EP4065187A1 - Coating for medical devices - Google Patents

Coating for medical devices

Info

Publication number
EP4065187A1
EP4065187A1 EP20803556.8A EP20803556A EP4065187A1 EP 4065187 A1 EP4065187 A1 EP 4065187A1 EP 20803556 A EP20803556 A EP 20803556A EP 4065187 A1 EP4065187 A1 EP 4065187A1
Authority
EP
European Patent Office
Prior art keywords
alkylene
single bond
group
coating
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20803556.8A
Other languages
German (de)
English (en)
French (fr)
Inventor
Mark BRASSIL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smart Reactors Service Ltd
Original Assignee
Smart Reactors Service Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1917529.8A external-priority patent/GB201917529D0/en
Application filed by Smart Reactors Service Ltd filed Critical Smart Reactors Service Ltd
Publication of EP4065187A1 publication Critical patent/EP4065187A1/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/04—Coating
    • C08J7/0427—Coating with only one layer of a composition containing a polymer binder
    • 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
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/064—Use of macromolecular materials obtained 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/04—Acids, Metal salts or ammonium salts thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F22/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides or nitriles thereof
    • C08F22/04—Anhydrides, e.g. cyclic anhydrides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/04—Acids; Metal salts or ammonium salts thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/04—Acids; Metal salts or ammonium salts thereof
    • C08F220/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/34—Introducing sulfur atoms or sulfur-containing groups
    • C08F8/36—Sulfonation; Sulfation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C08J7/14—Chemical modification with acids, their salts or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L35/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical, and containing at least one other carboxyl radical in the molecule, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L35/02—Homopolymers or copolymers of esters
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D133/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Coating compositions based on derivatives of such polymers
    • C09D133/04—Homopolymers or copolymers of esters
    • C09D133/14—Homopolymers or copolymers of esters of esters containing halogen, nitrogen, sulfur or oxygen atoms in addition to the carboxy oxygen
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F120/52—Amides or imides
    • C08F120/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F120/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-acryloyl morpholine
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2327/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers
    • C08J2327/02—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment
    • C08J2327/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment containing chlorine atoms
    • C08J2327/06—Homopolymers or copolymers of vinyl chloride
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
    • C08J2333/02—Homopolymers or copolymers of acids; Metal or ammonium salts thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2335/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical, and containing at least one other carboxyl radical in the molecule, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Derivatives of such polymers

Definitions

  • the invention relates to a coating for a medical device.
  • the invention further relates to a medical device comprising the coating, and to uses and methods involving the coating or the medical device comprising the coating.
  • the invention also relates to a method of manufacturing the coating and to a kit for coating a medical device.
  • Heparin is an anticoagulant that prevents the formation of blood clots.
  • Heparin is a glycosaminoglycan. It is can be difficult to coat onto a medical device and it is relatively expensive.
  • the use of heparin is also associated with several side effects, which include bleeding, severe pain (e.g. at the injection site), nausea and unusual tiredness. There are also serious side effects associated with the use of heparin, such as heparin-induced thrombocytopenia.
  • Heparin is contraindicated for several conditions, which include brain operation, operation on the spine, eye surgery, haemophilia, a deficiency of anti-clotting agents, significant uncontrolled high blood pressure, subacute infection of heart valve, a haemorrhage in the brain, bulge and tear of the aorta blood vessel wall, stomach or intestinal ulcer, ulcerative colitis, an inflammatory condition of the intestines, diverticulitis, severe liver disease, biliary and gallbladder problem, osteoporosis, and chronic kidney disease, which is stage 4 (severe) or stage 5 (failure).
  • the invention provides a coating for a medical device comprising: a surface layer; and optionally a base layer; wherein the surface layer comprises a polymer chain attached or bonded to an anti-clotting group.
  • the coating of the invention is non-thrombogenic and is hemocompatible.
  • the coating has a prophylactic effect in that it can prevent or inhibit the formation of blood clots, which, in turn, prevents or inhibits the onset, progression or recurrence of diseases and conditions associated with blood clots.
  • the inventors have discovered a polymeric material (e.g. polymer chain) that has advantageous properties for use as a coating for a medical device, particularly when it is attached to anti-clotting groups.
  • the anti-clotting groups may also be referred to as hemocompatible groups (i.e. the term “anti-clotting group” is synonymous with “hemocompatible group”).
  • the hemocompatible groups contribute to the overall hemocompatibility of the coating.
  • the anti-clotting group is a sulfonic acid group, a sulfonamide group, a sulfamic acid group, a hydrogen sulfate group or a conjugate base thereof.
  • the negatively charged conjugate base e.g. sulfonate group etc
  • the invention also provides a medical device.
  • the medical device has a surface coated with a coating of the invention.
  • the presence of the coating on a surface of the medical device prevents or inhibits the formation of blood clots on the device when it is used.
  • the invention further provides a polymeric compound.
  • the polymeric compound is represented by formula (C-2):
  • each Y 1 is selected from O , OH, NH , and NH2, preferably selected from O and OH;
  • Y 2 is selected from O and OH;
  • each U is C2-5 alkylene;
  • L 2 is C2-5 alkylene
  • R A is selected from H and C1-6 alkyl; n 1 is an integer; and n 2 is an integer.
  • the invention also provides a method of manufacturing a coating for a medical device.
  • the method may comprise attaching or bonding a compound comprising an anticlotting agent to a polymer using a coupling agent.
  • the anti-clotting agent may also be referred to as a hemocompatibility agent (i.e. the term “anti-clotting agent” is synonymous with the term “hemocompatibility agent”).
  • the method may produce a polymer compound, such as represented by formula (C-2) above.
  • the invention may further provide comprise a method of coating a surface of a medical device.
  • the method may comprise: optionally applying a base layer to a surface of the medical device, and applying a coating to a surface of the medical device.
  • a further aspect of the invention relates to a kit for coating a medical device.
  • the kit comprises: (a) a polymer, (b) compound comprising an anti-clotting group, (c) a coupling agent, and optionally (d) a coating for forming the base layer.
  • the invention further relates to uses of the coating and the medical device.
  • the coating of the invention or the medical device of the invention can be used in the treatment of the human or animal body by surgery or therapy and/or in a diagnostic method practised on the human or animal body.
  • the diagnostic method practised on the human or animal body is typically an in vivo diagnostic method.
  • the coating of the invention or the medical device of the invention is for use in reducing or preventing the clotting of blood.
  • the invention also provides a method of reducing or preventing the clotting of blood.
  • the method comprises contacting a medical device of the invention with blood.
  • An aspect of the method of the invention may be an in vitro method of reducing or preventing the clotting of blood, such as when processing the blood.
  • the method may comprise contacting the medical device with blood, wherein the blood has been removed from a human or animal body.
  • the blood may be contacted with the medical device to process the blood.
  • the processed blood may not be returned to the human or animal body, preferably the human or animal body from which the blood was removed.
  • Another aspect of the method of the invention is a method of reducing or preventing the clotting of blood in a diagnostic procedure.
  • the method may comprise contacting the medical device with blood to obtain diagnostic information.
  • Figure 1 is a histogram showing the clot weights of samples obtained from a whole blood assay experiment.
  • Figure 2 is a series of photographs showing the clots on samples from a whole blood assay experiment after a 12 h incubation time.
  • Figure 3 is a boxplot showing the clot weights (g) from samples obtained from a second whole blood assay experiment.
  • Figure 4 is a series of photographs showing the clots on samples from a second whole blood assay experiment.
  • Figure 5 is a graph showing the mean clot weights from samples obtained from a human whole blood assay experiment.
  • Figure 6 is a series of photographs showing the clots on samples from a human whole blood assay experiment after incubation overnight.
  • Figure 7 is a histogram showing levels of blood concentration of coagulation factor Thrombin-Antithrombin complex (TAT) in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • TAT coagulation factor Thrombin-Antithrombin complex
  • Figure 8 is a histogram showing mean platelet counts in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • Figure 9 is a histogram showing levels of b-Thromboglobulin (b-TG) in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • b-TG b-Thromboglobulin
  • Figure 10 is a histogram showing mean red blood cell counts in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • Figure 11 is a histogram showing mean white blood cell counts in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • Figure 12 is a histogram showing the mean hemolysis concentration in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • Figure 13 is a histogram showing the mean hemoglobin concentration in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard.
