Coatings for medical devices, medical devices comprising the coatings, and uses and methods involving coating, medical devices comprising the coatings, methods of making the coatings, and kits for coating medical devices

Abstract

Coatings for medical devices are described. The coatings comprise a surface layer and an optional base layer, where the surface layer comprises polymer chains attached to anti-clotting groups, where the anti-clotting groups are selected from sulfonic acid groups, sulfonamide groups, sulfamic acid groups, hydrogen sulfate groups, and their conjugate salts. Also described are medical devices comprising the coatings, and uses and methods involving the coatings and medical devices.

Description

[Technical Field]

[0001]

[0001] The present invention relates to coatings for medical devices. The present invention further relates to medical devices comprising the coatings, and to uses and methods involving coating or medical devices comprising the coatings. The present invention also relates to methods of producing the coatings and kits for coating medical devices. [Background technology]

[0002]

[0002] The formation of a blood clot (or blood clot) within an organ or tissue can indicate a potentially life-threatening condition. When using a medical device, blood may come into contact with the foreign surface of the device, potentially causing the formation of a blood clot. As a result, patients may be administered an anticoagulant before using the medical device to inhibit blood clotting and clot formation. However, there are significant side effects associated with the administration of anticoagulants that must be considered. It may not be safe to administer such anticoagulants to some patients.

[0003]

[0003] Some medical devices, such as stents, are coated with heparin, an anticoagulant that prevents blood clots from forming. Heparin is a glycosaminoglycan. It can be difficult to coat medical devices with heparin and is relatively expensive. Heparin use is also associated with several side effects, including bleeding, severe pain (e.g., at the injection site), nausea, and unusual fatigue. Serious side effects, such as heparin-induced thrombocytopenia, are also associated with heparin use. Heparin is contraindicated in several conditions, including brain surgery, spinal surgery, eye surgery, hemophilia, anticoagulant deficiency, significant uncontrolled high blood pressure, subacute infection of the heart valve, cerebral hemorrhage, bulging, and lacerations of the aortic blood vessel wall, stomach or intestinal ulcers, ulcerative colitis, intestinal inflammatory conditions, diverticulitis, severe liver disease, bile duct and gallbladder problems, osteoporosis, and chronic kidney disease that is stage 4 (severe) or stage 5 (impaired).

[0004]

[0004] Other types of coatings have been applied to medical devices. These coatings typically include multifunctional polymerizable compounds. The problem with such coatings is that they can have poor coating performance and degrade relatively quickly. If the coating lacks mechanical robustness, degradation by-products can leach into the patient, which may be undesirable for certain types of coatings. Summary of the Invention [Means for solving the problem]

[0005] Summary of the Invention

[0005] The present invention provides a coating for a medical device comprising a surface layer and an optional base layer, the surface layer comprising polymer chains attached or bonded to anti-clotting groups.

[0006]

[0006] The coatings of the present invention are non-thrombogenic and hemocompatible. The coatings have a prophylactic effect in that they can prevent or inhibit the formation of blood clots, which in turn prevents or inhibits the onset, progression, or recurrence of blood clot-related diseases and conditions.

[0007]

[0007] The present 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 with an anticoagulant group. The anticoagulant group is also sometimes referred to as a hemocompatible group (i.e., the term "anticoagulant group" is synonymous with "hemocompatible group"). The hemocompatible group contributes to the overall hemocompatibility of the coating.

[0008]

[0008] Typically, the anticoagulant group is a sulfonic acid group, a sulfonamide group, a sulfamic acid group, a hydrogen sulfate group, or a conjugate base thereof. Without wishing to be bound by theory, it is believed that when these groups in the coating are ionized, the negatively charged conjugate base (e.g., a sulfonic acid group) repels platelet adhesion, thereby inhibiting or preventing the formation of a blood clot on the surface of the coating.

[0009]

[0009] The present invention also provides a medical device having a surface coated with a coating of the present invention, which, when applied to the surface of the medical device, prevents or inhibits the formation of thrombus on the device during use.

[0010]

[0010] The present invention further provides a polymer compound having the formula (C-2): [ka] [In formula (C-2), Each Y 1 O - , OH, NH - and NH2, preferably O - and OH, Y 2 O - and OH, Each L 1 is C 2-5 is alkylene, L 2 is C 2-5 is alkylene, R A H and C 1-6 alkyl, n 1 is an integer, n 2 is an integer] It is expressed as:

[0011]

[0011] The present invention also provides a method for producing a coating for a medical device. The method can comprise attaching or bonding a compound comprising an anticoagulant to a polymer using a coupling agent. Anticoagulants are sometimes referred to as hemocompatible agents (i.e., the term "anticoagulant" is synonymous with the term "hemocompatible agent"). The method can produce a polymeric compound such as that represented by formula (C-2) above.

[0012]

[0012] The present invention may further provide a method of coating the surface of a medical device, which may optionally comprise applying a base layer to the surface of the medical device and applying a coating to the surface of the medical device.

[0013]

[0013] A further aspect of the present invention relates to a kit for coating a medical device, the kit comprising (a) a polymer, (b) a compound comprising an anticoagulant group, (c) a coupling agent, and optionally (d) a coating to form a base layer.

[0014]

[0014] The present invention further relates to the use of coatings and medical devices.

[0015]

[0015] The coatings of the invention or the medical devices of the invention can be used in the treatment of the human or animal body by surgery or therapy and / or in diagnostic methods performed on the human or animal body, which diagnostic methods performed on the human or animal body are typically in vivo diagnostic methods.

