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WO2002000762A1 - Materiaux polymeres fonctionnalises - Google Patents

Materiaux polymeres fonctionnalises Download PDF

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Publication number
WO2002000762A1
WO2002000762A1 PCT/GB2001/002790 GB0102790W WO0200762A1 WO 2002000762 A1 WO2002000762 A1 WO 2002000762A1 GB 0102790 W GB0102790 W GB 0102790W WO 0200762 A1 WO0200762 A1 WO 0200762A1
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Prior art keywords
moieties
polymer
functionalised
bio
moiety
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PCT/GB2001/002790
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English (en)
Inventor
John Neil Devine
David John Kemmish
Brian Wilson
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Victrex Manufacturing Ltd
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Victrex Manufacturing Ltd
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Priority to AU2001274326A priority Critical patent/AU2001274326A1/en
Publication of WO2002000762A1 publication Critical patent/WO2002000762A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • C08G65/48—Polymers modified by chemical after-treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

  • This invention relates to functionalised polymeric materials. Particularly, although not exclusively, the invention relates to bio-compatible polymeric materials and provides such a material per se, a method of producing such a material and the use of the material in medical treatment, for example in a prosthesis.
  • prosthetic devices such as orthopaedic, dental or maxillofacial implants.
  • prosthetic devices such as orthopaedic, dental or maxillofacial implants.
  • nearly half a million patients receive bone implants each year in the US with the majority being artificial hip and knee joints made from titanium or colbalt-chrome alloys.
  • these materials are too stiff leading to bone resorption, loosening of the implant and, consequently, have lifetimes of less than 10 years.
  • medical devices or prostheses such as pacemakers, vascular grafts, stents, heart valves, catheters and dental implants that contact body tissues or fluids of living persons or animals have been developed and used clinically.
  • the method including:
  • any alkyl, akenyl or alkynyl moiety suitably has up to 8, preferably up to 6, more preferably up to 4, especially up to 2, carbon atoms and may be of straight chain or, where possible, of branched chain structure.
  • methyl and ethyl are preferred alkyl groups and C 2 alkenyl and alkynyl groups are preferred.
  • optional substituents of an alkyl group may include halogen atoms, for example fluorine, chlorine, bromine and iodine atoms, and nitro, cyano, alkoxy, hydroxy, amino, alkylamino, sulphinyl, alkylsulphinyl , sulphonyl, alkylsulphonyl, amido, alkylamido, alkoxycarbonyl , haloalkoxycarbonyl and haloalkyl groups.
  • optionally substituted alkyl groups are unsubstituted.
  • said polymer has a moiety of formula
  • phenyl moieties in units I, II, and III are independently optionally substituted and optionally cross- linked; and wherein m,r,s,t,v,w and z independently represent zero or a positive integer, E and E' independently represent an oxygen or a sulphur atom or a direct link, G represents an oxygen or sulphur atom, a direct link or a -O-Ph-O- moiety where Ph represents a phenyl group and Ar is selected from one of the following moieties (i)*, (i)**, (i) to (x) which is bonded via one or more of its phenyl moieties to adjacent moieties
  • a phenyl moiety may have 1,4- or 1,3-, especially 1,4-, linkages to moieties to which it is bonded.
  • Said polymer may include more than one different type of repeat unit of formula I; more than one different type of repeat unit of formula II; and more than one different type of repeat unit of formula III. Preferably, however, only one type of repeat unit of formula I, II and/or III is provided.
  • Said moieties I, II and III are suitably repeat units.
  • units I, II and/or III are suitably bonded to one another - that is, with no other atoms or groups being bonded between units I, II, and III.
  • phenyl moieties in units I, II or III are optionally substituted, they may be optionally substituted by one or more halogen, especially fluorine and chlorine, atoms or alkyl, cycloalkyl or phenyl groups.
  • Preferred alkyl groups are C ⁇ - ⁇ o, especially C ⁇ - 4 , alkyl groups.
  • Preferred cycloalkyl groups include cyclohexyl and multicyclic groups, for example adamantyl .
  • said phenyl moieties are not optionally- substituted as described.
  • said polymer is cross-linked, it is suitably cross-linked so as to improve its properties.
  • Any suitable means may be used to effect cross-linking.
  • cross-linking between polymer chains may be effected via sulphur atoms on respective chains.
  • said polymer is not optionally cross-linked as described.
  • the respective phenylene moieties may independently have 1,4- or 1,3-linkages to the other moieties in the repeat units of formulae II and/or III.
  • said phenylene moieties have 1,4- linkages.
  • the polymeric chain of the polymer does not include a -S- moiety.
  • G represents a direct link.
  • a represents the mole % of units of formula I in said polymer, suitably wherein each unit I is the same;
  • "b” represents the mole % of units of formula II in said polymer, suitably wherein each unit II is the same;
  • "c” represents the mole % of units of formula III in said polymer, suitably wherein each unit III is the same.
  • a is in the range 45-100, more preferably in the range 45-55, especially in the range 48-52.
  • the sum of b and c is in the range 0-55, more preferably in the range 45-55, especially in the range 48- 52.
