GB2431104A - Microgel particles grafted to a substrate - Google Patents

Microgel particles grafted to a substrate Download PDF

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Publication number
GB2431104A
GB2431104A GB0520552A GB0520552A GB2431104A GB 2431104 A GB2431104 A GB 2431104A GB 0520552 A GB0520552 A GB 0520552A GB 0520552 A GB0520552 A GB 0520552A GB 2431104 A GB2431104 A GB 2431104A
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Prior art keywords
microgel particles
device according
substrate
active agent
preceding
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GB0520552D0 (en
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Victoria Cornelius
John Mitchell
Martin Snowdon
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University of Greenwich
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University of Greenwich
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/60Liquid-swellable gel-forming materials, e.g. super-absorbents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F13/00051Accessories for dressings
    • A61F13/00063Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/44Medicaments
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/04Acids; Metal salts or ammonium salts thereof
    • C08F220/06Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10Esters
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52Amides or imides
    • C08F220/54Amides
    • C08F220/56Acrylamide; Methacrylamide
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08KUse of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00Use of organic ingredients
    • C08K5/04Oxygen-containing compounds
    • C08K5/09Carboxylic acids; Metal salts thereof; Anhydrides thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/24Homopolymers or copolymers of amides or imides
    • C08L33/26Homopolymers or copolymers of acrylamide or methacrylamide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F13/06Bandages or dressings; Absorbent pads specially adapted for feet or legs; Corn-pads; Corn-rings
    • A61F13/064Bandages or dressings; Absorbent pads specially adapted for feet or legs; Corn-pads; Corn-rings for feet
    • A61F13/069Decubitus ulcer bandages
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F2013/00089Wound bandages
    • A61F2013/00157Wound bandages for burns or skin transplants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F2013/00361Plasters
    • A61F2013/00365Plasters use
    • A61F2013/00519Plasters use for treating burn
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F2013/00361Plasters
    • A61F2013/00902Plasters containing means
    • A61F2013/00927Plasters containing means with biological activity, e.g. enzymes for debriding wounds or others, collagen or growth factors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41Anti-inflammatory agents, e.g. NSAIDs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412Tissue-regenerating or healing or proliferative agents
    • A61L2300/414Growth factors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602Type of release, e.g. controlled, sustained, slow
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622Microcapsules
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L99/00Compositions of natural macromolecular compounds or of derivatives thereof not provided for in groups C08L89/00 - C08L97/00

Abstract

A device comprises microgel particles grafted to a substrate. The particles contain an active ingredient and swell in aqueous media to release the active ingredient on exposure to a changed environmental condition. The device is particularly intended for use as a wound dressing. The examples illustrate microgels comprised of acrylamide-acrylate polymers that contain ibuprofen.

Description

MICROGELS 2431104

--

ACTIVE AGENT RELEASE DEVICE AND A METHOD

jld of the invention The present invention relates to an active agent release device and a method for preparing such a device, and in particular to such devices which are capable of releasing an active agent according to the environmental conditions.

Background of the invention

Active agent release devices, such as controlled release drug delivery systems are known where, for example, the active agent is aggregated with a slowly soluble material and is released over a prolonged period of time as the slowly soluble material dissolves. A similar system is known for the controlled release of fertilisers into the soil.

Such devices suffer from the potential disadvantage that the rate of release of the active agent is independent of the environmental conditions and/or independent of the quantitative need of the system for the active agent. For example a wound dressing may incorporate a device for releasing a drug to be administered to a wound over a period of time. However, the optimum quantity of drug needed by the wound may well depend, for example, on the degree of infection. In such known systems either insufficient drug is released when the level of infection is high, or too much of the drug is released when the level of infection is low, which is wasteful and may even have undesirable side effects.

There is therefore a need for an active agent release device in a form which enables the rate of release to be dependant upon the environmental conditions.

* * . . * S* NICROGELS: : 7643B: . * * * I I * * * * I I * S S S I S II. III III S I S

SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided an active agent release device comprising: (i) a substrate; (ii) microgel particles grafted to the substrate, the microgel particles being reversibly swellable in aqueous media dependant upon at least one environmental condition; and (iii) an active agent trapped within the structure of the microgel particles, but not bonded thereto, the arrangement being such that when the environmental condition changes to swell the microgel particles, the release of the active agent therefrom is enhanced.

