WO2002000763A1 - Materiaux polymeres biocompatibles - Google Patents

Materiaux polymeres biocompatibles Download PDF

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Publication number
WO2002000763A1
WO2002000763A1 PCT/GB2001/002793 GB0102793W WO0200763A1 WO 2002000763 A1 WO2002000763 A1 WO 2002000763A1 GB 0102793 W GB0102793 W GB 0102793W WO 0200763 A1 WO0200763 A1 WO 0200763A1
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moieties
polymer
bio
compatible
groups
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PCT/GB2001/002793
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English (en)
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John Neil Devine
David John Kemmish
Brian Wilson
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Victrex Manufacturing Limited
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Priority to AU2001274328A priority Critical patent/AU2001274328A1/en
Publication of WO2002000763A1 publication Critical patent/WO2002000763A1/fr

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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • 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
    • 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
    • A61L31/08—Materials for coatings
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials

Definitions

  • This invention relates to bio-compatible polymeric materials and particularly, although not exclusively, provides a bio-compatible polymeric material, a method of producing such a material 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 bio-compatible polymeric material comprising a polymer having functionalised ketone groups in the polymer backbone, wherein ketone groups in the polymer backbone have been functionalised to provide at least two moieties per ketone group which moieties are associated with a part of a bio-compatible moiety.
  • 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 functionalised ketone groups may comprise -C- moieties in the polymer backbone wherein said -C- moieties are functionalised to provide at least two moieties per
  • 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 has improved or enhanced bio-compatibility compared to said polymer in the absence of associated bio-compatible moieties.
  • Bio-compatible moieties suitably include moieties arranged to reduce adverse biological reactions when the 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.
  • Said polymer having functionalised ketone groups may comprise an aliphatic polyketone wherein ketone groups thereof have been functionalised.
  • Said polymer having functionalised ketone groups may include a polymer back bone which includes moieties of formula
  • Aliphatic ketones which can be functionalised as described herein are sold under the Trade Marks CARILON and KETONEX by Shell and BP respectively.
  • said bio-compatible polymeric material comprises a polymer having phenyl groups, functionalised ketone groups and ether or thioether groups in the polymer backbone .
  • said bio-compatible polymeric material comprises a polymer having 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 1 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
  • said polymer includes ketone groups which have been functionalised to provide at least two moieties per ketone group which moieties are associated with a part of a bio- compatible moiety.
  • ketone groups of said polymer are replaced by -C- moieties in the polymer backbone, wherein said -C- moieties include at least two moieties per -C- moiety, each of which two moieties being associated with part of a bio-compatible moiety.
  • 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.
  • Polymers of the type described may be prepared as described in PCT/GB99/02833.
  • 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 ⁇ - ⁇ 0 , especially C ⁇ _ 4 , alkyl groups.
  • Preferred cycloalkyl groups include cyclohexyl and multicyclic groups, for example adamantyl.
  • Another group of optional substituents of the phenyl moieties in units I, II or III include alkyls, halogens,
  • 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; and
  • (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) , (iii) and (iv) and, of these, moieties (i)*, (i) and (iv) are preferred.
  • Other preferred moieties Ar are moieties (xi)*, (xii) , (xi) , (xiii) and (xiv) and, of these, moieties (xi)*, (xi) and (xiv) are especially preferred.
  • polymers which consist essentially of phenyl moieties in conjunction with ketone and/or ether moieties wherein ketone moieties have been functionalised as described. 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 :
  • the polymers described in (a) and (b) are preferred, with the polymer described in (a) being especially preferred.
  • at least some ketone groups have been functionalised as described.