  • the ratio of a to the sum of b and c is in the range 0.9 to 1.1 and, more preferably, is about 1.
  • the sum of a, b and c is at least 90, preferably at least 95, more preferably at least 99, especially about 100.
  • said polymer consists essentially of moieties I, II and/or III.
  • Said polymer may be a homopolymer having a repeat unit of general formula
  • A, B, C and D independently represent 0 or 1 and E,E' ,G,Ar,m, r, s, t,v,w and z are as described in any statement herein.
  • said polymer may be a homopolymer having a repeat unit of general formula
  • A, B, C, and D independently represent 0 or 1 and E, E', G, Ar, m, r, s, t, v, w and z are as described in any statement herein.
  • m is in the range 0-3, more preferably 0-2, especially 0-1.
  • r is in the range 0-3, more preferably 0-2, especially 0-1.
  • t is in the range 0-3, more preferably 0-2, especially 0-1.
  • s is 0 or 1.
  • v is 0 or 1.
  • w is 0 or 1.
  • z is 0 or 1.
  • said polymer is a homopolymer having a repeat unit of general formula IV.
  • Ar is selected from the following moieties (xi)*, (xi)**,(xi) to (xxi) :
  • the middle phenyl may be 1,4- or 1,3- substituted.
  • (xv) is selected from a 1,2-, 1,3-, or a 1,5- moiety
  • (xvi) is selected from a 1,6-, 2,3-, 2,6- or a 2,7- moiety
  • (xvii) is selected from a 1,2-, 1,4-, 1,5- , 1,8- or a 2,6- moiety.
  • One preferred class of polymers does not include any moieties of formula III, but suitably only includes moieties of formulae I and/or II .
  • said polymer is a homopolymer or random or block copolymer as described, said homopolymer or copolymer suitably includes a repeat unit of general formula IV.
  • Such a polymer may, in some embodiments, not include any repeat unit of general formula V.
  • Suitable moieties Ar are moieties (i)*, (i) , (ii) ,
  • polymers are polymers
  • the polymer does not include repeat units which include -S-, -S0 2 - or aromatic groups other than phenyl .
  • Preferred polymers of the type described include :
  • ketone moieties may be functionalised to provide a moiety
  • R 30 and R 31 may represent any groups which enable -CR 30 R 31 - to have the lower electron withdrawing effect described.
  • the atom in R 30 which links it to the moiety -C- may be a hydrogen (where R 30 represents a hydrogen atom) , carbon or oxygen atom.
  • a said carbon atom may be bonded to or a component of an optionally-substituted, saturated, unsaturated, linear, branched, acyclic and/or cyclic moiety.
  • acyclic moieties include alkyl, alkenyl and alkynyl moieties .
  • Examples of cyclic moieties include cycloalkyl, cycloalkenyl , cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl moieties.
  • An oxygen atom may be part of a hydroxy group or may be bonded to or a component of an optionally- substituted saturated, unsaturated, linear, branched, acyclic and/or cyclic moiety.
  • Examples of acyclic and cyclic moieties may be as described above for said carbon atom.
  • the atom in R 31 which links it to the moiety -C- may be as described above for R 30
  • the atom in group R 32 which links R 32 to the moiety -C- is preferably a nitrogen atom so that R 32 defines an i ine with the moiety -C- .
  • Said nitrogen atom may be bonded to an optionally-substituted, saturated, unsaturated, linear, branched, acyclic and/or cyclic moiety. Examples of such moieties are as described above for R 30 and/or R 31 .
  • epolymer may- be "subjected to one or a series of treatments prior to functionalisation of activated phenyl moieties in stage (2) .
  • the polymer may be functionalised to provide functionalities which have a lower electron withdrawing effect and such functionalities may be further functionalised, prior to stage (2) , to provide moieties which may participate in treatments or reactions which may be undertaken after functionalisation of said active phenyl moieties.
  • the polymer may be treated to provide said activated phenyl moieties; said activated phenyl moieties may be functionalised; and, optionally, there may then be further functionalisation of the funtionalities which have a lower electron withdrawing effect and/or functionalised activated phenyl moieties.
  • ketone moieties are functionalised to provide a moiety -CR 30 R 31 - as described
  • said polymer which includes moieties described in (A) , (B) and (C) may be subjected to a first treatment which is a reduction reaction for reducing carbonyl moieties.
  • a first treatment which is a reduction reaction for reducing carbonyl moieties.
  • Any suitable type of reducing agent may be used as described in the examples hereinafter.
  • Preferred reducing agents supply hydride ions or otherwise supply a nucleophile which can react with the carbonyl group. Examples include the use of lithium aluminium hydride or sodium borohydride and organometallic compounds, for example 4-lithiobenzonitrile, arranged to supply organic nucleophiles .
  • a said first treatment may result in the functionalisation of carbonyl moieties to form a moiety -CR 30 R 31 - wherein R 30 represents a hydrogen atom or a nucleophilic residue of the reducing agent used, for example a nucleophilic residue of an organometallic compound such as a benzonitrile moiety.
