Mucoadhesive Sustained Drug Delivery System Based on Cationic Polymer and Anionic Cyclodextrin/Triclosan Complex

In this study the interactions between a cationic polymer and an anionic cyclodextrin were investigated. The system has the potential for use in a sustained release dosage forms for use on mucous membranes. As mucous membranes are negatively charged the objective of this study was to investigate whether a drug delivery system based on a cationic polymer and an anionic cyclodextrin would be more mucoadhesive than a system containing a cationic polymer and a neutral cyclodextrin. For this purpose the cationic polymer hexadimethrine bromide (HDMBr) and anionic sulfobutylether -cyclodextrin (SBECD) were utilized as well as the neutral hydroxypropyl-cyclodextrin (HPCD). Triclosan was used as a model drug. The drug delivery system was formulated as a solution or semi-solid and its adhesion to porcine buccal mucosa and cation exchange media was measured. In addition the release of triclosan from the system was quantified. No difference was observed between the two systems when they were applied to the mucosal surface. However, the formulations showed improved adhesion, compared to the neutral cyclodextrin/drug delivery system, when they could also reach the underlying surface of the excised tissue. The drug delivery system was much better retained on the cation exchange media than the uncharged system. Significant interactions were observed between the negatively charged cyclodextrin and the positively charged polymer. The results indicate that the interactions could be used to obtain a mucoadhesive sustained drug delivery system under certain circumstances. The positive charge of HDMBr did not have the expected effect on the buccal mucosa and it can be concluded that although a positive charge is likely to promote mucoadhesion, other attributes of polymers, such as molecular weight and viscosity, may have equally beneficial effect.     

The Effects of Cyclodextrins on Hydrocortisone Permeability Through Semi-Permeable Membranes

Determinations of drug fluxes through semi-permeable cellophanemembranes are used to evaluate cyclodextrin complexes and cyclodextrin containingdrug formulations. In the present study we investigated how the cyclodextrin concentration,the membrane thickness and the molecular weight cut off (MWCO) of the membraneinfluence drug fluxes. The cyclodextrin used was 2-hydroxypropyl--cyclodextrin(HP--CD) and the sample drug was hydrocortisone. The MWCO ofthe membranes ranged from 500 to 14,000 and the HP--CD concentrationranged from 0 to 25% (w/v). The hydrocortisone flux from saturated solutions through the MWCO 500 membrane was unaffected by the cyclodextrin concentration. When MWCO of the membrane was greater than the molecular weight of the complex the flux fromsolutions saturated with hydrocortisone increased with increasing HP--CD concentration.This increase showed negative deviation from linearity. When the flux was correctedfor the viscosity increase with increasing HP--CD concentration then the fluxpattern could be described on the basis of Fick's first law and Stokes–Einsteinequation. However the flux did not correlate with the viscosity when it was increasedby adding polymer to the saturated drug solutions. It was shown that the observed fluxpattern was consistent with self-association of cyclodextrin complexes in the aqueousdonor phase.     

Effect of β-cyclodextrins based nanosponges on the solubility of lipophilic pharmacological active substances (repaglinide)

Cyclodextrin based nanosponges (CD-NS) are nanostructured cross-linked polymers, usually obtained by reacting cyclodextrin with a cross-linker such as carbonyldiimidazole, organic carbonates or (±) epichlorohydrin. They have been used to increase the solubility and stability of poorly soluble pharmacological active substances, as they combine the complex forming properties of CDs and properties of polymers (such as the high molecular weight). The affinity of CDs for certain lipophilic molecules is characteristic to the polymeric nano-structured system and allows the development of specific drug delivery systems. Knowing that cyclodextrin capacity to form inclusion complexes is maintained and enhanced when the CD molecules form aggregates, cross-link together or copolymerize with other compounds, we have synthesized cyclodextrin based nanosponges (from β-cyclodextrin and sulfobutylether-β-cyclodextrin). The complexing properties of the polymers were investigated against repaglinide (a hypoglycemic agent, practically insoluble in water). Solubility studies were performed according to the method reported by Higuchi and Connors and the phase solubility diagrams were plotted. The repaglinide-nanosponges complexes were prepared, lyophilized and the resulted inclusion complexes were characterized by FT-IR and NMR. The solubility profile and the loading capacity of the cyclodextrin based polymers were also determined.     

