WO2002000271A1 - Materiaux polymeres biocompatibles - Google Patents

Materiaux polymeres biocompatibles Download PDF

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Publication number
WO2002000271A1
WO2002000271A1 PCT/GB2001/002818 GB0102818W WO0200271A1 WO 2002000271 A1 WO2002000271 A1 WO 2002000271A1 GB 0102818 W GB0102818 W GB 0102818W WO 0200271 A1 WO0200271 A1 WO 0200271A1
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Prior art keywords
polymer
moieties
bio
compatible
functionalised
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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 AU66164/01A priority Critical patent/AU6616401A/en
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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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

  • This invention relates to bio-compatible polymeric materials and particularly, although not exclusively, relates to a method of producing a bio-compatible polymeric material, such a material per se and the use of such a 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.
  • a method of functionalising a polymer to produce a bio-compatible polymeric material which includes bio- compatible moieties and is for use in medical applications including the stages of: (1) treating a polymer which has a moiety of formula
  • aryl especially phenyl, moieties in said polymer (hereinafter referred to as "functionalised aryl moieties") at or adjacent a surface of the polymer whilst not .
  • functionalising corresponding aryl moieties in the bulk of said polymer wherein the phenyl moieties in units I, II, and III (prior to functionalisation) 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
  • 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
  • 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.
  • bio-compatible has generally been used to refer to a material which is compatible with use in medical applications, for example by not being toxic or otherwise harmful to living materials. It also encompasses materials which have a biological or physiological effect when associated with living materials.
  • Bio-compatible moieties 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.
  • said bio-compatible polymeric material produced in the method has improved or enhanced bio- compatibility compared to said polymer in the absence of bio-compatible moieties associated with functionalised aryl groups thereof .
  • 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.
  • 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.
  • a said bio-compatible moiety may be selected from an anticoagulant 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 avidin, 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, oxacillian, cefazolin
  • agent-, —a hydrophi ⁇ c—polymer ⁇ e.'g. poly(ethylene glycol)
  • PEG poly (ethylene oxide)
  • PEO poly (ethylene oxide)
  • PNVP poly (N-vinyl-2- pyrrolidone)
  • pHEMA poly (2-hydroxyethyl methacrylate
  • HEMA HEMA co-polymers
  • PVA polyacrylamide, its derivatives
  • PMMA suitably having a PEG chain on each of the side groups, polysiloxanes (e.g. polydimethylsiloxanes (PDMS) ) , ionic water-soluble polymers like poly (acrylic acid) (PAAc) ) and a polyurethane .
  • PDMS polydimethylsiloxanes
  • PAAc polyacrylic acid
  • 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 especially 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.
  • 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 (prior to any functionalisation in stage (1) of the method) , 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 ada antyl .
  • said phenyl moieties are not optionally- substituted (prior to any functionalisation ' in stage (1) of said method) .
  • 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) ,
  • An. especially preferred class of polymers are polymers which consist essentially of phenyl moieties in conjunction with ketone and/or ether moieties. That is, in the preferred class, 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:
  • B represents 0 (i .e.polyetherketone) ;
  • E' represent oxygen atoms
  • G represents a direct link
  • m represents 0, w represents 1, r represents 0, s represents 1 and
  • a and B represent 1. (i .e.polyetherketoneetherketoneketone) .
  • polymers described in (a) and (b) are preferred, with the polymer described in (a) being especially preferred.
  • 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 aryl moieties of said polymer such that the concentration of non-functionalised aryl moieties (i.e. aryl moieties not functionalised in the method) present within the bulk of the ' functionalised polymer is greater than the concentration of non-functionalised aryl moieties present at or adjacent the surface.
  • the concentration of bio-compatible moieties in the bulk is suitably less than present at 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 suitable 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 and associate bio-compatible moieties therewith.
  • the method preferably includes the step of treating said polymer after functionalisation of said aryl moieties in stage (1) 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 functionalised aryl moieties at a surface of said solid.
  • Said solid is preferably shaped so as to represent at least a part of a device for use in medical applications, as described above.
  • bio-compatible material formed is not engineered or otherwise treated in a manner -whrch—may result in substantial "depletion of the bio-compatible moieties associated with its surface.
  • Stage (1) preferably involves subjecting said polymer to an electrophilic aromatic substitution reaction.
  • the identity of the polymer, the identity of the electrophile and the conditions of the treatment may be selected to control the extent of electrophilic substitution (both in terms of the aryl moieties of said polymer which are substituted and the depth of substitution) .
  • the ease of electrophilic aromatic substitution on a particular phenyl moiety in a polymer of the types described is dependent upon the identity of groups to which the phenyl moiety is bonded. The more electron withdrawing the groups bonded to a phenyl moiety, the less susceptible the group is to electrophilic aromatic substitution.