  • ketone groups of said polymer at or adjacent to a surface of the bio-compatible material have been functionalised to provide said at least two moieties as described and, suitably, ketone groups within the bulk of said polymer are not functionalised.
  • the bulk of said polymer is different compared to a region of the polymer at or adjacent a surface thereof.
  • the concentration of ketone moieties within the bulk of said bio-compatible polymeric material is preferably greater than the concentration of ketone moieties at or adjacent the surface of said material.
  • Bio-compatible moieties are preferably associated with the surface of said bio-compatible polymeric material and, suitably, do not substantially penetrate the bulk of the material.
  • the concentration of bio-compatible moieties at a surface of said bio-compatible polymeric material is preferably greater than the concentration in the bulk of the material .
  • the invention 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 having phenyl groups, ketone groups and ether or thioether groups in the polymer backbone.
  • the polymer in the bulk and the polymer at the surface of said bio-compatible material are the same except that ketone moieties of said polymer at the surface have been functionalised.
  • the invention further extends to a bio-compatible polymeric material comprising a polymer having associated bio-compatible moieties, wherein the bulk of said bio- compatible polymeric material comprises a polymer having phenyl groups, ketone groups and ether or thioether groups in the polymer backbone and the surface of said bio- compatible polymeric material comprises a polymer which has a lower concentration of ketone groups compared to the concentration of ketone groups in the bulk, wherein bio- compatible moieties are associated with " said polymer at said surface.
  • said polymer having associated bio-compatible moieties is suitably present only at a surface of said bio-compatible - polymeric material and is present at a small fraction of the total weight of polymer (the majority of which will not include associated bio- compatible moieties) the existence of said bio-compatible moieties may have limited effect on the bulk properties of said bio-compatible polymeric material compared to said polymer in the absence of said associated bio-compatible moieties .
  • 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, (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 may consist essentially of a single type of polymer with associated bio-compatible moieties (although the bulk of the material may include a polymer which does not have associated bio- compatible moieties and/or functionalised ketone groups) .
  • the bulk of said bio-compatible polymeric material consists essentially of a single polymer.
  • said bio-compatible polymeric material for example the bulk thereof, may comprise a blend of polymers, suitably having different molecular weights.
  • a blend may comprise a relatively low molecular weight polymer and a relatively high molecular weight polymer.
  • a blend comprises a relatively low molecular weight polymer
  • the molecular weight of said low molecular weight polymer may be less than 14,000, but preferably greater than 2,000.
  • the relatively high molecular weight polymer may have a molecular weight of at least 14,000 and suitably less than 80,000, especially 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. 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 preferably has a flexural modulus (according to
  • the flexural modulus may be less than " 60, suitably " less than " 25, preferably less than
  • 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 50 GPa and a flexural strength of 620 MPa.
  • 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 an 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, 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.
  • said blend preferably includes at least two polymers of a type 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 bio-compatible polymeric material preferably includes a major amount of a higher molecular weight polymer.
  • 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 avid ⁇ n " , 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
  • 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 polysiloxanes
  • PDMS polydimethylsiloxanes
  • ionic water-soluble polymers like poly (acrylic acid)
  • 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 at least one of said at least two moieties of said polymer of said bio-compatible polymeric material, for example by being covalently bonded to said at least one of said 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. Especially preferred is hydroxyapatite, a synthetic Ca-P ceramic.