Cyclodextrin polymers in the pharmaceutical industry

The potential applications of cyclodextrin polymers (soluble and insoluble ones) in the pharmaceutical industry are reviewed. The soluble polymers are good solubilizers of drugs thus enhancing their bioavailability. When applied topically the insoluble bead polymer accelerates the healing of burns and ulcers. It can also be used for chromatography and to remove certain components from mixtures. The insoluble ground polymer is an effective tablet disintegrant in direct compression systems as well as in formulations made by wet granulation.Lecture, presented at the meeting Anwendungsmöglichkeiten von Cyclodextrin in der pharmazeutischen Industries, Berlin, 21/22 September 1987.     

Preparation and properties of insoluble films of cyclodextrin condensation polymers

The preparation and properties of smooth and stable films of cyclodextrin polymers are described. The commercially available water soluble prepolymers of-, -, and-cyclodextrin of low molecular masses were crosslinked with glutaric dialdehyde. Side-chain unreacted aldehyde groups were reduced with sodium borohydride. For the-cyclodextrin polymer, optimum film performance was found for a 1:10 mass ratio of glutaric dialdehyde to prepolymer, which corresponds to a molar ratio of glutaric dialdehyde to cyclodextrin units of about 1.75: 1. Such films, of thickness 2.4 µm, were prepared on metallic or glassy-carbon substrates for characterization by scanning-electron microscopy, and for studies with the electrochemical quartz-crystal microbalance.     

Crown ethers derived from cyclodextrin: Interaction with triphenylmethane derivatives

Periodate oxidation followed by borohydride reduction of beta cyclodextrin results in crown ether type derivatives. The polyaldehyde obtained by periodate oxidation has been reduced to polyalcohol and converted to a permethylated derivative. These macrorings are much more flexible than beta cyclodextrin itself.The interaction of beta cyclodextrin (-CD), methylated beta cyclodextrin (DIMEB), polyalcohol and permethylated crown ethers derived from beta cyclodextrin with two triphenylmethane, derivatives and their triphenyltin analogues has been studied. On the basis of the changes in the UV spectra and the solubility enhancement it can be concluded that cyclodextrins (-CD and DIMEB) form complexes only with the triphenylmethane, derivatives. On the other hand the crown ethers prepared from -CD give complexes only with the triphenyltin derivatives.     

The use of naphthalene fluorescence probes to study the binding sites on cyclodextrin polymers formed from reaction of cyclodextrin monomers with epichlorohydrin

Three naphthalene-based fluorescence probes were used as guest molecules to study host/guest binding with cyclodextrin (CD) polymer hosts prepared by treating -,-, or -cyclodextrin monomers with epichlorohydrin. The fluorescence data indicate that the binding interaction is much stronger for the probes with the CD polymers than with the CD monomers. Moreover, the fluorophore binding site on the CD polymers is also more hydrophobic than that on the CD monomers. Fluorescence lifetime data from one of the bound probes (2-(N-methylanilino) naphthalene-6-sulfonic acid) suggest that more than one type of binding site may exist on the CD polymers with this probe. A comparison of fluorescence data using different molecular weight ranges of the CD polymers appear to rule out the possibility of a 12 host/guest complex, where the two CD units come from the same polymer chain.     

Controlled Chemical Modifications of Chitosan. Characterization and Investigation of Original Properties

The main techniques developed to characterize chitosan are recalled. The interaction of chitosan with oppositely charged surfactants was investigated giving very important surface activity effects. A few chemical modifications are described and the new properties obtained are mentioned: alkylation gives amphiphilic polymers having interesting thickening behavior; grafting cyclodextrin (chit‐CD) gives a polymer able to include hydrophobic molecules; grafting adamantane gives an amphiphilic polymer able to specifically interact with chit‐CD forming a temporary network with gel‐like behavior.

