Classifications

• • D—TEXTILES; PAPER
  • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
  • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
  • D06M10/00—Physical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. ultrasonic, corona discharge, irradiation, electric currents, or magnetic fields; Physical treatment combined with treatment with chemical compounds or elements
  • D06M10/02—Physical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. ultrasonic, corona discharge, irradiation, electric currents, or magnetic fields; Physical treatment combined with treatment with chemical compounds or elements ultrasonic or sonic; Corona discharge
  • D06M10/025—Corona discharge or low temperature plasma
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/738—Cyclodextrins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
  • A61K8/8123—Compositions of homopolymers or copolymers of compounds having one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers, e.g. PVC, PTFE
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q13/00—Formulations or additives for perfume preparations
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
  • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
  • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
  • C09D105/16—Cyclodextrin; Derivatives thereof
• • D—TEXTILES; PAPER
  • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
  • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
  • D06M10/00—Physical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. ultrasonic, corona discharge, irradiation, electric currents, or magnetic fields; Physical treatment combined with treatment with chemical compounds or elements
  • D06M10/04—Physical treatment combined with treatment with chemical compounds or elements
  • D06M10/08—Organic compounds
  • D06M10/10—Macromolecular compounds
• • D—TEXTILES; PAPER
  • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
  • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
  • D06M15/00—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment
  • D06M15/01—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment with natural macromolecular compounds or derivatives thereof
  • D06M15/03—Polysaccharides or derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/60—Particulates further characterized by their structure or composition
  • A61K2800/61—Surface treated
  • A61K2800/62—Coated
  • A61K2800/624—Coated by macromolecular compounds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D1/00—Processes for applying liquids or other fluent materials
  • B05D1/18—Processes for applying liquids or other fluent materials performed by dipping
  • B05D1/185—Processes for applying liquids or other fluent materials performed by dipping applying monomolecular layers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D1/00—Processes for applying liquids or other fluent materials
  • B05D1/62—Plasma-deposition of organic layers

Definitions

• This invention relates to active substance-loaded substrates and their preparation and use, and to functionalised substrates which can be loaded with active substances.
• Active substances for which release might need to be controlled in this way include for example pharmaceuticals and fragrances.
• Cyclodextrins are particularly well suited to host-guest inclusion complex interactions, because of their inherent cavity geometry.
• Their basic structure consists of cyclic oligosaccharides, with the most commonly available having six, seven or eight glucopyranose units ( ⁇ -, ⁇ -, ⁇ -cyclodextrin respectively).
• the oligosaccharide ring forms a torus or "barrel" shape, with the glucose unit primary hydroxyl groups present towards the narrow end, and the secondary hydroxyl groups located around the wider part [12].
• a great variety of guest species are able to form inclusion complexes within the barrel cavity, leading to a range of surface-related applications including drug delivery control [13, 14, 15, 16], chromatography [17, 18], immobilisation of reactive chemicals [19, 20], solubility enhancement [21, 22], selective transport of compounds [23, 24] and perfume release [25, 26].
• WO-2010/021973 describes a multi-layer controlled release system comprising a decomposable film on a substrate.
• the film has at least two differently charged polymeric layers, from which an active substance can be released by sequential degradation of the polymers in a suitable liquid medium.
• the layers must include a hydrolysable electrolyte, and also a "polymeric cyclodextrin", ie a polymer either with a cyclodextrin backbone or with pendant cyclodextrin groups.
• the active substance is introduced into the cyclodextrin host molecules prior to deposition of the polymer layers, which can limit the techniques useable to deposit the polymers, in particular for sensitive active substances.
• Another drawback to this system is that active substance release requires degradation of the associated polymer layers, thus preventing its subsequent re-use.
• a delivery system for an active substance comprising a substrate on which the active substance is loaded for subsequent release, wherein: (i) the substrate has been coated, over at least a part of its surface, with a polymer, using plasma deposition;
• the active substance is present as a guest molecule within a cyclodextrin
• the cyclodextrin inclusion complex is bound to the polymer through a chemical linkage formed between a hydroxyl group on the cyclodextrin and a functional group on the polymer.
• the cyclodextrin inclusion complex is exposed at a surface of the polymer coating, so as to facilitate release of the active substance from the inclusion complex without degradation or removal of the polymer.
• delivery system in this context, is meant a system which is suitable for carrying an active substance, and subsequently delivering the active substance at or to a desired location.