  • bio-compatible moieties may be associated by any suitable means with said ketone group which have been functionalised, 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 at least two moieties or there are ionic interactions between said bio-compatible moieties and said at least two moieties.
  • Ketone groups (-CO-) in said polymer backbone for example at least one ketone group in moieties I, II and/or III, may be replaced by:
  • L 1 and L 4 represent linking groups which are disubstituted by moieties K 1 and K 2 either on the same or different atoms; L 2 and L 3 independently represent direct links or linking groups which are substituted by moieties K 3 and K 4 respectively; or BM 1 and BM 2 represent bio- compatible moieties associated with K 1 , K 2 , K 3 and K 4 , wherein BM 1 and BM 2 may represent separate moieties or may represent a single moiety which is associated with both K 1 and K 2 ; K 1 , K 2 , K 3 and K 4 represent moieties associated with bio-compatible moieties; and K 5 represents a moiety which may, but preferably does not, include a linking group and/or an associated bio-compatible moiety.
  • K 5 represents a moiety which is not associated and/or associatable with a bio-compatible moiety, for example a moiety BM 1 or BM 2 .
  • K 5 represents a hydrogen atom.
  • each moiety L 1 , L 2 , L 3 or L 4 may be functionalised with further moieties K 1 , K 2 , K 3 , K 4 and such further moieties may be associated with bio- compatible moieties.
  • L 1 , L 2 , L 3 and L 4 are substituted only by the number of moieties shown.
  • Each of K 1 , K 2 , K 3 and K 4 (and, optionally, K 5 ) may independently include one of the following functional groups or may include the residue of one of the following functional groups (after association with BM 1 and BM 2 ) thereby to enable K 1 , K 2 , K 3 and K 4 (and, optionally, K 5 ) to associate with bio-compatible moieties (e.g.
  • Each of L 1 , L 2 , L 3 and L 4 may independently 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. -O-aryl-alkyl, (hetero) heteroaryl e.g. -N-heteroaryl and (hetero) aryl e.g. -O-aryl.
  • Examples of groups of formula VII (excluding BM 1 and BM 2 ) include
  • Examples of groups of formula VIII include BM 1 and BM 2 .
  • a method of making a bio-compatible polymeric material for use in medical applications include the steps of : (i) selecting a polymer having ketone groups in the polymer backbone; and
  • Said polymer selected in step (i) may be as described in any statement herein. It is preferably a polymer having phenyl groups, ketone groups, optionally sulphone groups, and ether or thioether groups. For example, it may include moieties I, II, III, IV, IV*, V or V*, suitably prior to functionalisation of any ketone groups thereof and provided of course that the polymer includes ketone groups .
  • the moieties produced in step (ii) are not, in themselves, bio-compatible; preferably, ketone groups are functionalised to provide said at least two moieties and bio-compatible moieties are then associated with said at least two moieties.
  • the method involves functionalising ketone groups in said polymer which are present at or adjacent a surface thereof, and, suitably, ketone groups within the bulk of said polymer are not functionalised in the manner described.
  • the method preferably includes the step of functionalising said polymer so that the concentration of ketone moieties within the bulk of the polymer is greater than the concentration of ketone moieties at or adjacent the surface of said polymer.
  • said polymer is presented as a solid, suitably shaped so as to represent at least part of a device for use in medical applications, and 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.
  • Ketone groups in said polymer may be functionalised to provide said at least two moieties in a single treatment.
  • Example 1 hereinafter is of this type.
  • the method may include a series of treatments to provide said at least two moieties.
  • Examples 2, 3, 5, and 7 hereinafter are of this type.
  • functionalisation of ketone groups involves an initial step wherein said ketones groups are functionalised to form hydroxy groups. Hydroxy groups may be functionalised in subsequent treatments or may aid substitution or reaction of another group linked to the same carbon atom which carries a hydroxy group.
  • functionalisation of ketone groups may include a step comprising treatment of said ketone groups to form hydroxy groups.
  • the method preferably includes the step of treating said polymer after functionalisation of ketone groups to provide said at least two 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 herein.
  • 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 said at least two 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.
  • the 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.