Thus, the present invention makes use of microgel particle technology.

Microgel particles are cross-linked particles that are swollen in a good solvent, especially in water at room temperature. The particles can conveniently be prepared by solvent free emulsion polymerisation (SFEP) and may be considered as sterically stabilised particles without a core (see B R Saunders and B Vincent - Advances in Colloid and Interface Science 80 (1999) 1-25) These particles respond to external stimuli, such as temperature, pH or ionic strength, by shrinking and swelling reversibly in response to either an increase or decrease in solvent quality. When swollen, the interstitial regions within the polymer matrix become available. For example, microgel particles formed of poly Nisopropylacrylai (poly-NIPAJVI) have been prepared having a collapsed particle size of 325 - 335 nm and a swollen particle size of 590 - 685 nm (B R Saunders, B Vincent, J Chem. Soc. Faraday Trans. 92 (1996) 198) A number of applications have been proposed involving microgel particles, for example in the surface coatings, * . . * S 5(5 MICROGELS I: *: *: 764B:.

* a * a I I S S * S S I S S a * * I.. alt (IS a S S printing and pharmaceutical industries. Saunders and Vincent ibid propose the use of microgel particles for drug delivery within the body if suitable trigger systems can be found. Indeed, we are aware of international patent specification WO 0049991 (PHAIRSON MEDICAL INC) which discloses a method of treating an area affected by a trauma, such as a corneal wound or internal trauma, comprising administering to the affected area a trauma treating effective amount of a composition comprising a microgel comprising a cross-linked polyanionic polymer.

The microgel particles may be grafted to the substrate via ionic or a covalent bonds.

When the microgel particles are grafted to the substrate via ionic bonds, the microgel particles may have a positive surface charge and the substrate may have a negative surface charge. This can be achieved by deriving the microgel particles from a polymerisation process which employs 2,2- azobis (2-amidinopropane dihydrochloride) as a polymerisation initiator. The substrate may then be a natural material having a negative surface charge derived from surface hydroxyl -0- or carboxyl -CO groups, or a natural or synthetic material surface treated to provide a negative surface charge derived from surface -S03 groups.

Alternatively, when the microgel particles are grafted to the substrate via ionic bonds, the microgel particles may have a negative surface charge and the substrate may have a positive surface charge. This can be achieved by providing the microgel particles with surface -C02 groups or surface -S03 groups, for example by deriving the microgel particles from a polymerisatjon process which employs 4,4-azobis(4- cyanovaleric acid) or potassium persulphate as a polymerisation initiator. In this case, the substrate may be a natural or synthetic material surface treated to * . . I * *II MICROGELS: 764B: :.

* I * I * I I * * I I * * I I * S I.. III III * * provide cationic surface groups, such as aminated cotton.

Preferably, the substrate is a flexible material, such as a textile material, especially a cellulose fibre based fabric such as cotton.

The active agent is preferably hydrophobic or water- insoluble. The active agent may comprise a medicament, for example antibiotics, fungal agents, pain killers or anti- inflammatories such as isobutyl phenyl propionic acid ("Ibuprofen") , or proteins such as alantonin or human growth hormones.

The environmental conditions which trigger the swelling of the microgel particles may include changes in pH, temperature, pressure, ionic strength, solvency, light intensity, relative humidity or the influence of an applied

electric or magnetic field.

Where temperature is the trigger, useful microgels are those where the volume phase transition temperature is between 10 C and 55 C, such as about 34 C.

Where pH is the trigger, useful microgels are those where the volume phase transition pK is between 2 and 9, such as about 6.2.

Where ionic strength is the trigger, useful microgels are those where the volume phase transition ionic strength is between 0.OO1M and 0.1M, such as about 0.05r4.