  • said polymer which includes moieties described in (A) , (B) , and (C) may be subjected to an addition-elimination reaction, suitably by treatment with ammonia or, especially, a primary amine.
  • a first treatment of a polymer which includes phenyl moieties, sulphone moieties and ether or thioether moieties may be the reduction of the sulphone moieties, suitably to sulphide moieties.
  • said polymer may be treated to functionalise phenyl moieties thereof as described in stage (2) .
  • Treatment is preferably undertaken using reagents and/or conditions which could not be used to functionalise said phenyl moieties if the carbonyl and/or sulphone moieties had not been previously treated as described in stage (1) .
  • stage (2) involves an electrophilic aromatic substitution reaction of said activated phenyl moieties. Any type of electrophilic aromatic substitution reaction may be used, including Friedel-Crafts, alkylation, acylation, nitration, sulphonation, halogenation, chloromethylation, phosphonylation and lithiation reactions.
  • the • functionalised polymer- may -be further functionalised as ⁇ may be" desired.
  • functional groups on said activated phenyl moieties or functional groups which have replaced carbonyl or sulphone moieties may be functionalised.
  • it may be possible to assemble a polymer wherein functional groups, for example phenyl groups, which are pendent from said activated phenyl moieties and functional groups which have replaced carbonyl or sulphone moieties may be functionalised at the same time and/or under the same reaction conditions.
  • the method involves functionalising the polymer at or adjacent a surface thereof, such that the bulk of the polymer is not substantially functionalised.
  • the method preferably involves functionalising phenyl moieties of said polymer such that the concentration of non-functionalised phenyl moieties (i.e. phenyl moieties not functionalised in the method) present within the bulk of the functionalised polymer is greater than the concentration of non-functionalised phenyl moieties present at or adjacent the surface.
  • said polymer functionalised in the method is presented as a solid, suitably shaped so as to represent at least part of a device for use in medical applications, and then functionalised in the method.
  • said device may be a component of an implant for a human or animal body, for example an orthopaedic or dental implant or vascular graft.
  • Said solid may be -provided in -a desired shape -by any suitab ⁇ e- means, for example by injection or compression moulding or by film formation techniques or extrusion.
  • stages (1) and (2) of said method according to said first aspect are undertaken on said polymer in solid form, suitably so as to preferentially functionalise a surface region of said solid.
  • the method preferably includes the step of treating said polymer after functionalisation of said activated phenyl moieties with a material for providing bio- compatible moieties (hereinafter , BCM material").
  • BCM material may be arranged to provide any of the bio- compatible moieties described hereinafter.
  • Said polymer may be provided as a solid.
  • said bio-compatible moieties are caused to become associated with a surface of said solid, preferably with functional groups pendent from said activated phenyl moieties at a surface of said solid. They could, additionally, be caused to become associated with functional groups that have replaced carbonyl or sulphone moieties.
  • Said solid is preferably shaped so as to represent at .
  • the bi ' o-compatible material formed (referred to as "bio- compatible polymeric material") is not engineered or otherwise treated in a manner which may result in substantial depletion of the bio-compatible moieties associated with its surface.
  • said bio-compatible polymeric material has improved or enhanced bio-compatibility compared to said polymer prior to functionalisation in the method.
  • Bio-compatible moieties suitably include moieties arranged to reduce adverse biological reactions when the bio-compatible polymeric material is introduced into (or otherwise associated with) a human or animal body. For example, adverse biological reactions associated with introduction into a human or animal body of said polymer having said bio-compatible moieties may be less compared to use of the same polymer but which does not include associated bio-compatible moieties.
  • "Bio-compatible moieties" referred to herein suitably refer to moieties which are compatible with use in medical applications, for example by not being toxic or otherwise harmful to living material. Such bio-compatible moieties may be arranged to bond (for example to form ionic or covalent bonds) or otherwise interact with materials present in human or animal bodies in order to improve their integration and acceptance by such bodies.
  • a said bio-compatible moiety may be selected from an ant-icoagulant agent- such- -as heparin and-heparin sulfate, an antithrombotic agent, a clotting agent, a platelet agent, an anti-inflammatory agent, an antibody, an antigen, an immunoglobulin, a defence agent, an enzyme, a hormone, a growth factor, a neurotransmitter, a cytokine, a blood agent, a regulatory agent, a transport agent, a fibrous agent, a protein such as avidinj a glycoprotein, a globular protein, a structural protein, a membrane protein and a cell attachment protein, a peptide such as a glycopeptide, a structural peptide, a membrane peptide and a cell attachment peptide, a proteoglycan, a toxin, an antibiotic agent, an antibacterial agent, an antimicrobial agent such as pencillin, ticarcillin, carbenicillin, ampicillin, oxa
  • PEG poly (ethylene oxide)
  • PEO poly (ethylene oxide)
  • PNVP poly (N-vinyl-2- pyrrolidone)
  • PNVP poly (2-hydroxyethyl methacrylate
  • HEMA HEMA co-polymers
  • PVA poly (vinyl alcohol)
  • PVA polyacrylamide
  • PMMA polyacrylamide
  • PMMA polysiloxanes
  • PDMS polydimethylsiloxanes
  • PAAc polyurethane
  • said bio-compatible moieties may comprise bone morphogenic protein (BMP) as described in US4563489 and patents cited therein and the contents of the aforesaid are incorporated herein.