  • polyarylether ketones as an example, the ease of electrophilic aromatic substitution decreases down the following list, wherein Ph represents a phenyl group:
  • Polymers which include sulphone and/or thioether moieties may behave in a similar fashion. Compared to polyaryletherketones, -S-Ph-Ph-S- and -S-Ph-S- may be substitutable with about the same ease as for the ether equivalents. However, sulphone containing moieties may render phenyl groups less easy to sulphonate compared to the ketone equivalents. Thus, by careful selection of the polymers" "and' the" -cOnditr ⁇ ns for- electrophilic aromatic substitution, the electrophilic substitution can be carefully controlled and, consequently, the concentration and spacial distribution of sites where bio-compatible moieties may be associated with the polymer can be controlled. Thus, the method may be advantageously used to optimise the concentration and spacial distribution of bio-compatible moieties at or adjacent the surface of the polymer.
  • no -CO(Ph) n -CO- or -S0 2 - (Ph) n -S0 2 - moieties, where n is an integer, are substituted by an electrophile in the method.
  • no -CO- (Ph) n -0- , -C0(Ph) n -S-, -S0 2 - (Ph)n-O- or -S0 2 - (Ph) n -S- moieties are substituted by an electophile in the method.
  • the method may involve treating the polymer with any known reagent (s) arranged for electrophilic aromatic substitution.
  • electrophilic aromatic substitution reactions include sulphonation, chlorosulphonation, nitration, acylation, halogenation, chloromethylation, phosphonylation, lithiation and (optionally-substituted) alkylation reactions.
  • halogenation may be least preferred.
  • Preferred reactions involve contact of the polymer with a liquid.
  • Sulphonation may result in an -S0 3 H group being introduced onto an aryl, especially a phenyl moiety.
  • a sulphonic acid especially chlorosulphonic acid is used in the method.
  • Chlorosulphonation may involve a sulphonation reaction as described followed by chlorination of the sulphonate unit, for example using thionyl chloride or any other suitable chlorinating agent.
  • Nitration may be effected using a nitric acid/sulphuric acid mixture.
  • the mixture is selected so that any competing sulphonation is suppressed thereby leading to nitration only.
  • Acylation may be effected by a Friedel-Crafts reaction, for example using a reagent which includes a ketone group and aluminium chloride .
  • a compound R 20 COC1 may be used to introduce a moiety R 20 CO- wherein R 20 represents an optionally- substituted alkyl or aryl group.
  • a cyclic anhydride e.g. of formula CH 2 CH 2 CH 2 CO .0. CO glutaric anhydride
  • R 21 -R 22 - wherein R 22 represents an alkyl or alkenyl moiety, especially an alkyl moiety, and R 21 represents a functional group, suitably selected from a halogen, especially a chlorine, atom (in which case R 21 - R 22 - may represent a chloroalkyl, especially a chloromethyl group) and a sulphonate group.
  • R 21 represents a sulphonate group
  • a cyclic compound which includes a -S0 2 -0- moiety in its ring, for example a sultone may be used in the reaction.
  • Control of the electrophilic aromatic substitution reactions may involve selecting particular concentrations of electrophilic reagents .
  • Thin surface modifications may be preferred, for example to a depth of less than 50, preferably less than 30, more preferably less than 20, especially 10 Angstroms or less. A depth of 3-10 Angstroms may be preferred.
  • the sol-vent in- -which functionalisation is undertaken may be selected such that the polymer has low or substantially no solubility in the solvent .
  • the electrophilic aromatic substitution reaction is undertaken for a predetermined time.
  • steps are taken to stop the reactions, for example by removal of the polymer and/or by washing.
  • reagents may be selected whereby multiple functionalisation of aryl moieties of said polymer may take place.
  • no more than three, more preferably no more than two, especially only one hydrogen atom of an aryl moiety is substituted in an electrophilic reaction as described.
  • said polymer having functionalised aryl moieties may be associated with bio-compatible moieties as described, without any further treatment of said aryl moieties. However, it may be preferred for said polymer to be subjected to a further treatment thereby to functionalise the electrophilic moieties introduced in stage (1) , preferably to introduce a functional group pendent from the functionalised aryl moieties which can be associated with bio-compatible moieties in stage (2) .
  • functionalised aryl moieties may include functional groups selected from the following for association with bio-compatible moieties: -OH, -CHO, -NR 10 2, preferably -NH 2 or -NHR 10 , -SH, -C0NH 2 , -CONHR 10 , -COOH, -COC1 or -COOR 10 group, a halogen atom, especially a
  • BCM material described above may include any suitable functional group that is arranged to become associated with functional groups of said functionalised aryl moieties of said polymer and may be selected from any of the functional groups referred to above for said functionalised aryl moieties 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 when said functionalised polymer provides an isocyanate group and said BCM material provides a diisocyanate and a diol.
  • BCM material is suitably provided by use of 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.
  • Such treatment (s) may include reduction reactions (e.g. of nitro groups to amine groups), salt formation (e.g. to form -S0 3 Na) , halogenation (e.g. to form -S0 2 C1) or treatment with other linker or spacer moieties.
  • Linker or spacer moieties which may extend between aryl moieties functionalised in stage (1) and bio-compatible moieties introduced in stage (2) may include any suitable linking group and such linking groups may include saturated, unsaturated, linear, branched or cyclic moieties.
