WO2013024307A2 - Branched addition copolymers and their use - Google Patents
Branched addition copolymers and their use Download PDFInfo
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- WO2013024307A2 WO2013024307A2 PCT/GB2012/052034 GB2012052034W WO2013024307A2 WO 2013024307 A2 WO2013024307 A2 WO 2013024307A2 GB 2012052034 W GB2012052034 W GB 2012052034W WO 2013024307 A2 WO2013024307 A2 WO 2013024307A2
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
- A23L27/72—Encapsulation
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
- A23L27/74—Fixation, conservation, or encapsulation of flavouring agents with a synthetic polymer matrix or excipient, e.g. vinylic, acrylic polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/11—Encapsulated compositions
-
- 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
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
-
- 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
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D17/00—Detergent materials or soaps characterised by their shape or physical properties
- C11D17/0039—Coated compositions or coated components in the compositions, (micro)capsules
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/50—Perfumes
- C11D3/502—Protected perfumes
- C11D3/505—Protected perfumes encapsulated or adsorbed on a carrier, e.g. zeolite or clay
-
- 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
- A61K2800/10—General cosmetic use
Definitions
- the present invention relates to the use of reactive amphiphilic branched addition copolymers in the preparation of covalently cross-linked capsules via emulsion-templated encapsulation, a method for preparing same, and the use of the resultant capsules in the encapsulation of compounds.
- the present invention relates to the use of reactive amphiphilic branched addition copolymers in the preparation of covalently cross-linked capsules to encapsulate compounds such as for example: pharmaceuticals or agrochemicals; nutritional agents such as vitamins; cosmetics, catalysts, dyes, pigments, flavours, biocides, fragrances, lubricating oils, emollients, reactive resins, natural oils and waxes, and use with paints, inks, coatings, sealants, and as tissue engineering scaffolds.
- compounds such as for example: pharmaceuticals or agrochemicals
- nutritional agents such as vitamins
- emollients reactive resins, natural oils and waxes
- 'active' materials that is, materials of interest
- active materials typically hydrophobic compounds potentially in combination with an inert carrier
- cross-linked capsules can be prepared with additional functionalities present on the surface of the capsule or within the cross-linked structure, which can lead to further advantages such as enhanced surface recognition, responsive assembly and disassembly or the ability of the capsule to rupture when exposed to an external stimulus such as a change in temperature, pH, ionic strength, electromagnetic radiation or via a further chemical change.
- the internal phase present within the capsules can be washed or leached out to provide hollow casings which can then be used as a further depository for an additional active compound or the casings can be utilised as a hollow void in their own right, such as to provide a sink for hydrophobic materials or as fillers in, for example, the preparation of composite materials.
- emulsion encapsulation methodologies are typically achieved via the formation of stable emulsion droplets wherein an active material is dissolved or dispersed within the emulsifier-stabilised droplets.
- the emulsion droplets are reacted further to achieve a cross-linked particle or alternatively an additional cross-linker material, which may be present either within the encapsulated droplet or external to the emulsion droplet, is reacted to give a cross-linked shell.
- a common procedure to achieve encapsulation is through the use of a sol-gel reaction of an alkoxysilane.
- a stable emulsion is formed where an alkoxysilane, such as tetraethoxysilane, is emulsified in addition to a hydrophobic active or carrier material, following introduction of a base into the aqueous bulk phase an interfacial cross-linking reaction takes place whereby a silicate shell is formed at the oil-water interface giving rise to a cross-linked capsule.
- This methodology is particularly inefficient as a large amount of alkoxysilane must be used in order to achieve efficient shell formation in addition to undesirable non-controlled formation of cross- linked particles within and external to the capsule.
- An alternative mechanism to achieve cross-linked particles is via the direct physical or chemical cross-linking of the emulsifying agent.
- the emulsifier of choice is a block copolymer, where the self- assembly of the block copolymer leads to the efficient formation of the emulsion droplet.
- the subsequent cross-linking reaction is typically via the formation of an intermolecular covalent bond between copolymer chains at the same oil/water interface to achieve an intramolecularly cross-linked capsule.
- the initial emulsion droplet template is stabilised by the amphiphilic block copolymer, though unfortunately the tedious synthesis of these controlled polymer structures and the common use of toxic small molecule cross-linking agents, in addition to the subsequent clean-up steps post-reaction, renders these methodologies unsuitable for non-specialised applications.
- block copolymer stabilised droplets can also suffer from instability issues where droplet coalescence and demulsifications occur.
- the inventors have now found a method for obtaining cross-linked emulsion capsules through the use of reactive amphiphilic branched addition copolymer emulsifiers where post-emulsification cross-linking can be achieved through reaction of an inherent moiety within the polymer structure.
- branched addition copolymers can be designed to be efficient emulsion stabilisers. Additionally, the structures of these polymers can be tuned to allow demulsification and also emulsion droplet aggregation and de-aggregation via an external trigger, such as a change in pH.
- an external trigger such as a change in pH.
- reactive amphiphilic copolymer emulsifiers to form stable emulsion droplets followed by a post-emulsification reaction has now been shown to provide an industrially viable route to encapsulation of actives.
- encapsulation proceeds through reaction of suitable moieties on the copolymer chains without the addition of a cross-linker.
- the reaction preferably occurs via an intramolecular 'self-cross-linking' reaction between addition copolymers at the same oil/water interface.
- the branched addition copolymer emulsifiers can also be used in conjunction with other non-reactive emulsifiers.
- the capsules formed can be further post-modified with reagents to provide, for example, increased stability or surface recognition. Reactive links can be introduced into the cross-linked structure in order to facilitate rupturing of the capsules upon demand, for example via a change in temperature or pH.
- the capsules can be cross-linked together to give higher order structures such as "beads" or monoliths where the emulsion droplets have been aggregated prior to the final cross-linking step.
- the contents of the capsules can also be removed by a washing material to obtain hollow receptacles suitable for filling with other active materials, or for use in their own right in for example composites where they could be utilised as an additive to alter the opacity, dielectric constant or strength of a composite, coating or film.
- the reactive amphiphilic branched addition copolymers of the present invention are statistical, that is to say, random in structure.
- the distribution of the comonomers in the polymer structure is not controlled and is determined through factors such as relative monomer concentrations and their respective reactivity ratios. This negates the requirement to use controlled polymerisation techniques to achieve, for example, block copolymer structures or to control their molecular weights or polydispersities. Additionally, the polymerisation is through a conventional free-radical technique. These two properties result in a robust and industrially applicable polymerisation method.
- Branched polymers and copolymers are polymer molecules of a finite size which are branched. Branched polymers are soluble and differ from cross-linked polymer networks which tend towards an infinite size having interconnected molecules and which are generally not soluble but often swellable. In some instances, branched polymers have advantageous properties when compared to analogous linear polymers. For instance, solutions of soluble branched polymers are normally less viscous than solutions of analogous linear polymers. Moreover, higher molecular weights of branched copolymers can be solubilised more easily than those of corresponding linear polymers. Also, branched copolymers tend to have more end groups than a linear polymer and therefore generally exhibit strong surface-modification properties. Thus, branched copolymers are useful components of many compositions utilised in a variety of fields.
- Branched polymers are usually prepared via a step-growth mechanism through the polycondensation of monomers and are usually limited via the chemical functionality of the resulting polymer and the molecular weight.
- a one-step process can be used in which a multifunctional monomer is used to provide functionality in the polymer chain from which polymer branches may grow.
- a limitation on the use of conventional one-step processes is that the amount of multifunctional monomer must be carefully controlled, usually to substantially less than 0.5% w/w in order to avoid extensive cross-linking of the polymer and the formation of insoluble gels or hydrogels. It is difficult to avoid cross-linking using this method, especially in the absence of a solvent as diluent and/or at high conversion of monomer to polymer.
- the reactive amphiphilic branched addition copolymers in the present invention are soluble materials, that is they form isotropic solutions in hydrophilic or hydrophobic solvents, which have been designed to emulsify hydrophobic materials in an aqueous bulk medium and undergo chemical cross-linking reaction to yield capsules.
- the encapsulated phase is typically hydrophobic in nature and the encapsulation procedure consists of forming a stable oil-in-water emulsion followed by a post-emulsification reaction to yield a cross-linked capsule.
- the cross-linking reaction takes place via a reaction with another reactive cross-linking molecule or reactive addition copolymer emulsifier chain either at the same interface to form capsules or with an adjacent capsule to form higher scale monoliths.
- an oil-in water emulsion In order to form capsules, an oil-in water emulsion must first be formed where the hydrophobic active is stabilised in an aqueous medium in the form of a micelle.
- Many cosmetic, pharmaceutical or food products are in the form of emulsions, either as a dispersed hydrophobic phase in a continuous phase (oil- in-water or o/w), or as a hydrophilic phase dispersed in a continuous hydrophobic phase (water-in-oil or w/o) or as double emulsions, so-called water-in-oil-in-water (w/o/w) or the converse oil-in-water-in-oil (o/w/o).
- emulsions require the use of materials which can adsorb at the biphasic interface and prevent coalescence or demulsification of the droplets.
- Amphiphilic molecules such as surfactants or polymeric surfactants are typically used for the stabilisation of, for example, oil-in-water emulsions as one part of the surfactant interacts with the oil phase and the other interacts with the water phase.
- surfactants or polymeric surfactants are typically used for the stabilisation of, for example, oil-in-water emulsions as one part of the surfactant interacts with the oil phase and the other interacts with the water phase.
- Emulsions stabilised with inorganic or organic particles have been shown to have excellent stability, low foaming and reduced irritancy.
- these emulsions are formed by the use of finely divided inorganic particles such as silica, alumina, metal oxides etc.
- the driving force for particles stabilising an interface is the reduction in free energy as the particle adsorbs.
- particle-stabilised emulsions are extremely stable as the energy required to remove the particle from the surface is large, in some instances the particles which stabilise an emulsion droplet can be considered to be irreversibly adsorbed.
- Such particles are referred to as particulate, Pickering or Ramsden emulsifiers and are commonly inorganic species.
- organic particles have been investigated for use as Pickering emulsifiers.
- Hydrophobic actives such as drugs and fragrances
- Hydrophobic actives are often only useful if they can be stabilised in hydrophilic environments for sustained periods of time, such as in the body or in aqueous home and personal care formulations. Consequently significant efforts have been made towards developing suitable vehicles for such actives.
- self-assembled polymer structures such as micelles, have received significant attention due to their functionality and size.
- WO2008/071661 describes the use of branched addition copolymers in the formation of oil-in-water emulsions.
- the polymers are amphiphilic in nature and are comprised of a monofunctional monomer, a brancher and a chain transfer agent.
- the branched addition copolymers of the invention must contain a hydrophilic monofunctional monomer with a molecular weight of at least 1 ,000 Daltons.
- WO2009/144471 discloses the use of branched addition copolymers in the formation of oil-in-water emulsions capable of aggregating and de-aggregating.
- the copolymers in question stabilise a hydrophobic oil in an aqueous environment and are capable of associating and disassociating via an external trigger such as hydrogen-bonding via a change in pH.
- WO2008/079677 describes the encapsulation of hydrophobic actives via linear amphiphilic block copolymers prepared via nitroxide-mediated controlled radical polymerisation. The encapsulation occurs via association of the active compound with a crystallising or associating component in the amphiphilic block copolymer.
- a statistical amphiphilic branched copolymer obtainable by an addition polymerisation process, wherein the copolymer comprises:
- the two chains comprise at least one ethyleneically monounsatu rated monomer
- the bridge comprises at least one ethyleneically polyunsaturated monomer
- the copolymer comprises a residue of a chain transfer agent and a residue of an initiator
- At least one of the ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent is a hydrophilic residue; and at least one of one of the ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent is a hydrophobic residue, and
- mole ratio of ethyleneically polyunsaturated monomer(s) to ethyleneically monounsaturated monomer(s) is between a range of from 1 :100 to 1 :4,
- At least one of ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent comprises a moiety of Formula 1 that is capable of further reacting to form covalent bonds with any other mutually reactive moieties present via a sol gel process
- R1 comprises H or an optionally substituted alkyl group
- R2 and R3 comprise an optionally substituted alkyl group.
- the statistical amphiphilic branched addition copolymer R1 may comprise H or CH 3 .
- the statistical amphiphilic branched addition copolymer R2 may comprise an optionally substituted alkyl group of formula (CH 2 ) n where n is 2 to 5.
- n 3
- statistical amphiphilic branched addition copolymer R3 may comprise an optionally substituted methyl or ethyl group.
- the statistical amphiphilic branched addition copolymer is capable of self-crosslinking to form a capsule around a hydrophobic material in an aqueous medium via a change in solution pH.
- At least one of ethyleneically monounsaturated monomer(s) and ethyleneically polyunsaturated monomer(s) and chain transfer agent comprises a moiety that is capable of forming a covalent bond via a sol-gel process.
- a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention in the formation of an oil and water emulsion wherein the amphiphilic branched addition copolymer is used to stabilise the oil/water interface and allow droplet formation and wherein the crosslinking moieties present on the copolymers react at the same oil/water interface and between adjacent interfaces to form capsules.
- the cross-linking reaction takes place between adjacent amphiphilic branched addition copolymers at the same oil/water interfaces to form conjoined capsules.
- the cross-linking reaction takes place between adjacent amphiphilic branched addition copolymers at the same oil/water interfaces to form discrete capsules.
- the cross-linking reaction takes place between amphiphilic copolymers at adjacent oil/water interfaces to form cross-linked monoliths.
- a capsule comprising a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention wherein the cross-linking moieties present in the copolymers are cross-linked to form capsules.
- the capsule may incorporate an active ingredient.
- the active ingredient may comprises a bioactive compound selected from the group comprising:
- the active ingredient may also comprises a non-bioactive compound selected from the group comprising:
- cosmetics catalysts, dyes, pigments, flavours, fragrances, lubricating oils, emollients, natural oils, waxes and inks.
- the capsule may associate and dissociate via hydrogen-bonding.
- the active ingredient may be expelled to yield a hollow capsule.
- the surface of the capsule may be post-modified with additional functional groups.
- a fourth aspect of the present invention there is provided a method of preparing a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention by an addition polymerisation process, which comprises mixing together:
- the polymerisation process comprises a free-radical polymerisation process, and wherein the initiator comprises a free-radical initiator.
- a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention to encapsulate an active ingredient wherein the active ingredient is a bioactive compound selected from the group comprising: pharmaceuticals, agrochemicals; nutritional agents such as vitamins; biocides, cosmetics, catalysts, dyes, flavours, fragrances, emollients, natural oils, and inks.
- a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention to encapsulate an active ingredient wherein the active ingredient is a non-bioactive compound selected from the group comprising: cosmetics, catalysts, dyes, pigments, flavours, fragrances, reactive resins, lubricating oils, emollients, natural oils and waxes.
- the use of the statistical amphiphilic branched addition copolymer according to first aspect of the present invention may extend to the encapsulation of an active ingredient wherein the active ingredient is used in paints, inks, coatings or sealants.
- the use of the statistical amphiphilic branched addition copolymer according to first aspect of the present invention may extend to the encapsulation of an active ingredient for use in tissue engineering scaffolds.
- copolymers in the context of the present invention means statistical amphiphilic branched addition copolymers.
- the ethyleneically monounsatu rated monomer is also referred to as 'monofunctional monomer'.
- the ethyleneically polyunsaturated monomer is referred to as 'multifunctional monomer' or brancher.
- alkyl' refers to a branched or unbranched saturated hydrocarbon group which may contain from 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl etc. More preferably, an alkyl group contains from 1 to 6, preferably 1 to 4 carbon atoms. Methyl, ethyl and propyl groups are especially preferred.
- 'Substituted alkyl' refers to alkyl substituted with one or more substituent groups. Preferably, alkyl and substituted alkyl groups are unbranched.
- Typical substituent groups include, for example, halogen atoms, nitro, cyano, hydroxyl, cycloalkyl, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonato, arylsulfinyl, arylsulfonyl, arylsulfonato, phosphinyl, phosphonyl, carbamoyl, amido, alkylamido, aryl, aralkyl and quaternary ammonium groups, such as betaine groups.
- substituent groups halogen atoms, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, carboxyl, amido and quaternary ammonium groups, such as betaine groups, are particularly preferred.
- substituents represents or contains an alkyl or alkenyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4, carbon atoms.
- a cycloalkyl group may contain from 3 to 8, preferably from 3 to 6, carbon atoms.
- An aryl group or moiety may contain from 6 to 10 carbon atoms, phenyl groups being especially preferred.
- a halogen atom may be a fluorine, chlorine, bromine or iodine atom and any group which contains a halo moiety, such as a haloalkyl group, may thus contain any one or more of these halogen atoms.
- Molar percentages are based on the total monofunctional monomer content. Molecular weights of monomers and polymers are expressed as weight average molecular weights, except where otherwise specified.
- Reactive amphiphilic branched addition copolymers of the present invention are capable of stabilising and further cross-linking emulsion droplets in order to form capsules.
- the emulsions stabilised may be oil-in-water or water-in-oil, or so- called double emulsions.