  • Association of bio-compatible moieties with said at least two moieties may be effected in any suitable way which will depend on the nature of the BCM material and/or the identity of said at least two moieties formed by functionalising ketone groups of the polymer.
  • the method may include causing covalent bond formation between the polymer and said bio-compatible moieties.
  • association of said at least two moieties and bio-compatible moieties may be effected by other means, for example by ionic interactions. Bio-compatible moieties could be built up in a series of steps.
  • BCM material may include any suitable functional group that is arranged to become associated with functional groups resulting from functionalising ketone groups in the polymer backbone and may be selected from any of the functional groups referred to above for K 1 , K 2 , K 3 , K 4 and/or K 5 provided that a selected functional group is capable of becoming associated with, suitably reacting, with a said functional group resulting from functionalising ketone groups in the polymer backbone.
  • BCM material may be provided by reaction of one or more functional groups resulting from functionalising ketone groups in the polymer backbone with more than one functional group.
  • said bio- compatible moieties may include a polyurethane which may be prepared: when one or more functional groups resulting from functionalising ketone groups in the polymer backbone is/are hydroxy groups and BCM material provides a diisocyanate and a diol; or when one or more functional groups resulting from functionalising ketone groups in the polymer backbone include isocyanate groups and BCM material provides a diisocyanate and a diol.
  • BCM material may be provided by use of two different compounds.
  • ketone groups in said polymer are functionalised to:
  • L 1 , L 2 , L 3 and L 4 are as described above; J 1 , J 2 , J 3 and J 4 represent groups which can be associated with bio- compatible moieties; and J 5 represents a moiety which may be but is preferably not adapted to be associated with bio-compatible moieties.
  • J 5 preferably represents a hydrogen atom.
  • J 1 , J 2 , J 3 and J 4 may independently represent any of the functional groups described above for K 1 , K 2 , K 3 and ⁇ 4 -
  • the method may include the step(s) of treating a polymer which includes groups IX, X or XI with a material *BM 1 and/or *BM 2 arranged to supply bio-compatible moieties BM 1 and/or BM 2 as described above such that, after said treatment (s) , said groups IX, X, XI define groups VI, VII and VIII described above respectively.
  • BM 1 and/or BM 2 may be built up in a series of steps and, in this case, a polymer which includes group IX, X or XI may be treated with a material *BM 1 and/or *BM 2 arranged to supply parts of bio-compatible moieties BM 1 and/or BM 2 , with other parts thereof being supplied in subsequent treatment (s) .
  • *BM 1 and *BM 2 may be the same as BM 1 and BM 2 respectively; and J 1 , J 2 , J 3 and J 4 may be the same as K 1 , K 2 , K 3 and K 4 respectively.
  • *BM X and *BM 2 may include any functional groups arranged to become associated with J 1 , J 2 , J 3 or J 4 and may be selected from any of the functional groups described above for K 1 , K 2 , K 3 and K 4 provided that a selected functional group is capable of " becoming associated with, suitably reacting, with a selected functional group provided by J 1 , J 2 , J 3 and
  • *BM 1 and *BM 2 may be the same or different. Advantageously they are the same.
  • *BM 1 and *BM 2 may be respective parts of a single entity, for example a single chemical compound, whereby after treatment with IX, X or XI said single entity may provide a bridge between J 1 and J 2 ; or J 3 and J 4 .
  • *BM X and *BM 2 are not respective parts of a single entity.
  • Polymers described herein may be prepared as described in PCT/GB99/02833.
  • a device for use in medical applications wherein said device includes a bio- compatible polymeric material according to said first aspect or made in a method according to said second aspect .
  • 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 hip or knee 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 part 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; and treating material in said shape (preferably the surface thereof) thereby to functionalise ketone groups in said polymer to provide at least two moieties per ketone group which are associated with a bio-compatible moiety or which moieties are themselves bio-compatible moieties.
  • the invention extends to the use of a polymer having carbon atoms (suitably derived from ketone groups) in its polymer backbone which carbon atoms include one or more pendent groups which is/are associated with respective parts of one or more bio-compatible moieties, wherein at least two parts of one or more pendent groups of a respective said carbon atom are associated with at least two part(s) of one or more bio-compatible moieties.