The microgel particles are preferably formed of a cross- linked polymer, such as cross-linked polymerised methyl methacrylate, methacrylic acid, styrene, divinyl benzene, acrylic acid, N,N'-methylene bisacrylamide, or ethylene glycol dimethacrylate. However, most preferred is poly N- a * * . . 0.* MICROGELS: : : z764cB: . * I I I I S I * * , . I S * I S * S.. *I* laS I * S isopropylacrylamide.

Depending upon the nature of the active agent, it is preferred that the microgel particles incorporate carboxylic acid ester units (such as butyl (meth)acrylate units) to impart hydrophobicity and/or incorporate carboxylic acid units (such as (meth)acrylic acid units) to impart pH sensitivity.

The device according to the invention may be in the form of a wound dressing. Wound dressings incorporating hydrogels are known, for example from International patent specification wo 02/076518 (BRISTOL-MYERS SQUIBB COMPANY) The hydrogel in such devices swells to adsorb wound excreta and provide an efficient particle barrier that is non- adhesive, therefore removable/replaceable without causing damage to the new epidermis. Wound dressings according to the present invention incorporating microgels offer the same advantages, but as a consequence of their very high surface area to volume ratio compared to hydrogels, they have a much faster solution response.

Such a "smart" dressing may be used to treat chronic wounds, such as burns, pressure ulcers, venous stasis ulcers and diabetic ulcers. Wound fluid tends to have a slightly acidic pH of 5.8 to 6.6. Generally, the more acidic the wound, the more bacteria are present. As a result of the changing pH over the lifetime of a wound, not only can the dressing incorporate the desirable pharmaceutical actives required to treat the wound effectively but the dressing can also deliver the active when most needed.

Other useful applications in the medical field for the active agent release devices of the invention include hygienic textiles, bandages, gauzes, patches, implants and artificial organs.

MICROGELS: :L 1.

The invention also provides a method of forming an active agent release device comprising the steps of: (i) polymerising a monomer under such conditions as to form microgel particles; (ii) suspending the microgel particles in an aqueous medium at a concentration of less than 50 g/l; (iii) adding an active agent to the suspension whereby the active agent enters the porous interior of the microgel particles; (iv) adjusting at least one environmental condition thereby to trap the active agent within the structure of the microgel particles without the active agent being bonded thereto; (v) separating the microgel particles from the aqueous media; and (vi) grafting the microgel particles to a substrate.

The step of polymerising may be carried out by solvent free emulsion polymerisation (SFEP), ideally comprising the use of an ionic initiator.

The microgel particles are suspended in an aqueous medium at a concentration of less than 50 g/l, such as up to 20 g/l, for example about 5 gIl. Higher concentrations may be less preferred for viscosity reasons.

The step of adjusting at least one environmental condition preferably comprises raising the pH of the suspension.

The step of separating the microgel particles from the aqueous media may be achieved by spray-drying, freeze-drying or centrifuging the suspension.

Grafting the microgel particles to a substrate may be carried out before or after the active agent is added to the suspension. The step of grafting may comprise one or more * * . . * II* MICROGELS: : : .764B:.

* S S I S S S * S S S S * S * S Sue II. 555 * S S of: (i) the formation of an intermediate linkage between carbonyl or carboxylate groups of the substrate and amidine groups of the microgel particles; (ii) the formation of an ester linkage between hydroxyl groups of the substrate and carboxylate groups of the microgel particles; and (iii) the formation of an anhydride linkage between carboxylate groups of the substrate and carboxylate groups of the microgel particles.

The invention will now be further illustrated in the following nonlimiting examples.

EXAMPLES

Jjj Preparation of microgel particles and the graftjn2 thereof to a substrate

Example 1

Microgels were prepared from 5 g N-isopropylacrylamjde 5 g N,N' methylenebisacrylamide and 0.5 g 2,2'-azobis (2- methyipropionamidine dihydrochioride) 97% as the monomer, cross linker and initiator respectively using a surfactant- free emulsion polymerisation. Cotton was placed in the reaction vessel after 4 hours to allow the microgels to bind to the substrate while the reaction continued for a further 2 hours.