- the copolymers stabilise the emulsions efficiently at low dose without the need of additional co-stabilisers or surfactants.
- the emulsifier can be chemically cross-linked to give a shell around the encapsulated species or actives, this process can be achieved via reaction of functional moieties present in the copolymer chains.
- a particularly useful type of encapsulating procedure is to utilise an addition copolymer containing a functionality that can be further reacted to give a cross-linked capsule, such as branched addition copolymer containing trialkoxysilyl units, such as trimethylsiloxane moieties, which can be further reacted with each other to give a silica shell around the capsule.
- an addition copolymer containing a functionality that can be further reacted to give a cross-linked capsule such as branched addition copolymer containing trialkoxysilyl units, such as trimethylsiloxane moieties, which can be further reacted with each other to give a silica shell around the capsule.
- Amphiphilic branched addition copolymers can be used to stabilise oil-in-water emulsions, in particular branched variants are especially useful as they have been shown to form extremely stable emulsions at low dose due to their high molecular weight, branched architectures and specific chemical compositions. As has already been shown, these materials effectively stabilise oil-in-water emulsions more effectively than equivalent linear materials.
- a trialkoxysilyl-functional monomer such as trimethoxysilylpropylmethacrylate
- a further advantage of the invention is the facile preparation of the amphiphilic branched addition copolymers with the ability to tune their functionality through choice of polymer constituents such as monomers, and where applicable chain transfer agents for example.
- addition copolymer of the present invention must have the following attributes:
- the branched addition copolymer must be amphiphilic, containing moieties capable of associating with the internal and bulk phase of the emulsion; that is the copolymer must contain hydrophilic and hydrophobic units within the copolymer structure. Hydrophobicity is typically achieved by using hydrophobic monomers such as alkyl-functional monomers such as an alkyl methacrylate, and/or via a hydrophobic chain transfer agent such as an alkyl mercaptan such as dodecanethiol.
- the copolymer must have hydrophilic functionality, again typically achieved by the use of hydrophilic monomers, for example the monomer could be neutral for example polyethyleneglycol- functional monomers such as mono-methoxypoly(ethyleneglycol) methacrylate or the monomer could be charged in nature such as acrylic or methacrylic acid.
- the hydrophilic unit can be responsive in nature whereby the hydrophilicity can be altered by an external stimulus such as pH or temperature, such as in the case of N-isopropylacrylamide.
- the hydrophilic and hydrophobic units could also be introduced through the brancher or chain transfer agent where applicable, such as in the formation of branched addition copolymers.
- the addition copolymer must also possess a functional group or groups which are capable of reacting to give a covalent bond and therefore provide a cross- linked capsule.
- a preferred route is the intramolecular self-cross-linking of the copolymers where the functionality is introduced during the polymerisation process by the incorporation of a suitable functional monomer.
- Self-reacting groups include for example: alkoxysilane-functional monomers such as trimethoxysilylpropylmethacrylate where the crosslinking occurs via a sol-gel process, which is particularly preferred.
- Branched addition polymers have been shown to efficiently emulsify and ultimately cross-link a hydrophobic internal phase to form capsules or aggregated cross-linked structures.
- the polymer In order for the branched addition polymers to be suitable for use in encapsulation technologies the polymer must possess a number of structural components.
- the branched addition copolymers are used to emulsify, and ultimately encapsulate, a hydrophobic oil in an aqueous bulk phase.
- the branched addition polymer must be capable of forming a stable emulsion which can then be further reacted to give a stable cross-linked capsule.
- reaction can occur intramolecularly, it is preferred that it occurs without the addition of a further functional monomer; that is the branched addition copolymer emulsifier contains a functional group which can self-react to give a cross-linked shell around the capsule.
- the encapsulation procedure can occur efficiently without the need for additional, commonly toxic, cross-linkers.
- the copolymer acts as both emulsifier and cross-linker in one function.
- the emulsion or capsule can be further chemically reacted post-emulsification, or post- encapsulation, to give further chemical species at the surface of the emulsion or capsule which may be of benefit, for example in improved substrate affinity.
- Self-cross-linking can occur between copolymer residues on the same interface to form capsules or between copolymer emulsifiers on adjacent interfaces to form monoliths.
- amphiphilic addition copolymers of the current invention can also be used in combination with non-functional small molecule or polymeric emulsifiers.
- an emulsion prepared in accordance with the present invention comprises both reactive and non-reactive emulsifiers; post treatment of these emulsions results in capsule formation via the cross-linking of the reactive emulsifier species.
- This is of particular advantage where further functionality needs to be introduced in a capsule via the use for example of a non-functional emulsifier.
- the cost of preparing the capsules can be reduced by the use of commodity surfactants or emulsifiers with only minimal changes to existing formulation procedures being required.
- the internal payload of the capsules can be washed- out of the capsules following capsule formation by extraction with one or more suitable solvents, such as an alcohol, to leave hollow capsules.
- the hollow capsules can then be re-filled with a further payload or utilised as hollow spheres, for example, for sequestration.
- the hollow spheres can be dried completely and used in composite formations where they provide improved mechanical strength or impart and increased relative permittivity or dielectric constant for use in electrical or electronic applications.
- a high molecular weight material is incorporated into the capsule in combination with a suitable carrier oil, during encapsulation, extraction of the internal phase leaves hollow capsules containing a precipitated polymer akin to a baby's rattle.
- the branched addition copolymers may aggregate in solution upon application of an external trigger such as in the case of capsules decorated with carboxylic acid functionality.
- the formed capsules may assemble via hydrogen- bonding (with inherent changes in hydrophobicity) when below the pKa of the acid group and reversibly disassemble upon the application of an increase in pH.
- hydrophobic actives are of industrial relevance where a hydrophobic component is required to be delivered from, formulated in or isolated from an aqueous environment.
- the cross-linked capsule may protect an active compound from a hydrophilic formulation where the bulk aqueous environment can lead to degradation of the hydrophobic material or is, for example, rich in additional surfactants which can affect the performance of the hydrophobic active.
- the capsule may also be post-modified in order to improve the selectivity of the capsule, such as the covalent attachment of surface-substantive or bio-active materials, for example in the specific delivery of pharmaceutical agents.
- the capsules may also be designed to assemble and disassemble upon changes in the aqueous environment, such as pH, this is particularly desirable in the preparation of a "capsule concentrate" in the associated form for transportation purposes and formulation dilution at the required destination, that is 'on-site'.
- the payload of the capsule can also be washed-out to yield hollow spheroids which can be filled or used in their own right as, for example, in composite materials.
- Examples include but are not limited to: the encapsulation of bioactive compounds such as pharmaceuticals or agrochemicals; nutritional agents such as vitamins; cosmetics, biocides, reactive resins, catalysts, dyes, pigments, flavours, fragrances, lubricating oils, emollients, natural oils and waxes and their use with paints, inks, coatings and sealants and in tissue engineering scaffolds.
- bioactive compounds such as pharmaceuticals or agrochemicals
- nutritional agents such as vitamins
- the copolymers comprise at least two chains which are covalently linked by a bridge other than at their ends, is to be understood as a polymer wherein a sample of said polymer comprises on average at least two chains which are covalently linked by a bridge other than at their ends.
- a sample of the polymer is made there may be accidentally some polymer molecules which are unbranched, which is inherent to the production method (addition polymerisation process). For the same reason, a small quantity of the polymer will not have a CTA on the chain end.
- the hydrophilic monomer may be of high molecular weight, such that at least one of the monofunctional and multifunctional monomers and the chain transfer agent is a hydrophilic residue having a molecular weight of at least 1000 Daltons.
- the hydrophilic component is derived from the multifunctional monomer, more preferably from the chain transfer agent (during conventional free-radical polymerisation) or the initiator, but most preferably from a monofunctional monomer. In all cases, a combination of hydrophilic components is possible and may be desirable.
- hydrophobic component is derived from the multifunctional monomer, more preferably from the chain transfer agent (during conventional free-radical polymerisation) or the initiator, but most preferably from a monofunctional monomer. In all cases, a combination of hydrophobic components is possible and may be desirable.
- Linear polymers are formed from the free-radical addition polymerisation of a monofunctional monomer(s) a radical initiator and optionally a chain transfer agent.
- the monofunctional monomer(s) typically introduce the hydrophilicity and functionality of the resulting copolymer, where a chain transfer agent is used it can introduce the required hydrophobicity of the resulting copolymer by, for example, using an alkyl mercaptan, such as dodecyl mercaptan.
- Branched copolymers of the current invention are formed from the free-radical addition polymerisation of a monofunctional monomer(s) a radical initiator a multifunctional brancher and a chain transfer agent.
- the monofunctional monomer(s) typically introduce the hydrophilicity and functionality of the resulting copolymer
- the chain transfer agent can introduce the required hydrophobicity of the resulting copolymer by, for example, using an alkyl mercaptan, such as dodecyl mercaptan.
- Branched addition copolymers of the current invention tend to stabilise the emulsions in the pre-capsule formation to a better degree than chemically analogous linear copolymers, by function of their higher molecular weight and increased end-groups and branched architecture. This therefore can lead to better capsule formation in the crosslinking step as it reduces the requirement to complete the cross-linking step in a specific time period, that is, the emulsions do not have to be cross- linked immediately as in the case for the linear copolymer encapsulating agents.
- the chain transfer agent is a molecule which is known to reduce molecular weight during a free-radical polymerisation via a chain transfer mechanism.
- These agents may be any thiol-containing molecule and can be either monofunctional or multifunctional.
- the agent may be hydrophilic, hydrophobic, amphiphilic, anionic, cationic, neutral, zwitterionic or responsive.
- the molecule can also be an oligomer or a pre-formed polymer containing a thiol moiety.
- the agent may also be a hindered alcohol or similar free-radical stabiliser such as 2,4-diphenyl-4-methyl-1 -pentene).
- Catalytic chain transfer agents such as those based on transition metal complexes such as cobalt bis(borondifluorodimethyl-glyoximate) (CoBF) may also be used.
- Suitable thiols include but are not limited to C 2 -C-
- Thiol-containing oligomers or polymers may also be used such as poly(cysteine) or an oligomer or polymer which has been post-functionalised to give a thiol group(s), such as poly(ethyleneglycol) (di)thio glycollate, or a pre-formed polymer functionalised with a thiol group, for example, reaction of an end or side-functionalised alcohol such as polypropylene glycol) with thiobutyrolactone, to give the corresponding thiol-functionalised chain-extended polymer.
- a thiol group(s) such as poly(ethyleneglycol) (di)thio glycollate
- a pre-formed polymer functionalised with a thiol group for example, reaction of an end or side-functionalised alcohol such as polypropylene glycol) with thiobutyrolactone, to give the corresponding thiol-functionalised chain-extended polymer.
- Multifunctional thiols may also be prepared by the reduction of a xanthate, dithioester or trithiocarbonate end- functionalised polymer prepared via a Reversible Addition Fragmentation Transfer (RAFT) or Macromolecular Design by the Interchange of Xanthates (MADIX) living radical method.
- RAFT Reversible Addition Fragmentation Transfer
- MADIX Macromolecular Design by the Interchange of Xanthates
- Xanthates, dithioesters, and dithiocarbonates may also be used, such as cumyl phenyldithioacetate.
- Alternative chain transfer agents may be any species known to limit the molecular weight in a free-radical addition polymerisation including alkyl halides and transition metal salts or complexes. More than one chain transfer agent may be used in combination.
- the CTA is a hydrophobic compound.
- Hydrophobic CTAs include but are not limited to linear and branched alkyl and aryl (di)thiols such as dodecanethiol, octadecyl mercaptan, 2-ethylhexyl thioglycolate, 2- methyl-1 -butanethiol, butyl 3-mercaptopropionate, i-octyl 3-mercaptopropionate, t-dodecyl mercaptan, 1 ,9-nonanedithiol and 2,4-diphenyl-4-methyl-1 -pentene.
- Hydrophobic macro-CTAs (where the molecular weight of the CTA is at least 1000 Daltons) can be prepared from hydrophobic polymers synthesised by RAFT (or MADIX) followed by reduction of the chain end, or alternatively the terminal hydroxyl group of a preformed hydrophobic polymer can be post functionalised with a compound such as thiobutyrolactone.
- Hydrophilic CTAs typically contain hydrogen bonding and/or permanent or transient charges.
- Hydrophilic CTAs include but are not limited to thio-acids such as thioglycolic acid and cysteine, thioamines such as cysteamine and thio- alcohols such as 2-mercaptoethanol, 3-mercaptopropanoic acid,thioglycerol and ethylene glycol mono- (and di-)thio glycollate.
- Hydrophilic macro-CTAs (where the molecular weight of the CTA is at least 1000 Daltons) can be prepared from hydrophilic polymers synthesised by RAFT (or MADIX) followed by reduction of the chain end, or alternatively the terminal hydroxyl group of a preformed hydrophilic polymer can be post functionalised with a compound such as thiobutyrolactone.
- Responsive macro-CTAs can be prepared from responsive polymers synthesised by RAFT (or MADIX) followed by reduction of the chain end, or alternatively the terminal hydroxyl group of a preformed responsive polymer, such as polypropylene glycol), can be post functionalised with a compound such as thiobutyrolactone.
- the residue of the chain transfer agent may comprise 0 to 80 mole %, preferably 0 to 50 mole %, more preferably 0 to 40 mole % and especially 0.05 to 30 mole %, of the copolymer (based on the number of moles of monofunctional monomer).
- the initiator is a free-radical initiator and can be any molecule known to initiate free-radical polymerisation such as azo-containing molecules, persulfates, redox initiators, peroxides, phenyl benzyl ketones. These may be activated via thermal, photolytic or chemical means.
- Examples of these include but are not limited to 2,2'-azobisisobutyronitrile (AIBN), azobis(4-cyanovaleric acid), benzoyl peroxide, di-t-butyl peroxide (Luperox® Dl), t-butyl peroxybenzoate, (Luperox® P), cumylperoxide, 1 -hydroxycyclohexyl phenyl ketone, hydrogenperoxide/ascorbic acid. Iniferters such as benzyl-N,N- diethyldithiocarbamate can also be used. In some cases, more than one initiator may be used.
- the initiator may be a macroinitiator having a molecular weight of at least 1000 Daltons. In this case, the macroinitiator may be hydrophilic, hydrophobic, or responsive.
- the residue of the initiator in a free-radical polymerisation comprises 0 to 10% w/w, preferably 0.01 to 10% w/w and especially 0.01 to 8% w/w, of the copolymer based on the total weight of the monomers.
- Hydrophilic macroinitiators (where the molecular weight of the preformed polymer is at least 1000 Daltons) can be prepared from hydrophilic polymers synthesised by RAFT (or MADIX), or the terminal hydroxyl group of a preformed hydrophilic polymer can be post-functionalised with a compound such as 2- bromoisobutyryl bromide for use in Atom Transfer Radical Polymerisation (ATRP) with a suitable low valency transition metal catalyst, such as CuBr Bipyridyl.
- Hydrophobic macroinitiators (where the molecular weight of the preformed polymer is at least 1000 Daltons) can be prepared from hydrophobic polymers synthesised by RAFT (or MADIX), or the terminal hydroxyl group of a preformed hydrophilic polymer can be post-functionalised with a compound such as 2- bromoisobutyryl bromide for use with ATRP.
- Responsive macroinitiators (where the molecular weight of the preformed polymer is at least 1000 Daltons) can be prepared from responsive polymers synthesised by RAFT (or MADIX), or the terminal hydroxyl group of a preformed hydrophilic polymer can be post-functionalised with a compound such as 2- bromoisobutyryl bromide for use with ATRP.
- the monofunctional monomer may comprise any carbon-carbon unsaturated compound which can be polymerised by an addition polymerisation mechanism, for example vinyl and allyl compounds.
- the monofunctional monomer may be hydrophilic, hydrophobic, amphiphilic, anionic, cationic, neutral or zwitterionic in nature.
- the monofunctional monomer may be selected from, but not limited to, monomers such as vinyl acids, vinyl acid esters, vinyl aryl compounds, vinyl acid anhydrides, vinyl amides, vinyl ethers, vinyl amines, vinyl aryl amines, vinyl nitriles, vinyl ketones, and derivatives of the aforementioned compounds as well as corresponding allyl variants thereof.
- Suitable monofunctional monomers include hydroxyl-containing monomers and monomers which can be post-reacted to form hydroxyl groups, acid-containing or acid-functional monomers, zwitterionic monomers and quaternised amino monomers.
- Oligomeric, polymeric and di- or multi-functionalised monomers may also be used, especially oligomeric or polymeric (meth)acrylic acid esters such as mono(alk/aryl) (meth)acrylic acid esters of polyalkyleneglycol or polydimethylsiloxane or any other mono-vinyl or allyl adduct of a low molecular weight oligomer.
- Mixtures of more than one monomer may also be used to give statistical, graft, gradient or alternating copolymers.
- Vinyl acids and derivatives thereof include (meth)acrylic acid, fumaric acid, maleic acid, itaconic acid and acid halides thereof such as (meth)acryloyl chloride.