• the chemical linkage is a direct chemical linkage, ie one which does not involve a linker group, for example a methacrylate such as glycidyl methacrylate, or a diisocyanate, between the hydroxyl group on the cyclodextrin and the functional group on the polymer.
• the chemical linkage involves the use of a suitable linking moiety between the hydroxyl group of the cyclodextrin and the functional group on the polymer, for instance as described below.
• the chemical linkage is formed between a primary hydroxyl group on the cyclodextrin and a functional group on the polymer. Suitably, it is formed between a hydroxyl group (in particular a primary hydroxyl group) on an underivatised cyclodextrin molecule.
• the chemical linkage is an ether linkage. It has been found that such ether linkages can be readily formed between hydroxyl groups (in particular primary hydroxyl groups) on cyclodextrin molecules and alkylating groups on polymer molecules, via a Williamson ether synthesis reaction. This is an S N 2 reaction which typically takes place between an alkoxide ion and an alkylating agent such as a primary alkyl halide. It can allow a cyclodextrin to be immobilised on a polymer- coated substrate by a simple in situ reaction with the polymer.
• the ether synthesis reaction tends to take place at the primary hydroxyl groups (these being more nucleophilic and also having greater steric freedom than the secondary hydroxyl groups), it can help to orient the cyclodextrin molecules in a manner which enhances their ability to accept and release guest molecules, with the wider end of each "barrel" remote from the substrate and more accessible to the surrounding environment.
• Other forms of chemical linkage may be usable.
• a cyclodextrin hydroxyl group may be reacted with a linking moiety such as succinic anhydride, which may then be further reacted with a hydroxyl group present on the polymer, as when using a hydroxyl-substituted polymer such as poly(2-hydroxyethyl acrylate).
• a linking moiety such as succinic anhydride
• the cyclodextrin may then be loaded with an active substance, to form a host-guest inclusion complex of known type.
• the active substance (the "guest” molecule) can be captured on the substrate, but can subsequently be released from the cyclodextrin host molecules according to conventional release mechanisms.
• Such release can be easily achieved, in particular if the cyclodextrin host molecules are exposed at a surface of the polymer- coated substrate.
• the cyclodextrin host molecule can be relatively easily reloaded with a further active substance, thus making the invented system reuseable.
• Cyclodextrin inclusion complexes formed in this way have been found to allow extended release of the guest molecules.
• extended release is meant release which continues to occur over a period of time following loading of the complex with the guest molecule (the active substance), for example for 30 or more days, or for 60 or more days, or for 70 or 80 or more days, or in cases for 3 or 5 or even 8 or more months. Such release may for example continue for up to 10 months or for up to 9 or 8 or 7 months.
• the release will typically occur through replacement of the guest molecules by other, typically smaller, molecules from the surrounding environment. Other forms of release may however be possible, as described in more detail below.
• the present invention can thus make possible the gradual release of an active substance from a substrate, which can have a wide range of applications.
• the invention can provide a polymeric coating on a substrate, which is functionalised to allow the loading, and subsequent release, of an active substance.
• the substrate may be formed of any suitable material (typically a solid), depending on its intended use.
• the substrate is selected from textile materials (made from either woven or non- woven, natural or synthetic, fibres); metal; glass; ceramics; semiconductors; cellulosic materials; paper and card; wood; structural polymers such as polytetrafluoroethylene, polyethylene, polypropylene and polystyrene; and combinations thereof.
• the substrate is a textile material (either woven or non-woven). It may be any object to which an active substance-releasing coating is to be applied, including a thin substrate or film which is itself suitable and/or adapted and/or intended to be applied to the surface of another object.
• the substrate comprises an open structure, for example a network of fibres, which can serve as a scaffold for the cyclodextrin-derivatised polymer coating.
• the polymer is applied to the substrate by plasma deposition.
• Plasma or
• Plasmachemical deposition processes are well known in the art and involve the deposition of a monomer (polymer precursor) onto a substrate within an exciting medium such as a plasma, which causes the precursor molecules to polymerise as they are deposited.
• Plasma-activated polymer deposition processes have been widely documented in the past - see for example J P S Badyal, Chemistry in England 37 (2001): 45-46.
• a plasma deposition process may be carried out in the gas phase, typically under sub- atmospheric conditions, or on a liquid monomer or monomer-carrying vehicle as described in WO-03/101621.