The viscosities of adamantane‐chitosan, cyclodextrin‐chitosan, and unmodified chitosan solutions studied here.     

Cyclodextrins in Polymer Synthesis: Enzymatic Polymerization of a 2,6‐Dimethyl‐β‐Cyclodextrin/2,4‐Dihydroxyphenyl‐4′‐Hydroxybenzylketone Host‐Guest Complex Catalyzed by Horseradish Peroxidase (HRP)

This paper reports the enzymatic polymerization of the inclusion complex 2,4‐dihydroxyphenyl‐4′‐hydroxybenzylketone/2,6‐dimethyl‐β‐cyclodextrin by horseradish peroxidase (HRP) in aqueous media. The structure of the complex was determined by means of NOESY‐NMR and crystallographic analysis (indicating an orthorhombic structure). The enzymatic polymerization of the uncomplexed 2,4‐dihydroxyphenyl‐4′‐hydroxybenzylketone yields oligomers with molecular weights up to in organic‐aqueous media, but because of its poor solubility in aqueous systems, no polymerization is observed if water is used as solvent. An increase of the availability of the ketone in solution is achieved by complexing it with random‐methylated β‐cyclodextrin in water. We found that the use of methylated β‐cyclodextrin in equimolar concentration to the monomer increases the polymerization yield and the average molecular weight. The polymers formed were analyzed by GPC and ATR‐FTIR techniques.

Representation from X‐ray diffraction analysis of the 2,6‐dimethyl‐β‐cyclodextrin/2,4‐dihydroxyphenyl‐4′‐hydroxybenzylketone host‐guest complex ( 3 ).     

Poly(azomethine) Rotaxanes: Novel Water Soluble Supramolecular Polymers with High Molar Mass

A novel type of supramolecular poly(azomethine) was synthesized by the polycondensation of an inclusion complex of β‐cyclodextrin/poly(oxypropylene)diamine with one of β‐cyclodextrin/terephthaldehyde and a subsequent reaction with [60]fullerene as the end capping agent. Molar mass determination by gel permeation chromatography showed that the polymers had a high molar mass (about 150 kg · mol⁻¹) with a very narrow polydispersity. Isothermal titration calorimetric studies confirmed that each poly‐(oxypropylene)diamine unit could host seven cyclodextrin molecules, which was further supported by ¹H NMR spectroscopy and molecular modeling studies. Additional characterization by ¹³C NMR and FT‐IR spectroscopy, as well as by thermogravimetric analysis, confirmed the structure of the cyclodextrin‐based polyrotaxane.

     

Polymer and Membrane Design for Low Temperature Catalytic Reactions

Catalytically active asymmetric membranes have been developed with high loadings of palladium nanoparticles located solely in the membrane's ultrathin skin layer. The manufacturing of these membranes requires polymers with functional groups, which can form insoluble complexes with palladium ions. Three polymers have been synthesized for this purpose and a complexation/nonsolvent induced phase separation followed by a palladium reduction step is carried out to prepare such membranes. Parameters to optimize the skin layer thickness and porosity, the palladium loading in this layer, and the palladium nanoparticles size are determined. The catalytic activity of the membranes is verified with the reduction of a nitro‐compound and with a liquid phase Suzuki–Miyaura coupling reaction. Very low reaction times are observed.

     

Catalytic Behaviour of Carbonate β-CD Entrapped in PEEK-WC Membranes

O-octyloxycarbonyl cyclodextrins were immobilised in flat sheetPEEK-WC membranes. The membranes were prepared by phase inversion methodand characterised. cyclodextrin (CD) catalytic action in thep-nitrophenylacetate (PNPA) hydrolysis to p-nitrophenol (PNP) was studied. The CD acylic carbonate derivative shows an effective catalytic action whenincorporated in PEEK-WC membranes, by showing an enzyme-like behaviour. Themembranes were tested at different temperatures and substrate concentrations and thevalue of activation energy for the reaction was estimated. It is well known that CDhave a catalytic action, but their immobilisation in a polymeric matrix enhances thereaction rate, in fact the entrapment optimises the interaction with the substrate andincreases the chemical stability of the catalyst. In addition, CD show morestability when incorporated in the membrane, because of their chemical resistanceto alkaline attack.     