- Vinyl acid esters and derivatives thereof include C1-C20 alkyl(meth)acrylates (linear & branched) such as methyl (meth)acrylate, stearyl (meth)acrylate and 2-ethyl hexyl (meth)acrylate, aryl(meth)acrylates such as benzyl (meth)acrylate, tri(alkyloxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate and activated esters of (meth)acrylic acid such as N-hydroxysuccinamido (meth)acrylate.
- Vinyl aryl compounds and derivatives thereof include styrene, acetoxystyrene, styrene sulfonic acid, vinyl pyridine, vinylbenzyl chloride and vinyl benzoic acid.
- Vinyl acid anhydrides and derivatives thereof include maleic anhydride.
- Vinyl amides and derivatives thereof include (meth)acrylamide, N-(2-hydroxypropyl)methacrylamide, N-vinyl pyrrolidone, N-vinyl formamide, (meth)acrylamidopropyltrimethyl ammonium chloride, [3-((meth)acrylamido)propyl]dimethyl ammonium chloride, 3-[N-(3- (meth)acrylamidopropyl)-N,N-dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether and N-isopropyl(meth)acrylamide.
- Vinyl ethers and derivatives thereof include methyl vinyl ether.
- Vinyl amines and derivatives thereof include dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, diisopropylaminoethyl (meth)acrylate, mono-t-butylaminoethyl (meth)acrylate, morpholinoethyl(meth)acrylate and monomers which can be post-reacted to form amine groups, such as vinyl formamide.
- Vinyl aryl amines and derivatives thereof include vinyl aniline, vinyl pyridine, N-vinyl carbazole and vinyl imidazole.
- Vinyl nitriles and derivatives thereof include (meth)acrylonitrile.
- Vinyl ketones and derivatives thereof include acreolin.
- Hydroxyl-containing monomers include vinyl hydroxyl monomers such as hydroxyethyl (meth)acrylate, hydroxy propyl (meth)acrylate, glycerol mono(meth)acrylate and sugar mono(meth)acrylates such as glucose mono(meth)acrylate.
- Monomers which can be post-reacted to form hydroxyl groups include vinyl acetate, acetoxystyrene and glycidyl (meth)acrylate.
- Acid- containing or acid functional monomers include (meth)acrylic acid, styrene sulfonic acid, vinyl phosphonic acid, vinyl benzoic acid, maleic acid, fumaric acid, itaconic acid, 2-(meth)acrylamido 2-ethyl propanesulfonic acid, mono-2- ((meth)acryloyloxy)ethyl succinate and ammonium sulfatoethyl (meth)acrylate.
- Zwitterionic monomers include (meth)acryloyloxyethylphosphoryl choline and betaines, such as [2-((meth)acryloyloxy)ethyl] dimethyl-(3- sulfopropyl)ammonium hydroxide.
- Quaternised amino monomers include (meth)acryloyloxyethyltri-(alk/aryl)ammonium halides such as (meth)acryloyloxyethyltrimethyl ammonium chloride.
- Oligomeric and polymeric monomers include oligomeric and polymeric (meth)acrylic acid esters such as mono(alk/aryl)oxypolyalkyleneglycol(meth)acrylates and mono(alk/aryl)oxypolydimethyl-siloxane(meth)acrylates.
- esters include monomethoxyoligo(ethyleneglycol) mono(meth)acrylate, monomethoxyoligo(propyleneglycol) mono(meth)acrylate, monohydroxyoligo(ethyleneglycol) mono(meth)acrylate, monohydroxyoligo(propyleneglycol) mono(meth)acrylate, monomethoxy poly(ethyleneglycol) mono(meth)acrylate, monomethoxy poly(propyleneglycol) mono(meth)acrylate, monohydroxy poly(ethyleneglycol) mono(meth)acrylate and monohydroxy poly(propyleneglycol) mono(meth)acrylate.
- oligomers or polymers formed via ring-opening polymerisation such as oligo(caprolactam), oligo(caprolactone), poly(caprolactam) or poly(caprolactone), or oligomers or polymers formed via a living polymerisation technique such as poly(1 ,4- butadiene).
- monofunctional monomers are:
- Amide-containing monomers such as (meth)acrylamide, N-(2- hydroxypropyl)methacrylamide, N,N'-dimethyl(meth)acrylamide, N and/or N'- di(alkyl or aryl) (meth)acrylamide, N-vinyl pyrrolidone, [3- ((meth)acrylamido)propyl] trimethyl ammonium chloride, 3- (dimethylamino)propyl(meth)acrylamide, 3-[N-(3-(meth)acrylamidopropyl)-N,N- dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether and N-isopropyl(meth)acrylamide;
- (Meth)acrylic acid and derivatives thereof such as (meth)acrylic acid, (meth)acryloyl chloride (or any halide), (alkyl/aryl)(meth)acrylate, functionalised oligomeric or polymeric monomers such as monomethoxyoligo(ethyleneglycol) mono(meth)acrylate, monomethoxyoligo(propyleneglycol) mono(meth)acrylate, monohydroxyoligo(ethyleneglycol) mono(meth)acrylate, monohydroxyoligo(propyleneglycol) mono(meth)acrylatemonomethoxy poly(ethyleneglycol) mono(meth)acrylate, monomethoxy poly(propyleneglycol) mono(meth)acrylate, monohydroxy poly(ethyleneglycol) mono(meth)acrylate, monohydroxy poly(propyleneglycol) mono(meth)acrylate.
- glycerol mono(meth)acrylate and sugar mono(meth)acrylates such as glucose mono(meth)acrylate
- Vinyl amines such as aminoethyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, diisopropylaminoethyl (meth)acrylate, mono-t-butylamino (meth)acrylate, morpholinoethyl(meth)acrylate, vinyl aryl amines such as vinyl aniline, vinyl pyridine, N-vinyl carbazole, vinyl imidazole, and monomers which can be post- reacted to form amine groups, such as vinyl formamide;
- Vinyl aryl monomers such as styrene, vinyl benzyl chloride, vinyl toluene, cc- methyl styrene, styrene sulfonic acid and vinyl benzoic acid;
- Vinyl hydroxyl monomers such as hydroxyethyl (meth)acrylate, hydroxy propyl (meth)acrylate, glycerol mono(meth)acrylate or monomers which can be post- functionalised into hydroxyl groups such as vinyl acetate, acetoxy styrene and glycidyl (meth)acrylate;
- Acid-containing monomers such as (meth)acrylic acid, styrene sulfonic acid, vinyl phosphonic acid, vinyl benzoic acid, maleic acid, fumaric acid, itaconic acid, 2-(meth)acrylamido 2-ethyl propanesulfonic acid and mono-2- ((meth)acryloyloxy)ethyl succinate or acid anhydrides such as maleic anhydride; zwitterionic monomers such as (meth)acryloyloxyethylphosphoryl choline and betaine-containing monomers, such as [2-((meth)acryloyloxy)ethyl] dimethyl-(3- sulfopropyl)ammonium hydroxide;
- Quaternised amino monomers such as (meth)acryloyloxyethyltrimethyl ammonium chloride.
- Functional monomers i.e. monomers with reactive pendant groups which can be post or pre-modified with another moiety following polymerisation can also be used such as glycidyl (meth)acrylate, tri(alkoxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate, triethoxysilylpropyl(meth)acrylate, (meth)acryloyl chloride, maleic anhydride, hydroxyalkyl (meth)acrylates, (meth)acrylic acid, vinylbenzyl chloride, activated esters of (meth)acrylic acid such as N-hydroxysuccinamido (meth)acrylate and acetoxystyrene.
- glycidyl (meth)acrylate tri(alkoxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate, triethoxysilylpropyl(meth)acryl
- Macromonomers are generally formed by linking a polymerisable moiety, such as a vinyl or allyl group, to a pre-formed monofunctional polymer via a suitable linking unit such as an ester, an amide or an ether.
- suitable polymers include mono functional poly(alkylene oxides) such as monomethoxy[poly(ethyleneglycol)] or monomethoxy[poly(propyleneglycol)], silicones such as poly(dimethylsiloxane)s, polymers formed by ring-opening polymerisation such as poly(caprolactone) or poly(caprolactam) or mono- functional polymers formed via living polymerisation such as poly(1 ,4- butadiene).
- mono functional poly(alkylene oxides) such as monomethoxy[poly(ethyleneglycol)] or monomethoxy[poly(propyleneglycol)]
- silicones such as poly(dimethylsiloxane)s
- polymers formed by ring-opening polymerisation such as poly(caprolactone) or poly(caprolactam)
- mono- functional polymers formed via living polymerisation such as poly(1 ,4- butadiene).
- Preferred macromonomers include monomethoxy[poly(ethyleneglycol)] mono(methacrylate), monomethoxy[poly(propyleneglycol)] mono(methacrylate) and mono(meth)acryloxypropyl-terminated poly(dimethylsiloxane).
- Hydrophilic monofunctional monomers include (meth)acryloyl chloride, N- hydroxysuccinamido (meth)acrylate, styrene sulfonic acid, maleic anhydride, (meth)acrylamide, N-(2-hydroxypropyl)methacrylamide, N-vinyl pyrrolidinone, N- vinyl formamide, quaternised amino monomers such as (meth)acrylamidopropyltrimethyl ammonium chloride, [3-
- (meth)acryloyloxyethyltrimethyl ammonium chloride 3-[N-(3- (meth)acrylamidopropyl)-N,N-dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether, glycerol mono(meth)acrylate, monomethoxy and monohydroxyoligo(ethylene oxide) (meth)acrylate, sugar mono(meth)acrylates such as glucose mono(meth)acrylate, (meth)acrylic acid, vinyl phosphonic acid, fumaric acid, itaconic acid, 2-(meth)acrylamido 2-ethyl propanesulfonic acid, mono-2-((meth)acryloyloxy)ethyl succinate, ammonium sulfatoethyl (meth)acrylate, (meth)acryloyloxyethylphosphoryl choline and betaine-containing monomers such as [2-((meth)acryloyloxy)
- Hydrophilic macromonomers may also be used and include monomethoxy and monohydroxypoly(ethylene oxide) (meth)acrylate and other hydrophilic polymers with terminal functional groups which can be post-functionalised with a polymerisable moiety such as (meth)acrylate, (meth)acrylamide or styrenic groups.
- Functional monomers that is, monomers with reactive pendant groups which can be post or pre-modified with another moiety following polymerisation
- glycidyl (meth)acrylate tri(alkoxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate, triethoxysilylpropyl(meth)acrylate, (meth)acryloyl chloride, maleic anhydride, hydroxyalkyl (meth)acrylates, (meth)acrylic acid, vinylbenzyl chloride, activated esters of (meth)acrylic acid such as N-hydroxysuccinamido (meth)acrylate and acetoxystyrene.
- the multifunctional monomer or brancher may comprise a molecule containing at least two vinyl groups which may be polymerised via addition polymerisation.
- the molecule may be hydrophilic, hydrophobic, amphiphilic, neutral, cationic, zwitterionic, oligomeric or polymeric.
- Such molecules are often known as cross- linking agents in the art and may be prepared by reacting any di- or multifunctional molecule with a suitably reactive monomer. Examples include di- or multivinyl esters, di- or multivinyl amides, di- or multivinyl aryl compounds, di- or multivinyl alk/aryl ethers.
- a linking reaction is used to attach a polymerisable moiety to a di- or multifunctional oligomer or polymer.
- the brancher may itself have more than one branching point, such as T-shaped divinylic oligomers or polymers. In some cases, more than one multifunctional monomer may be used.
- Preferred multifunctional monomers include but are not limited to: divinyl aryl monomers such as divinyl benzene; (meth)acrylate diesters such as ethylene glycol di(meth)acrylate, propyleneglycol di(meth)acrylate and 1 ,3- butylenedi(meth)acrylate; polyalkylene oxide di(meth)acrylates such as tetraethyleneglycol di(meth)acrylate, poly(ethyleneglycol) di(meth)acrylate and poly(propyleneglycol) di(meth)acrylate; divinyl (meth)acrylamides such as methylene bisacrylamide; silicone-containing divinyl esters or amides such as (meth)acryloxypropyl-terminated poly(dimethylsiloxane); divinyl ethers such as poly(ethyleneglycol)divinyl ether; and tetra- or tri-(meth)acrylate esters such as pentaerythritol
- oligomers or polymers formed via ring- opening polymerisation such as oligo(caprolactam), oligo(caprolactone), poly(caprolactam) or poly(caprolactone), or oligomers or polymers formed via a living polymerisation technique such as oligo- or poly(1 ,4-butadiene).
- Macrocross-linkers or macrobranchers are generally formed by linking a polymerisable moiety, such as a vinyl or aryl group, to a pre-formed multifunctional polymer via a suitable linking unit such as an ester, an amide or an ether.
- suitable polymers include di-functional poly(alkylene oxides) such as poly(ethyleneglycol) or poly(propyleneglycol), silicones such as poly(dimethylsiloxane)s, polymers formed by ring-opening polymerisation such as poly(caprolactone) or poly(caprolactam) or poly-functional polymers formed via living polymerisation such as poly(1 ,4-butadiene).
- di-functional poly(alkylene oxides) such as poly(ethyleneglycol) or poly(propyleneglycol)
- silicones such as poly(dimethylsiloxane)s
- polymers formed by ring-opening polymerisation such as poly(caprolactone) or poly(caprolactam)
- poly-functional polymers formed via living polymerisation such as poly(1 ,4-butadiene).
- Preferred macrobranchers include poly(ethyleneglycol) di(meth)acrylate, poly(propyleneglycol) di(meth)acrylate, methacryloxypropyl-terminated poly(dimethylsiloxane), poly(caprolactone) di(meth)acrylate and poly(caprolactam) di(meth)acrylamide.
- Branchers include methylene bisacrylamide, glycerol di(meth)acrylate, glucose di- and tri(meth)acrylate, oligo(caprolactam) and oligo(caprolactone).
- Multi end- functionalised hydrophilic polymers may also be functionalised using a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group.
- Further branchers include divinyl benzene, (meth)acrylate esters such as ethyleneglycol di(meth)acrylate, propyleneglycol di(meth)acrylate and 1 ,3- butylene di(meth)acrylate, oligo(ethylene glycol) di(meth)acrylates such as tetraethylene glycol di(meth)acrylate, tetra- or tri- (meth)acrylate esters such as pentaerthyritol tetra(meth)acrylate, trimethylolpropane tri(meth)acrylate and glucose penta(meth)acrylate.
- Multi end-functionalised hydrophobic polymers may also be functionalised using a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group.
- Multifunctional responsive polymers may also be functionalised using a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group such as polypropylene oxide) di(meth)acrylate.
- a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group such as polypropylene oxide) di(meth)acrylate.
- the copolymer In order for the addition copolymers to emulsify and ultimately encapsulate the hydrophobic internal phase the copolymer must be amphiphilic in nature, this can be achieved by using a mixture of hydrophilic and hydrophobic components in the copolymer. Additionally, the copolymer must be able to react post- emulsification, it is preferred that this reaction occurs via a self-condensation reaction via a moiety present in the polymer and this is typically introduced via the use of a functional monomer in the polymer preparation.
- Preferred hydrophobic monofunctional monomers include:
- Preferred hydrophilic monofunctional monomers include:
- (meth)acrylic acid fumaric acid, maleic acid, itaconic acid, N- hydroxysuccinamido (meth)acrylate., acetoxystyrene, styrene sulfonic acid, vinyl pyridine, and vinyl benzoic acid, maleic anhydride, (meth)acrylamide, N-(2- hydroxypropyl)methacrylamide, N-vinyl pyrrolidone, N-vinyl formamide, (meth)acrylamidopropyltrimethyl ammonium chloride, [3-
- ((meth)acrylamido)propyl]dimethyl ammonium chloride 3-[N-(3- (meth)acrylamidopropyl)-N,N-dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether and N-isopropyl(meth)acrylamide, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, diisopropylaminoethyl (meth)acrylate, morpholinoethyl(meth)acrylate, acreolin, poly(ethyleneglycol) (meth)acrylate, hydroxyethyl (meth)acrylate, hydroxy propyl (meth)acrylate, 2-(meth)acrylamido 2-ethyl propanesulfonic acid, (meth)acryloyloxyethyltrimethyl ammonium chloride
- Preferred reactive monofunctional monomers include:
- Preferred polyfunctional monomers or branchers include:
- the branched amphiphilic copolymers are prepared by an addition polymerisation process, preferably a free-radical polymerisation process, which comprises mixing together. (a) at least one ethyleneically monounsatu rated monomer;
- an initiator optionally but preferably a free-radical initiator
- the copolymer is prepared by an addition polymerisation method, which is a conventional free-radical polymerisation technique using a chain transfer agent.
- a monofunctional monomer is polymerised with a multifunctional monomer or branching agent in the presence of a chain transfer agent and free- radical initiator.
- the polymerisations may proceed via solution, bulk, suspension, dispersion or emulsion procedures.
- the present invention relates to the cross-linking of the capsules prepared from an oil-in-water emulsion stabilised with a reactive amphiphilic copolymer which is formed from the subsequent crosslinking of the copolymer.
- the average size of the capsules is smaller than 20 ⁇ , more preferably smaller than 10 ⁇ .
