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.

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.

A new mixed acetal-type substitution pattern for alpha-cyclodextrin. Preparation of hexakis (3-O-benzyl)- alpha-cyclodextrin.

alpha-CD was converted into hexakis[2,6-di-O-(methoxydimethyl)methyl]-alpha-CD by a proton-catalyzed reaction with 2-methoxypropene. Subsequent benzylation under Brimacombe conditions resulted in the fully protected compound, from which the acid-sensitive acetal groups were removed to obtain hexakis(3-O-benzyl)-alpha-cyclodextrin. The structure of all of the compounds synthesized was confirmed by 13C J-ECHO, COSY, HETCOR and HMBC NMR measurements.

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.

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.

Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development.

As the first pharmaceutical products which contain highly soluble cyclodextrin (CD) derivatives (e.g. Sporanox=itraconazole/HP-beta-CD by Janssen and Clorocil=chloramphenicol/methyl-beta-CD by Oftalder) are already on the market it seems to be timely to give an overview on the technological and commercial aspects of the chemically modified water-soluble CDs as drug carriers. This chapter deals with the chemistry and general properties of water-soluble CDs and follows the trends in their development. The quality requirements of industrially relevant water-soluble CDs together with the quality-assurance-related analytical techniques, are thought help understand how difficult the characterization and approval processes of such novel excipients are. Literature data taken from Cyclolab's databank support the validity of statements in evaluation of trends of development of CD derivatives as pharmaceutical excipients.

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.

Medicinal applications of cyclodextrins.

Some cyclodextrins are produced industrially, and available in pharmaceutical quality, at reasonable prices. Their medicinal use means mainly--but not exclusively--the complexation of problematic drugs (poorly soluble, unstable, irritating, difficult to formulate substances). The CD complexation generally results in improved wettability, dissolution, and solubility; improved stability; reduced side effects; or in mildering of other undesired properties (e.g., bitter tastes, bad smells). CDs can be used advantageously practically in any drug forms: oral, rectal, pulmonary, external, ocular, etc. formulations. In oral solid and liquid formulations the chemical and physical stability and bioavailability, but particularly the role of absorption is improved. With appropriate highly soluble chemically modified CDs aqueous parenteral formulations can be prepared from poorly soluble drugs. Using CDs the transdermal penetration or nasal absorption of such drugs becomes possible, which earlier could not be administered through these ways. The direct therapeutic effects of CDs (or their derivatives) are demonstrated in several examples as well as the use of beta CD as vehicle in tabletting.

Water soluble complexes of C14 and C16 fatty acids and alcohols in media for cultivation of leprosy-derived psychrophilic mycobacteria.

Host-grown Mycobacterium leprae cell suspensions oxidized water-soluble complexes of palmitic acid, myristic acid, cetyl alcohol, and myristyl alcohol prepared with randomly methylated-beta-cyclodextrin as host molecules. Gas chromatography analysis showed that the water-soluble complexes retained their chemical structure following sterilization in the autoclave. Bioavailability of the two long-chain fatty acids and the corresponding long-chain alcohols was confirmed by Warburg manometric techniques with host-grown M. leprae cell suspensions. Inoculated with host-grown M. leprae cells in chemically well-defined, simple liquid and agar media, acid-fast bacilli were cultivable in primary cultures and subcultures at 10 degrees C with (NH4)2SO4 as the N source and water-soluble palmitic acid, myristic acid, cetyl alcohol or myristyl alcohol as the C and potent energy sources. M. phlei oxidized the complexed palmitic acid and myristic acid but not cetyl alcohol or myristyl alcohol. On agar media with any of these four carbon sources and (NH4)2SO4 but not ammonium thioglycolate as the N source, M. phlei grew abundantly at 36 degrees C. In liquid media only myristyl alcohol supported growth of M. phlei without any growth with palmitic acid, cetyl alcohol or myristic acid. The leprosy-derived, cold-loving cultures ("M. psychrophilum") were not fully tested for classification and identification. The cells are strongly acid-fast facultative psychrophiles, adapted in subcultures to mesophilic growth. They grow in chemically well-defined media with 14 and 16 C long-chain fatty acids or alcohols as the C and energy sources. None of the cultures grow on Low-enstein or 7H9 media. Heat-killed suspensions of the 4th and 6th subcultures provoke Mitsuda-type late skin reactions in tuberculoid, borderline and borderline-tuberculoid but not in lepromatous leprosy volunteers. When grown with (NH4)2SO4 as the N source (but not with the reducing agent ammonium thioglycolate) the subcultures multiplied abundantly in the foot pads of mice. It became evident that leprosy-derived, facultative psychrophilic mycobacteria really exist. Mycobacteria of this cluster do not distinguish between 14 or 16 C long chains with COOH or CH2OH as terminal bindings. Cells are quite aerophilic and grow preferentially on agar slant surfaces.(ABSTRACT TRUNCATED AT 400 WORDS)

Water soluble complex of palmitic acid in media for cultivation of leprosy-derived psychrophilic mycobacteria from Mycobacterium leprae infected tissues.