  • Figure 14 is a histogram showing the mean hematocrit concentration in the blood of donors at baseline and during/after a 60 min perfusion period (control tube and test item) in a Chandler-Loop model. Bars represent means and standard deviations.
  • biocompatible refers to the ability of a medical device or a material to perform with an appropriate host response in a specific application (e.g. as set out in ISO 10993-1 (2016)).
  • the definition of “biocompatibility”, its associated terms and tests for its evaluation in ISO 10993-1 (2018) are incorporated herein by reference.
  • biocompatibility refers to the ability of a medical device or a material to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appropriate beneficial cellular or tissue response in that specific situation, and optimising the clinically relevant performance of that therapy.
  • sulfonic group is used herein.
  • the term “sulfonic group” is a sulfonic acid group (-SO 3 H) or a sulfonate group (-SO 3 ) ⁇
  • the plural term “sulfonic groups” embraces sulfonic acid groups (-SO 3 H), sulfonate groups (-SO 3 ) or a combination of at least one sulfonic acid group (-SO 3 H) and at least one sulfonate group (-SO 3 ), unless the context indicates otherwise. It should be appreciated that in certain environments, such as physiological environments, the sulfonic acid group (-SO 3 H) may dissociate into a sulfonate group (-SO 3 ) or an equilibrium may exist therebetween.
  • sulfonic group precursor refers to a precursor group that can be hydrolysed to a sulfonic group as defined herein.
  • the precursor group may be a sulfonamide group (e.g. -SO 2 NH 2 , -SC> 2 NHR a or -SC> 2 NR a R b ) or a sulfonate ester group (-SChR 3 ).
  • R a and R b may each independently be selected from C1-C6 alkyl, phenyl and benzyl.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, and containing no unsaturation.
  • a “C1-6 alkyl” group contains one to six carbon atoms. Unless stated otherwise specifically in the specification, an alkyl group is unsubstituted or may be substituted by one or more substituents selected from hydroxy, Ci-e alkoxy and halo, which is preferably fluoro. It is preferred that the alkyl group is unsubstituted.
  • alkene refers to a straight or branched hydrocarbon chain radical group consisting of carbon and hydrogen atoms, and containing at least one carbon-carbon double bond.
  • alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where the alkyl group is defined above.
  • aryloxy refers to a radical bonded through an oxygen atom of the formula -O-aryl, where the aryl group is defined above.
  • aryl refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen atoms and carbon atoms, where at least one of the rings in the ring system is fully unsaturated (i.e. it contains a cyclic, delocalized [4n+2] tt-electron system in accordance with the Huckel theory).
  • the ring system from which aryl groups may be derived include, for example, benzene, indane, indene, tetralin and naphthalene.
  • aryl-alkyl refers to a radical bonded to an alkyl group, such as defined above, which alkyl group is further substituted by (or bonded to) an aryl group as defined above.
  • alkyl group such as defined above
  • alkyl group is further substituted by (or bonded to) an aryl group as defined above.
  • aryl-alkyl groups include benzyl (PhChh-) and phenylethyl.
  • alkylene refers to a straight or branched divalent hydrocarbon chain, which consists of carbon and hydrogen atoms, and contains no unsaturation.
  • alkylene groups include -CH2-, -CH2-CH2- , -CH2-CH2-CH2-, -CH(CH3)-, and -C(CH3)2-CH2-.
  • a “CMO alkylene” group contains one to ten carbon atoms. It is preferred that the alkylene is straight (e.g. unbranched).
  • alkenylene refers to a straight or branched divalent hydrocarbon chain, which consists of carbon and hydrogen atoms, and contains at least one double bond.
  • the alkene group may have a cis or a trans arrangement.
  • a “C2-10 alkenylene” group contains two to ten carbon atoms. When the alkenylene contains more than one double bond, then the double bonds may be conjugated or non-conjugated. It is preferred that the alkenylene group does not comprise an allene group. More preferably, it is preferred that the alkenylene group comprises a single double bond.
  • alkynylene refers to a straight or branched divalent hydrocarbon chain, which consists of carbon and hydrogen atoms, and contains at least triple double bond.
  • a “C 2 -io alkynylene” group contains two to ten carbon atoms. When the alkynylene contains more than one triple bond, then the triple bonds may be conjugated or non-conjugated.
  • an alkynylene group does not include a double bond (e.g. carbon-carbon double bond).
  • the alkynylene group comprises a single triple bond.
  • phenylene refers to a divalent radical derived from benzene (e.g. -CekU-).
  • the divalent radical e.g. a di-substituted benzene ring
  • the divalent radical may have an ortho arrangement of substituents, a meta arrangement of substituents or a para arrangement of substituents.
  • each group mentioned above e.g. alkyl, alkene, alkoxy, aryl, aryl-alkyl, alkylene, alkenylene, alkynylene, phenylene is unsubstituted.
  • the invention provides a coating for a medical device.
  • the coating reduces or prevents the clotting of blood.
  • the coating is typically an antithrombotic coating, such as an anticoagulant coating and/or an antiplatelet coating, preferably an antiplatelet coating.
  • the coating is typically a hemocompatible coating.
  • blood generally refers to the blood of a human or a non-human animal, such as a mammalian animal.
  • the invention can be used in veterinary applications.
  • the term “blood” preferably refers to the blood of a human.
  • the coating is biocompatible, preferably biocompatible and/or hemocompatible.
  • the coating comprises, or may consist essentially of, a surface layer.
  • the surface layer is the topmost layer of the coating.
  • the surface layer may be an outer surface layer of the coating or a coated medical device. In use, the surface layer of the coating comes into contact with blood.
  • the surface layer or the coating may be in the form of a gel, preferably a hydrogel.
  • the hydrogel may provide the medical device with a lubricious surface. When the surface layer or the coating is in the form of a gel, then it can be easily applied to the medical device.
  • the surface layer comprises, or may consist essentially of, a polymer chain attached or bonded (e.g. covalently bonded) to an anti-clotting group.
  • the anti-clotting group is typically selected from a sulfonic acid group, a sulfonamide group, a sulfamic acid group, a hydrogen sulfate group and a conjugate base thereof.
  • the structures of each group is shown below, where the squiggly line indicating the point of attachment of the group to the polymer chain, either directly or indirectly.
  • the anti-clotting group is selected from a sulfonic acid group, a sulfamic acid group, a hydrogen sulfate group and a conjugate base thereof.
  • the conjugate base of each group is shown below.
  • the conjugate base of each group refers to a sulfonate group, sulfonamide anion group, a sulfamate group or a sulfate group respectively.
  • the anti-clotting group is a conjugate base of the sulfonic acid group, the sulfamic acid group or the hydrogen sulfate group.
  • the anti clotting group is preferably a sulfonate group, a sulfamate group or a sulfate group, such as shown above.
  • the polymer chain is attached or bonded to a plurality of anti clotting groups.
  • Each anti-clotting group of the plurality of anti-clotting groups is typically selected from a sulfonic acid group, a sulfamic acid group, a hydrogen sulfate group and a conjugate base thereof, as defined above.
  • the anti-clotting group is attached or bonded to the polymer chain by a linker group.
  • any linker group may be used to connect the polymer chain to the anti-clotting group.
  • certain linker groups may provide, or contribute to, the advantageous properties of the coating.
  • the linker group covalently bonds at least one anti-clotting group to the polymer chain.
  • the linker group may have a first end that is covalently bonded to the polymer chain and a second end that is covalently bonded to at least one anti-clotting group.
  • a single anti-clotting group may be attached or bonded to the polymer chain by the linker group (e.g. a single linker group).
  • a plurality of anti-clotting groups such as two or three anti-clotting groups, may be bonded to the polymer chain by the linker group (e.g. a single linker group).
  • the polymer chain may be a linear polymer chain or a branched polymer chain.
  • the polymer chain is a linear polymer chain.
  • the surface layer is biocompatible. It is further preferred that the polymer chain is biocompatible.
  • the polymer chain typically has a number average (e.g. mean) molecular weight (M n ) of at least 300 g/mol, such as 300 to 50,000 g/mol, preferably 500 to 30,000 g/mol, more preferably 1,000 to 10,000 g/mol.