- the capsule has an internal oil phase and is formed in an aqueous bulk phase.
- the capsule comprises an active ingredient, wherein the active ingredient is incorporated in the dispersed phase.
- An oil-in-water emulsion may be prepared using equipment commonly employed for this purpose such as high shear mixers, or homogenisers, or any other commonly known apparatus.
- An oil or hydrophobic material is slowly poured into an aqueous solution of the polymer. By the mixing process the oil droplets are evenly dispersed, and the polymer will act as emulsifier which keeps the emulsion stable.
- the invention also provides a method of preparing a capsule, comprising a step wherein the preferred copolymer also according to an aspect of the present invention is mixed with a hydrophobic liquid at conditions where at least one of the monounsaturated monomer(s) and polyunsaturated monomer(s) and chain transfer agent do not form a non-covalent bond with any other of the monounsaturated monomer(s) and polyunsaturated monomer(s) and chain transfer agent. Under these conditions the polymer is in a non-interacting form.
- the hydrophobic liquid may contain an active ingredient.
- the emulsion is then crosslinked through a change in pH and via a sol-gel reaction of the trialkoxysilyl units present in the copolymer.
- CTAs Chain Transfer Agents
- T-SEC Triple-Detection Size-Exclusion Chromatography
- Emulsion droplet diameters and diameter distributions were measured using a Malvern Mastersizer 2000 equipped with a Hydro 2000 SM dispersion unit. A drop of emulsion was added to the dispersion unit containing approximately 100 ml_ water with a stirring rate of 1 150 rpm.
- the span is a measure of the distribution of the droplet size distribution and is expressed mathematically as:
- D(0.5) is the diameter under which 50% of the particles fall
- D(0.1 ) is the diameter under which 10 % of the particles fall.
- PEGMA 5 molar equivalents, 0.233g
- TMSPMA 95 molar equivalents, 1 .00g
- branching monomer ELDMA, 10 molar equivalents, 0.084g
- chain transfer agent DDT, 10 molar equivalents, 0.086g
- anhydrous methanol 14ml_
- Linear addition copolymers were prepared by an analogous synthetic procedure to the branched addition copolymers in the absence of an ethylenically polyunsaturated monomer (also referred to as a multifunctional monomer or brancher) for example EGDMA.
- EGDMA ethylenically polyunsaturated monomer
- Subscripts represent target molar equivalences.
- the copolymer emulsifier (BP1 ) was dissolved at 3 w/v % in cineole. An equal volume of distilled water was added and the biphasic mixture sheared for 2 minutes using a T 25 digital Ultra-Turrax homogeniser operating at 24,000 rpm. The resulting oil-in-water emulsion was allowed to rest for 20 minutes after which time they were characterised by light microscopy and laser diffraction to ensure stability.
- the reactive copolymer emulsifier was cross-linked at the droplet periphery by diluting (typically 2ml_ of emulsion into 30 ml_ distilled water), stable droplets followed by addition of triethylamine (nominally 1 ml_ to the above volumes) with gentle stirring.
- the cross-linked droplets were characterized by laser diffraction and light microscopy to ensure that no destabilisation occurred during the cross-linking process.
- the cross-linked droplets could be flushed by the addition of ethanol until the dispersion turned transparent to the eye.
- Loaded BP1 capsules were prepared using an identical procedure, however the desired encapsulate (exemplified here using either a hydrophobic fluorescent dialkylcarbocyanine dye, DiO or poly(vinylstearate)) was first dissolved in cineole prior to emulsification in the desired concentration.
- desired encapsulate exemplified here using either a hydrophobic fluorescent dialkylcarbocyanine dye, DiO or poly(vinylstearate)
- Figure 1 depicts three graphs illustrating droplet size distributions of:
- TMSPMA/MAA capsules were imaged by digital camera and light microscopy at pH 10, pH 2 and reverting back to pH 10. These images revealed clear aggregation and de-aggregation in response to the addition of acid and base, respectively. pH-responsivitv of TMSPMA/PEGMA capsules
- Emulsion droplets stabilised with the TMSPMA 95 /MAA 5 EGDMA-10D DT-10 branched copolymer (BP3) were prepared as above (3 w/v % polymer in cineole using distilled water) and allowed to 'cream', that ism the emulsion was allowed to separate for 24 hours at room temperature into an oil rich top phase on top of an aqueous phase.
- the droplets were purified by 3 centrifugation-redispersion cycles to remove excess polymer surfactant. Dropping the resulting emulsion into neutral/basic water immediately dispersed the droplets.
- the creamed emulsion droplets were dropped into acidic water (HCI, 1 M) where they cross- linked within 5 seconds to give spheres.
- the sphere sizes were controlled by the volume of emulsion dripped and could be decanted into ethanol solution to flush out the internal oil and remaining water.
- Different shaped aggregates could be prepared by varying the conditions under which the droplets were acidified and by using templates. The spheres could then be redispersed in water and were shown to swell and contract on addition of base (pH 10) and acid (pH 2), respectively.
- Material may be encapsulated within the inter-capsule conjoined monoliths by dissolution or dispersion within the oil prior to emulsion formation.
- the dissolved/dispersed material is preferably hydrophobic and not substantially surface active.
- Figure 2 there is illustrated spheroidal monoliths comprising multiple conjoined capsules, (a) Following cross-linking in water, (b) following cross- linking and washing out the internal oil and water phase (in ethanol) and (c) encapsulating a hydrophobic dye following cross-linking to produce encapsulating spheroidal monoliths of different size.
- TMSPMA95/MAA5EGDMA-10DDT-10 branched copolymer (BP3) was dissolved in cineole oil (0.05 w/v % in 3ml_) and homogenised with an equal volume of an aqueous solution of a conventional (non-reactive) aqueous surfactant solution (sodium dodecyl sulphate, 1 .0 w/v %).
- Triethylamine typically, a nominal concentration of 30 volume/volume % of total oil used
- linear and branched addition copolymers may be prepared which may emulsify and ultimately encapsulate a hydrophobic payload.
- the process is essentially achieved in two steps, firstly the addition copolymer acts as an emulsifier to typically provide an oil-in-water emulsion where the copolymer stabilises the micellar structure.
- a second step is then preformed whereby a cross-linking reaction takes place between the copolymer emulsifier molecules to render a cross-linked capsule. If cross-linking is restricted to the same capsule discrete capsules with dimensions commensurate with the initial emulsion droplet are produced.
- the copolymer can be prepared via a one-step process utilising monofunctional monomers, polyfunctional monomers and a chain transfer agent.
- monofunctional monomers polyfunctional monomers
- chain transfer agent In order for the branched addition polymer to emulsify the hydrophobic oil it must be amphiphilic in nature, this is achieved through the choice of hydrophobic monomers, multifunctional monomers or chain transfer agents.
- the post-emulsification cross-linking reaction occurs intramolecularly, that is between adjacent emulsifier molecules at the oil-water interface, without the addition of an additional cross-linker molecule. This can occur through choice of a suitable functional monomer in the copolymer synthesis, that is a monomer which can self-cross-link through a change in, for example, solution pH.
- Figure 3 depicts emulsion and capsule formation using the amphiphilic addition copolymers. That is, Figure 3 is a schematic representation of the formation of discrete capsules and conjoined capsules depicted in Figure 3 by steps 1 to 4.
- 'A' represents one emulsion phase, typically oil.
- 'B' represents a second emulsion phase, typically water.
- step 1 The self-cross-linking branched addition copolymer is initially dissolved or dispersed in one phase (optionally both).
- step (1 ) an energy input forms a multi-phased emulsion in which the self-cross-linking addition copolymer is located at the interface.
- step 2 the emulsion is retained in a disperse state and is self-cross-linked to give a discrete capsule (step 3).
- step 3 The discrete capsule may be optionally washed out using a mutually good solvent for each phase (C) to give hollow capsule.
- step 4 the emulsion is concentrated in terms of the volume fraction of the internal phase and is self-cross-linked to give conjoined capsules where the reactive residues react both around the same droplet and between droplets to form a monolith (step 3).
- the conjoined capsule monoliths may be optionally washed out using a mutually good solvent for each phase (C) to give hollow conjoined capsule monoliths.
- the inventors have found that whilst it is possible to form capsules according to the present invention from both linear and branched addition copolymers, the linear polymers LP1 /LP2 form less stable emulsions and therefore less stable capsules.
- branched addition copolymers BP1 to BP3 form more stable emulsions and hence more stable capsules. That is, the efficiency of forming stable capsules is improved with branched addition copolymers.
- Figure 4 which demonstrates normalized kinetic experiments monitoring the change in volume-averaged droplet diameters of the branched and linear copolymer stabilized uncross-linked and crosslinked droplets as a function of time it can be seen that, the increased stability of branched emulsions over linear systems.
- the linear, un-crosslinked emulsions show reduced kinetic stability, although if crosslinked just after formation, the stability (size) of the emulsion droplets is locked-into the structure and there is no reduction in volume-averaged droplet size over time.
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Abstract
The present invention relates to statistical amphiphilic branched addition copolymers, methods for their preparation, and their use in the formation of covalently linked capsules wherein the copolymers are able to emulsify and ultimately self-condense to form covalently cross-linked capsules capable of containing active agents.
Description
BRANCHED ADDITION COPOLYMERS AND THEIR USE
The present invention relates to the use of reactive amphiphilic branched addition copolymers in the preparation of covalently cross-linked capsules via emulsion-templated encapsulation, a method for preparing same, and the use of the resultant capsules in the encapsulation of compounds. More specifically, the present invention relates to the use of reactive amphiphilic branched addition copolymers in the preparation of covalently cross-linked capsules to encapsulate compounds such as for example: pharmaceuticals or agrochemicals; nutritional agents such as vitamins; cosmetics, catalysts, dyes, pigments, flavours, biocides, fragrances, lubricating oils, emollients, reactive resins, natural oils and waxes, and use with paints, inks, coatings, sealants, and as tissue engineering scaffolds.
There is currently a high demand for the encapsulation of 'active' materials (that is, materials of interest) in order to protect, isolate and deliver a payload or carrier within or from a formulation. The encapsulation of active materials, typically hydrophobic compounds potentially in combination with an inert carrier, is typically achieved by the formation of a physically or chemically-linked shell around the payload. This can be achieved by, for example, the formation of an oil-in-water emulsion followed by an intra-molecular cross-linking reaction at the oil/water interface.
These cross-linked capsules can be prepared with additional functionalities present on the surface of the capsule or within the cross-linked structure, which can lead to further advantages such as enhanced surface recognition, responsive assembly and disassembly or the ability of the capsule to rupture when exposed to an external stimulus such as a change in temperature, pH, ionic strength, electromagnetic radiation or via a further chemical change.
In some cases the internal phase present within the capsules can be washed or leached out to provide hollow casings which can then be used as a further depository for an additional active compound or the casings can be utilised as a
hollow void in their own right, such as to provide a sink for hydrophobic materials or as fillers in, for example, the preparation of composite materials.
Current emulsion encapsulation methodologies are typically achieved via the formation of stable emulsion droplets wherein an active material is dissolved or dispersed within the emulsifier-stabilised droplets. Typically, the emulsion droplets are reacted further to achieve a cross-linked particle or alternatively an additional cross-linker material, which may be present either within the encapsulated droplet or external to the emulsion droplet, is reacted to give a cross-linked shell. A common procedure to achieve encapsulation is through the use of a sol-gel reaction of an alkoxysilane. In this methodology a stable emulsion is formed where an alkoxysilane, such as tetraethoxysilane, is emulsified in addition to a hydrophobic active or carrier material, following introduction of a base into the aqueous bulk phase an interfacial cross-linking reaction takes place whereby a silicate shell is formed at the oil-water interface giving rise to a cross-linked capsule. This methodology is particularly inefficient as a large amount of alkoxysilane must be used in order to achieve efficient shell formation in addition to undesirable non-controlled formation of cross- linked particles within and external to the capsule. In addition, the emulsion droplets, once formed, must be reacted swiftly as the alkoxysilane is hydrolytically unstable and there is also the possibility of reaction with a reactive hydrophobic active or carrier payload. Furthermore the multi-component nature of this synthesis complicates scale-up processes and can impact on the reproducibility of the synthesis.
An alternative mechanism to achieve cross-linked particles is via the direct physical or chemical cross-linking of the emulsifying agent. In many of these strategies, the emulsifier of choice is a block copolymer, where the self- assembly of the block copolymer leads to the efficient formation of the emulsion droplet. The subsequent cross-linking reaction is typically via the formation of an intermolecular covalent bond between copolymer chains at the same oil/water interface to achieve an intramolecularly cross-linked capsule. The initial emulsion droplet template is stabilised by the amphiphilic block copolymer, though unfortunately the tedious synthesis of these controlled
polymer structures and the common use of toxic small molecule cross-linking agents, in addition to the subsequent clean-up steps post-reaction, renders these methodologies unsuitable for non-specialised applications. In addition, block copolymer stabilised droplets can also suffer from instability issues where droplet coalescence and demulsifications occur.
The inventors have now found a method for obtaining cross-linked emulsion capsules through the use of reactive amphiphilic branched addition copolymer emulsifiers where post-emulsification cross-linking can be achieved through reaction of an inherent moiety within the polymer structure.
Previously, the inventors have shown that branched addition copolymers can be designed to be efficient emulsion stabilisers. Additionally, the structures of these polymers can be tuned to allow demulsification and also emulsion droplet aggregation and de-aggregation via an external trigger, such as a change in pH. The use of reactive amphiphilic copolymer emulsifiers to form stable emulsion droplets followed by a post-emulsification reaction has now been shown to provide an industrially viable route to encapsulation of actives.
Preferably, encapsulation proceeds through reaction of suitable moieties on the copolymer chains without the addition of a cross-linker. In addition, the reaction preferably occurs via an intramolecular 'self-cross-linking' reaction between addition copolymers at the same oil/water interface. The branched addition copolymer emulsifiers can also be used in conjunction with other non-reactive emulsifiers. The capsules formed can be further post-modified with reagents to provide, for example, increased stability or surface recognition. Reactive links can be introduced into the cross-linked structure in order to facilitate rupturing of the capsules upon demand, for example via a change in temperature or pH. Similarly, the capsules can be cross-linked together to give higher order structures such as "beads" or monoliths where the emulsion droplets have been aggregated prior to the final cross-linking step. Once formed, the contents of the capsules can also be removed by a washing material to obtain hollow receptacles suitable for filling with other active materials, or for use in their own
right in for example composites where they could be utilised as an additive to alter the opacity, dielectric constant or strength of a composite, coating or film.
The reactive amphiphilic branched addition copolymers of the present invention are statistical, that is to say, random in structure. The distribution of the comonomers in the polymer structure is not controlled and is determined through factors such as relative monomer concentrations and their respective reactivity ratios. This negates the requirement to use controlled polymerisation techniques to achieve, for example, block copolymer structures or to control their molecular weights or polydispersities. Additionally, the polymerisation is through a conventional free-radical technique. These two properties result in a robust and industrially applicable polymerisation method.
Branched Polymers
Branched polymers and copolymers are polymer molecules of a finite size which are branched. Branched polymers are soluble and differ from cross-linked polymer networks which tend towards an infinite size having interconnected molecules and which are generally not soluble but often swellable. In some instances, branched polymers have advantageous properties when compared to analogous linear polymers. For instance, solutions of soluble branched polymers are normally less viscous than solutions of analogous linear polymers. Moreover, higher molecular weights of branched copolymers can be solubilised more easily than those of corresponding linear polymers. Also, branched copolymers tend to have more end groups than a linear polymer and therefore generally exhibit strong surface-modification properties. Thus, branched copolymers are useful components of many compositions utilised in a variety of fields.
Branched polymers are usually prepared via a step-growth mechanism through the polycondensation of monomers and are usually limited via the chemical functionality of the resulting polymer and the molecular weight. In an addition polymerisation process, a one-step process can be used in which a multifunctional monomer is used to provide functionality in the polymer chain from which polymer branches may grow. However, a limitation on the use of
conventional one-step processes is that the amount of multifunctional monomer must be carefully controlled, usually to substantially less than 0.5% w/w in order to avoid extensive cross-linking of the polymer and the formation of insoluble gels or hydrogels. It is difficult to avoid cross-linking using this method, especially in the absence of a solvent as diluent and/or at high conversion of monomer to polymer.
The reactive amphiphilic branched addition copolymers in the present invention are soluble materials, that is they form isotropic solutions in hydrophilic or hydrophobic solvents, which have been designed to emulsify hydrophobic materials in an aqueous bulk medium and undergo chemical cross-linking reaction to yield capsules. The encapsulated phase is typically hydrophobic in nature and the encapsulation procedure consists of forming a stable oil-in-water emulsion followed by a post-emulsification reaction to yield a cross-linked capsule. The cross-linking reaction takes place via a reaction with another reactive cross-linking molecule or reactive addition copolymer emulsifier chain either at the same interface to form capsules or with an adjacent capsule to form higher scale monoliths.
The ability of addition copolymers to be designed to efficiently emulsify and further react to efficiently encapsulate active materials or form cross-linked capsules is of great industrial benefit.
