Fluorescence enhancement of several hallucinogenic drugs in cyclodextrin media

The fluorescence characteristics of selected hallucinogenic drugs dissolved in solutions of α-cyclodextrin and β-cyclodextrin are reported. Fluorescence intensity enhancements in cyclodextrin media relative to aqueous solution range from 1.2 to 4.0, probably because inclusion of the drugs into cyclodextrin increases the quantum yield. Calibration graphs are linear over 2–3 orders of magnitude; limits of detection are 6–13 μg l^?1 for ibogaine and N,N-dimethyltryptamine. The mescaline derivatives show limits of detection in the 0.8–1.4 ppm range. The role of cyclodextrin in enhancing the fluorescence intensities and some of the criteria for this fluorescence enhancement are discussed.     

Complexation behaviour of polymers with pendant cyclodextrin side groups

The influence of the chain conformation on the formation of polymeric supramolecular complexes as well as the influence of the complexation on the conformation of the polymer chain has been studied. The complexation of pyrene into the cavity of β-cyclodextrin (β-CD) was investigated in aqueous solutions of β-CD substituted poly(allylamine) (PAA) under variation of external parameters, i.e. temperature, pH, ionic strength and addition of urea. The observed changes of the complexation constant K for the formation of the 2:1 β-CD/pyrene complex can be explained by a change of the chain flexibility which leads to a variation of the mean distance between neighbouring β-CD-moieties along the polymer chain. The intra-chain association of the decyl group with β-CD in PAA with co-pendant decyl and β-CD is disrupted by the addition of 1-adamantanamine HCl resulting in a more extended structure of the polymer. The β-CD moiety in PAA-CD shows one order of magnitude greater affinity to 2-(p-toluidyl)naphthalene-6-sulfonate than the native β-CD and the affinity increases further by the presence of decyl side groups.     

Effect of several enhancers on the skin permeation of water-soluble drugs

Since the percutaneous absorption rates of water-soluble drugs are low in general, an enhancing system is needed when using the skin as an administration site for the drugs. We have investigated the effect of various penetration enhancers on the in vitro and in vivo percutaneous absorptions of catecholamine analogs, i.e. levodopa (LD), dopamine hydrochloride (DPH) and isoproterenol hydrochloride (IPH), as model water-soluble drugs. It was found that medium-chain glycerides (Sefsol 318) markedly enhanced the in vitro permeation of the drugs through excised hairless rat skin among the enhancers tested in the present experiments; the permeation rates with 5% Sefsol 318 in water were about 65, 34 and 53 times higher than the corresponding control (without enhancer) for LD, DPH and IPH, respectively. In addition, the in vivo percutaneous absorption experiments showed that the blood levels of these drugs after application of aqueous gels containing 5% Sefsol 318 on rat skin were higher than those in the absence of enhancer. Drug levels in the liver and kidney were also higher than without Sefsol 318. Percutaneous administration of DPH with Sefsol 318 to hairless rats resulted in lower diastolic blood pressure and a slightly higher heart rate with as compared to administration without the enhancer. These results suggest that Sefsol 318 is a potential candidate to enhance the transdermal absorption of water-soluble drugs.     

Complexation of water-soluble polymers and photosensitizer

Water-soluble polymers poly-N-methacryloyloxyethyl-N,N,N-trimethylammonium methyl sulfate and poly(methacrylic acid) are found on the basis of spectral, thermophysical, structural, and morphological studies to form stable complexes with Photodithazine photosensitizer.     

Complexation of copper(II)-montmorillonite with a modified cyclodextrin

The uptake reaction of Cu(II)-montmorillonite with mono-(6--aminoethylamino-6-deoxy)--cyclodextrin (CDen) has been examined at 25°C. The CDen molecules in their neutral or cationic forms are taken up by forming complexes with the interlayer Cu(II) ions (Cu_int) and by displacing protons at the clay surface. At low uptakes of CDen, 11 complexes of CDen with Cu_int are intercalated as a monolayer of 13.7 Å in thickness, with their opening faces parallel to the interlayer surface. At higher contents, the CDen-Cu_int complexes are more voluminously packed to form two intercalated phases with larger spacings until a bilayer of 23.9 Å in thickness is formed. The uptake by the mode of ion exchange proceeds increasingly at the intermediate uptake stage. At higher levels, however, this additional uptake is decreased rapidly due to the increase in the pH of solution, resulting in a maximum in the curve of CDen uptake against CDen added.     

Sustained release applications of a fluoroalkyl ester-functionalized amphiphilic cyclodextrin by inclusion complex formation with water-soluble drugs in supercritical carbon dioxide

An amphiphilic γ-cyclodextrin, selectively functionalized with perfluorobutanoyl group, octakis(6-O-perfluorobutanoyl)-γ-cyclodextrin (γ-CyD-F), was investigated as a potential sustained release carrier for hydrophilic drugs, taking molsidomine (MOL) as a model drug. Supercritical carbon dioxide, an environmentally benign solvent, was used for the preparation of MOL/γ-CyD-F inclusion complexes. The molecular encapsulation of MOL by the amphiphilic cyclodextrin was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) studies. Additionally, ¹H NMR spectroscopy was used to investigate the inclusion mode of drug with the γ-CyD-F. The in-vitro release of MOL from the peanut oil suspensions into aqueous phase was found to be significantly retarded by the complexation with γ-CyD-F, mainly due to the hydrophobic properties associated with the γ-CyD-F.     