  • the number average (e.g. mean) molecular weight (M n ) can be determined by light scattering.
  • the anti-clotting group is a sulfonic acid group or a sulfonate group. It is preferred that each anti-clotting group of the plurality of anti-clotting groups is a sulfonic acid group or a sulfonate group.
  • sulfonic group is used herein as a shorthand to refer to a sulfonic acid group (-SO 3 H) or a sulfonate group (-SO 3 ) ⁇
  • sulfonic groups refers to sulfonic acid groups (-SO 3 H), sulfonate groups (-SO 3 ) or a combination of at least one sulfonic acid group (-SO 3 H) and at least one sulfonate group (-SO 3 ), unless the context indicates otherwise.
  • the surface layer comprises, or may consist essentially of, a polymer chain attached or bonded to a plurality of sulfonic groups.
  • the anti-clotting groups can be attached to the polymer chain after it has been formed by polymerisation, instead of polymerising monomers that include anti-clotting groups.
  • the polymer chain attached or bonded to an anti-clotting group or a plurality of anti-clotting groups may be referred to herein as a polymer chain linked or coupled to an anti-clotting group or a plurality of anti-clotting groups, particularly when the or each anti-clotting group is a sulfonic group.
  • Each sulfonic group may be linked or coupled to the polymer chain by a linker group.
  • the linker group should be relatively short (e.g. 1 to 3 atoms in length) to ensure that the surface of the coating presents a high negative charge density to platelets.
  • longer linker groups e.g. 1 to 3 atoms in length
  • the surface of the coating it is possible for the surface of the coating to have a disordered arrangement of anti-clotting groups, particularly sulfonic groups, due to the conformational flexibility of the linker group. This can reduce the negative charge density provided by the surface of the coating.
  • the linker group is biocompatible.
  • the polymer chain may include a repeating unit comprising a moiety as represented by formula (A-0): wherein: each G 1 is the same or different and is independently selected from O, NH, and NR 1A ; and each R 1A is independently selected from C1-6 alkyl, C6-10 aryl and Ce-io aryl-Ci-6 alkyl.
  • each G 1 is the same.
  • the polymer chain may include a repeating unit represented by formula (A-1) below.
  • X 1A is selected from O , OH, OR 1A , NH2, NHR 1A and A 1A ;
  • X 1B is selected from O , OH, OR 1B , NH 2 , NHR 1B and A 1B ; each of R 1A and R 1B is independently selected from C1-6 alkyl, C6-10 aryl and Ce-io aryl-Ci-6 alkyl; each of A 1A and A 1B is independently represented by formula (S-1):
  • Z 1 is selected from O, NH and NR 1 ;
  • R 1 is selected from C1-6 alkyl, C6-10 aryl and C6-10 aryl-Ci- 6 alkyl;
  • Y 1 is selected from O and OH
  • P 1 is selected from a single bond, C MO alkylene, C 2.i o alkenylene,
  • Q 1 is selected from a single bond, O, NH, NR 1C and phenylene;
  • W 1 is selected from a single bond, C MO alkylene, C 2 -io alkenylene,
  • R 1C is selected from C1-6 alkyl, Ce-io aryl and Ce-io aryl-Ci-e alkyl.
  • the repeating unit represented by formula (A-1) above may, for example, be obtainable from a maleic acid monomer or a maleimide monomer.
  • the moiety -L 1 - represents the linker group.
  • the polymer chain that is linked or coupled to a plurality of sulfonic groups may include a repeating unit represented by any one of formulae (A-1) to (A-3) described herein.
  • each unit in the repeating unit represented by formula (A-1) may be the same or different.
  • the surface layer comprises a plurality of polymeric compounds (e.g. a distribution), wherein each polymer compound comprises a polymer chain including a repeating unit as represented by any one of formulae (A-1) to (A-3) described herein.
  • each polymer compound comprises a polymer chain including a repeating unit as represented by any one of formulae (A-1) to (A-3) described herein.
  • the linker group and sulfonic group are attached to the polymer chain after polymerisation of an appropriate monomer, such as maleic acid or maleimide.
  • the linker group and sulfonic group are introduced into the repeating unit, such as by a reaction at the carbonyl group. This can be achieved by reacting a compound comprising an anti clotting agent with a polymer using a coupling agent, as described below. It is possible that some of the carbonyl groups do not undergo a reaction (i.e. there is not 100% conversion) to include the linker and sulfonic groups.
  • X 1A may be O , OH, OR 1A , NH 2 or NHR 1A and/or (b) X 1B may be O , OH, OR 1B , NH 2 or NHR 1B .
  • the surface layer comprises a plurality of polymeric compounds
  • at least 90% of the units represented by formula (A-1) include A 1A and/or A 1B as defined above (i.e. X 1A is A 1A and/or X 1B is A 1B ), more preferably at least 95% of the units represented by formula (A-1) include A 1A and/or A 1B , and even more preferably at least 99% of the units represented by formula (A-1) include A 1A and/or A 1B .
  • each unit in the repeating unit represented by formula (A-1) includes at least one of A 1A or A 1B as defined above (i.e. X 1A is A 1A or X 1B is A 1B ), more preferably each unit in the repeating unit represented by formula (A-1) includes A 1A and A 1B as defined above (i.e. X 1A is A 1A and X 1B is A 1B ). Thus, both X 1A is A 1A and X 1B is A 1B .
  • each unit in the repeating unit represented by formula (A-1) is the same.
  • the polymer chain may include a repeating unit represented by formula (A-2) below.
  • R 1C is as defined above, and wherein at least one of X 1A is A 1A or X 1B is A 1B , and n 1 is an integer.
  • X 1A is selected from O , OH, OR 1A and A 1A ; and X 1B is selected from O , OH, OR 1B and A 1B . More preferably, X 1A is selected from O , OH and A 1A ; and X 1B is selected from O , OH, and A 1B . Even more preferably, X 1A is A 1A ; and X 1B is A 1B , such as represented in formula (A-3) below.
  • R 1A when X 1A is OR 1A or NHR 1A , then it is preferred that R 1A is Ci- 6 alkyl, particularly methyl or ethyl.
  • R 1B when X 1B is OR 1B or NHR 1B , then it is preferred that R 1B is Ci- 6 alkyl, particularly methyl or ethyl.
  • a 1A and A 1B may be the same or different. In general, it is preferred that A 1A and A 1B are the same.
  • R 1 is Ci- 6 alkyl, particularly methyl or ethyl.
  • each Z 1 in the formulae (A-1) to (A-3) above, is preferably selected from O and NH.
  • Each Z 1 may be O. More preferably, each Z 1 is NH.
  • the linker group is attached to the polymer chain by an ester or amide group, which is typically a biocompatible group.
  • Amide groups in particular, have biocompatibility because, for example, they are present in peptides.
  • each U may be the same or different. It is preferred that each U is the same.
  • Each P 1 is typically selected from a single bond, CMO alkylene and phenylene; and each W 1 may be selected from a single bond, C MO alkylene and phenylene. More preferably, each P 1 may be selected from a single bond and CMO alkylene; and each W 1 may be selected from a single bond and CMO alkylene.
  • each P 1 is selected from C MO alkylene, C 2-10 alkenylene and C 2-10 alkynylene; each Q 1 is selected from O, NH and NR 1C and each W 1 is a single bond.
  • each Q 1 is selected from O and NH.
  • the anti-clotting group is a sulfamate group, a sulfate group or a conjugate base thereof.
  • Q 1 is O
  • P 1 is not a single bond. More preferably, when Q 1 is O, it is preferred that P 1 is CMO alkylene, more preferably P 1 is C2-4 alkylene.
  • W 1 is not a single bond. More preferably, when Q 1 is O, it is preferred that P 1 is CMO alkylene and W 1 is CMO alkylene, more preferably P 1 is C2-4 alkylene and W 1 is C2-4 alkylene.
  • Q 1 is phenylene
  • P 1 is a single bond or C MO alkylene and W 1 is a single bond or C MO alkylene. More preferably, when Q 1 is phenylene, it is preferred that P 1 is a single bond or C1-3 alkylene and W 1 is a single bond or C1-3 alkylene.