In order to form capsules, an oil-in water emulsion must first be formed where the hydrophobic active is stabilised in an aqueous medium in the form of a micelle. Many cosmetic, pharmaceutical or food products are in the form of emulsions, either as a dispersed hydrophobic phase in a continuous phase (oil- in-water or o/w), or as a hydrophilic phase dispersed in a continuous hydrophobic phase (water-in-oil or w/o) or as double emulsions, so-called water-in-oil-in-water (w/o/w) or the converse oil-in-water-in-oil (o/w/o). The formation of stable emulsions requires the use of materials which can adsorb at the biphasic interface and prevent coalescence or demulsification of the droplets. Amphiphilic molecules such as surfactants or polymeric surfactants are typically used for the stabilisation of, for example, oil-in-water emulsions as
one part of the surfactant interacts with the oil phase and the other interacts with the water phase. These types of emulsions have considerable disadvantages such as their kinetic instability, low foaming and irritancy due to the surfactant molecules, to name but a few.
Emulsions stabilised with inorganic or organic particles have been shown to have excellent stability, low foaming and reduced irritancy. Typically, these emulsions are formed by the use of finely divided inorganic particles such as silica, alumina, metal oxides etc. The driving force for particles stabilising an interface is the reduction in free energy as the particle adsorbs. In many cases particle-stabilised emulsions are extremely stable as the energy required to remove the particle from the surface is large, in some instances the particles which stabilise an emulsion droplet can be considered to be irreversibly adsorbed. Such particles are referred to as particulate, Pickering or Ramsden emulsifiers and are commonly inorganic species. Additionally, organic particles have been investigated for use as Pickering emulsifiers.
Hydrophobic actives, such as drugs and fragrances, are often only useful if they can be stabilised in hydrophilic environments for sustained periods of time, such as in the body or in aqueous home and personal care formulations. Consequently significant efforts have been made towards developing suitable vehicles for such actives. In this context, self-assembled polymer structures, such as micelles, have received significant attention due to their functionality and size.
Following the emulsification of the hydrophobe, encapsulation follows to provide crosslinked capsules.
WO2008/071661 describes the use of branched addition copolymers in the formation of oil-in-water emulsions. The polymers are amphiphilic in nature and are comprised of a monofunctional monomer, a brancher and a chain transfer agent. The branched addition copolymers of the invention must contain a hydrophilic monofunctional monomer with a molecular weight of at least 1 ,000 Daltons.
WO2009/144471 discloses the use of branched addition copolymers in the formation of oil-in-water emulsions capable of aggregating and de-aggregating. The copolymers in question stabilise a hydrophobic oil in an aqueous environment and are capable of associating and disassociating via an external trigger such as hydrogen-bonding via a change in pH.
WO2008/079677 describes the encapsulation of hydrophobic actives via linear amphiphilic block copolymers prepared via nitroxide-mediated controlled radical polymerisation. The encapsulation occurs via association of the active compound with a crystallising or associating component in the amphiphilic block copolymer.
Therefore according to a first aspect of the present invention there is provided a statistical amphiphilic branched copolymer obtainable by an addition polymerisation process, wherein the copolymer comprises:
at least two chains which are covalently linked by a bridge other than at their ends;
wherein the two chains comprise at least one ethyleneically monounsatu rated monomer, and
wherein the bridge comprises at least one ethyleneically polyunsaturated monomer, and
wherein the copolymer comprises a residue of a chain transfer agent and a residue of an initiator, and
wherein at least one of the ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent is a hydrophilic residue; and at least one of one of the ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent is a hydrophobic residue, and
wherein the mole ratio of ethyleneically polyunsaturated monomer(s) to ethyleneically monounsaturated monomer(s) is between a range of from 1 :100 to 1 :4,
and wherein at least one of ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent
comprises a moiety of Formula 1 that is capable of further reacting to form covalent bonds with any other mutually reactive moieties present via a sol gel process,
Formula (1 )
H2C=C(R1 )-C(0)-0-R2-Si(OR3)3
wherein in Formula 1 :
R1 comprises H or an optionally substituted alkyl group; and
R2 and R3 comprise an optionally substituted alkyl group.
Preferably in the statistical amphiphilic branched addition copolymer R1 may comprise H or CH3. Also, in the statistical amphiphilic branched addition copolymer R2 may comprise an optionally substituted alkyl group of formula (CH2)n where n is 2 to 5.
Further in the statistical amphiphilic branched addition copolymer n may be 3.
It is also preferred that in the statistical amphiphilic branched addition copolymer R3 may comprise an optionally substituted methyl or ethyl group.
It is further preferred that the statistical amphiphilic branched addition copolymer is capable of self-crosslinking to form a capsule around a hydrophobic material in an aqueous medium via a change in solution pH.
It is preferred in the statistical amphiphilic branched addition copolymer according that at least one of ethyleneically monounsaturated monomer(s) and ethyleneically polyunsaturated monomer(s) and chain transfer agent comprises a moiety that is capable of forming a covalent bond via a sol-gel process.
According to a second aspect of the present invention there is provided the use of a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention in the formation of an oil and water emulsion wherein the amphiphilic branched addition copolymer is used to stabilise the oil/water interface and allow droplet formation and wherein the crosslinking
moieties present on the copolymers react at the same oil/water interface and between adjacent interfaces to form capsules.
For the use it is preferred that for the statistical amphiphilic branched addition copolymer the cross-linking reaction takes place between adjacent amphiphilic branched addition copolymers at the same oil/water interfaces to form conjoined capsules.
For the use it is also preferred that for the statistical amphiphilic branched addition copolymer the cross-linking reaction takes place between adjacent amphiphilic branched addition copolymers at the same oil/water interfaces to form discrete capsules.
For the use it is also preferred that for the statistical amphiphilic branched addition copolymer the cross-linking reaction takes place between amphiphilic copolymers at adjacent oil/water interfaces to form cross-linked monoliths.
According to a third aspect of the present invention there is provided a capsule comprising a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention wherein the cross-linking moieties present in the copolymers are cross-linked to form capsules.
The capsule may incorporate an active ingredient. The active ingredient may comprises a bioactive compound selected from the group comprising:
pharmaceuticals or agrochemicals, nutritional agents, cosmetics, catalysts, dyes, flavours, fragrances, emollients, natural oils.
The active ingredient may also comprises a non-bioactive compound selected from the group comprising:
cosmetics, catalysts, dyes, pigments, flavours, fragrances, lubricating oils, emollients, natural oils, waxes and inks.
Further, the capsule may associate and dissociate via hydrogen-bonding.
In addition, the active ingredient may be expelled to yield a hollow capsule.
Furthermore, the surface of the capsule may be post-modified with additional functional groups.
According to a fourth aspect of the present invention there is provided a method of preparing a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention by an addition polymerisation process, which comprises mixing together:
(a) at least one ethyleneically monounsatu rated monomer;
(b) from 1 to 25 mole% (based on the number of moles of ethyleneically monofunctional monomer(s)) of at least one ethyleneically polyunsaturated monomer;
(c) a chain transfer agent; and
(d) an initiator;
and subsequently reacting said mixture to form a branched copolymer.
It is preferred that in the method of preparing a statistical amphiphilic branched addition copolymer by an addition polymerisation process, the polymerisation process comprises a free-radical polymerisation process, and wherein the initiator comprises a free-radical initiator.
According to a fifth aspect of the present invention there is provided the use of a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention to encapsulate an active ingredient wherein the active ingredient is a bioactive compound selected from the group comprising: pharmaceuticals, agrochemicals; nutritional agents such as vitamins; biocides, cosmetics, catalysts, dyes, flavours, fragrances, emollients, natural oils, and inks.
Also according to a fifth aspect of the present invention there is provided the use of a statistical amphiphilic branched addition copolymer according to the first aspect of the present invention to encapsulate an active ingredient wherein the active ingredient is a non-bioactive compound selected from the group
comprising: cosmetics, catalysts, dyes, pigments, flavours, fragrances, reactive resins, lubricating oils, emollients, natural oils and waxes.
Also the use of the statistical amphiphilic branched addition copolymer according to first aspect of the present invention may extend to the encapsulation of an active ingredient wherein the active ingredient is used in paints, inks, coatings or sealants.
Furthermore, the use of the statistical amphiphilic branched addition copolymer according to first aspect of the present invention may extend to the encapsulation of an active ingredient for use in tissue engineering scaffolds. Definitions
Throughout the text, reference to copolymers in the context of the present invention means statistical amphiphilic branched addition copolymers.
The following definitions pertain to chemical structures, molecular segments and substituents:
The ethyleneically monounsatu rated monomer is also referred to as 'monofunctional monomer'. The ethyleneically polyunsaturated monomer is referred to as 'multifunctional monomer' or brancher.
The term 'alkyl' as used herein refers to a branched or unbranched saturated hydrocarbon group which may contain from 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl etc. More preferably, an alkyl group contains from 1 to 6, preferably 1 to 4 carbon atoms. Methyl, ethyl and propyl groups are especially preferred. 'Substituted alkyl' refers to alkyl substituted with one or more substituent groups. Preferably, alkyl and substituted alkyl groups are unbranched.
Typical substituent groups include, for example, halogen atoms, nitro, cyano, hydroxyl, cycloalkyl, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonato, arylsulfinyl, arylsulfonyl, arylsulfonato, phosphinyl, phosphonyl, carbamoyl, amido, alkylamido, aryl, aralkyl and
quaternary ammonium groups, such as betaine groups. Of these substituent groups, halogen atoms, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, carboxyl, amido and quaternary ammonium groups, such as betaine groups, are particularly preferred. When any of the foregoing substituents represents or contains an alkyl or alkenyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4, carbon atoms. A cycloalkyl group may contain from 3 to 8, preferably from 3 to 6, carbon atoms. An aryl group or moiety may contain from 6 to 10 carbon atoms, phenyl groups being especially preferred. A halogen atom may be a fluorine, chlorine, bromine or iodine atom and any group which contains a halo moiety, such as a haloalkyl group, may thus contain any one or more of these halogen atoms.
Terms such as '(meth)acrylic acid' embrace both methacrylic acid and acrylic acid. Analogous terms should be construed similarly.
Terms such as 'alk/aryl' embrace alkyl, alkaryl, aralkyl (e.g. benzyl) and aryl groups and moieties.
Molar percentages are based on the total monofunctional monomer content. Molecular weights of monomers and polymers are expressed as weight average molecular weights, except where otherwise specified.
Detailed description
Reactive amphiphilic branched addition copolymers of the present invention are capable of stabilising and further cross-linking emulsion droplets in order to form capsules. The emulsions stabilised may be oil-in-water or water-in-oil, or so- called double emulsions. The copolymers stabilise the emulsions efficiently at low dose without the need of additional co-stabilisers or surfactants. Once formed, the emulsifier can be chemically cross-linked to give a shell around the encapsulated species or actives, this process can be achieved via reaction of functional moieties present in the copolymer chains. A particularly useful type of encapsulating procedure is to utilise an addition copolymer containing a functionality that can be further reacted to give a cross-linked capsule, such as branched addition copolymer containing trialkoxysilyl units, such as
trimethylsiloxane moieties, which can be further reacted with each other to give a silica shell around the capsule.
Type of polymer used
Amphiphilic branched addition copolymers can be used to stabilise oil-in-water emulsions, in particular branched variants are especially useful as they have been shown to form extremely stable emulsions at low dose due to their high molecular weight, branched architectures and specific chemical compositions. As has already been shown, these materials effectively stabilise oil-in-water emulsions more effectively than equivalent linear materials. The inclusion of a trialkoxysilyl-functional monomer such as trimethoxysilylpropylmethacrylate in the copolymer structure results in a functional emulsifier which can self-crosslink under basic or acidic conditions to give a covalently bonded capsule without the need for a further reactive molecule or subsequent chemical steps. A further advantage of the invention is the facile preparation of the amphiphilic branched addition copolymers with the ability to tune their functionality through choice of polymer constituents such as monomers, and where applicable chain transfer agents for example.
To achieve this, the addition copolymer of the present invention must have the following attributes:
These structural features are typically associated within the copolymer structure via the choice of functional monomers, and where applicable, branchers or chain transfer agents or combinations thereof.
Amphiphilicity:
The branched addition copolymer must be amphiphilic, containing moieties capable of associating with the internal and bulk phase of the emulsion; that is the copolymer must contain hydrophilic and hydrophobic units within the copolymer structure. Hydrophobicity is typically achieved by using hydrophobic monomers such as alkyl-functional monomers such as an alkyl methacrylate, and/or via a hydrophobic chain transfer agent such as an alkyl mercaptan such as dodecanethiol. Additionally, the copolymer must have hydrophilic
functionality, again typically achieved by the use of hydrophilic monomers, for example the monomer could be neutral for example polyethyleneglycol- functional monomers such as mono-methoxypoly(ethyleneglycol) methacrylate or the monomer could be charged in nature such as acrylic or methacrylic acid. The hydrophilic unit can be responsive in nature whereby the hydrophilicity can be altered by an external stimulus such as pH or temperature, such as in the case of N-isopropylacrylamide. The hydrophilic and hydrophobic units could also be introduced through the brancher or chain transfer agent where applicable, such as in the formation of branched addition copolymers.
Functionality:
The addition copolymer must also possess a functional group or groups which are capable of reacting to give a covalent bond and therefore provide a cross- linked capsule. A preferred route is the intramolecular self-cross-linking of the copolymers where the functionality is introduced during the polymerisation process by the incorporation of a suitable functional monomer.
Self-reacting groups include for example: alkoxysilane-functional monomers such as trimethoxysilylpropylmethacrylate where the crosslinking occurs via a sol-gel process, which is particularly preferred.
Branched addition polymers for emulsion encapsulation
Branched addition polymers have been shown to efficiently emulsify and ultimately cross-link a hydrophobic internal phase to form capsules or aggregated cross-linked structures. In order for the branched addition polymers to be suitable for use in encapsulation technologies the polymer must possess a number of structural components. Predominantly the branched addition copolymers are used to emulsify, and ultimately encapsulate, a hydrophobic oil in an aqueous bulk phase. Essentially the branched addition polymer must be capable of forming a stable emulsion which can then be further reacted to give a stable cross-linked capsule. If this reaction can occur intramolecularly, it is preferred that it occurs without the addition of a further functional monomer; that is the branched addition copolymer emulsifier contains a functional group which can self-react to give a cross-linked shell around the capsule.
Post emulsification - self condensation
Where the post-emulsification cross-linking reaction takes place through reaction of functional groups already present within the copolymer emulsifiers the encapsulation procedure can occur efficiently without the need for additional, commonly toxic, cross-linkers. Thus the copolymer acts as both emulsifier and cross-linker in one function. Additionally, the emulsion or capsule can be further chemically reacted post-emulsification, or post- encapsulation, to give further chemical species at the surface of the emulsion or capsule which may be of benefit, for example in improved substrate affinity. Self-cross-linking can occur between copolymer residues on the same interface to form capsules or between copolymer emulsifiers on adjacent interfaces to form monoliths.
The amphiphilic addition copolymers of the current invention can also be used in combination with non-functional small molecule or polymeric emulsifiers. In these cases an emulsion prepared in accordance with the present invention comprises both reactive and non-reactive emulsifiers; post treatment of these emulsions results in capsule formation via the cross-linking of the reactive emulsifier species. This is of particular advantage where further functionality needs to be introduced in a capsule via the use for example of a non-functional emulsifier. Additionally, the cost of preparing the capsules can be reduced by the use of commodity surfactants or emulsifiers with only minimal changes to existing formulation procedures being required.
The internal payload of the capsules, typically hydrophobic oils, can be washed- out of the capsules following capsule formation by extraction with one or more suitable solvents, such as an alcohol, to leave hollow capsules. The hollow capsules can then be re-filled with a further payload or utilised as hollow spheres, for example, for sequestration. The hollow spheres can be dried completely and used in composite formations where they provide improved mechanical strength or impart and increased relative permittivity or dielectric constant for use in electrical or electronic applications. Where a high molecular weight material is incorporated into the capsule in combination with a suitable
carrier oil, during encapsulation, extraction of the internal phase leaves hollow capsules containing a precipitated polymer akin to a baby's rattle.
Where the branched addition copolymers have associating functionality, such as H-bonding groups, they may aggregate in solution upon application of an external trigger such as in the case of capsules decorated with carboxylic acid functionality. In this case, the formed capsules may assemble via hydrogen- bonding (with inherent changes in hydrophobicity) when below the pKa of the acid group and reversibly disassemble upon the application of an increase in pH.