Complexation of sodium picosulphate with beta cyclodextrin: NMR spectroscopic study in solution

Sodium Picosulphate (SPL) is a synthetic drug, widely used for thorough evacuation of the bowel, usually for patients who are preparing to undergo a colonoscopy. Cyclodextrins (CDs) are chiral, truncated cone shaped, cyclic oligosaccharides that can encapsulate a variety of drug molecules into inclusion complexes, thereby increasing their stability and solubility. ¹H NMR spectroscopic studies showed the inclusion complexation between β-CD and SPL, based on the upfield shift changes in the β-CD cavity protons (H-3′ and H-5′) and downfield shift changes in the guest (SPL) protons. The structure of inclusion complexes was determined by 2D ROESY spectral data. The 1:1 stoichiometry and overall association constant (Ka) were determined by using Scott’s plot method to be 450 M^?1.     

Complexation of morin with three kinds of cyclodextrin. A thermodynamic and reactivity study

Properties of inclusion complexes between morin (M) and beta-cyclodextrin (betaCD), 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and Heptakis (2,6-O-di methyl) beta-cyclodextrin (DMbetaCD) such as aqueous solubility and the association constants of this complex have been determined. The water solubility of morin was increased by inclusion with cyclodextrins. The phase-solubility diagrams drawn from UV spectral measurements are of the A(L)-type. Also ORAC(FL) studies were done. An increase in the antioxidant reactivity is observed when morin form inclusion complex with the three cyclodextrin studied. Finally, thermodynamics studies of cyclodextrin complexes indicated that for DMbetaCD the inclusion is primarily enthalpy-driven process meanwhile betaCD and HPbetaCD are entropy-driven processes. This is corroborated by the different inclusion geometries obtained by 2D-NMR.     

Water soluble cyclodextrin polymers: Their interaction with drugs

The complex forming ability of a water-soluble -cyclodextrin epichlorohydrin, polymer (CDPS) and its different molecular weight fractions was studied and compared with the complexing properties of -cyclodextrin (CD) and dimethyl-CD (DM-CD). CDPS was separated into two main fractions. CDPS and its fractions formed well soluble inclusion compounds with the studied drugs. The low molecular weight fraction formed rather stable complexes with small guest molecules, the high molecular weight fraction was found to be more efficient in binding larger substrates. Structural studies of furosemide-CD complexes were attempted by NMR spectroscopy.Presented at the Fourth International Symposium on Inclusion Phenomena and the Third International Symposium on Cyclodextrins, Lancaster, U.K., 20–25 July 1986.     

Skin permeability of water-soluble drugs

The permeabilities of several water-soluble drugs through excised hairless rat skin from their aqueous suspensions were investigated by using newly designed two-chamber diffusion cells. Disodium cromoglycate, diclofenac sodium, dopamine hydrochloride, isoproterenol hydrochloride, diltiazem hydrochloride and papaverine hydrochloride were selected as water-soluble drugs. Indomethacin, a lipophilic drug, and deuterium oxide (D2O) were used for comparison. The skin permeability coefficients of these water-soluble drugs were 100--1000 times lower than that of indomethacin. Since these drugs have high solubility in the donor solution (distilled water or lactate buffer), however, the skin permeation rates, which are in general proportional to the product of skin permeability coefficient and solubility of drugs in the drug-donor compartment, were comparable to or higher than that of indomethacin (1.7 micrograms/cm2/h): the skin permeation rate of dopamine hydrochloride (458 micrograms/cm2/h) was about 300 times higher than that of indomethacin. The water-soluble drugs with lower molecular weight and higher solubility in water showed higher skin permeation rates. These results suggest that some water-soluble drugs with low molecular weight and high solubility in water might be good candidates for transdermal drug delivery.     

Photoprocesses of photosensitizing drugs within cyclodextrin cavities

Recently some interest has been focused on the photobehavior of CD-drug inclusion complexes in relation to the problem of the biological photosensitization by drugs. This review is dedicated to the illustration of the mechanistic aspects of the photoprocesses occurring in some non-steroidal anti-inflammatory drugs (NSAIDs), with photosensitising side effects, within CD cavities. It is shown how the photobehavior of the CD-drug associates can help to model the photoreactivity of the drugs in biological sites. The limitations for the use of CDs as protective systems for the clinical administration of photosensitising drugs is also evidenced.     