• the polymer is applied to the substrate using a pulsed plasma deposition process. In an embodiment, it is applied using an atomised liquid spray plasma deposition process, in which, again, the plasma may be pulsed.
• a pulsed electrical discharge can result in structurally well-defined coatings.
• the advantages of using (pulsed) plasma deposition can include its potential applicability to a wide range of substrate materials and geometries, with the resulting deposited layer conforming well to the underlying surface.
• the technique can provide a straightforward and effective method for functionalising solid surfaces, being a single step, solventless and substrate-independent process.
• the inherent reactive nature of the electrical discharge can ensure good adhesion to the substrate via free radical sites created at the interface during ignition of the plasma.
• the level of surface functionality can be tailored by simply pre-programming the plasma duty cycle.
• pulsed plasma deposited functional films include poly(glycidyl methacrylate), poly(bromoethyl-acrylate), poly(vinyl aniline), poly(vinylbenzyl chloride), poly(allylmercaptan), poly(N-acryloylsarcosine methyl ester), poly(4-vinyl pyridine) and poly(hydroxy ethyl methacrylate).
• any suitable conditions may be employed for the plasma deposition of the polymer onto the substrate, depending on the nature of the monomer and of the coating needed on the substrate.
• a power (or in the case of a pulsed plasma, a peak power) of from 10 to 70 W, or from 20 to 50W, such as about 30 or 40 W.
• a duty cycle on-period of from 10 to 200 ⁇ , or from 50 to 150 ⁇ , such as about 100 ⁇ .
• a duty cycle off-period of from 0.5 to 20 ms, or from 1 to 10 ms, or from 1 to 5 ms, such as about 4 ms.
• a ratio of duty cycle on-period to off-period of from 0.001 to 0.05, or from 0.01 to 0.05, such as about 0.025.
• a polymer which has been applied to a substrate using plasma deposition will typically exhibit good adhesion to the substrate surface.
• the applied polymer will typically form as a uniform conformal coating over the entire area of the substrate which is exposed to the relevant monomer during the deposition process, regardless of substrate geometry or surface morphology.
• Such a polymer will also typically exhibit a high level of structural retention of the relevant monomer, particularly when the polymer has been deposited at relatively high flow rates and/or low average powers such as can be achieved using pulsed plasma deposition or atomised liquid spray plasma deposition.
• the cyclodextrin molecule is bound to the polymer coating at the exposed surface of the coating.
• the polymer may be applied to the substrate in the form of a single coating layer.
• the polymer coating may have any appropriate thickness. It may for example have a thickness of 1 nm or greater, or of 10 or 50 nm or greater, or of 75 or 100 nm or greater, or in cases of 0.5 or 1 or 10 ⁇ or greater. This thickness may be up to 100 ⁇ , or up to 10 or 1 ⁇ , or up to 500 or 200 nm.
• the cyclodextrin-derivatised polymer may contain one or more pores, in particular macropores: in such a case, a cyclodextrin inclusion complex may be exposed at an internal surface of a pore.
• a porous cyclodextrin-derivatised polymer layer may display a gradient in porosity which decreases from the outer surface towards the substrate interface, to help increase mass transport of guest molecules. In particular, it may have smaller pores at and close to the substrate-polymer interface than at the external polymer surface.
• a (macro )porous structure may be achieved by inducing the formation of a water-in- oil emulsion within the cyclodextrin-derivatised polymer layer.
• This has been found to be possible without the need for additional emulsion stabilising agents such as surfactants, provided the overall derivatised polymer system is amphiphilic in nature (ie incorporates both hydrophilic and hydrophobic entities, for example the hydrophilic pendant cyclodextrin molecules linked to a hydrophobic polymer such as a
• poly(vinylbenzyl) polymer poly(vinylbenzyl) polymer). Indeed, in such systems, spontaneous emulsification can occur during the formation of the polymer-cyclodextrin linkages, and can result in a macroporous polyHIPE (high internal phase emulsion) structure in which pendant ⁇ - cyclodextrin groups are present at exposed surfaces both inside the pores and at the external polymer surface.
• HIPE high internal phase emulsion
• such a porous system comprises a three-level hierarchical porous structure, incorporating nanoporosity (the cyclodextrin cavities) supported on a polyHIPE structure (with pore diameters typically of the order of several ⁇ ), which in turn is fixed onto an open substrate scaffold, such as a network of fibres with interfibre spacings of the order of several hundred ⁇ .