  • BMP bone morphogenic protein
  • Said BMP may be provided in combination, for example in admixture, with a physiologically acceptable biodegradable organic polymer and said biodegradable polymer may be associated with said at least two moieties of said polymer of said bio- compatible polymeric material, for example by being covalently bonded to said at least two moieties.
  • the combination of said biodegradable polymer and BMP defines said bio-compatible moieties.
  • Said biodegradable polymer is preferably a biodegradable polylactic acid; or alternatively, other physiologically acceptable .
  • biodegradable organic polymers which are structurally equivalent to polylactic acid can be used as the delivery system for BMP. Examples include poly(hydroxy organic carboxylic acids) e.g. poly(hydroxy aliphatic carboxylic acids) , polyglycollic acid, polyglactin, polyglactic acid and poly adonic acids.
  • said bio-compatible moieties may be selected from inorganic crystalline structures, inorganic amorphous structures, organic crystalline structures and organic amorphous structures .
  • Preferred bio-compatible moieties are phosphorous based ceramics, for example calcium-phosphorous ceramics .
  • Phosphates in general are suitable but calcium phosphates and calcium apatite are preferred.
  • hydroxyapatite, a synthetic Ca-P ceramic is particularly preferred.
  • bio-compatible moieties may be associated by any suitable means with the functionalised polymer, for example by covalent bond(s), hydrogen bond(s) , encapsulation in a matrix which is bonded to or otherwise interacts with said functionalised groups, or by ionic interaction (s) , it is preferred that there are covalent bonds between the bio-compatible moieties and said polymer or there are ionic interactions between said bio- compatible moieties and said polymer.
  • the invention extends to a method of making a bio-compatible polymeric material for use in medical applications, the method including associating bio- compatible moieties with a functionalised polymer of a type or when prepared as described according to said first aspect.
  • Said functionalised polymer preferably includes functional groups arranged to become associated with suitable functional groups provided by BCM material.
  • Said polymer may include functional groups selected from the following: -OH, -CHO, -NR 10 2 , preferably
  • said functional groups are components of moieties pendent from activated phenyl moieties of said polymer.
  • Said functional groups could be components of groups that have replaced carbonyl or sulphone moieties of said polymer.
  • BCM material may include any suitable functional group that is arranged to become associated with functional groups of said functionalised polymer and may be selected from any of the functional groups referred to above for said functionalised polymer provided that a selected functional group on said functionalised polymer is capable of becoming associated with, suitably reacting with, a selected functional group provided by BCM material.
  • a bio-compatible moiety may be provided by reaction of said functionalised polymer with more than one functional group.
  • a bio-compatible moiety may be a polyurethane which may be prepared: when said functionalised polymer provides a hydroxy group and said BCM material provides a diisocyanate and a diol; or wherein said functionalised polymer provides an isocyanate group and said BCM material provides a diisocyanate and a diol.
  • said BCM material may provide two different compounds.
  • BCM material may be provided by a monomer or monomers having a functional group arranged to react with said functionalised polymer and being arranged to polymerise to provide a polymeric bio-compatible moiety.
  • said functionalised polymer may include ionic functional groups, for example -COOM or - S0 3 M, and such groups may be arranged to ionically associate with an ionic moiety provided by BCM material .
  • an amide bond may be formed between said functionalised polymer and BCM material.
  • said functionalised polymer may be multi-functional, thereby enabling it to associate with a plurality of bio-compatible moieties.
  • multi- functionality may be provided by dendritic or hyperbranched end groups .
  • the invention extends to a functionalised polymeric material, preferably a bio-compatible polymeric material, wherein the bulk of said material comprises a polymer of a type which includes, in the polymer backbone, the following:
  • a surface of said material comprises a functionalised derivative of said polymer present in the
  • a surface of said material comprises a greater concentration of functionalised phenyl moieties compared to the concentration of functionalised phenyl moieties in the bulk.
  • the surface may include a greater concentration of functionalised carbonyl and/or sulphone moieties compared to the concentration of functionalised carbonyl and/or sulphone moieties in the bulk.
  • said functionalised polymeric material is suitably only functionalised at or adjacent its surface and functionalised polymer represents only a small fraction of the total weight of the polymer, the existence of functionalised polymer may have a limited effect on the bulk properties of the polymeric material .
  • the glass transition temperature (T g ) of said polymer may be at least 135°C, suitably at least 150°C, preferably at least 154°C, more preferably at least 160°C, especially at least 164°C. In some cases, the Tg may be at least 170°C, or at least 190°C or greater than 250°C or even 300°C.
  • Said polymer suitably the bulk thereof, (in the absence of associated bio-compatible moieties) may have an inherent viscosity (IV) of at least 0.1, suitably at least 0.3, preferably at least 0.4, more preferably at least 0.6, especially at least 0.7 (which corresponds to a reduced viscosity (RV) of least 0.8) wherein RV is measured at 25°C on a solution of the polymer in concentrated sulphuric acid of density 1.84gcm ⁇ 3 , said solution containing lg of polymer per 100cm "3 of solution. IV is measured at 25°C on a solution of polymer in concentrated sulphuric acid of density 1.84gcm 3 , said solution containing O.lg of polymer per 100cm 3 of solution.