  • Preferred linking groups include optionally - -substituted- alkyl, alkenyl, alkynyl, heteroalkyl e.g. -N-alkyl, aryl, heteroaryl, e.g. pyridyl, alkylaryl, hetero (aryl) alkyl, e.g. -0-aryl-alkyl, (hetero) heteroaryl e.g. -N-heteroaryl and (hetero) aryl e.g. -O- aryl .
  • a bio- compatible polymeric material wherein the bulk of the material comprises a polymer having a moiety of formula I and/or of formula II and/or formula III as described according to said first aspect, wherein a surface of said material comprises a functionalised derivative of said polymer present in the bulk wherein bio-compatible moieties are associated with functionalised aryl moieties at or adjacent said surface.
  • 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 i-nherent viscosity (-IV-)—of-at- least 0.1, - suitably at least
  • RV reduced 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, (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). Alternatively, crystallinity may be assessed by Differential Scanning Calorimetry (DSC) .
  • DSC Differential Scanning Calorimetry
  • 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) of at least 80, preferably at least 90, especially at least 95 MPa.
  • the tensile strength may be less than 360, suitably less than 250, preferably less than 140 MPa. It preferably has an elongate at break (according to ISO R527) of at least 40, preferably at least 50%. It preferably has a tensile modulus (according to ISO R527) of greater than 2.5, preferably greater than 3, especially greater than 3.5 GPa.
  • the tensile modulus may be less than 40, suitably less than 30, preferably less than 20, more preferably less than 10 GPa.
  • flexural strength (according to ASTM D695) of at least 100, more preferably at least 110, especially at least 115 MPa.
  • the flexural strength may be less than 650, preferably less than 400, more preferably less than 260, especially less than 200 MPa.
  • 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 elongation of 2%, a flexural modulus of SO GPa and a flexural strength of 620 MPa.
  • a polyaryletherketone 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 bio-compatible polymeric material includes a major amount of said polymer having moieties I, II and/or III.
  • 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.
  • Said bio-compatible polymeric material may comprise a blend which includes at least two polymers of a type described according to said first aspect.
  • said at least two polymers preferably include moieties I, II and/or III as ' described above.
  • a said blend preferably includes a major amount of higher (or the highest) number average molecular weight polymer.
  • Said functionalised and/or bio-compatible polymeric material preferably includes a major amount of a higher molecular weight polymer .
  • bio-compatible moieties are associated with moieties which are pendent from aryl moieties of the polymer at or adjacent the surface thereof.
  • Polymers of the type described 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 second aspect or made in a method according to said first 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 example 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 part of a device for use in medical applications wherein said material comprises a polymer having moieties I, II and/or III as described herein; and functionalising said polymer as described according to said first aspect.
  • the invention extends to the use of a polymer functionalised as described according to said first or said second aspects in the manufacture of a device for use in a medical treatment, for example in surgery.
  • PEEK (Trade Mark) referred to hereinafter is a polyetheretherketone obtained from Victrex Pic.
  • Example 3 Calcium Phosphate Deposition on a modified PEEKTM sample from example 1.
  • a supersaturated calcium phosphate solution containing 5mM CaCl 2 , 1.5mM KH 2 P0 4 and 1.5mM Na2HP04 was prepared by mixing 1.5ml of 0. IM Na2HP04 stock solution into 92ml of deionised water, followed by the slow addition of 5.0ml of 0.1M CaCl2 solution. The combined solution was stirred for 3 minutes and modified PEEKTM film from example 1 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 PEEKTM sample from example 2 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing
  • the modified PEEKTM sample from Example 1 was placed in a 700ml flanged flask fitted with a reflux condenser, magnetic follower and a nitrogen inlet and outlet and charged with thionyl chloride (250ml) and dimethylformamide (30ml) . Under a nitrogen atmosphere and with continuous stirring the mixture was heated to reflux for 15 hours. The reaction mixture was allowed to cool to room temperature, the sample was then removed and washed with ether and dried in vacuo.
  • the dried sample was then placed in a 100ml Schlenk flask and the flask placed under a nitrogen atmosphere.
  • a 5% w/v solution of p-aminobenzoic acid solution in acetic acid (50ml) was added to the flask and the reaction mixture stirred at room temperature for 72h.
  • the film was removed and washed with acetic acid followed by distilled water and acetone, before being dried at room temperature overnight .
  • the surface modified PEEKTM from Example 5 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; 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un procédé de fonctionnalisation d'un polymère afin de produire un matériau polymère biocompatible comprenant des fragments biocompatibles et destiné à des applications médicales. Dans des modes de réalisations préférés, ce procédé consiste à traiter un polymère sulfone/polyaryléthercétone ( par ex. polyéthercétone ou polyétheréthercétone) afin de fonctionnaliser des fragments phényle de celui-ci sur une surface ou au voisinage d'une surface de ce polymère, les fragments phényle correspondant dans la masse dudit polymère n'étant pas fonctionnalisés, et les fragments biocompatibles étant associés avec lesdits fragments phényle fonctionnalisés afin que lesdits fragments biocompatibles soient sur la surface du polymère ou adjacents à celle-ci.
PCT/GB2001/002818 2000-06-24 2001-06-22 Materiaux polymeres biocompatibles Ceased WO2002000271A1 (fr)