• the deposited polymer coating may be necessary for the deposited polymer coating to have a certain minimum thickness, for example of 150 nm or greater.
• cyclodextrin-derivatised porous polymer coatings in accordance with the invention, can bring significant benefits. It can combine the inherent advantages of plasmachemical functionalisation (which is a substrate-independent, solventless, single-step deposition process) with the spontaneous, stabiliser- free emulsification of the ⁇ -cyclodextrin-derivatised polymer layer. As a result, there exists the potential to apply this hierarchical macro- to nanoporous structure methodology to other high surface area substrates. High surface area (macro )porous polymers can be difficult and/or expensive to make.
• Conventional polyHIPEs are formed by template polymerisation around the aqueous phase of a water-in-oil emulsion, which needs to be stabilised using an appropriate surfactant.
• the present invention can provide a relatively simple and cheap route to cyclodextrin- derivatised polyHIPE structures, which can function as high loading capacity active substance capture and/or release systems.
• polymer in the context of the present invention, also embraces a copolymer.
• the polymer should comprise a substituent (ie a functional group such as an acid, aldehyde or alkyl halide) which is capable of reacting with a hydroxyl group on the cyclodextrin molecule (or with a derivative of such a group, for example an alkoxide ion) in order to generate the required chemical linkage.
• the polymer comprises an alkylating group capable of reacting with the cyclodextrin hydroxyl group or derivative under appropriate conditions, for instance via a Williamson ether synthesis reaction.
• the alkylating group suitably includes a leaving group which may be displaced by a nucleophile, such as an alkoxide ion, formed from the cyclodextrin hydroxyl group.
• the leaving group is a halide, for example chloride.
• the polymer may thus be a halogenated, in particular chlorinated, polymer.
• Its alkylating group is suitably a primary alkyl or aryl-alkyl halide, including for instance a benzyl halide.
• the polymer is a vinyl polymer, in particular a halogenated vinyl polymer.
• the polymer is a poly(vinylbenzyl halide), for example a poly(4-vinylbenzyl chloride).
• the polymer is a hydroxyl- substituted polymer such as a hydroxyl-substituted acrylate, for example poly(2-hydroxyethyl acrylate).
• At least 40% of the relevant functional groups on the polymer are bound to cyclodextrin molecules through chemical linkages. In an embodiment, at least 50%) of the relevant functional groups are so bound, or in cases at least 60%>. It is possible, using the present invention, to achieve relatively high polymer-cyclodextrin attachment densities, and hence relatively high active substance-carrying capacities, on a substrate surface, for instance compared to those achievable using prior art cyclodextrin-based delivery systems.
• the active substance may be any substance which it is desired to carry on the substrate for subsequent release and which is capable of being held as a guest molecule within a cyclodextrin inclusion complex. It may for example comprise a substance selected from pharmaceutically active substances (including antimicrobial agents such as antibacterial or antifungal agents); flavourings; perfumes; dyes; cosmetics; and mixtures thereof. In an embodiment, it comprises a volatile substance such as a perfume. In an embodiment, the active substance comprises a lipophilic substance, or a substance having one or more lipophilic substituents. This can help improve its uptake into the host cyclodextrin molecule, as discussed in more detail below.
• the active substance comprises an essential oil (also known as a volatile oil, an ethereal oil or an aetherolea).
• it comprises an essential oil selected from lavender, sandalwood, jasmine, rosemary, lemon, vanilla and mixtures thereof; or from sandalwood, jasmine, rosemary, vanilla and mixtures thereof; or from sandalwood, rosemary, vanilla and mixtures thereof; or from jasmine, rosemary, vanilla and mixtures thereof; or from rosemary, vanilla and mixtures thereof.
• the active substance comprises an aromatic compound, ie a compound containing one or more aromatic (for example phenyl) rings.
• the cyclodextrin used in the present invention may be selected from ⁇ -, ⁇ - and ⁇ - cyclodextrins and mixtures thereof. In an embodiment, it is a ⁇ -cyclodextrin.
• the present invention provides a method for preparing a functionalised substrate on which an active substance can be loaded for subsequent release, the method comprising:
• the reaction is suitably such that the cyclodextrin molecule is then exposed at a surface of the polymer coating, so as to facilitate loading of an active substance into, and/or release of an active substance from, the cyclodextrin molecule without degradation or removal of the polymer.