The encapsulation of hydrophobic actives is of industrial relevance where a hydrophobic component is required to be delivered from, formulated in or isolated from an aqueous environment. For example the cross-linked capsule may protect an active compound from a hydrophilic formulation where the bulk aqueous environment can lead to degradation of the hydrophobic material or is, for example, rich in additional surfactants which can affect the performance of the hydrophobic active. The capsule may also be post-modified in order to improve the selectivity of the capsule, such as the covalent attachment of surface-substantive or bio-active materials, for example in the specific delivery of pharmaceutical agents. The capsules may also be designed to assemble and disassemble upon changes in the aqueous environment, such as pH, this is particularly desirable in the preparation of a "capsule concentrate" in the associated form for transportation purposes and formulation dilution at the required destination, that is 'on-site'. The payload of the capsule can also be washed-out to yield hollow spheroids which can be filled or used in their own right as, for example, in composite materials. Examples include but are not limited to: the encapsulation of bioactive compounds such as pharmaceuticals or agrochemicals; nutritional agents such as vitamins; cosmetics, biocides, reactive resins, catalysts, dyes, pigments, flavours, fragrances, lubricating oils, emollients, natural oils and waxes and their use with paints, inks, coatings and sealants and in tissue engineering scaffolds.
When the amphiphilic copolymers according to the present invention are branched, the branched, non-cross-linked addition polymers may include statistical, graft, gradient and alternating branched copolymers. The copolymers comprise at least two chains which are covalently linked by a bridge other than at their ends, is to be understood as a polymer wherein a sample of said polymer comprises on average at least two chains which are covalently linked by a bridge other than at their ends. When a sample of the polymer is made there may be accidentally some polymer molecules which are unbranched, which is inherent to the production method (addition polymerisation process). For the same reason, a small quantity of the polymer will not have a CTA on the chain end.
The hydrophilic monomer may be of high molecular weight, such that at least one of the monofunctional and multifunctional monomers and the chain transfer agent is a hydrophilic residue having a molecular weight of at least 1000 Daltons. Preferably, the hydrophilic component is derived from the multifunctional monomer, more preferably from the chain transfer agent (during conventional free-radical polymerisation) or the initiator, but most preferably from a monofunctional monomer. In all cases, a combination of hydrophilic components is possible and may be desirable.
Higher molecular weight hydrophobic species are typically more hydrophobic than lower molecular weight hydrophobic species. Preferably, the hydrophobic component is derived from the multifunctional monomer, more preferably from the chain transfer agent (during conventional free-radical polymerisation) or the initiator, but most preferably from a monofunctional monomer. In all cases, a combination of hydrophobic components is possible and may be desirable.
Linear polymer definition
Linear polymers are formed from the free-radical addition polymerisation of a monofunctional monomer(s) a radical initiator and optionally a chain transfer agent. The monofunctional monomer(s) typically introduce the hydrophilicity and functionality of the resulting copolymer, where a chain transfer agent is used it
can introduce the required hydrophobicity of the resulting copolymer by, for example, using an alkyl mercaptan, such as dodecyl mercaptan.
Branched polymer definition
Branched copolymers of the current invention are formed from the free-radical addition polymerisation of a monofunctional monomer(s) a radical initiator a multifunctional brancher and a chain transfer agent. The monofunctional monomer(s) typically introduce the hydrophilicity and functionality of the resulting copolymer, the chain transfer agent can introduce the required hydrophobicity of the resulting copolymer by, for example, using an alkyl mercaptan, such as dodecyl mercaptan. Branched addition copolymers of the current invention tend to stabilise the emulsions in the pre-capsule formation to a better degree than chemically analogous linear copolymers, by function of their higher molecular weight and increased end-groups and branched architecture. This therefore can lead to better capsule formation in the crosslinking step as it reduces the requirement to complete the cross-linking step in a specific time period, that is, the emulsions do not have to be cross- linked immediately as in the case for the linear copolymer encapsulating agents.
The chain transfer agent (CTA) is a molecule which is known to reduce molecular weight during a free-radical polymerisation via a chain transfer mechanism. These agents may be any thiol-containing molecule and can be either monofunctional or multifunctional. The agent may be hydrophilic, hydrophobic, amphiphilic, anionic, cationic, neutral, zwitterionic or responsive. The molecule can also be an oligomer or a pre-formed polymer containing a thiol moiety. (The agent may also be a hindered alcohol or similar free-radical stabiliser such as 2,4-diphenyl-4-methyl-1 -pentene). Catalytic chain transfer agents such as those based on transition metal complexes such as cobalt bis(borondifluorodimethyl-glyoximate) (CoBF) may also be used. Suitable thiols include but are not limited to C2-C-|8 alkyl thiols such as dodecane thiol, thioglycolic acid, thioglycerol, cysteine and cysteamine. Thiol-containing oligomers or polymers may also be used such as poly(cysteine) or an oligomer or polymer which has been post-functionalised to give a thiol group(s), such as poly(ethyleneglycol) (di)thio glycollate, or a pre-formed polymer functionalised
with a thiol group, for example, reaction of an end or side-functionalised alcohol such as polypropylene glycol) with thiobutyrolactone, to give the corresponding thiol-functionalised chain-extended polymer. Multifunctional thiols may also be prepared by the reduction of a xanthate, dithioester or trithiocarbonate end- functionalised polymer prepared via a Reversible Addition Fragmentation Transfer (RAFT) or Macromolecular Design by the Interchange of Xanthates (MADIX) living radical method. Xanthates, dithioesters, and dithiocarbonates may also be used, such as cumyl phenyldithioacetate. Alternative chain transfer agents may be any species known to limit the molecular weight in a free-radical addition polymerisation including alkyl halides and transition metal salts or complexes. More than one chain transfer agent may be used in combination.
Where the polymer is comprised of primarily hydrophilic monomers and branchers it is preferred that the CTA is a hydrophobic compound. Hydrophobic CTAs include but are not limited to linear and branched alkyl and aryl (di)thiols such as dodecanethiol, octadecyl mercaptan, 2-ethylhexyl thioglycolate, 2- methyl-1 -butanethiol, butyl 3-mercaptopropionate, i-octyl 3-mercaptopropionate, t-dodecyl mercaptan, 1 ,9-nonanedithiol and 2,4-diphenyl-4-methyl-1 -pentene. Hydrophobic macro-CTAs (where the molecular weight of the CTA is at least 1000 Daltons) can be prepared from hydrophobic polymers synthesised by RAFT (or MADIX) followed by reduction of the chain end, or alternatively the terminal hydroxyl group of a preformed hydrophobic polymer can be post functionalised with a compound such as thiobutyrolactone.
Hydrophilic CTAs typically contain hydrogen bonding and/or permanent or transient charges. Hydrophilic CTAs include but are not limited to thio-acids such as thioglycolic acid and cysteine, thioamines such as cysteamine and thio- alcohols such as 2-mercaptoethanol, 3-mercaptopropanoic acid,thioglycerol and ethylene glycol mono- (and di-)thio glycollate. Hydrophilic macro-CTAs (where the molecular weight of the CTA is at least 1000 Daltons) can be prepared from hydrophilic polymers synthesised by RAFT (or MADIX) followed by reduction of the chain end, or alternatively the terminal hydroxyl group of a preformed hydrophilic polymer can be post functionalised with a compound such as thiobutyrolactone.
Responsive macro-CTAs can be prepared from responsive polymers synthesised by RAFT (or MADIX) followed by reduction of the chain end, or alternatively the terminal hydroxyl group of a preformed responsive polymer, such as polypropylene glycol), can be post functionalised with a compound such as thiobutyrolactone.
The residue of the chain transfer agent may comprise 0 to 80 mole %, preferably 0 to 50 mole %, more preferably 0 to 40 mole % and especially 0.05 to 30 mole %, of the copolymer (based on the number of moles of monofunctional monomer).
The initiator is a free-radical initiator and can be any molecule known to initiate free-radical polymerisation such as azo-containing molecules, persulfates, redox initiators, peroxides, phenyl benzyl ketones. These may be activated via thermal, photolytic or chemical means. Examples of these include but are not limited to 2,2'-azobisisobutyronitrile (AIBN), azobis(4-cyanovaleric acid), benzoyl peroxide, di-t-butyl peroxide (Luperox® Dl), t-butyl peroxybenzoate, (Luperox® P), cumylperoxide, 1 -hydroxycyclohexyl phenyl ketone, hydrogenperoxide/ascorbic acid. Iniferters such as benzyl-N,N- diethyldithiocarbamate can also be used. In some cases, more than one initiator may be used. The initiator may be a macroinitiator having a molecular weight of at least 1000 Daltons. In this case, the macroinitiator may be hydrophilic, hydrophobic, or responsive.
Preferably, the residue of the initiator in a free-radical polymerisation comprises 0 to 10% w/w, preferably 0.01 to 10% w/w and especially 0.01 to 8% w/w, of the copolymer based on the total weight of the monomers.
The use of a chain transfer agent and an initiator is preferred. However, some molecules can perform both functions.
Hydrophilic macroinitiators (where the molecular weight of the preformed polymer is at least 1000 Daltons) can be prepared from hydrophilic polymers
synthesised by RAFT (or MADIX), or the terminal hydroxyl group of a preformed hydrophilic polymer can be post-functionalised with a compound such as 2- bromoisobutyryl bromide for use in Atom Transfer Radical Polymerisation (ATRP) with a suitable low valency transition metal catalyst, such as CuBr Bipyridyl.
Hydrophobic macroinitiators (where the molecular weight of the preformed polymer is at least 1000 Daltons) can be prepared from hydrophobic polymers synthesised by RAFT (or MADIX), or the terminal hydroxyl group of a preformed hydrophilic polymer can be post-functionalised with a compound such as 2- bromoisobutyryl bromide for use with ATRP.
Responsive macroinitiators (where the molecular weight of the preformed polymer is at least 1000 Daltons) can be prepared from responsive polymers synthesised by RAFT (or MADIX), or the terminal hydroxyl group of a preformed hydrophilic polymer can be post-functionalised with a compound such as 2- bromoisobutyryl bromide for use with ATRP.
The monofunctional monomer may comprise any carbon-carbon unsaturated compound which can be polymerised by an addition polymerisation mechanism, for example vinyl and allyl compounds. The monofunctional monomer may be hydrophilic, hydrophobic, amphiphilic, anionic, cationic, neutral or zwitterionic in nature. The monofunctional monomer may be selected from, but not limited to, monomers such as vinyl acids, vinyl acid esters, vinyl aryl compounds, vinyl acid anhydrides, vinyl amides, vinyl ethers, vinyl amines, vinyl aryl amines, vinyl nitriles, vinyl ketones, and derivatives of the aforementioned compounds as well as corresponding allyl variants thereof. Other suitable monofunctional monomers include hydroxyl-containing monomers and monomers which can be post-reacted to form hydroxyl groups, acid-containing or acid-functional monomers, zwitterionic monomers and quaternised amino monomers. Oligomeric, polymeric and di- or multi-functionalised monomers may also be used, especially oligomeric or polymeric (meth)acrylic acid esters such as mono(alk/aryl) (meth)acrylic acid esters of polyalkyleneglycol or polydimethylsiloxane or any other mono-vinyl or allyl adduct of a low molecular
weight oligomer. Mixtures of more than one monomer may also be used to give statistical, graft, gradient or alternating copolymers.
Vinyl acids and derivatives thereof include (meth)acrylic acid, fumaric acid, maleic acid, itaconic acid and acid halides thereof such as (meth)acryloyl chloride. Vinyl acid esters and derivatives thereof include C1-C20 alkyl(meth)acrylates (linear & branched) such as methyl (meth)acrylate, stearyl (meth)acrylate and 2-ethyl hexyl (meth)acrylate, aryl(meth)acrylates such as benzyl (meth)acrylate, tri(alkyloxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate and activated esters of (meth)acrylic acid such as N-hydroxysuccinamido (meth)acrylate. Vinyl aryl compounds and derivatives thereof include styrene, acetoxystyrene, styrene sulfonic acid, vinyl pyridine, vinylbenzyl chloride and vinyl benzoic acid. Vinyl acid anhydrides and derivatives thereof include maleic anhydride. Vinyl amides and derivatives thereof include (meth)acrylamide, N-(2-hydroxypropyl)methacrylamide, N-vinyl pyrrolidone, N-vinyl formamide, (meth)acrylamidopropyltrimethyl ammonium chloride, [3-((meth)acrylamido)propyl]dimethyl ammonium chloride, 3-[N-(3- (meth)acrylamidopropyl)-N,N-dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether and N-isopropyl(meth)acrylamide. Vinyl ethers and derivatives thereof include methyl vinyl ether. Vinyl amines and derivatives thereof include dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, diisopropylaminoethyl (meth)acrylate, mono-t-butylaminoethyl (meth)acrylate, morpholinoethyl(meth)acrylate and monomers which can be post-reacted to form amine groups, such as vinyl formamide. Vinyl aryl amines and derivatives thereof include vinyl aniline, vinyl pyridine, N-vinyl carbazole and vinyl imidazole. Vinyl nitriles and derivatives thereof include (meth)acrylonitrile. Vinyl ketones and derivatives thereof include acreolin.
Hydroxyl-containing monomers include vinyl hydroxyl monomers such as hydroxyethyl (meth)acrylate, hydroxy propyl (meth)acrylate, glycerol mono(meth)acrylate and sugar mono(meth)acrylates such as glucose mono(meth)acrylate. Monomers which can be post-reacted to form hydroxyl groups include vinyl acetate, acetoxystyrene and glycidyl (meth)acrylate. Acid- containing or acid functional monomers include (meth)acrylic acid, styrene
sulfonic acid, vinyl phosphonic acid, vinyl benzoic acid, maleic acid, fumaric acid, itaconic acid, 2-(meth)acrylamido 2-ethyl propanesulfonic acid, mono-2- ((meth)acryloyloxy)ethyl succinate and ammonium sulfatoethyl (meth)acrylate. Zwitterionic monomers include (meth)acryloyloxyethylphosphoryl choline and betaines, such as [2-((meth)acryloyloxy)ethyl] dimethyl-(3- sulfopropyl)ammonium hydroxide. Quaternised amino monomers include (meth)acryloyloxyethyltri-(alk/aryl)ammonium halides such as (meth)acryloyloxyethyltrimethyl ammonium chloride.
Oligomeric and polymeric monomers include oligomeric and polymeric (meth)acrylic acid esters such as mono(alk/aryl)oxypolyalkyleneglycol(meth)acrylates and mono(alk/aryl)oxypolydimethyl-siloxane(meth)acrylates. These esters include monomethoxyoligo(ethyleneglycol) mono(meth)acrylate, monomethoxyoligo(propyleneglycol) mono(meth)acrylate, monohydroxyoligo(ethyleneglycol) mono(meth)acrylate, monohydroxyoligo(propyleneglycol) mono(meth)acrylate, monomethoxy poly(ethyleneglycol) mono(meth)acrylate, monomethoxy poly(propyleneglycol) mono(meth)acrylate, monohydroxy poly(ethyleneglycol) mono(meth)acrylate and monohydroxy poly(propyleneglycol) mono(meth)acrylate. Further examples include vinyl or allyl esters, amides or ethers of pre-formed oligomers or polymers formed via ring-opening polymerisation such as oligo(caprolactam), oligo(caprolactone), poly(caprolactam) or poly(caprolactone), or oligomers or polymers formed via a living polymerisation technique such as poly(1 ,4- butadiene).
The corresponding allyl monomers to those listed above can also be used where appropriate.
Examples of monofunctional monomers are:
Amide-containing monomers such as (meth)acrylamide, N-(2- hydroxypropyl)methacrylamide, N,N'-dimethyl(meth)acrylamide, N and/or N'- di(alkyl or aryl) (meth)acrylamide, N-vinyl pyrrolidone, [3- ((meth)acrylamido)propyl] trimethyl ammonium chloride, 3- (dimethylamino)propyl(meth)acrylamide, 3-[N-(3-(meth)acrylamidopropyl)-N,N-
dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether and N-isopropyl(meth)acrylamide;
(Meth)acrylic acid and derivatives thereof such as (meth)acrylic acid, (meth)acryloyl chloride (or any halide), (alkyl/aryl)(meth)acrylate, functionalised oligomeric or polymeric monomers such as monomethoxyoligo(ethyleneglycol) mono(meth)acrylate, monomethoxyoligo(propyleneglycol) mono(meth)acrylate, monohydroxyoligo(ethyleneglycol) mono(meth)acrylate, monohydroxyoligo(propyleneglycol) mono(meth)acrylatemonomethoxy poly(ethyleneglycol) mono(meth)acrylate, monomethoxy poly(propyleneglycol) mono(meth)acrylate, monohydroxy poly(ethyleneglycol) mono(meth)acrylate, monohydroxy poly(propyleneglycol) mono(meth)acrylate. glycerol mono(meth)acrylate and sugar mono(meth)acrylates such as glucose mono(meth)acrylate;
Vinyl amines such as aminoethyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, diisopropylaminoethyl (meth)acrylate, mono-t-butylamino (meth)acrylate, morpholinoethyl(meth)acrylate, vinyl aryl amines such as vinyl aniline, vinyl pyridine, N-vinyl carbazole, vinyl imidazole, and monomers which can be post- reacted to form amine groups, such as vinyl formamide;
Vinyl aryl monomers such as styrene, vinyl benzyl chloride, vinyl toluene, cc- methyl styrene, styrene sulfonic acid and vinyl benzoic acid;
Vinyl hydroxyl monomers such as hydroxyethyl (meth)acrylate, hydroxy propyl (meth)acrylate, glycerol mono(meth)acrylate or monomers which can be post- functionalised into hydroxyl groups such as vinyl acetate, acetoxy styrene and glycidyl (meth)acrylate;
Acid-containing monomers such as (meth)acrylic acid, styrene sulfonic acid, vinyl phosphonic acid, vinyl benzoic acid, maleic acid, fumaric acid, itaconic acid, 2-(meth)acrylamido 2-ethyl propanesulfonic acid and mono-2- ((meth)acryloyloxy)ethyl succinate or acid anhydrides such as maleic anhydride;
zwitterionic monomers such as (meth)acryloyloxyethylphosphoryl choline and betaine-containing monomers, such as [2-((meth)acryloyloxy)ethyl] dimethyl-(3- sulfopropyl)ammonium hydroxide;
Quaternised amino monomers such as (meth)acryloyloxyethyltrimethyl ammonium chloride.