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GBGB0015427.8A GB0015427D0 (en) 2000-06-24 2000-06-24 Bio-compatible polymeric materials

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EP1348454A1 (fr) * 2002-03-28 2003-10-01 Depuy Products, Inc. Prothèse avec un composant de polyaryléthercétone
WO2005023327A1 (fr) * 2003-09-11 2005-03-17 Seft Holding Sa Aiguille en plastique et dispositifs comportant cette aiguille
WO2013023997A1 (fr) 2011-08-12 2013-02-21 Solvay Specialty Polymers Usa, Llc Polyarylène éther cétones
WO2019034207A3 (fr) * 2017-08-14 2019-04-18 Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) Procédé de réalisation d'une couche biocompatible sur une surface d'implant
CN110656492A (zh) * 2019-10-15 2020-01-07 吉林大学 一种基于聚醚醚酮的高性能油水分离材料、制备方法及其应用

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1348454A1 (fr) * 2002-03-28 2003-10-01 Depuy Products, Inc. Prothèse avec un composant de polyaryléthercétone
US6711755B2 (en) 2002-03-28 2004-03-30 Depuy Products, Inc. Prosthetic device having a polyaryletherketone component with enhanced wettability and a method for making the same
US7022798B2 (en) 2002-03-28 2006-04-04 Depuy Products, Inc. Prosthetic device having a polyaryletherketone component with enhanced wettability and method for making the same
AU2003203473B2 (en) * 2002-03-28 2009-04-09 Depuy Products, Inc. Prosthetic device having a polyaryletherketone, component with enhanced wetability and a method for making the same
WO2005023327A1 (fr) * 2003-09-11 2005-03-17 Seft Holding Sa Aiguille en plastique et dispositifs comportant cette aiguille
US8202258B2 (en) 2003-09-11 2012-06-19 Seft Holding Sa Plastic needle and devices comprising it
WO2013023997A1 (fr) 2011-08-12 2013-02-21 Solvay Specialty Polymers Usa, Llc Polyarylène éther cétones
EP2592104A1 (fr) 2011-11-10 2013-05-15 Solvay Specialty Polymers USA, LLC. Polyarylène éther cétones
WO2019034207A3 (fr) * 2017-08-14 2019-04-18 Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) Procédé de réalisation d'une couche biocompatible sur une surface d'implant
CN110656492A (zh) * 2019-10-15 2020-01-07 吉林大学 一种基于聚醚醚酮的高性能油水分离材料、制备方法及其应用

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