• the chemical linkage may be a direct chemical linkage. It may be an ether linkage. It may be formed between a primary hydroxyl group on the cyclodextrin and a functional group on the polymer.
• the reaction step (ii) may be an S N 2 nucleophilic substitution reaction. In an embodiment, it is a Williamson ether synthesis reaction. Such a reaction is suitably carried out under basic conditions, for example in the presence of a base such as sodium or potassium hydroxide, or sodium (bi)carbonate, in order to convert hydroxyl groups on the cyclodextrin into alkoxide ions.
• the reaction may be carried out in solution, for example in aqueous solution. Suitable solvents, temperatures and reaction times - and catalysts if appropriate - will naturally depend on the nature of the polymer.
• the reaction is allowed to proceed until at least 40% of the relevant functional groups on the polymer are bound to cyclodextrin molecules through the chemical linkages, or at least 50 or 60%. In an embodiment, the reaction is allowed to proceed until the polymer surface is saturated with chemically- linked cyclodextrin molecules, or at least 98 or 95 or 90 or 80 or 70%> saturated.
• the method of the second aspect of the invention may also comprise applying the polymer to the substrate prior to the reaction step (ii). As described above, this may involve the use of a pulsed plasma deposition process.
• the method may comprise loading the cyclodextrin with an active substance following the reaction step (ii), so as to generate a cyclodextrin inclusion complex, attached to the polymer, containing an active substance guest molecule.
• the loading step may be carried out by any suitable means, for example by immersing the substrate in the active substance, or in a solution or dispersion of the active substance, or by washing the polymer coating with the active substance or a solution or dispersion thereof. Such a method may be used to prepare an active substance-loaded delivery system in accordance with the first aspect of the invention.
• the functionalised substrate may be loaded with a further quantity of the, or another, active substance in a similar fashion.
• the substrate may effectively be "recharged” with more of the same active substance and/or with another active substance.
• a third aspect of the invention provides a functionalised substrate for use as part of a delivery system according to the first aspect, and/or which has been prepared according to the method of the second aspect, which substrate has been coated, over at least a part of its surface, with a polymer, using plasma deposition, and in which the polymer is bound to a cyclodextrin molecule via a chemical linkage (in particular an ether linkage) formed between a hydroxyl group on the cyclodextrin and a functional group on the polymer.
• a chemical linkage in particular an ether linkage
• the cyclodextrin molecule is suitably exposed at a surface of the polymer coating, so as to facilitate loading of an active substance into, and/or release of an active substance from, the cyclodextrin molecule without degradation or removal of the polymer.
• such a functionalised substrate may be used to "capture" an active substance from an environment.
• the active substance may be captured as a guest molecule within the cyclodextrin molecule.
• Such a substance may be removed from the environment, within the cyclodextrin molecule, and subsequently, if appropriate, released therefrom, following which the functionalised substrate may be reused to capture another active substance.
• a fourth aspect of the invention provides a method for capturing a first active substance from a first environment containing it, the method comprising introducing into the first environment a functionalised substrate according to the third aspect of the invention, and allowing the first active substance to enter a cyclodextrin molecule as a guest molecule. The invention can thus be used to remove an active substance from an environment containing it.
• the method of the fourth aspect of the invention may comprise subsequently releasing the first active substance, or at least a portion thereof, from the cyclodextrin host molecule.
• An active substance may be released from a cyclodextrin host molecule (ie from a cyclodextrin inclusion complex) by any suitable means.
• the active substance may be extracted into a suitable solvent system, for example by washing the functionalised substrate or delivery system with the solvent system.
• the active substance may be released by modifying it in some way, such that the modified form of the substance is less well suited (for example energetically and/or sterically suited) to reside within the cyclodextrin host molecule: such a modification may for example be achieved by changing the pH of the environment to which the active substance is exposed.
• the active substance may be replaced by a competitor molecule which is better suited to occupying the cyclodextrin host molecule: such a competitor molecule may for example be water, for instance atmospheric moisture, and may suitably be smaller than the active substance.
• underpin host-guest inclusion complex formation relate to thermodynamic interactions between the various constituents (ie ⁇ - cyclodextrin, guest, and solvent), which give rise to a net energetic driving force which compels the guest molecule to dock into the cyclodextrin cavity. If this driving force can be overcome, then release and/or substitution of the guest molecule can be achieved.