  • IV inherent viscosity
  • both RV and IV both suitably employ a viscometer having a solvent flow time of approximately 2 minutes .
  • the main peak of the melting endotherm (Tm) for said polymer suitably the bulk thereof, (if crystalline) may be at least 300°C.
  • said polymer suitably the bulk thereof,
  • crystallinity in the absence of associated bio-compatible moieties, has at least some crystallinity or is crystallisable.
  • the existence and/or extent of crystallinity in a polymer is preferably measured by wide angle X-ray diffraction, for example as described by Blundell and Osborn (Polymer 24, 953, 1983) .
  • crystallinity may be assessed by Differential Scanning Calorimetry (DSC) .
  • Said polymer suitably the bulk thereof, (in the absence of associated bio-compatible moieties) may have a number average molecular weight in the range 2000-80000.
  • said molecular weight is at least 14,000.
  • the molecular weight may be less than 60 , 000 .
  • Said bio-compatible polymeric material suitably has a
  • tensile strength ("according to " ISO R527)" erf- at" least 80, preferably at least 90, especially at least 95 MPa.
  • the tensile strength may be less than 360, suitably less than
  • the tensile modulus may be less than 40, suitably less than 30, preferably less than 20, more preferably less than 10 GPa. It preferably has a flexural strength
  • the flexural strength may be less than 650, preferably less than 400, more preferably less than 260, especially less than 200 MPa. It preferably has a flexural modulus (according to ISO R178) of at least 3, preferably at least 3.5, especially at least 4 GPa.
  • the flexural modulus may be less than 60, suitably less than 25, preferably less than 20, especially less than 10 GPa.
  • the aforementioned properties can be adjusted by appropriate selection of polymers and/or any reinforcement means included in said support material to suit particular applications.
  • a continuous carbon fibre polyetheretherketone may typically have a tensile strength of about 350 MPa, a tensile modulus of 36 GPa, an i, elongation of 2%, a flexural modulus of 50 GPa and a flexural strength of 620 MPa.
  • a polyaryetherketone with 30% . of high performance fibres may typically have a tensile strength of 224 MPa, a tensile modulus of 13 GPa, a tensile elongation of 2%, a flexural modulus of 20 GPa and a flexural strength of 250 MPa.
  • Said bio-compatible polymeric material may include one or more fillers for providing desired properties.
  • Said material preferably incorporates an X-ray contrast medium. Fillers and/or said X-ray contrast medium is/are preferably distributed substantially uniformly throughout said material .
  • an X-ray contrast medium suitably comprises less than 25wt%, preferably less than 20wt%, more preferably less than 15wt%, especially less than 10wt% of said bio-compatible material. Where it is provided, at least 2wt% may be included.
  • Preferred X-ray contrast mediums are particulate and preferably are inorganic . They preferably have low solubility in body fluids. They preferably also have a sufficient density compared to that of the polymer to create an image if a compounded mixture of the polymer and contrast medium are X-ray imaged. Barium sulphate and zirconium oxide are examples . Said particulate material is suitably physically held in position by entrapment within the polymer.
  • said functionalised and/or bio-compatible polymeric material includes a major amount of said polymer, especially one having moieties I, II and/or III, described according to said first aspect.
  • a “major” amount may mean greater than 50 wt%, suitably greater than 65 wt%, preferably greater than 80 wt%, more preferably greater than 95 wt%, especially greater than 98 wt% of the referenced material is present relative to the total weight of relevant material present .
  • the " invention” further extends to a" ' bio-compatible polymeric material comprising a polymer having bio- compatible moieties associated with its surface and a lower concentration of bio-compatible moieties associated with its bulk, wherein the bulk comprises a polymer of a type which includes, in the polymer backbone, the following:
  • bio-compatible moieties are associated with moieties which are pendent from phenyl moieties of the polymer at or adjacent the surface thereof.
  • Bio-compatible moieties may, optionally, be associated with moieties pendent from -C- moieties which are components of the polymer backbone, suitably at or near the surface of the polymer.
  • Polymers as described herein may be prepared as described in PCT/GB99/02833.
  • a device for use in medical applications wherein said device comprises a bio- compatible polymeric material according to said first aspect or made in a method according to said second aspect or as described in any invention described herein.
  • Said device is preferably a prosthetic device, for example an implant such as an orthopaedic, dental or maxillofacial implant or a component thereof; or a device, for exampl-e- a ⁇ catheter, -which-- -is - arranged to be temporarily associated with a human or animal body.
  • Said device is preferably a prosthetic device as described.
  • An orthopaedic device may be an implant for a body joint, for example a knee or hip joint or spine fusion device.
  • a said device may include a part or parts made out of said bio-compatible polymeric material and a part or parts made out of other materials.