  • PEEK Trade Mark
  • All PEEKTM films used were approximately 120 ⁇ m thick. Film samples were prepared from samples of Victrex PEEKTM (Melt Viscosity 0.45 kNgm “2 at 1000 sec "1 at 400°C) powder which was compression moulded between metal plates using a Moore laboratory hot press at 400°C for 5 to 10 minutes. The PEEKTM melt was quenched in ice-cold water in order to obtain 120 ⁇ m thick amorphous samples. The film samples were refluxed in acetone for 72 hours prior to use.
  • Victrex PEEKTM Melt Viscosity 0.45 kNgm "2 at 1000 sec "1 at 400°C
  • the PEEKTM melt was quenched in ice-cold water in order to obtain 120 ⁇ m thick amorphous samples.
  • the film samples were refluxed in acetone for 72 hours prior to use.
  • Example 1 Reaction of PEEKTM film with 4- lithiobenzonitrile.
  • 4- bromobenzonitrile (3.0g, 16.50mmol).
  • To this solution was added (10.3ml, 16.50mmol) of 1.6M n-butyl lithium at -78 °C.
  • the reaction solution was then stirred at -78 °C for lh.
  • the reaction solution was transferred via cannulae to a test tube containing PEEKTM films (1cm x 5cm) under a nitrogen atmosphere.
  • the solution was then allowed to warm to room temperature and stirred for a further 24 hours.
  • the films were then removed and washed with isopropanol (3 x 50ml) , methanol (3 x 50ml) and acetone (2 x 50ml) before being dried at room temperature for 24h.
  • a film from example 1 was placed in a 250ml round bottomed flask fitted with a reflux condenser. To the flask was added 80ml of a 10% aqueous sodium hydroxide and 15ml of ethanol in order to facilitate complete hydrolysis of the nitrile to the carboxylic acid. The solution was heated to reflux for 12-24 hours in order to ensure complete hydrolysis. The solution was cooled and the film removed and placed in a solution of glacial acetic acid followed by washing with 2M HCl and distilled water. The sample was dried at room temperature overnight .
  • Example 3 Partial hydrolysis of the nitrile group of a modified PEEKTM film
  • a film from example 1 was placed in a 250ml round bottomed flask fitted with a reflux condenser. To the flask was added 65ml of ethanol followed by 5ml of 25% sodium hydroxide. The solution was stirred whilst 50ml of 27.5% hydrogen peroxide was run into the flask via dropping funnel . The addition took place such that the temperature of the reaction solution was within the 40- 50 °C range. When the exothermic reaction was complete the reaction mixture was heated to 50 °C for 24h. The film was then removed from the solution and washed with 2M HCl solution followed by distilled water.
  • Example 5 Reaction of a modified PEEKTM film with p- a inobenzoic acid.
  • PEEKTM film from example 4 was 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 then removed and washed with acetic acid followed by distilled water and acetone, before being dried at room temperature overnight .
  • Dimethylsulfoxide (300ml) and sodium borohydride (2.4g, 63.5mmol) were introduced to a 500ml reaction flask and the solution stirred at 120°C.
  • a PEEKTM film sample (2 x 10cm) was totally immersed in the reaction solution and stirred at 120 °C for 6h. The film was then removed ana washed successively " with methanol, water and ethanol. The sample was then dried at room temperature overnight .
  • PEEKTM film was immersed into a solution of 2,4, 6-triaminopyrimidine (5.4g, 43.2mmol) in ethanol (15ml) and water (3ml). Sodium hydroxide (1.8g, 45mmol) was then added portionwise over 30 minutes. The reaction mixture was then heated to 40 °C and stirred for 24h before being stirred at reflux for 72h. The film sample was then removed and washed successively with 10% aqueous HCl, water, methanol and hexane. The sample was then dried at room temperature overnight .
  • a lcm x 4cm strip of modified PEEKTM film from example 6 was immersed into a 3% (w/v) solution of glutamic acid in acetic acid containing H 2 S0 4 (0.5%) as a catalyst. The reaction mixture was heated to 90-110°C and stirred for
  • a surface modified PEEKTM film from Example 8 was stirred at 10°C for 1 hr under an atmosphere of nitrogen in an aqueous solution of the water soluble carbodiimide, l-ethyl-3- (3-dimethylamino propyl) -carbodiimide) (0.4g) -dissolved in- buffer at pH 4.5 (0.1M 2-(N- morpholino) ethanesulphonic acid) (40ml). The sample of PEEK was removed and washed with buffer solution.
  • the functionalised PEEKTM was washed successively with phosphate buffer and distilled water. Each carboxyl group ⁇ of the functionalised PEEKTM reacts with a separate peptide.
  • a modified PEEKTM sample from example 7 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing
  • a modified PEEKTM sample from example 7 was placed in a 250ml round-bottomed flask fitted with a magnetic follower and a nitrogen inlet and outlet and containing N,N-dimethylacetamide (60ml) , and disuccinimidylsuberate