Example 2

Microgels were prepared from 4 g N-isopropylacrylamide 0.5 g butyl acrylate, 0.5 g methacrylic acid, 5 g N,N' methylenebisacrylamide and 0.5 g 2,2'-azobis (2- methylpropjonamjdjne dihydrochloride) 97% as the three monomers, cross linker and initiator respectively using a surfactant free emulsion polymerisation A concentrated * * . . . I,.

MICROGELS: : : 2764B:.

* a a a a S I S * I * S S I S a S ISa III 555 5 S dispersion (25 g/l) was sonicated f or 1 hour in the presence of cotton allow the interaction between the microgels and the substrate.

Example 3

Microgels were prepared from 4 g N-isopropylacrylamide, 1 g butyl acrylate, 5 g N,N' methylenebisacrylamide and 0.5 g 2,2' -azobis (2-methylpropionamidjne dihydrochioride) 97% as the two monomers, cross linker and initiator respectively using a surfactant free emulsion polymerisation. The microgels where then freeze dried and placed in a supercritical reactor with cotton. The reactor was then flushed with carbon dioxide for 2 minutes. The reactor was then pressurised with carbon dioxide from atmospheric up to 200 bar and the temperature was raised from ambient to 35 C to create the desired supercritical conditions for the reactor.

The microgels and cotton were maintained under these conditions for 2 hours to allow the polymeric components and the cotton to interact fully. The pressure was then removed to atmospheric and the temperature lowered to ambient so the reaction product may be removed from the reactor.

Example 4

Cotton was oxidised in the presence of periodic acid, cleaving the vicinal diols to form aldehyde functionalities on the cellulose backbone. This oxidised cotton (2 g) was placed in a vessel with concentrated microgel dispersion (50 g/l) at pH 4.3 and 25 C. The microgels were prepared from 3 g N-isopropylacrylamjde, 2 g methacrylic acid, 0.5 g N,N' methylenebisacrylamide and 0.5 g potassium persulphate as the two monomers, cross linker and initiator respectively.

The reaction was allowed to proceed for 2 hours when the cotton was removed and washed.

* . * * S 555 MICROGELS: : : 1764B * * S I S I I S a I I I * I I * S II. SI* III I I *

Example 5

Cotton was oxidised in the presence of periodic acid, cleaving the vicinal diols to form aldehyde functionalities on the cellulose backbone. This oxidised cotton (2 g) was placed in a vessel with concentrated micro gel dispersion (50 g/l) at 45 C. The microgels were prepared from 3 g Nisopropylacrylamide, 0.5 g N,N' methylenebisacrylamide and 0.5 g 4,4' azobis (4- cyanovaleric acid)as the monomer, cross linker and initiator respectively. The reaction was allowed to proceed for 2 hours when the cotton was removed and washed.

iii) Trapping an active agent within the structure of microgel iarticles

Example 6

Microgels were prepared from 3 g N-isopropylacrylamide, 2 g acrylic acid, 0.5 g N,N' methylenebisacrylamide and 0.5 g 4,4' azobis (4-cyanovaleric acid) as the two monomers, cross-linker and initiator respectively using a standard surfactant free emulsion polymerisation technique. The dispersion was then concentrated (20 g/l) and combined with a saturated solution of Ibuprofen. The Ibuprofen was allowed to permeate into the porous cavities of the microgel for 24 hours. The dispersion was then heated to 345 K to collapse the microgel and trap incorporated Ibuprof en then plunged into liquid nitrogen to quick freeze the gel, maintaining the collapsed structure, before freeze drying. The microgel was re-dispersed in 10 ml of water at pH 3 and 345 K in the presence 2 g cotton. The interaction was allowed to proceed for 48 hours when the drug loaded microgel cotton substrate complex was removed and dried.

Example 7

Microgels were prepared from 4 g N-isopropylacrylamjde 0.5 g butyl acrylate, 0.5 g methacrylic acid, 0.5 g N,N' * * * * . *1* MICROGELS: : L'26423g:.

* 8 8 0 S * * * I * S I I S 1 S I.. 885 885 S - 10 methylenebisacrylamide and 0.5 g 4,4' azobis (4- cyanovaleric acid) as the three monomers, cross linker and initiator respectively.