Controlling the Optical Properties of Hyperbranched Conjugated Polyazomethines through Terminal‐Backbone Interactions

A simple approach to tune the optical properties of the hyperbranched conjugated polymers by only adjusting the terminal‐backbone interactions has been reported in this article. Hyperbranched conjugated polyazomethines have been successfully prepared by the reaction of tetramine and dialdehyde. Not only varying the monomer feed ratio to change the quantity of terminal amino groups, but also adopting protonation or complexion with proper dopants (SnCl₂ and β‐cyclodextrin), can alter the interactions between amino terminals and imine bonds in the backbone. Correspondingly, the optical properties of the resulting hyperbranched polymers are controlled.

     

Synthesis of Cyclic Glycerol Ether Cyclodextrin Derivatives and Investigation of their Binding Properties with Drugs

Epichlorohydrin was reacted with cyclodextrins to form the non-cyclic and cyclic glycerol ethers of - and -cyclodextrin (abbreviated as glyc-CD). Cyclic substitution extends the cyclodextrin cavity in a way that is as rigid and non-polar as the cavity of the parent cyclodextrin. Derivatives with extended cavities should better accommodate large or odd shaped molecules. The binding of drugs to the new cyclodextrin derivatives was investigated, through degradation rate studies and solubilization studies, and compared to that of -cyclodextrin, -cyclodextrin and hydroxypropyl--cyclodextrin. The inclusion binding of small molecules such as acetazolamide, ethoxyzolamide and chlorambucil, in the glyc-CDs was either increased or decreased compared to the other cyclodextrins. However, larger molecules, such as indomethacin and hydrocortisone, always bound better to the glyc-CDs with up to 180% increase in the stability constant. The degradation rate within the cyclodextrin cavity was not affected by the above derivation.     

Light‐Switchable Self‐Healing Hydrogel Based on Host–Guest Macro‐Crosslinking

A self‐healing hydrogel is prepared by crosslinking acrylamide with a host–guest macro‐crosslinker assembled from poly(β‐cyclodextrin) nanogel and azobenzeneacrylamide. The photoisomerizable azobenzene moiety can change its binding affinity with β‐cyclodextrin, therefore the crosslinking density and rheology property of the hydrogel can be tuned with light stimulus. The hydrogel can repair its wound autonomously through the dynamic host–guest interaction. In addition, the wounded hydrogel will lose its ability of self‐healing when exposed to ultraviolet light, and the self‐healing behavior can be recovered upon the irradiation of visible light. The utilizing of host–guest macro‐crosslinking approach manifests the as‐prepared hydrogel reversible and light‐switchable self‐healing property, which would broaden the potential applications of self‐healing polymers.

     

The GC separation of C2-naphthalene isomers using cyclodextrins and crown ethers

Summary The twelve structural C₂ isomers of naphthalene are resolved on a single capillary column using , , or cyclodextrin as the stationary phase. A change in elution order is seen upon going from to and then cyclodextrin which can be related to the size of the cyclodextrin cavity and the stereochemical fit of the isomer. A crown-ether column and a liquid-crystal column were found to be unable to separate all of the isomers.     