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

Abstract

L'invention concerne un matériau polymère biocompatible, conçu pour être utilisé dans des applications médicales, par exemple dans une prothèse orthopédique, et comprenant un polymère possédant des groupes cétone fonctionnalisés dans le squelette polymère, lesquels groupes cétone ont été fonctionnalisés de manière à fournir au moins deux fractions par groupe cétone, ces fractions étant associées à une partie d'une fraction biocompatible. Un polymère particulièrement préféré est un polymère comportant, dans le squelette polymère, des fractions phényle, des groupes cétone fonctionnalisés, éventuellement des fractions sulfone, et des fractions éther ou thioéther.
PCT/GB2001/002793 2000-06-24 2001-06-22 Materiaux polymeres biocompatibles WO2002000763A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013023997A1 (fr) 2011-08-12 2013-02-21 Solvay Specialty Polymers Usa, Llc Polyarylène éther cétones
EP2749300A1 (fr) 2012-12-26 2014-07-02 Universidad Del Pais Vasco-Euskal Herriko Unibertsitatea Polymère polyaryléthercétone modifié (PAEK) et procédé pour l'obtenir

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1411267A (en) * 1971-10-06 1975-10-22 Astra Laekemedel Ab Process for preparing water swellable polymers

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1411267A (en) * 1971-10-06 1975-10-22 Astra Laekemedel Ab Process for preparing water swellable polymers

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HENNEUSE C ET AL: "Surface carboxylation of PEEK film by selective wet-chemistry", POLYMER, ELSEVIER SCIENCE PUBLISHERS B.V, GB, vol. 39, no. 4, 1 February 1998 (1998-02-01), pages 835 - 844, XP004099267, ISSN: 0032-3861 *
HENNEUSE-BOXUS C ET AL: "Surface amination of PEEK film by selective wet-chemistry", POLYMER, ELSEVIER SCIENCE PUBLISHERS B.V, GB, vol. 39, no. 22, 1 October 1998 (1998-10-01), pages 5359 - 5369, XP004129111, ISSN: 0032-3861 *
NOISET O ET AL: "SURFACE REDUCTION OF POLY(ARYL ETHER ETHER KETONE) FILM: UV SPECTROPHOTOMETRIC, 3H RADIOCHEMICAL, AND X-RAY PHOTOELECTRON SPECTROSCOPIC ASSAYS OF THE HYDROXYL FUNCTIONS", MACROMOLECULES, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 30, no. 3, 10 February 1997 (1997-02-10), pages 540 - 548, XP000678014, ISSN: 0024-9297 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP2749300A1 (fr) 2012-12-26 2014-07-02 Universidad Del Pais Vasco-Euskal Herriko Unibertsitatea Polymère polyaryléthercétone modifié (PAEK) et procédé pour l'obtenir
WO2014102435A2 (fr) 2012-12-26 2014-07-03 Universidad Del Pais Vasco/Euskal Herriko Unibertsitatea Polymère de polyaryléthercétone modifié (paek) et son procédé d'obtention
WO2014102435A3 (fr) * 2012-12-26 2014-10-23 Universidad Del Pais Vasco/Euskal Herriko Unibertsitatea Polymère de polyaryléthercétone modifié (paek) et son procédé d'obtention
CN105473169A (zh) * 2012-12-26 2016-04-06 巴斯克大学 改性聚芳醚酮(paek)聚合物及其获得方法

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