Cotton was oxidised in the presence of periodic acid, cleaving the vicinal diols to form aldehyde functionalities on the cellulose backbone. This oxidised cotton (2 g) was placed in a vessel with concentrated microgel dispersion (50 g/l) at 45 C. The reaction was allowed to proceed for 2 hours, after which the cotton was removed and washed. The complex textile was then freeze-dried before being placed in the presence of a saturated salicylic acid solution as an experimental drug. The microgel was allowed to swell in this solution for 48 h at pH 5 in a water bath at 25 C, thereby to form an experimental wound dressing.

Diffusion of the drug from the dressing was analysed using Franz-cell technology at a range of pHs. The flux of salicylic acid through a silicone membrane into a receptor solution was as follows: flux (, ug/cm2/h) + 0.5 3 4 4 4 5 4 6 3 7 3 This data shows a flux comparable to the saturated solution independent of the microgel and cotton substrate and indicates increased delivery at lower pHs.

Claims (29)

* S S * * **S MICROGELS: : : 764:. * S S S S I U S U S I I S I I S III III III I S - 11 - CLAIMS
1. An active agent release device comprising: (i) a substrate; (ii) microgel particles grafted to the substrate, the microgel particles being reversibly swellable in aqueous media dependant upon at least one environmental condition; and (iii) an active agent trapped within the structure of the microgel particles, but not bonded thereto, the arrangement being such that when the environmental condition changes to swell the microgel particles, the release of the active agent therefrom is enhanced.
2. A device according to claim 1, wherein the microgel particles are grafted to the substrate via ionic or a covalent bonds.
3. A device according to claim 2, wherein the microgel particles are grafted to the substrate via ionic bonds, the microgel particles have a positive surface charge and the substrate has a negative surface charge.
4. A device according to claim 3, wherein the microgel particles are derived from a polymerisation process which employs 2,2-azobis (2amidinopropane dihydrochloride) as a polymerisation initiator.
5. A device according to claim 3 or 4, wherein the substrate is a natural material having a negative surface charge derived from surface -C02 groups.
* * S S S 555 MICROGELS 764:.
* S a, S I S S I S I I S * * S S SSI 555 III S S S - 12 -
6. A device according to any one of claims 3 to 5, wherein the substrate is a natural or synthetic material surface treated to provide a negative surface charge derived from surface -S03 groups.
7. A device according to claim 2, wherein the microgel particles are grafted to the substrate via ionic bonds, the microgel particles have a negative surface charge and the substrate has a positive surface charge.
8. A device according to claim 7, wherein the microgel particles have surface -C02 groups or surface -S03 groups.
9. A device according to claim 8, wherein the microgel latex particles are derived from a polymerisation process which employs 4,4-azobis(4cyanovaleric acid) or potassium persulphate as a polymerisation initiator.
10. A device according to claim 7, 8 or 9, wherein the substrate is a natural or synthetic material surface treated to provide cationic surface groups.
11. A device according to any preceding claim, wherein the substrate is a flexible material, such as a textile material, especially a fabric comprising cotton.
12. A device according to any preceding claim, wherein the active agent is hydrophobic or water-insoluble.
13. A device according to any preceding claim, wherein the active agent comprises a medicament.
14. A device according to any preceding claim, wherein the active agent comprises a protein, such as a human growth hormone.
V S S S 555 MICROGELS: : : 1-Z264l:.
S S S S S S S S
S S S I S I I V S
all II, 115 5 S S - 13 -
15. A device according to any preceding claim, wherein the microgel particles are sensitive to changes in pH, temperature, pressure, ionic strength, ambient light conditions or relative humidity.
16. A device according to any preceding claim, wherein the microgel particles comprise a cross-linked polymer.
17. A device according to any preceding claim, wherein the microgel particles comprise poly N- isopropylacrylamide.
18. A device according to any preceding claim, wherein the microgel particles incorporate carboxylic acid ester units to impart hydrophobicity.
19. A device according to claim 18, wherein the carboxylic acid ester units comprise butyl (meth)acrylate units.
20. A device according to any preceding claim, wherein the microgel particles incorporate carboxylic acid units to impart pH sensitivity.
21. A device according to any preceding claim, wherein the carboxylic acid units comprise (meth)acrylic acid units.
22. A device according to any preceding claim, in the form of a wound dressing.
* I 4 a 141 MICROGELS: : 12643, * , I i I I a * I I I 4 4 * I I III III III * - 14 -
23. A method of forming an active agent release device comprising the steps of: (i) polymerising a monomer under such conditions as to form microgel particles; (ii) suspending the microgel particles in an aqueous medium at a concentration of less than 50 g/l; (iii) adding an active agent to the suspension whereby the active agent enters the porous interior of the microgel particles; (iv) adjusting at least one environmental condition thereby to trap the active agent within the structure of the microgel particles without the active agent being bonded thereto; (v) separating the microgel particles from the aqueous media; and (vi) grafting the microgel particles to a substrate.
24. A method according to claim 23, wherein the step of polymerising comprises the use of an ionic initiator.
25. A method according to claim 23 or 24, wherein the step of adjusting at least one environmental condition comprises raising the pH of the suspension.
26. A method according to claim 23, 24 or 25, wherein the step of separating the microgel particles from the aqueous media comprises spraydrying the suspension.
V
MICROGELS: r{264t11.
a j I * P p a a as. p, aa a * * - 15 -
27. A method according to any one of claims 23 to 26, wherein the step of grafting the microgel particles to a substrate comprises one or more of: (i) the formation of an intermediate linkage between amidine groups of the substrate and carboxylate groups of the microgel particles; (ii) the formation of an ester linkage between hydroxyl groups of the substrate and carboxylate groups of the microgel particles; and (iii) the formation of an anhydride linkage between carboxylate groups of the substrate and carboxylate groups of the microgel particles.
28. An active agent release device substantially as hereinbefore described with reference to the accompanying
examples.
29. A method of forming an active agent release device substantially as hereinbefore described with reference to the accompanying examples.
GB0520552A 2005-10-10 2005-10-10 Microgel particles grafted to a substrate Withdrawn GB2431104A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2253665A1 (en) 2009-04-22 2010-11-24 Dr. Suwelack Skin & Health Care AG Freeze-dried composition
WO2011009867A2 (en) 2009-07-22 2011-01-27 Glaxo Group Limited Novel composition
WO2015070233A1 (en) * 2013-11-11 2015-05-14 Georgia Tech Research Corporation Functionalized microgels with fibrin binding elements