  • each P 1 is selected from C MO alkylene, C2-10 alkenylene and C2-10 alkynylene; each Q 1 is a single bond and each W 1 is a single bond. More preferably, each P 1 is C MO alkylene, particularly C2-6 alkylene, such as C2-5 alkylene. Even more preferably each P 1 is butylene, propylene or ethylene, preferably ethylene.
  • S-1 the moiety represented by (S-1) can be formed from taurine. Taurine is naturally found in the human body and can be formed if degradation of the polymeric compound occurs.
  • n 1 is at least 5, preferably at least 10.
  • n 1 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the polymer chain may be anionic, such as when X 1A , X 1B or Y 1 is O . When the polymer chain is anionic, then Na + or K + may be present as a counter cation.
  • the repeating unit represented by formulae (A-0) to (A-3) is referred to herein using the label the “first repeating unit”.
  • the label “first” in this context is used to distinguish this repeating unit from other types of repeating unit. It does not require the “first repeating unit” to be present when reference is made to a “second repeating unit”, a “third repeating unit” etc.
  • the polymer chain may include a repeating unit comprising a moiety as represented by formula (B-0): wherein:
  • G 2 is selected from O, NH, and NR 2A ;
  • R 2A is independently selected from Ci-e alkyl, Ce-io aryl and Ce-io aryl-Ci- 6 alkyl;
  • R A is selected from H and Ci-e alkyl.
  • the polymer chain may include a repeating unit represented by formula (B-1).
  • R A is selected from H and Ci-e alkyl
  • X 2 is selected from O , OH, OR 2A , NH 2 , NHR 2A and A 2 ;
  • R 2A is selected from C alkyl, Ce-io aryl and Ce-io aryl-Ci-e alkyl;
  • a 2 is represented by formula (S-2):
  • R 2 is selected from Ci-e alkyl, Ce-io aryl and Ce-io aryl-Ci-6 alkyl;
  • Y 2 is selected from O and OH
  • P 2 is selected from a single bond, C MO alkylene, C2-10 alkenylene, C2-10 alkynylene and phenylene;
  • Q 2 is selected from a single bond, O, NH, NR 2C and phenylene;
  • W 2 is selected from a single bond, C MO alkylene, C2-10 alkenylene, C2-10 alkynylene and phenylene;
  • R 2C is selected from C1-6 alkyl, Ce-io aryl and Ce-io aryl-Ci-e alkyl.
  • the repeating unit represented by formula (B-1) above may, for example, be obtainable from an acrylic acid monomer, a methacrylic acid monomer, an acrylamide monomer or a methacrylamide monomer.
  • the polymer chain that is linked or coupled to a plurality of sulfonic groups may include a repeating unit represented by any one of formulae (B-1) to (B-3) described herein.
  • each unit in the repeating unit represented by formula (B-1) may be the same or different.
  • the surface layer comprises a plurality of polymeric compounds (e.g. a distribution), wherein each polymer compound comprises a polymer chain including a repeating unit as represented by any one of formulae (B-1) to (B-3) described herein.
  • the linker group and sulfonic group are attached to the polymer chain after polymerisation of an appropriate monomer, such as acrylic acid or methacrylic acid.
  • the linker group and sulfonic group are introduced into the repeating unit, such as by a reaction at the carbonyl group. It is possible that some of the carbonyl groups do not undergo a reaction (i.e. there is not 100% conversion) to include the linker and sulfonic groups. When this happens, then X 2 may be O , OH, OR 2A , NH 2 or NHR 2A .
  • the surface layer comprises a plurality of polymeric compounds
  • each unit in the repeating unit represented by formula (B-1) includes A 2 (i.e. X 2 is A 2 ).
  • each unit in the repeating unit represented by formula (B-1) is the same.
  • the polymer chain may include a repeating unit represented by formula (B-2) below.
  • each of R A , X 2 , R 2A , A 2 , Z 2 , R 2 , Y 2 , L 2 , P 2 , Q 2 , W 2 and R 2C is as defined above, and wherein n 2 is an integer.
  • X 2 is selected from O , OH, OR 2A and A 2 . More preferably, X 2 is selected from O , OH and A 2 . Even more preferably, X 2 is A 2 , such as represented in formula (B-3) below.
  • R A is selected from H and C1-3 alkyl, preferably R A is selected from H and methyl. Even more preferably, R A is H.
  • R 2A is C alkyl, particularly methyl or ethyl.
  • Z 2 is NR 2
  • R 2 is Ci- 6 alkyl, particularly methyl or ethyl.
  • Z 2 in the formulae (B-1) to (B-3) above, is preferably selected from O and NH.
  • Z 2 may be O. More preferably, Z 2 is NH.
  • the linker group is attached to the polymer chain by an ester or amide group, which is typically a biocompatible group.
  • Amide groups in particular, are biocompatible because they are present in peptides.
  • P 2 is typically selected from a single bond, CMO alkylene and phenylene; and W 2 may be selected from a single bond, CM O alkylene and phenylene. More preferably, P 2 may be selected from a single bond and CMO alkylene; and W 2 may be selected from a single bond and CMO alkylene.
  • P 2 is selected from CM O alkylene, C2-10 alkenylene and C2-10 alkynylene; Q 2 is selected from O, NH and NR 2C and W 2 is a single bond. More preferably Q 2 is selected from O and NH.
  • the anti-clotting group is a sulfamate group, a sulfate group or a conjugate base thereof.
  • Q 2 is O
  • P 2 is not a single bond. More preferably, when Q 2 is O, it is preferred that P 2 is CMO alkylene, more preferably P 2 is C2-4 alkylene.
  • W 2 is not a single bond. More preferably, when Q 2 is O, it is preferred that P 2 is CMO alkylene and W 2 is CMO alkylene, more preferably P 2 is C2-4 alkylene and W 2 is C2-4 alkylene.
  • Q 2 is phenylene
  • P 2 is a single bond or CMO alkylene and W 2 is a single bond or CMO alkylene. More preferably, when Q 2 is phenylene, it is preferred that P 2 is a single bond or C1-3 alkylene and W 2 is a single bond or C1-3 alkylene.
  • P 2 is selected from CMO alkylene, C2-10 alkenylene and C2-10 alkynylene; Q 2 is a single bond and W 2 is a single bond. More preferably, P 2 is CMO alkylene, particularly C2-6 alkylene, such as C2-5 alkylene. Even more preferably P 2 is butylene, propylene or ethylene, preferably ethylene. When P 2 is ethylene and both Q 2 and W 2 are single bonds, then the moiety represented by (S-2) can be formed from taurine. As mentioned above, taurine can be formed if degradation of the polymeric compound occurs. [0131] Typically, the integer represented by n 2 is at least 5, preferably at least 10. For example, n 2 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the polymer chain may be anionic, such as when X 2 or Y 2 is O .
  • Na + or K + may be present as a counter cation.
  • the repeating unit represented by formulae (B-0) to (B-3) is referred to herein using the label the “second repeating unit”.
  • the label “second” in this context is used to distinguish this repeating unit from the “first repeating unit”. As mentioned above, this label does not require that the “first repeating unit” must be present in addition to the “second repeating unit”.
  • the polymer chain that is linked or coupled to a plurality of sulfonic groups may be a copolymer.
  • the copolymer may be an alternating copolymer comprising a first repeating unit represented by any one of formulae (A-0) to (A-3) and a second repeating unit represented by any one of formulae (B-0) to (B-3).
  • the alternating copolymer comprises alternating first and second repeating units (e.g. -(A-1)-(B-1)-(A-1)-(B-1 )-...), preferably regularly alternating first and second repeating units.
  • the alternating copolymer can, for example, be represented by the formula:
  • n is an integer.
  • n is at least 5, preferably at least 10.
  • n may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the copolymer may be a block copolymer, such as a block copolymer as represented by formula (C-1) below. are as defined above for any of formulae (A-1) to (A-3), and R A , X 2 , R 2A , A 2 , Z 2 , R 2 , Y 2 , L 2 , P 2 , Q 2 , W 2 , R 2C and n 2 are as defined above for any one of formulae (B-1) to (B-3).