The corresponding allyl monomer, where applicable, can also be used in each case.
Functional monomers, i.e. monomers with reactive pendant groups which can be post or pre-modified with another moiety following polymerisation can also be used such as glycidyl (meth)acrylate, tri(alkoxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate, triethoxysilylpropyl(meth)acrylate, (meth)acryloyl chloride, maleic anhydride, hydroxyalkyl (meth)acrylates, (meth)acrylic acid, vinylbenzyl chloride, activated esters of (meth)acrylic acid such as N-hydroxysuccinamido (meth)acrylate and acetoxystyrene.
Macromonomers (monomers having a molecular weight of at least 1000 Daltons) are generally formed by linking a polymerisable moiety, such as a vinyl or allyl group, to a pre-formed monofunctional polymer via a suitable linking unit such as an ester, an amide or an ether. Examples of suitable polymers include mono functional poly(alkylene oxides) such as monomethoxy[poly(ethyleneglycol)] or monomethoxy[poly(propyleneglycol)], silicones such as poly(dimethylsiloxane)s, polymers formed by ring-opening polymerisation such as poly(caprolactone) or poly(caprolactam) or mono- functional polymers formed via living polymerisation such as poly(1 ,4- butadiene).
Preferred macromonomers include monomethoxy[poly(ethyleneglycol)] mono(methacrylate), monomethoxy[poly(propyleneglycol)] mono(methacrylate) and mono(meth)acryloxypropyl-terminated poly(dimethylsiloxane).
Hydrophilic monofunctional monomers include (meth)acryloyl chloride, N- hydroxysuccinamido (meth)acrylate, styrene sulfonic acid, maleic anhydride, (meth)acrylamide, N-(2-hydroxypropyl)methacrylamide, N-vinyl pyrrolidinone, N-
vinyl formamide, quaternised amino monomers such as (meth)acrylamidopropyltrimethyl ammonium chloride, [3-
((meth)acrylamido)propyl]trimethyl ammonium chloride and
(meth)acryloyloxyethyltrimethyl ammonium chloride, 3-[N-(3- (meth)acrylamidopropyl)-N,N-dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether, glycerol mono(meth)acrylate, monomethoxy and monohydroxyoligo(ethylene oxide) (meth)acrylate, sugar mono(meth)acrylates such as glucose mono(meth)acrylate, (meth)acrylic acid, vinyl phosphonic acid, fumaric acid, itaconic acid, 2-(meth)acrylamido 2-ethyl propanesulfonic acid, mono-2-((meth)acryloyloxy)ethyl succinate, ammonium sulfatoethyl (meth)acrylate, (meth)acryloyloxyethylphosphoryl choline and betaine-containing monomers such as [2-((meth)acryloyloxy)ethyl] dimethyl-(3- sulfopropyl)ammonium hydroxide. Hydrophilic macromonomers may also be used and include monomethoxy and monohydroxypoly(ethylene oxide) (meth)acrylate and other hydrophilic polymers with terminal functional groups which can be post-functionalised with a polymerisable moiety such as (meth)acrylate, (meth)acrylamide or styrenic groups.
Functional monomers, that is, monomers with reactive pendant groups which can be post or pre-modified with another moiety following polymerisation can also be used such as glycidyl (meth)acrylate, tri(alkoxy)silylalkyl(meth)acrylates such as trimethoxysilylpropyl(meth)acrylate, triethoxysilylpropyl(meth)acrylate, (meth)acryloyl chloride, maleic anhydride, hydroxyalkyl (meth)acrylates, (meth)acrylic acid, vinylbenzyl chloride, activated esters of (meth)acrylic acid such as N-hydroxysuccinamido (meth)acrylate and acetoxystyrene.
The multifunctional monomer or brancher may comprise a molecule containing at least two vinyl groups which may be polymerised via addition polymerisation. The molecule may be hydrophilic, hydrophobic, amphiphilic, neutral, cationic, zwitterionic, oligomeric or polymeric. Such molecules are often known as cross- linking agents in the art and may be prepared by reacting any di- or multifunctional molecule with a suitably reactive monomer. Examples include di- or multivinyl esters, di- or multivinyl amides, di- or multivinyl aryl compounds, di- or multivinyl alk/aryl ethers. Typically, in the case of oligomeric or polymeric di-
or multifunctional branching agents, a linking reaction is used to attach a polymerisable moiety to a di- or multifunctional oligomer or polymer. The brancher may itself have more than one branching point, such as T-shaped divinylic oligomers or polymers. In some cases, more than one multifunctional monomer may be used.
The corresponding allyl monomers to those listed above can also be used where appropriate.
Preferred multifunctional monomers include but are not limited to: divinyl aryl monomers such as divinyl benzene; (meth)acrylate diesters such as ethylene glycol di(meth)acrylate, propyleneglycol di(meth)acrylate and 1 ,3- butylenedi(meth)acrylate; polyalkylene oxide di(meth)acrylates such as tetraethyleneglycol di(meth)acrylate, poly(ethyleneglycol) di(meth)acrylate and poly(propyleneglycol) di(meth)acrylate; divinyl (meth)acrylamides such as methylene bisacrylamide; silicone-containing divinyl esters or amides such as (meth)acryloxypropyl-terminated poly(dimethylsiloxane); divinyl ethers such as poly(ethyleneglycol)divinyl ether; and tetra- or tri-(meth)acrylate esters such as pentaerythritol tetra(meth)acrylate, trimethylolpropane tri(meth)acrylate or glucose di- to penta(meth)acrylate. Further examples include vinyl or allyl esters, amides or ethers of pre-formed oligomers or polymers formed via ring- opening polymerisation such as oligo(caprolactam), oligo(caprolactone), poly(caprolactam) or poly(caprolactone), or oligomers or polymers formed via a living polymerisation technique such as oligo- or poly(1 ,4-butadiene).
Macrocross-linkers or macrobranchers (multifunctional monomers having a molecular weight of at least 1000 Daltons) are generally formed by linking a polymerisable moiety, such as a vinyl or aryl group, to a pre-formed multifunctional polymer via a suitable linking unit such as an ester, an amide or an ether. Examples of suitable polymers include di-functional poly(alkylene oxides) such as poly(ethyleneglycol) or poly(propyleneglycol), silicones such as poly(dimethylsiloxane)s, polymers formed by ring-opening polymerisation such as poly(caprolactone) or poly(caprolactam) or poly-functional polymers formed via living polymerisation such as poly(1 ,4-butadiene).
Preferred macrobranchers include poly(ethyleneglycol) di(meth)acrylate, poly(propyleneglycol) di(meth)acrylate, methacryloxypropyl-terminated poly(dimethylsiloxane), poly(caprolactone) di(meth)acrylate and poly(caprolactam) di(meth)acrylamide.
Branchers include methylene bisacrylamide, glycerol di(meth)acrylate, glucose di- and tri(meth)acrylate, oligo(caprolactam) and oligo(caprolactone). Multi end- functionalised hydrophilic polymers may also be functionalised using a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group.
Further branchers include divinyl benzene, (meth)acrylate esters such as ethyleneglycol di(meth)acrylate, propyleneglycol di(meth)acrylate and 1 ,3- butylene di(meth)acrylate, oligo(ethylene glycol) di(meth)acrylates such as tetraethylene glycol di(meth)acrylate, tetra- or tri- (meth)acrylate esters such as pentaerthyritol tetra(meth)acrylate, trimethylolpropane tri(meth)acrylate and glucose penta(meth)acrylate. Multi end-functionalised hydrophobic polymers may also be functionalised using a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group.
Multifunctional responsive polymers may also be functionalised using a suitable polymerisable moiety such as a (meth)acrylate, (meth)acrylamide or styrenic group such as polypropylene oxide) di(meth)acrylate.
Preferred copolymer constituents:
In order for the addition copolymers to emulsify and ultimately encapsulate the hydrophobic internal phase the copolymer must be amphiphilic in nature, this can be achieved by using a mixture of hydrophilic and hydrophobic components in the copolymer. Additionally, the copolymer must be able to react post- emulsification, it is preferred that this reaction occurs via a self-condensation reaction via a moiety present in the polymer and this is typically introduced via the use of a functional monomer in the polymer preparation.
Preferred hydrophobic monofunctional monomers include:
Methyl (meth)acrylate, ethyl(meth)acrylate, n-butyl(meth)acrylate, t- butyl(meth)acrylate, lauryl (meth)acrylate, stearyl (meth)acrylate, benzyl (meth)acrylate, vinylbenzyl chloride, methyl vinyl ether, vinyl formamide, (meth)acrylonitrile, styrene.
Preferred hydrophilic monofunctional monomers include:
(meth)acrylic acid, fumaric acid, maleic acid, itaconic acid, N- hydroxysuccinamido (meth)acrylate., acetoxystyrene, styrene sulfonic acid, vinyl pyridine, and vinyl benzoic acid, maleic anhydride, (meth)acrylamide, N-(2- hydroxypropyl)methacrylamide, N-vinyl pyrrolidone, N-vinyl formamide, (meth)acrylamidopropyltrimethyl ammonium chloride, [3-
((meth)acrylamido)propyl]dimethyl ammonium chloride, 3-[N-(3- (meth)acrylamidopropyl)-N,N-dimethyl]aminopropanesulfonate, methyl (meth)acrylamidoglycolate methyl ether and N-isopropyl(meth)acrylamide, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, diisopropylaminoethyl (meth)acrylate, morpholinoethyl(meth)acrylate, acreolin, poly(ethyleneglycol) (meth)acrylate, hydroxyethyl (meth)acrylate, hydroxy propyl (meth)acrylate, 2-(meth)acrylamido 2-ethyl propanesulfonic acid, (meth)acryloyloxyethyltrimethyl ammonium chloride
Preferred reactive monofunctional monomers include:
Trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, allyl methacrylate, ethyleneglycol dicyclopentenyl ether methacrylate or 5- norbornene-2-methanol methacrylate and vinylbenzyl chloride.
Preferred polyfunctional monomers or branchers include:
Divinyl benzene, ethyleneglycol di(meth)acrylate, 1 ,4 butanediol di(methacrylate), poly(ethyleneglycol) di(meth)acrylate and N, N'- methylenebisacrylamide.
In the present invention the branched amphiphilic copolymers are prepared by an addition polymerisation process, preferably a free-radical polymerisation process, which comprises mixing together.
(a) at least one ethyleneically monounsatu rated monomer;
(b) from 1 to 25 mole% (based on the number of moles of monofunctional monomer(s)) of at least one ethyleneically polyunsaturated monomer;
(c) a chain transfer agent; and
(d) an initiator, optionally but preferably a free-radical initiator;
and subsequently reacting said mixture to form a branched copolymer.
The copolymer is prepared by an addition polymerisation method, which is a conventional free-radical polymerisation technique using a chain transfer agent.
To produce a branched polymer by a conventional radical polymerisation process, a monofunctional monomer is polymerised with a multifunctional monomer or branching agent in the presence of a chain transfer agent and free- radical initiator.
The polymerisations may proceed via solution, bulk, suspension, dispersion or emulsion procedures.
Encapsulation:
In addition, the present invention relates to the cross-linking of the capsules prepared from an oil-in-water emulsion stabilised with a reactive amphiphilic copolymer which is formed from the subsequent crosslinking of the copolymer.
Preferably the average size of the capsules is smaller than 20μιτι, more preferably smaller than 10μιτι. Preferably the capsule has an internal oil phase and is formed in an aqueous bulk phase.
In a preferred embodiment the capsule comprises an active ingredient, wherein the active ingredient is incorporated in the dispersed phase.
An oil-in-water emulsion may be prepared using equipment commonly employed for this purpose such as high shear mixers, or homogenisers, or any other commonly known apparatus. An oil or hydrophobic material is slowly poured into an aqueous solution of the polymer. By the mixing process the oil
droplets are evenly dispersed, and the polymer will act as emulsifier which keeps the emulsion stable.
The invention also provides a method of preparing a capsule, comprising a step wherein the preferred copolymer also according to an aspect of the present invention is mixed with a hydrophobic liquid at conditions where at least one of the monounsaturated monomer(s) and polyunsaturated monomer(s) and chain transfer agent do not form a non-covalent bond with any other of the monounsaturated monomer(s) and polyunsaturated monomer(s) and chain transfer agent. Under these conditions the polymer is in a non-interacting form. The hydrophobic liquid may contain an active ingredient.
Preferably the emulsion is then crosslinked through a change in pH and via a sol-gel reaction of the trialkoxysilyl units present in the copolymer.
EXAMPLES
The present invention will now be explained in more detail by reference to the following non-limiting examples.
In the following examples, copolymers are described using the following nomenclature:
(MonomerG)g (Monomer J)j (Brancher L)i (Chain Transfer Agent) d wherein the values in subscript are the molar ratios of each constituent normalised to give the monofunctional monomer values as 100, that is, g + j = 100. Linear polymers do not contain an ethyleneically unsaturated monomer (or brancher) and may or may not contain a chain transfer agent. The degree of branching or branching level is denoted by I, and d refers to the molar ratio of the chain transfer agent.
For example:
Methacrylic acid-mo Ethyleneglycol dimethacrylate-i5 Dodecane thiols
would describe a branched addition copolymer containing
methacrylic acid ethyleneglycol dimethacrylate : dodecane thiol at a molar ratio of 100:15:15.
Abbreviations:
Monomers:
TMSPMA - Trimethoxysilylpropyl methacrylate
PEGMA - Poly(ethyleneglycol) methacrylate
MAA - Methacrylic acid
Branchers:
EGDMA - Ethyleneglycol dimethacrylate
Chain Transfer Agents (CTAs)
DDT - Dodecanethiol
Initiators
AIBN -Azobisisobutyrylnitrile Solvents
THF - Tetrahydrofuran
EtOH - ethanol
All materials were obtained from the Aldrich Chemical Company.
Triple-Detection Size-Exclusion Chromatography (TD-SEC):
Molecular weights, molecular weight distributions and Mark-Houwink a-values were measured using Viscotek TDA-302 triple-detection size exclusion chromatography equipped with two ViscoGel HHR-N columns and guard column with a mobile phase of THF and triethylamine (2.5 %) at 35 °C and a flow rate of 1 mL.min"1.
NMR: Polymer compositions were determined by 1 H NMR and were recorded in CDCI3 using a Bruker DPX-400 spectrometer operating at 400 MHz.
Laser Diffraction:
Emulsion droplet diameters and diameter distributions were measured using a Malvern Mastersizer 2000 equipped with a Hydro 2000 SM dispersion unit. A drop of emulsion was added to the dispersion unit containing approximately 100 ml_ water with a stirring rate of 1 150 rpm. The volume-average droplet diameters (D4/3) quoted are obtained from at least 5 repeat runs (D4/3 = ∑D/4/V/7∑D/3/V/). The span is a measure of the distribution of the droplet size distribution and is expressed mathematically as:
(D(0.9) - D(0.1 )) / D(0.5), where D(0.9) is the diameter under which 90 % of the particles fall,
D(0.5) is the diameter under which 50% of the particles fall, and
D(0.1 ) is the diameter under which 10 % of the particles fall.
Following measurements the measurement cell was repeatedly rinsed with water.
General synthetic procedure:
Synthesis of PEGMA^/TMPSPMAg^EGDMA-mDDT-m branched addition copolymer (BP1 )
PEGMA (5 molar equivalents, 0.233g), TMSPMA (95 molar equivalents, 1 .00g), branching monomer (EGDMA, 10 molar equivalents, 0.084g), chain transfer agent (DDT, 10 molar equivalents, 0.086g) and anhydrous methanol (14ml_) were added to a glass vessel equipped with stirrer bar in pre-determined molar ratios and degassed by nitrogen purge for 30 minutes. The solution was heated to 65 °C under an inert atmosphere. Polymerisation was started by the addition of AIBN (14mg) and the reaction was left stirring and heating for 48 hours. After this time monomer conversions in excess of 99 % were typically achieved and dry ethanol was removed by evaporation at reduced pressure. The copolymer was characterized by Triple Detection-Size Exclusion Chromatography TD-SEC and 1H NMR.
Synthesis of linear addition polymer (no EDGMA present) - LP1
Linear addition copolymers were prepared by an analogous synthetic procedure to the branched addition copolymers in the absence of an ethylenically polyunsaturated monomer (also referred to as a multifunctional monomer or brancher) for example EGDMA.