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0481443A1 (en) * 1990-10-17 1992-04-22 Vectorpharma International S.P.A. Transdermal therapeutic compositions
WO2003082316A1 (en) * 2002-03-29 2003-10-09 The Regents Of The University Of California Microgel particles for the delivery of bioactive materials
US20050008828A1 (en) * 2002-07-25 2005-01-13 Trustees Of Stevens Institute Of Technology Patterned polymer microgel and method of forming same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0481443A1 (en) * 1990-10-17 1992-04-22 Vectorpharma International S.P.A. Transdermal therapeutic compositions
WO2003082316A1 (en) * 2002-03-29 2003-10-09 The Regents Of The University Of California Microgel particles for the delivery of bioactive materials
US20050008828A1 (en) * 2002-07-25 2005-01-13 Trustees Of Stevens Institute Of Technology Patterned polymer microgel and method of forming same

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2253665A1 (en) 2009-04-22 2010-11-24 Dr. Suwelack Skin & Health Care AG Freeze-dried composition
US9822243B2 (en) 2009-04-22 2017-11-21 Dr. Suwelack Skin & Health Care Ag Freeze-dried composition
WO2011009867A2 (en) 2009-07-22 2011-01-27 Glaxo Group Limited Novel composition
WO2011009867A3 (en) * 2009-07-22 2011-10-20 Glaxo Group Limited An oral care composition for the treatment of dentine hypersensitivity comprising responsive or non-responsive microgel particles
WO2015070233A1 (en) * 2013-11-11 2015-05-14 Georgia Tech Research Corporation Functionalized microgels with fibrin binding elements
US10195304B2 (en) 2013-11-11 2019-02-05 Georgia Tech Research Corporation Functionalized microgels with fibrin binding elements

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