  • formula (C-1) represented by formula (C-1) below. are as defined above for any of formulae (A-1) to (A-3), and R A , X 2 , R 2A , A 2 , Z 2 , R 2 , Y 2 , L 2 , P 2 , Q 2 , W 2 , R 2C and n 2 are as defined above for any one of formulae (B-1) to (B-3).
  • X 1A is A 1A and/or X 1B is A 1B and/or X 2 is A 2 .
  • at least one of X 1A , X 1B and X 2 is A 1A , A 1B and A 2 respectively.
  • X 2 is A 2 and at least one of X 1A and X 1B is A 1A and A 1B respectively.
  • X 1A is A 1A , X 1B is A 1B and X 2 is A 2 , such as represented in formula (C-2) below.
  • R A is selected from H and C1-3 alkyl, preferably R A is selected from H and methyl. Even more preferably, R A is H.
  • R 1A when X 1A is OR 1A or NHR 1A , then it is preferred that R 1A is C1-6 alkyl, particularly methyl or ethyl; when X 1B is OR 1B or NHR 1B , then it is preferred that R 1B is C1-6 alkyl, particularly methyl or ethyl; and when X 2 is OR 2A or NHR 2A , then it is preferred that R 2A is C1-6 alkyl, particularly methyl or ethyl.
  • a 1A and A 1B may be the same or different. In general, it is preferred that A 1A and A 1B are the same.
  • R 1 when Z 1 is NR 1 , then it is preferred that R 1 is C1-6 alkyl, particularly methyl or ethyl; and when Z 2 is NR 2 , then it is preferred that R 2 is C1-6 alkyl, particularly methyl or ethyl.
  • each Z 1 is preferably selected from O and NH; and Z 2 is preferably selected from O and NH.
  • Z 2 and each Z 1 may be O. More preferably, Z 2 and each Z 1 is NH.
  • each U may be the same or different. It is preferred that each U is the same.
  • Q 1 When Q 1 is O, it is generally preferred that P 1 is not a single bond. When Q 2 is O, it is generally preferred that P 2 is not a single bond. More preferably, when Q 1 is O, it is preferred that P 1 is CMO alkylene; and when Q 2 is O, it is preferred that P 2 is CMO alkylene; more preferably P 1 is C2-4 alkylene and P 2 is C2-4 alkylene.
  • Q 1 is O and P 1 is not a single bond, it may be preferable that W 1 is not a single bond.
  • W 1 is not a single bond.
  • Q 2 is O and P 2 is not a single bond, it may be preferable that W 2 is not a single bond. More preferably, when Q 1 is O, it is preferred that P 1 is CMO alkylene and W 1 is CMO alkylene; and when Q 2 is O, it is preferred that P 2 is CMO alkylene and W 2 is CMO alkylene; more preferably P 1 is C2-4 alkylene; W 1 is C2-4 alkylene; P 2 is C2-4 alkylene and W 2 is C2-4 alkylene.
  • Q 1 is phenylene
  • P 1 is a single bond or C MO alkylene and W 1 is a single bond or C MO alkylene. More preferably, when Q 1 is phenylene, it is preferred that P 1 is a single bond or C1-3 alkylene and W 1 is a single bond or C1-3 alkylene.
  • Q 2 is phenylene
  • P 2 is a single bond or CMO alkylene and W 2 is a single bond or CMO alkylene. More preferably, when Q 2 is phenylene, it is preferred that P 2 is a single bond or C1-3 alkylene and W 2 is a single bond or C1-3 alkylene.
  • each P 1 is selected from CMO alkylene, C2-10 alkenylene and C2-10 alkynylene; each Q 1 is a single bond; each W 1 is a single bond; P 2 is selected from CMO alkylene, C2-10 alkenylene and C2-10 alkynylene; Q 2 is a single bond and W 2 is a single bond. More preferably, each P 1 is CMO alkylene, particularly C2-6 alkylene, such as C2-5 alkylene; and P 2 is CMO alkylene, particularly C2-6 alkylene, such as C2-5 alkylene. Even more preferably each P 1 is ethylene and P 2 is ethylene.
  • n 1 is at least 5, preferably at least 10.
  • n 1 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • n 2 is typically at least 5, preferably at least 10.
  • n 2 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the polymer chain may be anionic, such as when X 1A , X 1B , X 2 , Y 1 or Y 2 is O .
  • Na + or K + may be present as a counter cation.
  • the polymer chain When the polymer chain is linked or coupled to a plurality of sulfonic groups, then the polymer chain (e.g. before it is linked or coupled to the plurality of sulfonic groups) has a number average (e.g. mean) molecular weight (M n ) of at least 300 g/mol, such as 300 to 50,000 g/mol, preferably 500 to 30,000 g/mol, more preferably 1,000 to 10,000 g/mol.
  • M n number average molecular weight
  • the polymer chain linked or coupled to an anti-clotting group has advantageous properties, particularly when it includes a repeating unit as represented by any one of formula (A-0) to (A-3), and especially when represented by formulae (C-1) or (C-2).
  • the surface layer or coating may be a hydrogel.
  • the coating may be biodegradable because degradation of the polymer chain linked or coupled to an anti-clotting group may result in the formation of biocompatible by-products.
  • the anti-clotting component of the surface layer may also have excellent stability and relatively cheap, particularly when compared to other anti-clotting components in the art, such as heparin.
  • polymerisation of a monomer comprising an anti-clotting group can provide the polymer chain attached or bonded to an anti-clotting group.
  • the monomer itself comprises, for example, a sulfonic group or a sulfonic group precursor.
  • the polymer chain attached or bonded to an anti clotting group or a plurality of anti-clotting groups may be referred to herein as a polymer comprising an anti-clotting group or a plurality of anti-clotting groups, particularly when the or each anti-clotting group is a sulfonic group.
  • the monomer comprising a sulfonic group may be a compound comprising an alkene group and a sulfonic group.
  • examples of such compounds include vinyl sulfonic acid, styrene sulfonic acid (e.g. 4-styrene sulfonic acid), 2-acrylamido-2-methylpropane sulfonic acid or the conjugate base thereof (e.g. the sulfonate).
  • the monomer comprising a sulfonic precursor group may be a compound comprising an alkene group and a sulfonic precursor group.
  • the polymer comprising sulfonic groups may be a homopolymer.
  • the polymer is a homopolymer comprising sulfonic groups.
  • Examples of a homopolymer comprising sulfonic groups include polyvinyl sulfonic acid, polystyrene sulfonic acid, poly(2-acrylamido-2-methylpropanesulfonic acid) or a conjugate base thereof. It is preferred that the homopolymer comprising sulfonic groups is poly(2-acrylamido-2-methylpropanesulfonic acid).
  • the polymer comprising sulfonic groups may be a copolymer (e.g. a copolymer comprising sulfonic groups).
  • the copolymer comprising sulfonic groups may be an alternating copolymer or a block copolymer.
  • the copolymer comprising sulfonic groups may be obtained from at least two monomers or from only two monomers.
  • the copolymer comprising sulfonic groups may be obtained from a first monomer and a second monomer, where the first monomer is different to the second monomer.
  • the copolymer may be obtained by copolymerisation of the first monomer and the second monomer.
  • the first monomer comprises a sulfonic group or a sulfonic group precursor.
  • the monomer comprising a sulfonic group may be a compound comprising an alkene group and a sulfonic group. Examples of such compounds include vinyl sulfonic acid, styrene sulfonic acid (e.g. 4-styrene sulfonic acid), 2-acrylamido-2-methylpropane sulfonic acid or the conjugate base thereof (e.g. the sulfonate). It is preferred the first monomer is 2- acrylamido-2-methylpropane sulfonic acid or the conjugate base thereof.
  • the monomer comprising a sulfonic precursor group may be a compound comprising an alkene group and a sulfonic precursor group.
  • the second monomer comprises an alkene group.
  • the second monomer may be selected from acrylic acid, itaconic acid, vinyl acetate and maleic acid. It is preferred that the second monomer is maleic acid.
  • the copolymer comprising sulfonic groups may, for example, be poly(styrenesulfonic acid-co-maleic acid) or poly(2-acrylamido-2-methylpropanesulfonic acid-co-maleic acid), preferably poly(2-acrylamido-2-methylpropanesulfonic acid-co- maleic acid).