基于环糊精的高度支化聚合物*

环糊精（CD）与高度支化聚合物都存在空腔结构,若将两者结合起来可构筑出含有两种不同疏水空腔且具有特异物理化学功能的高分子体系,并有望在分子包合与识别、药物控释、基因传输等领域得到新的应用。本文根据高度支化聚合物与环糊精结合方式的不同,从以环糊精为核的高度支化聚合物、外端悬挂环糊精的高度支化聚合物、高度支化聚合物的结构单元与环糊精包合、环糊精与客体分子包合后自组装成高度支化聚合物,以及用功能化的环糊精单体合成超支化聚合物等5个方面对其研究进展进行了总结和评述,并在此基础上展望了该类聚合物的研究方向和发展趋势。     

Redox‐Switchable Supramolecular Graft Polymer Formation via Ferrocene–Cyclodextrin Assembly

The redox switchable formation of very well‐defined supramolecular graft polymers in aqueous solution driven by host–guest interactions between ferrocene (Fc) and cyclodextrin (CD) is presented. The Fc‐containing acrylic backbone copolymer (PDMA‐stat‐Fc) is prepared via reversible addition–fragmentation chain transfer (RAFT) copolymerization of N,N‐dimethyl­acrylamide (DMA) and the novel monomer N‐(ferrocenoylmethyl)acrylamide (NFMA). Via the RAFT process, copolymers containing variable Fc ratios (5‐10 mol%) are prepared, affording polymers of molecular masses of close to 11 000 g mol⁻¹ and molar mass dispersities (Đ) of 1.2. The β‐cyclodextrin (β‐CD) containing building block is synthesized via RAFT‐polymerization, too, in order to afford a polymer with well‐defined molecular mass and low dispersity ( = 10 300 g mol⁻¹, Đ = 1.1), employing a propargyl‐functionalized chain transfer agent for the polymerization of N,N‐diethylacrylamide (DEA). The polymerization product is subsequently terminated with β‐CD via the regiospecific copper (I)‐catalyzed 1,3‐cycloaddition (PDEA‐βCD). Host–guest interactions between Fc and CD lead to the formation of supramolecular graft‐polymers, verified via nuclear Overhauser enhancement spectroscopy (NOESY). Importantly, their redox‐responsive character is clearly confirmed via cyclic voltammetry (CV). The self‐assembly of the statistical Fc‐containing lateral polymer chain in aqueous solution leads to mono‐ and multi‐core micelle‐aggregates evidenced via TEM. Only diffused cloud‐like, non‐spherical nanostructures are observed after addition of PDEA‐βCD (TEM).

     

Graft‐crosslinked Copolymers Based on Poly(arylene ether ketone)‐gc‐sulfonated Poly(arylene ether sulfone) for PEMFC Applications

Novel poly(arylene ether ketone) polymers with fluorophenyl pendants and phenoxide‐terminated wholly sulfonated poly(arylene ether sulfone) oligomers are prepared via Ni(0)‐catalyzed and nucleophilic polymerization, respectively, and subsequently used as starting materials to obtain graft‐crosslinked membranes as polymer electrolyte membranes. The phenoxide‐terminated sulfonated moieties are introduced as hydrophilic parts as well as crosslinking units. The chemical structure and morphology of the obtained membranes are confirmed by ¹H NMR and tapping‐mode AFM. The properties required for fuel cell applications, including water uptake and dimensional change, as well as proton conductivity, are investigated. AFM results show a clear nanoscale phase‐separation microstructure of the obtained membranes. The membranes show good dimensional stability and reasonably high proton conductivities under 30–90% relative humidity. The anisotropic proton conductivity ratios (σ_⟂/||) of the membranes in water are in the range 0.65–0.92, and increase with an increase in hydrophilic block length. The results indicate that the graft‐crosslinked membranes are promising candidates for applications as polymer electrolyte membranes.

     

The effect of water vapour on the cyclodextrin-solute interaction in gas-solid chromatography

The effect of water vapour on the interaction between the solutes and a cyclodextrin was studied chromatographically in a gas/solid system. It has been shown that all the sorbates capable of forming inclusion complexes with -CD are affected by the presence of water, in contrast to the sorbates that do not interact with -CD, which are unaffected. The measurements were carried out with the cyclodextrin deposited on a solid carrier (Chromosorb W) and with water vapour contained in the mobile phase. Some advantages of this system have been demonstrated for an analytical application.Presented at the Fourth International Symposium on Inclusion Phenomena and the Third International Symposium on Cyclodextrins, Lancaster, U.K., 20–25 July 1986.