• the ionised or charged form of the molecule will exhibit poorer binding to cyclodextrins compared to the non- ionised or neutral form of the molecule (ie where the pH of the surrounding medium is greater than the pI of the molecule).
• Such release mechanisms may also be used to facilitate release of an active substance from a delivery system according to the first aspect of the invention.
• a method according to the fourth aspect of the invention may comprise subsequently re-using the functionalised substrate, following release of the first active substance, in order to capture a second active substance (which may be the same as, or different to, the first active substance) from a second environment which contains the second active substance.
• the second environment may be the same as, or different to, the first environment.
• the functionalised substrate may be used and re-used any number of times, as desired.
• a method for preparing an active substance delivery system for example a system according to the first aspect of the invention
• the method comprising loading an active substance onto a functionalised substrate according to the third aspect, so as to generate an active substance-containing cyclodextrin inclusion complex attached to the polymer. This method may also be used to "recharge" a functionalised substrate or delivery system, as described above.
• a sixth aspect of the invention provides a product which is formed from or
• the product may be for example a garment, an item of footwear or a personal accessory (including an item of jewellery). It may be an item of furniture (including a car seat), or of soft furnishing (for example a curtain, or a wall or floor covering). It may be a household product such as an air freshener or laundry treatment product. It may be a cosmetic or toiletry product; a dressing or sanitary product; or a deodorant product, including for example a shoe insert such as an insole. It may be an item of packaging, for example food packaging. It may be a scaffold structure for use in tissue engineering. The product may incorporate one or more additional active substances such as antimicrobial (including antifungal), deodorant or anti-perspirant agents.
• additional active substances such as antimicrobial (including antifungal), deodorant or anti-perspirant agents.
• the active substance may be loaded into any suitable host molecule, in particular a cavitand such as a cyclodextrin.
• the host molecule may be bound to the polymer through a chemical linkage formed between a functional group (in particular a hydroxyl group) on the host molecule and a functional group on the polymer.
• the linkage may be a direct chemical linkage; it may be an ether linkage.
• a delivery system, functionalised substrate or method according to the invention may be used for the purpose of controlling (in particular extending) the release of an active substance from a substrate. It may be used for the purpose of capturing an active substance from an environment which contains the substance.
• the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, mean “including but not limited to”, and do not exclude other moieties, additives, components, integers or steps.
• the singular encompasses the plural unless the context otherwise requires: in particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
• Figure 1 shows schematically a method in accordance with the invention
• Figure 2 is a graph showing the variation of polymer surface chlorine concentration (by X-ray photoelectron spectroscopy) with ⁇ -cyclodextrin solution concentration, following reaction of a surface polymer layer with a ⁇ -cyclodextrin solution in Example 1 below
• Figures 3 and 4 show infrared spectra for materials used and produced in Example 1 ;
• Figure 5 shows quartz crystal microbalance measurements taken during vanillin exposure to cyclodextrin-derivatised and underivatised polymer layers produced in Example 1;
• Figure 6 shows vanillin release rates from cyclodextrin-derivatised and underivatised polymer layers produced in Example 1 ;
• Figure 7 shows essential oil loadings in derivatised polymer layers produced in
• Example 2 and their rates of change during subsequent storage.
• Figure 1 shows how, in accordance with the invention, a B-cyclodextrin "barrel” 1 can be tethered to a substrate 2 via an intermediate polymer layer 3.
• a thin polymer layer is deposited on the substrate using for instance a pulsed plasma deposition technique.
• the polymer in this case is poly(4-vinylbenzyl chloride), which on the surface of the substrate presents pendent benzyl chloride groups 4.
• the polymer layer is then reacted with the B-cyclodextrin in the presence of a base such as a hydroxide.
• a base such as a hydroxide.
• the base converts the primary hydroxyl groups on the
• the thus-immobilised cyclodextrin barrels may then be loaded with an active substance such as a perfume (not shown in Figure 1), for subsequent release.
• an active substance such as a perfume (not shown in Figure 1)
• the approach provided by the present invention allows the use of unmodified cyclodextrins as immobilised carriers for active substances.
• Figure 1 shows schematically how the cyclodextrin molecule adopts the approximate shape of an axially extended torus or hollow frustocone.
• the narrower end of the molecule is oriented towards the polymer surface through the ether linkages with the polymer benzyl groups.
• the wider end is remote from the surface, and so is better able to accept and release guest molecules.