  • the polymer e.g. including the sulfonic groups
  • M n molecular weight
  • the coating may further comprise an antimicrobial agent.
  • the base layer and/or the surface layer may comprise the antimicrobial agent.
  • the antimicrobial agent may, for example, be mixed with the components of the surface layer or the base layer.
  • the antimicrobial agent may comprise silver.
  • the coating of the invention is typically disposed on a surface of a medical device.
  • the surface of the medical device may be an inner or an internal surface of the medical device (e.g. the inner surface inside a catheter) or an outer surface of the medical device.
  • the coating may be disposed on a surface of the medical device that will come into with blood or a blood product containing platelets.
  • the coating may provide complete or partial coverage of the surface of the medical device.
  • the surface layer is disposed on a surface of the medical device.
  • the surface layer may be directly disposed on a surface of the medical device.
  • the surface layer is in direct contact with the surface of the medical device.
  • the surface layer may be directly applied to a surface of the medical device, particularly if it is able to adhere or bond to this surface.
  • the surface of the medical device may be functionalised with a group that is able to bond to the polymer chain, such as by applying a base coating.
  • the surface of the medical device may have amine groups. The amine groups can react with carbonyl groups in the polymer chain to form amide groups thereby bonding the surface layer of the coating to the surface of the medical device.
  • a plurality of layers may be disposed on a surface of the medical device.
  • Each layer may comprise a polymer chain attached or bonded to an anti-clotting agent as defined above.
  • the top or outermost layer will be the surface layer described above.
  • the coating may also comprise a base layer.
  • the base layer is typically disposed under the surface layer.
  • the surface layer may be directly disposed on the base layer.
  • the surface layer is directly disposed on the base layer.
  • the surface layer is typically coated onto the base layer.
  • the base layer may be disposed on a surface of the medical device.
  • the base layer is typically directly disposed on a surface of the medical device. Thus, the base layer is in direct contact with the surface.
  • the base layer adheres or bonds, preferably adheres, to a surface of the medical device.
  • the base layer is biocompatible.
  • the base layer may comprise, or consist essentially of, a protein, preferably a human protein.
  • the protein may be albumin. It is preferred that the albumin is human albumin, preferably recombinant human albumin.
  • Albumin particularly recombinant human albumin, can mimic the albumin found in the circulatory system of a human. It can adhere to a wide variety of surfaces, especially surfaces of medical devices, by means of a static attraction. It also provides a biopassive surface that can protect against platelet activation.
  • the surface layer of the coating is bonded to the base layer.
  • the surface layer may be adhesively bonded to the base layer or covalently bonded to the base layer.
  • the base layer comprises albumin
  • the albumin may covalently bond to the polymer chain.
  • the invention also provides a medical device.
  • the medical device may be used where it comes into contact with blood or a blood product containing platelets.
  • the coating is disposed on a surface of the medical device.
  • the medical device has a surface coated with the coating of the invention .
  • the surface coated with the coating of the invention is referred to as the “coated surface”.
  • the coated surface is for use in contact with blood or a blood product containing platelets, preferably blood.
  • the coating has a thickness of from 0.05 pm to 300 pm, preferably 0.1 pm to 200 pm, and more preferably 1 pm to 100 pm.
  • the thickness of the coating is selected so that it does not significantly increase the profile of the medical device for use within a patient.
  • the medical device may be coated with a single layer of the coating of the invention.
  • the medical device may be coated with a plurality of layers of the coating of the invention.
  • a surface of the medical device may be coated with several alternating layers of the base layer and the layer comprising the polymer chain attached to an anti-clotting group.
  • the medical device can be an implantable medical device or an extracorporeal medical device.
  • the implantable medical device may be a permanently implantable medical device or a temporarily implantable medical device.
  • the medical device may be a transient blood contacting device, which may, for example, not be implantable or extracorporeal.
  • the medical device may be for in vivo use or for in vitro use.
  • the medical device is preferably for in vivo use.
  • the medical device may have a component for in vivo use. It is preferred that at least a surface of the component is coated with the coating of the invention.
  • the coated surface of the medical device or the component of the medical device may be inserted into an area of a body, such as an afflicted area of the body.
  • the area of the body may, for example, be an artery or a vein, such as a coronary artery or vein, a carotid artery or vein; a renal artery or vein; an iliac artery or vein; a femoral artery or vein; a popliteal artery or vein; a subclavian artery or vein; an intercranial artery or vein; the aorta; the vena cava; or a peripheral artery or vein.
  • a coronary artery or vein such as a coronary artery or vein, a carotid artery or vein; a renal artery or vein; an iliac artery or vein; a femoral artery or vein; a popliteal artery or vein; a subclavian artery or vein; an intercranial artery or vein; the
  • the coated surface prevents blood coagulation on and around the medical device or the component of the medical device, thereby inhibiting thrombosis, particularly sub-acute device thrombosis.
  • the medical device or component thereof may be a needle, catheter, a stent, a graft, a shunt, a dressing, a surgical staple, a guidewire, a cannula, a surgical instrument, an endoscope, an artificial organ or organoid (e.g. insulin secreting device), an implantable monitor or sensor, a defibrillator, a ventricular assist device, a pacemaker (e.g. cardiac pacemaker), an implantable pump (e.g. intra-aortic balloon pump or a ventricular assist pump), a cell reservoir (e.g. for stem cell placement), a prosthetic device (e.g.
  • prosthetic heart valve an orthopaedic device, an electrostimulation lead or lead tip, an implantable vascular access port, a blood storage bag, blood tubing, a breast implant, a pain management device, a prostate cancer treatment device, a dental implant, a focal epilepsy treatment device, a nerve regeneration conduit, a vena cava filter, a spinal repair device, a spinal cord stimulator, an internal hearing aid, a neuro aneurysm treatment device, a heart valve repair device, a intravitreal drug delivery device, a joint replacement, an ophthalmic implant, a blood oxygenator, a blood filter, a septal defect device, a haemodialysis unit, a hemoperfusion unit, a plasmapheresis unit or an anastomosis device.
  • catheters include a balloon or an inflation catheter, an injection catheter, a central venous catheter, an arterial catheter and an aspiration catheter. It may be preferable that the medical device is a central venous catheter or an aspiration catheter.
  • grafts include vascular grafts, stent grafts or bypass grafts. It may be preferable that the medical device is a bypass graft.
  • stents include a vascular stent, a urethra stent, a bile duct stent, a biliary stent, an oesophageal stent, and a tracheal or bronchial stent.
  • the medical device is selected from a central venous catheter, an aspiration catheter, a bypass graft, a perfusion line, a cardia bypass machine, and extracorporeal oxygenation and heat exchange circuitry.
  • the medical device or component thereof may comprise a metal, a polymeric material, glass or a ceramic.
  • the coating of the invention may be coated onto a surface comprising a metal, a plastic or a ceramic.
  • the metal may, for example, be stainless steel, titanium, nickel, tantalum, cobalt, chromium, nickel, molybdenum, manganese, gold, platinum, iridium, silver, tungsten, a titanium alloy (e.g. nitinol), a nickel-chromium alloy (e.g. Inconel), a cobalt chromium alloy (e.g. elgiloy), a ferrous alloy, a palladium alloy, a rhenium alloy or a magnesium alloy.
  • a titanium alloy e.g. nitinol
  • a nickel-chromium alloy e.g. Inconel
  • cobalt chromium alloy e.g. elgiloy
  • ferrous alloy e.g. a palladium alloy, a rhenium alloy or a magnesium alloy.
  • the polymeric material may, for example, be cellulose acetate, cellulose nitrate, silicone, polyethylene terephthalate, polyurethane, polyamide, polyester (e.g. Nylon), polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, polyethylene or polytetrafluoroethylene.
  • the ceramic may, for example, include an oxide, a carbide, or a nitride of a transition metal, such as titanium oxides, hafnium oxides, iridium oxides, chromium oxides, aluminum oxides, and zirconium oxides.
  • a transition metal such as titanium oxides, hafnium oxides, iridium oxides, chromium oxides, aluminum oxides, and zirconium oxides.
  • the invention also provides a polymeric compound.