  • said device includes at least 50wt%, preferably at least 65wt%, more preferably at least 80wt%, especially at least 95wt% of said bio-compatible polymeric material.
  • said device may consist essential of said bio- compatible polymeric material .
  • a method of making a device according to the third aspect comprising: forming a material into a shape which represents or is a precursor of a device or a part of a device for use in medical applications wherein said material comprises a polymer which includes moieties (A) ,
  • the invention extends to the use of a functionalised polymer as described herein in the manufacture of a device for use in a medical treatment, for example in surgery.
  • PEEK Trade Mark
  • PEK Trade Mark
  • PEES polyetherethersulphone
  • polyaryletherketone films of approximately 120 ⁇ m thick were used.
  • the film samples were prepared from samples of Victrex PEEKTM (Melt Viscosity 0.45kNs ⁇ rf 2 , at lOOOsec "1 at 400 °C) and of Victrex PEKTM (Melt Viscosity 0.22kNsm “2 , at lOOOsec "1 at 400 °C) powder which was compression moulded between metal plates using a Moore laboratory hot press at 400 °C for between 5 and 10 minutes.
  • the PEEKTM and PEKTM melt was quenched in ice-cold water in order to obtain 120 ⁇ m thick amorphous samples.
  • the film samples were refluxed in acetone for 72h prior to use.
  • a solution of 1,3 -propane sultone (7.32g, 60mmol) and aluminium chloride (0.15g, l.lmmol) was prepared in a boiling tube, under a nitrogen atmosphere.
  • a sample of PEEKTM film from example 1 was then immersed in the solution and the solution heated to 40 °C for 24h. The film was then removed and washed with methanol and distilled water followed by acetone.
  • a solution of 1, 5-diaminopentane (2.66g, 26mmol) in acetic acid (50ml) was introduced into a 100ml round bottomed flask.
  • a sample of modified PEEKTM film from example 3 was immersed in the reactive solution and stirred, at room temperature, for 3 days. The film sample was then removed and rinsed with acetic acid before being dried under vacuum for 6 hours .
  • the surface modified PEEKTM from Example 4 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, 1- ethyl-3- (3-dimethylaminopropyl) -carbodiimide) (0.4g) dissolved in buffer at pH 4.5 (0.1M 2-(N- morpholino) ethanesulphonic acid) (40ml).
  • the sample of PEEKTM was removed and washed with buffer solution.
  • the sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS
  • a solution of 1,3-propane sultone (7.32g, 60mmol) and aluminium chloride (0.15g, l.lmmol) was prepared in a boiling tube, under a nitrogen atmosphere.
  • a sample of PEKTM film from example 2 was then immersed in the solution and the solution heated to 40 °C for 24h. The film was then removed and washed with methanol and distilled water followed by acetone.
  • a solution of 4-aminobenzoic acid (3.6g, 26mmol) in acetic acid (50ml) was introduced into a 100ml round bottomed flask.
  • a sample of modified PEKTM film from example 6 was immersed in the reactive solution and stirred, at room temperature, for 3 days. The film sample was then removed and rinsed with acetic acid and acetone before being dried under vacuum for 6 hours .
  • Example 8 N-protection of p-aminobenzoic acid
  • a mixture of dioxane (20ml) , water (10ml) and 1M sodium hydroxide (10ml) and p-aminobenzoic acid (5.75g) was stirred and cooled in an ice water bath.
  • Di-t-butyl pyrocarbonate (9.6g, 44mmol) was added and stirring continued for 30 minutes at room temperature.
  • the reactive solution was concentrated in vacuo to about 10- 15ml, cooled in an ice water bath, covered with a layer of ethyl acetate (30ml) and acidified with dilute aqueous potassium hydrogen sulphate solution.
  • the aqueous phase was extracted with ethyl acetate.
  • the combined extracts were washed with water and dried over anhydrous magnesium sulphate and evaporated in vacuo .
  • para N-Boc protected benzoic acid (9.44g, 40mmol) from example 8 was dissolved in 10ml of 4M sodium hydroxide solution and cooled to 0°C in an ice bath.
  • Ethyl chloroformate (4.45g, 41mmol) and sodium hydroxide (10ml of 4.0M) was added alternately, with shaking and cooling, over 30minutes.
  • the mixture was allowed to warm to room temperature over Ih, then extracted with ether.
  • the aqueous phase was acidified with dilute hydrochloric acid.
  • the liberated oil was extracted with ether, the combined extracts were washed dried over magnesium sulphate and the solvent removed by evaporation, to yield the desired activated ester.
  • Example 10 Friedel Crafts reaction of modified PEEKTM film with Jf-protected activated ester of p-aminobenzoic acid
  • N-protected activated ester of p-aminobenzoic acid from example 9 (6.18g, 20mmol) and aluminium chloride (0.15g, l.lmmol) were dissolved in freshly distilled dichloromethane in a boiling tube, under a nitrogen atmosphere.
  • a sample of PEEKTM film from example 1 was then immersed in the solution and the solution heated to 40 °C for 24h. The film was then removed and washed with methanol and distilled water followed by acetone.
  • a solution of 4-aminobenzoic acid (3.6g, 26mmol) in acetic acid (50ml) was introduced into a 100ml round bottomed flask.