Palmitic acid and palmitates were transformed into water soluble complexes with crystalline heptakis-2,6-di-0-methyl-beta-cyclodextrin. This formulation was incorporated into liquid and solid chemically well-defined media. The fatty acid served as C and energy source, ammonium thioglycolate as the sole source of N with the SH group as further source of energy. Minute amount of dimethyl-sulfoxide added was used for its known effect on cell membrane permeability. The media were inoculated with host grown Mycobacterium leprae cells isolated from human, armadillo and Nu mice foot pad lepromata. No growth occurred in the liquid medium at 22 or 32 degrees C, but cultures and subcultures of acid fast rods were grown at 10 degrees C. Bacilli in the cultures were solid, strongly acid fast rods, growing in clumps like globi. Growth on the semisolid media was visible as smooth round colonies, of white to ivory in colour, slowly expanding flatly at the periphery of the colony on the agar surface. Colonies developed within 2-3 weeks and reached maximum size at 50-80 days depending on the size of inoculum. Subcultures grow faster and more abundantly with adaptation to the media. No growth was seen without the water soluble complexes of palmitic acid or palmitates in the media. The free fatty acid or its salts had an equal growth supporting effect. Identical psychrophilic cultures were obtained from 7 out of 9 armadillo, 12 out of 12 Nu mice and 1 out of 2 human lepromata. None of the cultures grow on Loewenstein, Dubos or 7H9 media at 10 degrees C, 20 degrees C or 32 degrees C, respectively. The tested 4th to 7th subcultures of the strains were strongly positive for phenolic glycolipid-1. Heat killed suspensions of up to 7th subcultures gave negative late skin reaction in all of 16 LL cases. In 19 I, B and T cases the late skin reactions were all similar to that obtained with authentic human lepromin.

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.

Aggregation of amphotericin B in the presence of gamma-cyclodextrin.

The macrolide antibiotic amphotericin B (AmB) forms an inclusion complex with gamma-cyclodextrin (gamma-CDx), resulting in a molecularly dispersed state of the drug. The state of aggregation of AmB in different solvents has been studied by absorption (uv-vis) and CD spectroscopy. While in aqueous solutions AmB forms colloid-like multimolecular aggregates, in the presence of gamma-CDx true solutions can be prepared, which show similar spectral properties as AmB dissolved in organic solvents. The AmB-gamma-CDx complex can be isolated as an amorphous, stable, water-soluble powder, indicating that gamma-CDx is a good carrier for the solubilization of this antibiotic. Using gamma-CDx as a carrier, the danger of precipitation of the drug during parenteral or intravenous administration can be largely reduced.

Resolution of chiral barbiturates into enantiomers by reversed-phase high-performance liquid chromatography using methylated beta-cyclodextrins.

The correlation between the capacity factors of enantiomers of chiral barbiturates and the concentrations of beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin dissolved in the mobile phase was studied using LiChrosorb RP-18 as the stationary phase. Owing to the very strong adsorption of permethylated beta-cyclodextrin on the ODS surface a chiral stationary phase is generated dynamically and forms complexes with the solutes; this mechanism has been found to be the only factor responsible for the chiral recognition of the investigated compounds at all applied concentrations. The inclusion of barbiturates in the cavities of permethylated beta-cyclodextrin involves a distinct and entirely new kind of enantioselectivity compared with that observed for beta-cyclodextrin and its dimethyl derivative. Using permethylated beta-cyclodextrin baseline resolutions have been obtained with barbiturates containing a chiral centre in the heterocyclic ring or in the aliphatic side-chain.

Enhanced percutaneous absorption of homogenized tolnaftate/beta-cyclodextrin polymer ground mixture.

The absorption of tolnaftate after external application of tolnaftate-cyclodextrin polymer homogenized ground mixtures was investigated in comparison with that of tolnaftate alone and non-homogenized mixtures. To evaluate their percutaneous absorption, samples were applied to the shaved back skin of mice. It was found that homogenized ground mixture samples showed the highest level of percutaneous absorption, and also resulted in the highest blood level concentrations.