  • the polymeric compound is represented by formula (C-2): wherein: each Y 1 is selected from O and OH;
  • Y 2 is selected from O and OH; each U is C2-5 alkylene;
  • L 2 is C2-5 alkylene
  • R A is selected from H and C alkyl, preferably selected from H and methyl; n 1 is an integer; and n 2 is an integer.
  • each L 1 is ethylene and L 2 is ethylene.
  • R A is preferably selected from H and methyl. More preferably, R A is H.
  • n 1 is at least 5, preferably at least 10.
  • n 1 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • n 2 is typically at least 5, preferably at least 10.
  • n 2 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the coating or a medical device comprising the coating can be used in the treatment of the human or animal body by surgery or therapy and/or in a diagnostic method practised on the human or animal body.
  • the diagnostic method practised on the human or animal body is typically an in vivo diagnostic method.
  • the diagnostic method or the treatment by surgery or therapy typically involves the coating, or the medical device comprising the coating, coming into contact with blood.
  • the coating or a medical device comprising the coating is for use in reducing or preventing the clotting of blood, preferably reducing or preventing the clotting of blood on the coated surface of the medical device.
  • the invention also provides a method of reducing or preventing the clotting of blood.
  • the method comprises contacting a medical device of the invention with blood.
  • the medical device is used in its normal manner, except that the presence of coating inhibits or prevents the formation of blood clots, particularly on the coated surface of the medical device.
  • the method may be an in vitro method of reducing or preventing the clotting of blood when processing the blood.
  • the blood may be processed to produce processed blood or a blood product, such as a blood product for storage.
  • the method may comprise contacting the medical device with blood, wherein the blood has been removed from a human or animal body.
  • the blood may be contacted with the medical device to process the blood.
  • the method may not include a step of administering the processed blood or the blood product to the human or animal body.
  • the blood product or processed blood may not be returned to the human or animal body, preferably the human or animal body from which the blood was removed.
  • a further aspect of the method is a diagnostic method, particularly an in vitro and/or ex vivo diagnostic method.
  • the method may relate to a method of reducing or preventing the clotting of blood in a diagnostic procedure.
  • the method may comprise contacting the medical device with blood to obtain diagnostic information.
  • the medical device may be contacted with pre-obtained or pre-delivered blood.
  • the diagnostic procedure is not carried out on the human or animal body or the diagnostic procedure is carried out on a non-living (e.g. dead) human or animal body.
  • the diagnostic method may not include a step of removing blood from a human or animal body, particularly a living human or animal body.
  • the invention also provides a method of manufacturing a coating for a medical device, particularly a coating comprising a surface layer, which comprises a polymer chain attached or bonded to an anti-clotting group according to the first aspect.
  • the method comprises attaching or bonding (e.g. by a coupling reaction) a compound comprising an anti-clotting agent to a polymer using a coupling agent.
  • the compound comprising an anti-clotting agent may be attached or bonded to the polymer by forming an amide group.
  • the invention further provides a kit for coating a medical device, particularly when the coating has a surface layer, which comprises a polymer chain attached or bonded to an anti-clotting group according to the first aspect.
  • the kit comprises: (a) a polymer, (b) compound comprising an anti-clotting group, (c) a coupling agent, and optionally (d) a coating for forming the base layer.
  • the polymer may, for example, be a dispersed in a solution or a gel.
  • the polymer forms the polymer chain, which is attached or bonded to an anti-clotting group.
  • the polymer includes a repeating unit represented by formula (D-1) below.
  • X 3 is selected from OH, OR 3A , NH2 and NHR 3A ; and R 3A is selected from C1-6 alkyl, Ce-io aryl and Ce-io aryl-Ci-6 alkyl.
  • X 3 is selected from OH and NH2, more preferably X 3 is OH.
  • the repeating unit represented by formula (D-1) above may, for example, be obtainable from a maleic acid monomer or a maleimide monomer.
  • the polymer may include a repeating unit represented by formula (D-2) below.
  • X 3 is as defined above and n 1 is an integer. Typically, n 1 is at least 5, preferably at least 10. For example, n 1 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the polymer may be a copolymer.
  • the copolymer is typically a block copolymer, such as a block copolymer as represented by formula (D-3) below.
  • X 3 and n 1 are as defined above for formulae (D-1) or (D-2);
  • R A is selected from H and Ci-e alkyl;
  • X 4 is selected from OH, OR 4 , NH2 and NHR 4 ;
  • R 4 is selected from C1-6 alkyl, Ce-io aryl and Ce-io aryl-Ci- 6 alkyl; and
  • n 2 is an integer.
  • R A is preferably selected from H and C1-3 alkyl. More preferably R A is selected from H and methyl. Even more preferably, R A is H.
  • X 4 is selected from OH and NH2, more preferably X 4 is OH.
  • n 2 is at least 5, preferably at least 10.
  • n 2 may be from 5 to 500, such as from 10 to 300, more preferably from 15 to 100.
  • the compound comprising an anti-clotting group may be represented by formula (E-1):
  • Z 3 is selected from OH, NH 2 and NHR 3 ;
  • R 3 is selected from C1-6 alkyl, Ce-io aryl and Ce-io aryl-Ci-e alkyl;
  • L 3 is represented by formula (L-3):
  • P 3 is selected from a single bond, C MO alkylene, C2-10 alkenylene, C2-10 alkynylene and phenylene;
  • Q 3 is selected from a single bond, O, NH, NR 3C and phenylene;
  • W 3 is selected from a single bond, C MO alkylene, C2-10 alkenylene, C2-10 alkynylene and phenylene;
  • R 3C is selected from C1-6 alkyl, Ce-io aryl and Ce-io aryl-Ci-e alkyl. [0245] It is preferred that Z 3 is NH2.
  • P 3 is typically selected from a single bond, CMO alkylene and phenylene; and W 3 may be selected from a single bond, CM O alkylene and phenylene. More preferably, P 3 may be selected from a single bond and CMO alkylene; and W 3 may be selected from a single bond and CMO alkylene.
  • P 3 is selected from CM O alkylene, C2-10 alkenylene and C2-10 alkynylene; Q 3 is selected from O, NH and NR 3C and W 3 is a single bond. More preferably Q 3 is selected from O and NH.
  • Q 3 When Q 3 is O, it is generally preferred that P 3 is not a single bond. More preferably, when Q 3 is O, it is preferred that P 3 is CMO alkylene, more preferably P 3 is C2-4 alkylene.
  • W 3 is not a single bond. More preferably, when Q 3 is O, it is preferred that P 3 is CMO alkylene and W 3 is CMO alkylene, more preferably P 3 is C2-4 alkylene and W 3 is C2-4 alkylene.
  • Q 3 is phenylene
  • P 3 is a single bond or CMO alkylene and W 3 is a single bond or CMO alkylene. More preferably, when Q 3 is phenylene, it is preferred that P 3 is a single bond or C1-3 alkylene and W 3 is a single bond or C1-3 alkylene.
  • P 3 is selected from CMO alkylene, C2-10 alkenylene and C2-10 alkynylene; Q 3 is a single bond and W 3 is a single bond. More preferably, P 3 is CMO alkylene, particularly C2-6 alkylene, such as C2-5 alkylene. Even more preferably P 3 is butylene, propylene or ethylene, preferably ethylene.
  • the compound represented by formula (E-1) may be taurine.
  • the coupling agent may be a carbodiimide coupling agent.
  • carbodiimide coupling agents include /V,/V-dicyclohexylcarbodiimide (DCC), N,N’- diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
  • the coupling agent is EDC.
  • the coupling agent may be a powder.
  • the coating for forming the base layer may be a solution, a suspension or a gel comprising a protein, preferably a human protein. It is preferred that the coating for forming the base layer is a solution, such as a stabilised solution.
  • the protein may be albumin. It is preferred that the albumin is human albumin, preferably recombinant human albumin.
  • the method of manufacture of the invention involves coupling a carboxylic acid or an amide group of the polymer to a hydroxy group or an amino group of the compound comprising an anti-clotting agent using the coupling agent. Such coupling reactions are known in the art.
  • the coupling reaction produces a polymer chain attached or bonded to an anti clotting group. Any remaining coupling agent can be removed to form a coating, such as by rinsing with water.
  • the coating can be applied to a surface of the medical device by, for example, dip-coating, spray, wash, brush, roller, or spin coating.