  • a sample of modified PEEKTM film from example 10 was immersed in the reactive solution and stirred, at room temperature, for 3 days. The film sample was then removed and rinsed with acetic acid and acetone before being dried under vacuum for 6 hours .
  • Example 15 Calcium Phosphate Deposition on modified PEKTM film from example 14
  • a supersaturated calcium phosphate solution containing 5mM CaCl 2 , 1.5mM KH 2 P0 4 and 1.5mM Na 2 HP0 4 was prepared by mixing 1.5ml of 0. IM Na 2 HP0 4 stock solution into 92ml of deionised water, followed by the slow addition of 5.0ml of 0.1M CaCl 2 solution. The combined solution was stirred for 3 minutes and modified PEKTM film (example 14) was immersed in the solution and taken out just before the solution precipitated (1 hour) . The films were then rinsed with deionised water and blown dry with nitrogen. The process can be repeated several times to achieve a desired thickness.
  • modified PEKTM film from example 15 was immersed into a 100ml solution of 10 per cent sodium hydroxide and refluxed for 12 hours . The sample was removed and washed thoroughly with dilute sulphuric acid followed by distilled water. The sample was then removed and dried overnight at room temperature.
  • the surface modified PEKTM from Example 16 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, 1- ethyl-3- (3-dimethylaminopropyl) -carbodiimide) (0.4g) dissolved in buffer at pH 4.5 (0.1M 2- (N- morpholino) ethanesulphonic acid) (40ml).
  • the sample of PEKTM was removed and washed with buffer solution.
  • the sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS (160mg) in phosphate-buffered saline solution (40ml) (Na 2 HP0 4 , 1.15g; KH 2 P0 4 , 0.2g; NaCl, 8g; KC1, 0.2g; MgCl 2 , O.lg; CaCl 2 , 0. lg in 1 litre of distilled water).
  • the functionalised PEKTM was washed successively with phosphate buffer and distilled water.
  • the surface modified PEEKTM from Example 11 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, 1- ethyl-3- (3-dimethylaminopropyl) -carbodiimide) (0.4g) dissolved in buffer at pH 4.5 (0.1M 2- (N- morpholino) ethanesulphonic acid) (40ml).
  • the sample of PEEKTM was removed and washed with buffer solution.
  • the sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of the peptide GRGDS (160mg) in phosphate-buffered saline solution (40ml) (Na 2 HP0 4 , 1.15g; KH 2 P0 4 , 0.2g; NaCl, 8g; KCl, 0.2g; MgCl 2 ,
  • Example 19 Deprotection of the surface modified PEEKTM film from example 18.
  • modified PEEKTM sample from example 19 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing
  • the surface modified PEEKTM from Example 11 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, 1- ethyl-3- (3-dimethylaminopropyl) -carbodiimide) (0.4g) dissolved in buffer at pH 4.5 (0.1M 2-(N- morpholino) ethanesulphonic acid) (40ml).
  • the sample of PEEKTM was removed and washed with buffer solution.
  • the sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of aspartic acid in phosphate- buffered saline solution (40ml) (Na 2 HP0 4 , 1.15g; KH 2 P0 4 , 0.2g; NaCl, 8g; KC1, 0.2g; MgCl 2 , O.lg; CaCl 2 , O.lg in 1 litre of distilled water) .
  • the functionalised PEEKTM was washed successively with phosphate buffer and distilled water.
  • Example 22 Deprotection of the surface modified PEEKTM film from example 21.
  • modified PEEKTM sample from example 22 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing
  • the dried sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in a solution of arginine in an aqueous buffer solution (40ml), pH 9.
  • the functionalised PEEKTM was washed successively with the buffer solution and ether.
  • Example 24 Deprotection/Coupling of modified PEEKTM sample from example 19.
  • the surface modified PEEKTM from Example 19 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, 1- ethyl-3- (3-dimethylaminopropyl) -carbodiimide) (0.4g) dissolved in buffer at pH 4.5 (0.1M 2- (N- morpholino) ethanesulphonic acid) (40ml).
  • the sample of PEEKTM was removed and washed with buffer solution.
  • the sample was stirred at 20°C for 24 hr under an atmosphere of nitrogen in phosphate-buffered saline solution (40ml) (Na 2 HP0 4 , 1.15g; KH 2 P0 4 , 0.2g; NaCl, 8g; KC1, 0.2g; MgCl 2 , O.lg; CaCl 2 , O.lg in 1 litre of distilled water) .
  • phosphate-buffered saline solution 40ml
  • Na 2 HP0 4 1.15g
  • KH 2 P0 4 0.2g
  • KC1 0.2g
  • MgCl 2 O.lg
  • CaCl 2 O.lg in 1 litre of distilled water
  • Example 26 Surface Reduction of ⁇ polyetheretherketone/PEES (70/30) co-polymer with Dibal-H
  • a sample of polyetheretherketone/PEES (70/30) copolymer from example 25 was immersed in 200ml of a 1.0M solution of diisobutylaluminium hydride (Dibal-H) in toluene. The mixture was then refluxed under nitrogen for 96hours and eventually cooled to room temperature. The sample was removed and washed with ethanol (100ml) , followed by water (200ml) , and concentrated hydrochloric acid (100ml) . The sample was then rinsed with water and allowed to dry at room temperature overnight.