• the ether synthesis reaction - together with the inherent steric flexibility of the polymer layer 3 - helps to orientate the cyclodextrin complex appropriately, with the axis of the frustocone approximately perpendicular to the polymer/substrate surface.
• substrates prepared as shown in Figure 1 were loaded with perfumes.
• the guest-host interactions between the perfume molecules and the immobilised ⁇ -cyclodextrin barrels were characterised by infrared spectroscopy, quartz crystal microbalance (QCM) and human sensory testing, demonstrating extended release of the perfumes from the cyclodextrin inclusion complexes.
• QCM quartz crystal microbalance
• Pulsed plasma deposition of 4-vinylbenzyl chloride (+98%, Aldrich, purified using several freeze-pump-thaw cycles) was carried out in an electrodeless cylindrical glass reactor (5 cm diameter, 520 cm 3 volume, base pressure of 1 x 10 ⁇ 3 mbar, and with a leak rate better than 1.8 x 10 ⁇ 9 kg s "1 ) enclosed in a Faraday cage.
• the chamber was fitted with a gas inlet, a Pirani pressure gauge, a 30 L min "1 two-stage rotary pump attached to a liquid cold trap, and an externally wound copper coil (4 mm diameter, 9 turns, spanning 8-15 cm from the precursor inlet). All joints were grease free.
• An L-C network was used to match the output impedance of a 13.56 MHz radio frequency (RF) power generator to the partially ionised gas load.
• the RF power supply was triggered by a signal generator and the pulse shape monitored with an oscilloscope.
• the reactor chamber was cleaned by scrubbing with detergent and rinsing in water and propan-2-ol, followed by oven drying. The system was then reassembled and evacuated. Further cleaning consisted of running an air plasma at 0.2 mbar pressure and 50 W power for 30 minutes.
• Inclusion complexes between guest vanillin (4-hydroxy-3-methoxybenzaldehyde, Aldrich) molecules with the surface derivatised ⁇ -cyclodextrin were prepared by immersion in a 75 mM ethanolic vanillin solution for periods of up to 72 hours.
• Film thickness measurements were carried out using an nkd-6000 spectrophotometer (Aquila Instruments Ltd). The acquired transmittance-reflectance curves (350 - 1000 nm wavelength range) were fitted to a Cauchy model for dielectric materials employing a modified Levenberg-Marquardt method [48].
• XPS X-ray photoelectron spectroscopy
• FTIR Fourier transform infrared analysis of the layers at each stage of reaction was carried out using a Perkin-Elmer Spectrum One spectrometer equipped with a liquid nitrogen cooled MCT detector operating across the 700 - 4000 cm “1 wavenumber range. Reflection-absorption (RAIRS) measurements were performed using a variable angle accessory (Specac Inc) set at 66° with a KRS-5 polariser fitted to remove the s- polarised component. All spectra were averaged over 5000 scans at a resolution of 4 cm "1 .
• RAIRS Reflection-absorption
• Pulsed plasma poly(4-vinylbenzyl chloride) 90.6 ⁇ 0.1 - 9.4 ⁇ 0.1
• Figure 2 shows the XPS chlorine concentration (% CI) at the surface of the polymer layer, following reaction with ⁇ -cyclodextrin, as a function of solution concentration: it can be seen that ⁇ - cyclodextrin solution concentrations of 20 ⁇ and higher yielded surface saturation, whilst lower dilutions yielded sub-mono layer coverages. Table 1 and Figure 2 together show that at higher ⁇ -cyclodextrin solution
• CH2-CI groups detected following surface tethering correspond to either unreacted CH2-CI groups at the surface (not all primary hydro xyl centres on the ⁇ -cyclodextrin barrel need attach to the surface for successful binding) or they are located within the subsurface region of the pulsed plasma deposited poly(4-vinylbenzyl chloride) layer. Also O-H stretching associated with the ⁇ -cyclodextrin barrels was evident by the broad band centred around 3250 cm "1 . 2.2 Perfume release
• Figure 4 shows infrared spectra of (a) the polymer layer derivatised with the 20 ⁇ ⁇ - cyclodextrin solution; (b) vanillin; and (c) the derivatised polymer layer following its exposure to a 75 mM solution of vanillin.
