After oral administration of 14C-labelled salicylic acid and its beta-cyclodextrin complex to rats, the blood radioactivity-level increases in the first 2 h than decreases. The blood level obtained with the inclusion complex is somewhat but not significantly lower than with free acid. Since the resorption of cyclodextrin is a considerably slower process, it is very likely that the resorption of salicylic acid take place in the form of free acid after dissociation of the complex. The urinary excretion cumulative curves show that the free salicylic acid is completely excreted, while about 10% of the salicylic acid administered in the form of complex is lost. The cyclodextrin complex formation increases the pK value of all hydroxy-benzoic acids. Direct observations reveals that complex formation decreases the stomach-irritating effect of salicylic acid. The ratio of radioactivity was nearly the same in the organs of animals treated by both free salicylic and cyclodextrin complex.

Cyclodextrin-stabilized volatile substances for inhalation therapy.

Diapulmon (Chinoin) which comprise camphor, 1-menthol, eucalyptus oil and quinine dissolved in sunflower oil (Oleum helianthi) is marketed in ampoules of 2 ml but utilized almost exclusively for inhalation therapy. Complexing the active ingredients of Diapulmon with beta-cyclodextrin (beta-CD) a stable non hygroscopic microcrystalline substance is obtained. When this powder sprinkled on hot water, the included volatile compounds are gradually released and the desired pharmacological effect can be brought about.

Preparation, properties and biological activity of beta-cyclodextrin inclusion complex of menadione.

The molar ratio of menadione (vitamin K3) to beta-cyclodextrin in the microcrystalline inclusion complex showed this to be 1:3 with a menadione content of approximately 4.1-4.3%. Complexes with higher vitamin content could not be prepared. Bound and free vitamin can be readily separated by sublimation in vacuum. The menadione is highly stable in complexed form; in dry state it is released only when cyclodextrin is destroyed by heating to about 300 degrees C. Complexed menadione does not react with amino acids. Solubility and dissolution rate are strongly increased. Treating hypovitaminotic chickens with equivalent doses of menadione or menadione-beta-cyclodextrin complex and monitoring blood clotting times, recalcification times and prothrombin times the complex proved to be at least as effective as--or even somewhat more potent than--free vitamin. 1.5-2.0 micrograms/animal/d free or complexed menadione was sufficient to cover the daily vitamin K needs of chickens.