Tuning the interactions in cyclodextrin polymer nanoassemblies

The aim of this paper was to study the associations between a neutral β-cyclodextrin polymer and amphiphilic dextrans substituted with two kinds of groups able to make inclusion complexes with β-cyclodextrin. The first kind of substituent is purely hydrophobic (dodecyl C₁₂ or adamantyl Ada groups) and the second one, cyclohexancarboxylic acid group CHX, brings pH-dependent charge density on the dextran chains. Synthesis and characterization of the di-substituted dextrans have been detailed in a first part where it has been shown that the incorporation of CHX groups (up to 7 mol.%) did not modify the self assembling properties of the amphiphilic dextrans. Affinity of the amphiphilic dextrans for β-cyclodextrin polymer has been studied by different methods including isothermal titration calorimetry, dynamic light scattering and zeta potential. An original pH sensitive behaviour has been obtained for polymer–polymer associations at low concentrations. Nanoassemblies are formed at pH around 4 which are destabilized at lower pH and swollen into soluble aggregates at higher pH. The nanoassemblies formed at pH 4 have also been evidenced by transmission electron microscopy and have revealed a spherical shape of few hundred nanometers.     

Complexation of polyvalent cyclodextrin ions with oppositely charged guests: entropically favorable complexation due to dehydration

Thermodynamic parameters for complexation of polyvalent cyclodextrin (CD) cation and anion with oppositely charged guests have been determined in D2O containing 0.02 M NaCl by means of 1H-NMR spectroscopy. Protonated heptakis(6-amino-6-deoxy)-beta-CD (per-NH3+-beta-CD) forms stable inclusion complexes with monovalent guest anions. The enthalpy (deltaH) and entropy changes (deltaS) for complexation of per-NH3+-beta-CD with p-methylbenzoate anion (p-CH3-Ph-CO2-) are 3.8 +/- 0.7 kJ mol(-1) and 88.6 +/- 2.2 J mol(-1) K(-1), respectively. The deltaH and deltaS values for the native beta-CD-p-CH3-Ph-CO2- system are -8.6 +/- 0.1 kJ mol(-1) and 15.3 +/- 0.7 J mol(-1) K(-1), respectively. The thermodynamic parameters clearly indicate that dehydration from both the host and guest ions accounts for the entropic gain in inclusion process of p-CH3-Ph-CO2- into the per-NH3+-beta-CD cavity. The fact that the neutral guests such as 2,6-dihydroxynaphthalene and p-methylbenzyl alcohol hardly form the complexes with per-NH3+-beta-CD exhibits that van der Waals and/or hydrophobic interactions do not cause the complexation of the polyvalent CD cation with the monovalent anion. The acetate anion is not included into the per-NH3+-beta-CD cavity, while the butanoate and hexanoate anions form the inclusion complexes. The complexation of the alkanoate anions is entropically dominated. Judging from these results, it may be concluded that Coulomb interactions cooperated with inclusion are required for realizing the large entropic gain due to extended dehydration. Entropically favorable complexation was also observed for the anionic CD-cationic guest system. The present study might present a general mechanism for ion pairing in water.     

Evaluation of cyclodextrin polymer as a disintegrating agent

Cyclodextrin polymer was compared to other well known disintegrants concerning the swelling properties /water uptake, moisture uptake, hydration capacity, sedimentation volume in water/. Its high disintegrating effect was proved in directly compressed tablets as well as in tablets made by wet granulation. A remarkable improvement in tablet properties was observed. Not only the disintegration of tablets and the dissolution of the drug was accelerated but also the hardness increased when CDP was used as disintegrant.     

Complexation and back extraction of various metals by water-soluble diglycolamide.

Water-soluble ligands, N,N,N',N'-tetramethyldiglycolamide (TMDGA), N,N,N',N'-tetraethyldiglycolamide (TEDGA), N,N,N',N'-tetrapropyldiglycolamide (TPDGA) and N,N-dipropyldiglycolamic acid (DPDGAc) were prepared and their abilities to complex with and to back-extract the metal cations were investigated. These results indicate that the DGA series and DPDGAc have a stronger complexing ability with Am(III) and Pu(IV) than comparable carboxylic and aminopolycarboxylic acids. Among these ligands, the trend of the strength of their complexing ability is TPDGA approximately TEDGA > TMDGA approximately DPDGAc. TPDGA has significant loss to the extraction solvent due to its high hydrophobicity. It is evident from the present work that TEDGA is the best reagent for the reverse-extraction of not only An(III), (IV) but also Ca(II), Sc(III), Y(III), Zr(IV), La(III), Hf(IV), and Bi(III).     

Complexation and (templated) synthesis of rhenium complexes with cyclodextrins and cyclodextrin dimers in water

Several small, lipophilic rhenium complexes form inclusion complexes with native beta-cyclodextrin (beta-CD) and beta-CD dimers. Association constants larger than 10(9)M(-1) were obtained using dimers. The use of beta-CD also enabled the synthesis of these rhenium complexes in water, in excellent yields, through complexation of the otherwise insoluble corresponding ligands. The influence of the reaction time and temperature on the configuration of the reaction products has been investigated in depth for one of these complexes. Using a beta-CD dimer, it proved possible to specifically template the formation of one configuration. The strength of the complexes of the rhenium complexes in cyclodextrin dimers may allow radiolabeling of biomolecules.