  • the coating may be pumped through the medical device, such as to coat an inner surface of the medical device.
  • the thickness of the coating may be controlled by altering soaking time, flow rate etc and the number of coating steps.
  • Each coating can be provided on a surface of the medical device as described herein in a series of applications.
  • the number of applications may be selected to provide individual coated layers of suitable thickness, as well as a desired total number of multiple coatings, as desired.
  • the coating comprises a base layer
  • the base layer may be applied to a surface of the medical device before the surface layer.
  • the surface of the medical device may be coated with a solution, a suspension or a gel comprising a protein, preferably a human protein.
  • the protein may be albumin. It is preferred that the albumin is human albumin, preferably recombinant human albumin.
  • the invention may also provide a method of coating a surface of a medical device.
  • the method comprises applying a coating, such as described above, to a surface of the medical device.
  • the coating is applied to form a surface layer and may, for example, be applied as described above.
  • the coating for the surface layer may be pre-formed.
  • the polymer chain attached or bonded to an anti-clotting group in accordance with the invention may be directly applied to a surface of the medical device or, when present, to a base layer on a surface of the medical device.
  • the polymer chain attached or bonded to an anti-clotting group may be formed (e.g. in situ) on a surface of the medical device or, when present, a base layer on a surface of the medical device.
  • the coating can be manufactured on a surface of the medical device or the base layer, preferably in accordance with the method of manufacturing a coating for a medical device.
  • a compound comprising an anti clotting agent, a polymer and a coupling agent may be applied to a surface of the medical device or, when present, the base layer.
  • the compound comprising an anti-clotting agent may be attached or bonded to the polymer using the coupling agent (e.g. to form the coating), as described for the method of manufacturing a coating for a medical device.
  • the method may comprise attaching or bonding a compound comprising an anti clotting agent to a polymer using a coupling agent.
  • the anti-clotting agent may also be referred to as a hemocompatibility agent (i.e. the term “anti-clotting agent” is synonymous with the term “hemocompatibility agent”).
  • the surface of the medical device may have already been coated with a base layer.
  • the method may also comprise applying a base layer to a surface of the medical device or applying a coating to a medical device to form a base layer, such as described above.
  • the coating in this context, is the coating for forming a base layer.
  • the coating applied to form a surface layer may be applied to the base layer on a surface of the medical device.
  • a bovine serum albumin solution was prepared in a distilled water buffer at a pH of 4.5 (via HCI & NaOH titration) and a concentration of approximately 25 mg/100 ml_.
  • a 1 mL/200 ml_ solution of poly(maleic acid-co-acrylic acid) polymer at pH 4.5 was prepared. Samples were incubated at room temperature in this solution for 0-1 hr with gentle swirling. All samples were subsequently soaked for 15 minutes with de ionised (Dl) water and dried. [0273] To crosslink the albumin and the poly(maleic-co-acrylic acid), 500 g of EDC (1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in distilled water at pH 4.5 was used. The samples coated with both albumin and the poly(maleic-co-acrylic acid) were incubated in this solution for 15 mins to 1 hr. The coated samples were then removed and rinsed with Dl water and dried.
  • EDC 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the coated samples were treated with toluidine blue.
  • Toluidine blue has a high affinity for acidic groups, such as any sulfonic acid groups present in the coating.
  • the coated samples showed a blue/purple colour, which confirmed the presence of the sulfonic acid groups.
  • a commercially available coating was obtained from Coatings2GoTM and applied to a substrate using the instructions that were provided.
  • the coating was a hydrophilic coating and contained polymeric repeating units derived from an acrylate. Heparin was bound to the coated substrate by chemical crosslinking using EDC as described above.
  • Clots were weighed on a fine balance (see Table 7 and Figure 3) as described previously and were also photographed (see Figure 4).
  • Coating number 5 is the coating of the invention (the sulfonic acid group modified coating) and was prepared as described in Example 1. The length of each coated sample was 47 cm and “n” is the number of blood donors.
  • both a blood sample control was used to provide a baseline and an uncoated tube was used as a reference.
  • the in-vitro Chandler-Loop model is a closed system in which the effect of artificial surfaces to initiate the different cascade reactions of the human hemostatic system (coagulation, cell alteration, complement and inflammation) can be investigated.
  • the Chandler Loop System polymer tubes, partly filled with blood, are formed into re-closable loops and are rotated with a rotation speed between 10-40 RPM in a temperature controlled water basin, to simulate arterial flow conditions.
  • a multiparametric approach was used to assess the surfaces, which was not only restricted to the thrombosis evaluation, but also measured expressive markers having central importance within the hemostatic system. Coating tubing were tested for their hemocompatibility by using an in- vitro Chandler-Loop model with fresh human whole blood.
  • control baseline
  • each coated tube was subjected to 60 minutes of blood perfusion in the loop.
  • Blood was used from 5 healthy volunteers. The quality of the blood used for these experiments is of decisive importance. The following exclusion criteria for the blood donators have to be strictly fulfilled: hemostasis-affecting drug-taking in the last 2 weeks.
  • TAT complex Blood-material contact initiates intrinsic coagulation via factors XII, XI, and further factor X which modulates prothrombin conversion.
  • factors XII, XI, and further factor X which modulates prothrombin conversion.
  • the pro-thrombin fragment F 1+2 gets split off.
  • the generated thrombin gets inactivated by complex-formation with antithrombin forming the so-called TAT complex.
  • the plasma concentration of TAT is a marker for detection of coagulation activation and was measured immunochemically using a SiemensTM automatic immunoassay analyzer with ELISA.
  • Activation of platelets occurs in four steps: shape change with formation of pseudopodia, adhesion, aggregation, and release of platelet factors out of the a-granules (platelet factor 4, b-TG, etc.).
  • concentration of b-Thromboglobulin (b-TG) in plasma corresponds with the degree of platelet activation.
  • the concentration of b-TG was measured immunochemically (ELISA, Diagnostica Stago S.A.S, Asnieres sur Seine, France).
  • Red blood cells RBC
  • white blood cells WBC
  • WBCs in contact with any artificial surface may stick to this surface and try to fight against the supposed pathologic invader. This reaction leads to a drop in WBC count and is a critical marker for the hemocompatibility of blood contacting devices. If the membranes of RBCs are destroyed by high shear forces this reaction leads to a drop in RBCs.
  • HGB Hemoglobin
  • HCT Hematocrit
  • the method is designed to determine the biological response of mammalian cells in vitro.
  • Murine fibroblast L929 cells were used cultured in Growth Medium: L929 cells (serum supplemented Dulbecco's MOD Medium (modified) with Earle's salts).
  • Samples of the coating of the invention were prepared as described in Example 1. To achieve the extraction ratio required, 6 cm 2 /ml, two samples each representing an internal surface area of 285.89 cm 2 were extracted separately, each with 47.7 ml of Extraction Medium: L929 cells inside of each tube, under agitation conditions. After extraction, the extractants were pooled into sterile glass bottles. The extractant was prepared from Minimum Essential Medium Eagle's (modified) with Earle's salts, supplemented with foetal calf serum (5%) and penicillin and streptomycin (50001 U). Calculations took into account the area of all major surfaces, but not the edges or any porous nature of the test article.
  • the interfacial area of the positive and negative control material per millilitre of final extract volume was calculated to be not less than 0.5 cm 2 per ml.
  • a piece of polythene tubing (Scientific Laboratory Supplies product code: TUB3708) known not to produce a cytotoxic response in this test was used.
  • the negative control was 2.0 cm long with an outside diameter of 0.6 cm and an inside diameter of 0.4 mm, representing a total surface area of 6.3 cm 2 which was extracted in 12.6 ml of extraction medium, under agitation condition.
  • the test procedure was performed in accordance with ISO 10993-5 and MV033. The samples and the controls were extracted at 37 ⁇ 1°C for 24 hours. The following concentrations of the test article extract and positive control extract were used in the test: 100%, 50%, 25%, 13% and 6%.
  • the cell cultures were exposed to the extracts at 37 ⁇ 1°C for 24 hours. Microscopical examination of the cell cultures was made on completion of exposure to extracts without fixing and staining. The determination of cytotoxicity was performed qualitatively and observations graded numerically. The degree of cytotoxicity observed in each culture was numerically graded as follows.

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