• the mass detected by the quartz crystal microbalance increased rapidly upon exposure of the surface tethered ⁇ -cyclodextrin barrels to vanillin, reaching saturation after approximately 55 seconds. Termination of the vanillin feed, followed by evacuation, produced a drop in mass reading correlating to a loss of vanillin molecules from the ⁇ - cyclodextrin barrels under vacuum.
• a theoretical monolayer coverage level of 5.65 x 10 13 molecules cm “2 can be calculated using a ⁇ -cyclodextrin surface area footprint of 1.77 nm 2 [56], with the barrel aligned vertical to the surface so as to facilitate host- guest molecule interactions (see Figure 1).
• the quartz crystal microbalance measurements yield approximately 4.54 x 10 13 vanillin molecules cm "2 which equates to approximately an 80% surface coverage by cyclodextrin barrels.
• a second exposure to a vanillin feed recorded less than a 2% drop in their overall inclusion complex forming capability, thereby exemplifying the surface anchored ⁇ -cyclodextrins' recharging behaviour.
• Example 1 20 ⁇ ⁇ -cyclodextrin- functionalised pulsed plasma deposited poly(4- vinylbenzyl chloride) on non- woven polypropylene cloth, prepared as in Example 1.
• the complexes were made by exposing the functionalised polymer-coated cloth to a 75 mM ethanolic solution of the relevant oil for 72 hours. Subsequent washing with ethanol and propan-2-ol, followed by drying at 35°C for 60 minutes, removed any unbound guest molecules.
• Essential oil guest molecule loading concentrations were calculated by extraction with an ethanol/water (50:50 v/v) mixture for 12 hours followed by UV-vis absorption spectroscopy measurement at a wavelength of 276 nm (absorption maxima for all essential oils studied) at regular time intervals.
• Aroma activities of the freshly charged inclusion complexes were evaluated by sensory tests that entailed placing the functionalised non-woven polypropylene cloths in insulated booths stored at room temperature. They were nosed (ie smelt) at regular intervals in order to detect the scent. The levels of fragrance release from the inclusion complexes were compared with control samples comprising the underivatised pulsed plasma deposited poly(4-vinylbenzyl chloride) layer on non-woven polypropylene cloth. Both sets of aroma nosing assessments were undertaken by several individuals according to single-blinded experimental conditions [52] in which each insulated booth's scent was correctly identified before proceeding with scent intensity evaluation.
• Table 2 shows the results of the human sensorial evaluation performed with these essential oil- loaded ⁇ -cyclodextrin-derivatised polymer layers.
• control underivatised polymer layer (also deposited onto nonwoven polypropylene cloth) displayed no scent after 14 days. Recharging of the ⁇ - cyclodextrin-derivatised samples yielded no deterioration in human response over each subsequent 280 day trial period.
• the high surface packing density of the ⁇ -cyclodextrin barrels is indicative of the ⁇ -cyclodextrin barrels being suitably oriented both to accept and release guest molecules. This is probably a consequence of the overall inherent steric flexibility of the underlying polymeric linker layer, which can allow for a greater range of surface orientations to help maximise host-guest inclusion complex formation.
• All of the essential oils contain lipophilic (fatty-type) alkane segments [59] which, like cholesterol (a lipid binding molecule), are capable of forming inclusion complexes inside the ⁇ -cyclodextrin cavities [60, 61].
• the driving force towards complex formation is the displacement of high enthalpy polar-apolar interactions (eg between the apolar cyclodextrin cavity and polar water molecules initially solvated within the cyclodextrin) for apolar-apolar interactions (between the guest and the cyclodextrin cavity) [1] caused by the disruption and loss of water molecules.
• Subsequent slow release of guest molecules occurs as water molecules interpose the apolar-apolar interactions between guest and host over time [62], thereby leading to volatility of the guest molecule.
• cyclodextrin- functionalised polymers such as those produced in Examples 1 and 2, can have a wide range of potential applications.
• ⁇ -cyclodextrin can be incorporated into shoe insoles to help in removing sweat so as to inhibit microbial growth and malodours [1, 5, 63]: the cyclodextrin could be supported on a substrate, and loaded with a perfume, in accordance with the invention, allowing the gradual release of perfume coincident with the removal of sweat.
• Other products, such as fabrics and articles made from them, could provide a "smart" dual-mechanism perfume release in a similar manner, with large guest perfume molecules being displaced by malodorous small molecules to assist in masking offensive smells. Such products could remain effective for several months, and if necessary could be
• the present invention can provide the potential for many more applications in the future involving controlled molecule release.

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