  • Dibal-H diisobutylaluminium hydride
  • a solution of 1,3 -propane sultone (7.32g, 60mmol) and aluminium chloride (0.15g, l.lmmol) was prepared in a boiling tube at 60 °C, under a nitrogen atmosphere.
  • a sample of modified polyetheretherketone/PEES (70/30) film was then immersed in the solution and stirred at 60 °C for 24h. The film was then removed and washed with methanol and distilled water followed by acetone.

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Abstract

L'invention concerne un procédé de fonctionnalisation d'un polymère d'un type comprenant, dans le squelette polymère, des fractions phényle, des fractions carbonyle et/ou sulfone, et des fractions éther et/ou thioéther. Ce procédé est caractérisé en ce qu'il comprend les étapes consistant à traiter le polymère pour fonctionnaliser les fractions carbonyle et/ou sulfone, afin d'obtenir des fonctionnalités qui possèdent un effet moindre d'enlèvement d'électrons sur les fractions phényle du squelette polymère par comparaison avec les fractions carbonyle et/ou sulfone que ces fractions phényle remplacent, et enfin à traiter le matériau polymère préparé de manière à fonctionnaliser ces fractions phényle activées. Des modes préférés de réalisation concernent la préparation d'un matériau polymère biocompatible que l'on peut utiliser dans des applications médicales en fonctionnalisant le polymère (par exemple d'une polyétheréthercétone ou d'une polyéthercétone) et en le traitant avec des fractions biocompatibles.
PCT/GB2001/002790 2000-06-24 2001-06-22 Materiaux polymeres fonctionnalises Ceased WO2002000762A1 (fr)

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Cited By (4)

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DE102004008314A1 (de) * 2004-02-20 2005-09-15 Friadent Gmbh Verwendung von Zirkonoxid-haltigen Polyaryletherketonen zur Herstellung von Zahnersatz
WO2012008837A3 (fr) * 2010-07-16 2012-05-10 X-Flow Bv Poly(arylsulfone) greffée et procédé de greffage d'une poly(arylsulfone)
GB2536388A (en) * 2016-06-29 2016-09-14 Invibio Ltd Polymer and articles
GB2536387A (en) * 2016-06-29 2016-09-14 Victrex Mfg Ltd Polymer method, particles and intermediates

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US6117967A (en) * 1999-06-04 2000-09-12 Xerox Corporation Arylene ether alcohol polymers

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LINDFORS B E ET AL: "HETEROGENEOUS HYDROLYSIS OF POLY(ARYL ETHER KETIMINE)S-AN ALTERNATIVE SYNTHETIC ROUTE TO SEMICRYSTALLINE POLY(ARYL ETHER KETONE)S", MAKROMOLEKULARE CHEMIE, RAPID COMMUNICATIONS, HUTHIG UND WEPF VERLAG. BASEL, CH, vol. 12, no. 6, 1 June 1991 (1991-06-01), pages 337 - 345, XP000232516 *
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THOMPSON S A ET AL: "A NOVEL METHOD FOR CROSSLINKING POLYETHERETHERKETONE", JOURNAL OF APPLIED POLYMER SCIENCE, JOHN WILEY AND SONS INC. NEW YORK, US, vol. 36, no. 5, 20 August 1988 (1988-08-20), pages 1113 - 1120, XP000149412, ISSN: 0021-8995 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004008314A1 (de) * 2004-02-20 2005-09-15 Friadent Gmbh Verwendung von Zirkonoxid-haltigen Polyaryletherketonen zur Herstellung von Zahnersatz
DE102004008314B4 (de) * 2004-02-20 2006-02-09 Friadent Gmbh Verwendung von Zirkonoxid-haltigen Polyaryletherketonen zur Herstellung von Zahnersatz
WO2012008837A3 (fr) * 2010-07-16 2012-05-10 X-Flow Bv Poly(arylsulfone) greffée et procédé de greffage d'une poly(arylsulfone)
AU2011277176B2 (en) * 2010-07-16 2014-08-21 X-Flow Bv Grafted poly(arylsulfone) and a process for grafting a poly(arylsulfone)
US8889824B2 (en) 2010-07-16 2014-11-18 X-Flow Bv Grafted poly(arylsulfone) and a process for grafting a poly(arylsulfone)
GB2536388A (en) * 2016-06-29 2016-09-14 Invibio Ltd Polymer and articles
GB2536387A (en) * 2016-06-29 2016-09-14 Victrex Mfg Ltd Polymer method, particles and intermediates
GB2536387B (en) * 2016-06-29 2017-05-10 Victrex Mfg Ltd Preparation of phosphate stabilised polyetheretherketone (PEEK)
GB2536388B (en) * 2016-06-29 2017-05-10 Invibio Ltd Phosphate stabilised polyetheretherketone (PEEK) and use thereof

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