Table 1 - Table of copolymer compositions and analyses.
Subscripts represent target molar equivalences.
Conv - conversion
ND - Not determined
Mn - number average molecular weight
Mw - weight average molecular weight
PDI - polydispersion index
MHcc - Mark Howink Value
Preparation of emulsions and capsules
The copolymer emulsifier (BP1 ) was dissolved at 3 w/v % in cineole. An equal volume of distilled water was added and the biphasic mixture sheared for 2 minutes using a T 25 digital Ultra-Turrax homogeniser operating at 24,000 rpm. The resulting oil-in-water emulsion was allowed to rest for 20 minutes after which time they were characterised by light microscopy and laser diffraction to ensure stability. The reactive copolymer emulsifier was cross-linked at the droplet periphery by diluting (typically 2ml_ of emulsion into 30 ml_ distilled water), stable droplets followed by addition of triethylamine (nominally 1 ml_ to the above volumes) with gentle stirring. The cross-linked droplets were characterized by laser diffraction and light microscopy to ensure that no destabilisation occurred during the cross-linking process. The cross-linked
droplets could be flushed by the addition of ethanol until the dispersion turned transparent to the eye.
Loaded BP1 capsules were prepared using an identical procedure, however the desired encapsulate (exemplified here using either a hydrophobic fluorescent dialkylcarbocyanine dye, DiO or poly(vinylstearate)) was first dissolved in cineole prior to emulsification in the desired concentration.
Characterisation of the emulsions and capsules
Figure 1 depicts three graphs illustrating droplet size distributions of:
(a) initial branched copolymer stabilized emulsion droplets,
(b) encapsulated droplets following base catalysed self-condensation of (a), and
(c) hollow capsules following flushing of (b) with ethanol.
Distributions (a) and (b) were obtained using laser diffraction, (c) was obtained by manual sizing of greater than 500 capsules from light micrograph images. pH-responsivitv of TMSPMA/MAA capsules
Laser diffraction measurements of the cross-linked TMSPMA/MAA branched copolymer (BP3) capsules showed aggregation and de-aggregation in response to addition of acid (pH 2) and base (pH 10), respectively.
The cross-linked TMSPMA/MAA capsules (BP3) were imaged by digital camera and light microscopy at pH 10, pH 2 and reverting back to pH 10. These images revealed clear aggregation and de-aggregation in response to the addition of acid and base, respectively. pH-responsivitv of TMSPMA/PEGMA capsules
Laser diffraction of the cross-linked TMSPMA95/PEGMA5 branched copolymer capsules (BP1 ) showed aggregation and de-aggregation in response to the addition of acid (pH 2) and base (pH 10), respectively. Laser diffraction of the cross-linked TMSPMA85/PEGMA 5 branched copolymer capsules (BP2) showed no evidence of any aggregation irrespective of solution pH due to the additional steric barrier provided by the excess PEGMA residues.
Preparation of Monoliths and spheroids from TMSPMA/MA branched copolymers
Emulsion droplets stabilised with the TMSPMA95/MAA5EGDMA-10D DT-10 branched copolymer (BP3) were prepared as above (3 w/v % polymer in cineole using distilled water) and allowed to 'cream', that ism the emulsion was allowed to separate for 24 hours at room temperature into an oil rich top phase on top of an aqueous phase. The droplets were purified by 3 centrifugation-redispersion cycles to remove excess polymer surfactant. Dropping the resulting emulsion into neutral/basic water immediately dispersed the droplets. The creamed emulsion droplets were dropped into acidic water (HCI, 1 M) where they cross- linked within 5 seconds to give spheres. The sphere sizes were controlled by the volume of emulsion dripped and could be decanted into ethanol solution to flush out the internal oil and remaining water. Different shaped aggregates could be prepared by varying the conditions under which the droplets were acidified and by using templates. The spheres could then be redispersed in water and were shown to swell and contract on addition of base (pH 10) and acid (pH 2), respectively. Material may be encapsulated within the inter-capsule conjoined monoliths by dissolution or dispersion within the oil prior to emulsion formation. The dissolved/dispersed material is preferably hydrophobic and not substantially surface active.
In Figure 2 there is illustrated spheroidal monoliths comprising multiple conjoined capsules, (a) Following cross-linking in water, (b) following cross- linking and washing out the internal oil and water phase (in ethanol) and (c) encapsulating a hydrophobic dye following cross-linking to produce encapsulating spheroidal monoliths of different size.
Preparation of cross-linked SDS-stabilized emulsions using TMSPMA/MA branched copolymers as additives
The TMSPMA95/MAA5EGDMA-10DDT-10 branched copolymer (BP3) was dissolved in cineole oil (0.05 w/v % in 3ml_) and homogenised with an equal volume of an aqueous solution of a conventional (non-reactive) aqueous surfactant solution (sodium dodecyl sulphate, 1 .0 w/v %). Triethylamine
(typically, a nominal concentration of 30 volume/volume % of total oil used) was added and the droplets flushed with ethanol and light microscopy performed to determine whether capsules had been created. Hollow collapsed spheres could be observed on the slides which confirmed that successful cross-linking occurred.
Therefore in accordance with the present application linear and branched addition copolymers may be prepared which may emulsify and ultimately encapsulate a hydrophobic payload. The process is essentially achieved in two steps, firstly the addition copolymer acts as an emulsifier to typically provide an oil-in-water emulsion where the copolymer stabilises the micellar structure. A second step is then preformed whereby a cross-linking reaction takes place between the copolymer emulsifier molecules to render a cross-linked capsule. If cross-linking is restricted to the same capsule discrete capsules with dimensions commensurate with the initial emulsion droplet are produced. If cross-linking occurs both around the same droplet and between adjacent droplets multiply-conjoined capsule aggregates are formed with dimensions greater than the initial emulsion droplet. The copolymer can be prepared via a one-step process utilising monofunctional monomers, polyfunctional monomers and a chain transfer agent. In order for the branched addition polymer to emulsify the hydrophobic oil it must be amphiphilic in nature, this is achieved through the choice of hydrophobic monomers, multifunctional monomers or chain transfer agents. It is preferred that the post-emulsification cross-linking reaction occurs intramolecularly, that is between adjacent emulsifier molecules at the oil-water interface, without the addition of an additional cross-linker molecule. This can occur through choice of a suitable functional monomer in the copolymer synthesis, that is a monomer which can self-cross-link through a change in, for example, solution pH.
Once formed, the internal phase of the capsules can be flushed-out through washing with a suitable solvent to yield hollow capsules or spheres. Additionally, if the copolymer emulsifier contains a carboxylic moiety, then capsules with acidic functionality can be prepared, these capsules can associate and disassociate through changes in the bulk pH. This process is
illustrated in Figure 3 which depicts emulsion and capsule formation using the amphiphilic addition copolymers. That is, Figure 3 is a schematic representation of the formation of discrete capsules and conjoined capsules depicted in Figure 3 by steps 1 to 4. In Figure 3, 'A' represents one emulsion phase, typically oil. 'B' represents a second emulsion phase, typically water. The self-cross-linking branched addition copolymer is initially dissolved or dispersed in one phase (optionally both). In step (1 ), an energy input forms a multi-phased emulsion in which the self-cross-linking addition copolymer is located at the interface. There are then 2 options: Firstly, (step 2) the emulsion is retained in a disperse state and is self-cross-linked to give a discrete capsule (step 3). The discrete capsule may be optionally washed out using a mutually good solvent for each phase (C) to give hollow capsule. Secondly, (step 4), the emulsion is concentrated in terms of the volume fraction of the internal phase and is self-cross-linked to give conjoined capsules where the reactive residues react both around the same droplet and between droplets to form a monolith (step 3). The conjoined capsule monoliths may be optionally washed out using a mutually good solvent for each phase (C) to give hollow conjoined capsule monoliths.
Therefore, the inventors have found that whilst it is possible to form capsules according to the present invention from both linear and branched addition copolymers, the linear polymers LP1 /LP2 form less stable emulsions and therefore less stable capsules.
Consequently, the efficiency of forming stable capsules is reduced with linear addition copolymers.
In contrast, branched addition copolymers BP1 to BP3 form more stable emulsions and hence more stable capsules. That is, the efficiency of forming stable capsules is improved with branched addition copolymers.
For example in Figure 4 which demonstrates normalized kinetic experiments monitoring the change in volume-averaged droplet diameters of the branched and linear copolymer stabilized uncross-linked and crosslinked droplets as a
function of time it can be seen that, the increased stability of branched emulsions over linear systems. The linear, un-crosslinked emulsions show reduced kinetic stability, although if crosslinked just after formation, the stability (size) of the emulsion droplets is locked-into the structure and there is no reduction in volume-averaged droplet size over time.
Claims
1 . A statistical amphiphilic branched copolymer obtainable by an addition polymerisation process, wherein the copolymer comprises:
at least two chains which are covalently linked by a bridge other than at their ends;
wherein the two chains comprise at least one ethyleneically monounsatu rated monomer, and
wherein the bridge comprises at least one ethyleneically polyunsaturated monomer, and
wherein the copolymer comprises a residue of a chain transfer agent and a residue of an initiator, and
wherein at least one of the ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent is a hydrophilic residue; and at least one of one of the ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent is a hydrophobic residue, and
wherein the mole ratio of ethyleneically polyunsaturated monomer(s) to ethyleneically monounsaturated monomer(s) is between a range of from 1 :100 to 1 :4,
and wherein at least one of ethyleneically monounsaturated monomer(s) and/or ethyleneically polyunsaturated monomer(s) and/or chain transfer agent comprises a moiety of Formula 1 that is capable of further reacting to form covalent bonds with any other mutually reactive moieties present via a sol gel process,
Formula (1 )
H2C=C(R1 )-C(0)-0-R2-Si(OR3)3
wherein in Formula 1 :
R1 comprises H or an optionally substituted alkyl group; and
R2 and R3 comprise an optionally substituted alkyl group.
2. A statistical amphiphilic branched addition copolymer according to claim 1 wherein R1 comprises H or CH3.
3. A statistical amphiphilic branched addition copolymer according to claim 1 or 2 wherein R2 comprises an optionally substituted alkyl group of formula (CH2)n where n is 2 to 5.
4. A statistical amphiphilic branched addition copolymer according to claim 3 wherein n is 3
5. A statistical amphiphilic branched addition copolymer according to any of claims 1 to 4 wherein R3 comprises an optionally substituted methyl or ethyl group.
6. A statistical amphiphilic branched addition copolymer according to claim 1 wherein the copolymer is capable of self-crosslinking to form a capsule around a hydrophobic material in an aqueous medium via a change in solution pH.
7. A statistical amphiphilic branched addition copolymer according to claim 1 wherein at least one of ethyleneically monounsatu rated monomer(s) and ethyleneically polyunsaturated monomer(s) and chain transfer agent comprises a moiety that is capable of forming a covalent bond via a sol-gel process.
8. Use of a statistical amphiphilic branched addition copolymer in the formation of an oil and water emulsion wherein the amphiphilic branched addition copolymer is used to stabilise the oil/water interface and allow droplet formation and wherein the crosslinking moieties present on the copolymers react at the same oil/water interface and between adjacent interfaces to form capsules.
9. Use of a statistical amphiphilic branched addition copolymer according to claim 8 wherein the cross-linking reaction takes place between adjacent amphiphilic branched addition copolymers at the same oil/water interfaces to form conjoined capsules.
10. Use of a statistical amphiphilic branched addition copolymer according to claim 8 wherein the cross-linking reaction takes place between adjacent amphiphilic branched addition copolymers at the same oil/water interfaces to form discrete capsules.
1 1 . Use of a statistical amphiphilic branched addition copolymer according to claim 12 wherein the cross-linking reaction takes place between amphiphilic copolymers at adjacent oil/water interfaces to form cross-linked monoliths.
12. A capsule comprising a statistical amphiphilic branched addition copolymer as described in any of claims 1 to 7 wherein the cross-linking moieties present in the copolymers are cross-linked to form capsules.
13. A capsule according to claim 12 wherein an active ingredient is incorporated in the capsule.
14. A capsule according to claim 13 wherein the active ingredient comprises a bioactive compound selected from the group comprising:
pharmaceuticals or agrochemicals, nutritional agents, cosmetics, catalysts, dyes, flavours, biocides, fragrances, emollients, natural oils.
15. A capsule according to claim 13 wherein the active ingredient comprises a non-bioactive compound selected from the group comprising:
cosmetics, catalysts, dyes, reactive resins, pigments, flavours, fragrances, lubricating oils, emollients, natural oils, waxes and inks.
16. A capsule according to claim 12 or 13 wherein where the capsule may associate and dissociate via hydrogen-bonding.
17. A capsule according to claim 13 wherein the active ingredient can be expelled to yield a hollow capsule.
18. A capsule according to any of claims 12 to 17 wherein the surface of the capsule can be post-modified with additional functional groups.
19. A method of preparing a statistical amphiphilic branched addition copolymer according to claim 1 by an addition polymerisation process, which comprises mixing together:
(a) at least one ethyleneically monounsatu rated monomer;
(b) from 1 to 25 mole% (based on the number of moles of ethyleneically monofunctional monomer(s)) of at least one ethyleneically polyunsaturated monomer;
(c) a chain transfer agent; and
(d) an initiator;
and subsequently reacting said mixture to form a branched copolymer.
20. A method of preparing a statistical amphiphilic branched addition copolymer according to claim 19 by an addition polymerisation process, wherein the polymerisation process comprises a free-radical polymerisation process, and wherein the initiator comprises a free-radical initiator.
21 . Use of a statistical amphiphilic branched addition copolymer according to any of claims 1 to 7 to encapsulate an active ingredient wherein the active ingredient is a bioactive compound selected from the group comprising: pharmaceuticals, agrochemicals; nutritional agents; cosmetics, catalysts, dyes, flavours, fragrances, emollients, natural oils, and inks.
22. Use of a statistical amphiphilic branched addition copolymer according to any of claims 1 to 7 to encapsulate an active ingredient wherein the active ingredient is a non-bioactive compound or is used in the areas selected from the group comprising: cosmetics, catalysts, dyes, pigments, flavours, biocides, fragrances, lubricating oils, emollients, natural oils and waxes, paints and inks.
23. Use of a statistical amphiphilic branched addition copolymer according to any of claims 1 to 7 to encapsulate an active ingredient wherein the active ingredient is used as a paint, ink, coating or sealant.
24. Use of a statistical amphiphilic branched addition copolymer according to any of claims 1 to 7 to encapsulate an active ingredient for use in tissue engineering scaffolds.
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WO2015053716A1 (en) * | 2013-10-11 | 2015-04-16 | Agency For Science, Technology And Research | Direct synthesis of ph-responsive polymer particles and application in control release of hydrophobic therapeutic compounds |
WO2016124925A1 (en) * | 2015-02-05 | 2016-08-11 | The University Of Liverpool | Nanoemulsions |
JP2018516289A (en) * | 2015-04-15 | 2018-06-21 | ピーピージー・インダストリーズ・オハイオ・インコーポレイテッドPPG Industries Ohio,Inc. | Curable film-forming composition containing encapsulated catalyst component |
WO2018109469A1 (en) * | 2016-12-14 | 2018-06-21 | Itaconix (U.K.) Limited | Novel process |
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WO2008071661A1 (en) | 2006-12-12 | 2008-06-19 | Unilever Plc | Polymers |
WO2008079677A2 (en) | 2006-12-20 | 2008-07-03 | Arkema Inc. | Polymer encapsulation and/or binding |
WO2009144471A1 (en) | 2008-05-29 | 2009-12-03 | Unilever N.V. | Amphiphilic branched polymers and their use as emulsifiers |
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WO2008071661A1 (en) | 2006-12-12 | 2008-06-19 | Unilever Plc | Polymers |
WO2008079677A2 (en) | 2006-12-20 | 2008-07-03 | Arkema Inc. | Polymer encapsulation and/or binding |
WO2009144471A1 (en) | 2008-05-29 | 2009-12-03 | Unilever N.V. | Amphiphilic branched polymers and their use as emulsifiers |
Cited By (6)
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WO2015053716A1 (en) * | 2013-10-11 | 2015-04-16 | Agency For Science, Technology And Research | Direct synthesis of ph-responsive polymer particles and application in control release of hydrophobic therapeutic compounds |
WO2016124925A1 (en) * | 2015-02-05 | 2016-08-11 | The University Of Liverpool | Nanoemulsions |
CN107205930A (en) * | 2015-02-05 | 2017-09-26 | 利物浦大学 | Nanoemulsions |
US10463618B2 (en) | 2015-02-05 | 2019-11-05 | The University Of Liverpool | Nanoemulsions |
JP2018516289A (en) * | 2015-04-15 | 2018-06-21 | ピーピージー・インダストリーズ・オハイオ・インコーポレイテッドPPG Industries Ohio,Inc. | Curable film-forming composition containing encapsulated catalyst component |
WO2018109469A1 (en) * | 2016-12-14 | 2018-06-21 | Itaconix (U.K.) Limited | Novel process |
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