[0016]

[0016] The coating of the present invention or the medical device of the present invention is for use in reducing or preventing blood clotting.

[0017]

[0017] The present invention also provides a method for reducing or preventing blood clotting, the method comprising contacting the medical device of the present invention with blood.

[0018]

[0018] One aspect of the method of the present invention can be an in vitro method for reducing or preventing blood clotting, such as when treating blood. The method can include contacting a medical device with blood, where the blood has been removed from a human or animal body. The blood can be treated by contacting the medical device. The treated blood may not be returned to the human or animal body, preferably the human or animal body from which the blood was removed.

[0019]

[0019] Another embodiment of the method of the present invention is a method of reducing or preventing blood clotting in a diagnostic procedure, which may comprise contacting a medical device with blood to obtain diagnostic information. [Brief explanation of the drawings]

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The invention is further described below with reference to the accompanying drawings.

[0021] [Figure 1] FIG. 1 is a histogram showing the clot weights of samples obtained from whole blood assay experiments. [Figure 2]

[0022] FIG. 2 is a series of photographs showing blood clots on samples from a whole blood assay experiment after a 12 hour incubation period. [Figure 3]

[0023] FIG. 3 is a box plot showing clot weight (g) from samples obtained from the second whole blood assay experiment. [Figure 4]

[0024] FIG. 4 is a series of photographs showing blood clots on samples from a second whole blood assay experiment. [Figure 5]

[0025] FIG. 5 is a graph showing the average clot weight from samples obtained from a human whole blood assay experiment. [Figure 6]

[0026] FIG. 6 is a series of photographs showing blood clots on samples from a human whole blood assay experiment after overnight incubation. [Figure 7]

[0027] Figure 7 is a histogram showing the levels of blood concentration of the coagulation factor thrombin-antithrombin complex (TAT) in donor blood at baseline and during / after a 60-minute perfusion period in the Chandler loop model (control tube and test item). Bars represent the mean and standard deviation. [Figure 8]

[0028] Figure 8 is a histogram showing the mean platelet count in donor blood at baseline and during / after a 60-minute perfusion period in the Chandler loop model (control tube and test item). Bars represent the mean and standard deviation. [Figure 9]

[0029] Figure 9 is a histogram showing the levels of β-thromboglobulin (β-TG) in donor blood at baseline and during / after a 60-minute perfusion period in the Chandler loop model (control tube and test item). Bars represent the mean and standard deviation. [Figure 10]

[0030] Figure 10 is a histogram showing the mean red blood cell count in donor blood at baseline and during / after a 60-minute perfusion period in the Chandler loop model (control tube and test item). Bars represent the mean and standard deviation. [Figure 11]

[0031] Figure 11 is a histogram showing the mean white blood cell counts in donor blood at baseline and during / after the 60-minute perfusion period in the Chandler loop model (control tube and test item). Bars represent the mean and standard deviation. [Figure 12]

[0032] Figure 12 is a histogram showing the mean hemolyzed concentration in donor blood (control tube and test item) at baseline and during / after 60 minutes of perfusion in the Chandler loop model. Bars represent the mean and standard deviation. [Figure 13]

[0033] Figure 13 is a histogram showing the mean hemoglobin concentration in donor blood at baseline and during / after a 60 minute perfusion period in the Chandler loop model (control tubes and test items). Bars represent the mean and standard. [Figure 14]

[0034] Figure 14 is a histogram showing the mean hematocrit concentration in donor blood at baseline and during / after a 60-minute perfusion period in the Chandler loop model (control tubes and test items). Bars represent the mean and standard deviation. DETAILED DESCRIPTION OF THE INVENTION

[0022] definition

[0035] As used herein, the term "biocompatibility," particularly in the context of coatings or components thereof, refers to the ability of a medical device or material to function with an appropriate host response in a particular application (e.g., as established in ISO 10993-1(2018)). The definition of "biocompatibility," its related terminology, and the tests for evaluation in ISO 10993-1(2018) are incorporated herein by reference. Generally, biocompatibility refers to the ability of a medical device or material to perform its desired function with respect to a medical therapy without inducing undesirable local or systemic effects in the recipient or beneficiary of that therapy, but to generate the most appropriate and beneficial cells or tissues in that particular situation, optimizing the clinically relevant performance of that therapy.

[0023]

[0036] For convenience, the term "sulfonic acid group" is used herein. Generally, the term "sulfonic acid group" refers to a sulfonic acid group (-SO3H) or a sulfonate group (-SO3- ). The plural term "sulfonic acid group" refers to a sulfonic acid group (-SO3H), a sulfonate group (-SO3 - ), or at least one sulfonic acid group (-SO3H) and at least one sulfonate group (-SO3 - In certain environments, such as physiological environments, sulfonic acid groups (-SO3H) can be converted to sulfonate groups (-SO3 - ), or there may be an equilibrium between them.

[0024]

[0037] Generally, as used herein, the term "sulfonic acid group precursor" refers to a precursor group that can be hydrolyzed to a sulfonic acid group as defined herein. The precursor group can be a sulfonamide group (e.g., -SO2NH2, -SO2NHR a or -SO2NR a R b ) or sulfonate ester group (-SO3R a ) can be R a and R b may each independently be selected from C1-C6 alkyl, phenyl and benzyl.

[0025]

[0038] The term "alkyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms and containing no unsaturation. 1-6 An "alkyl" group contains 1 to 6 carbon atoms. Unless otherwise specified in the specification, alkyl groups are unsubstituted or include hydroxy, C 1-6 It may be substituted with one or more substituents selected from alkoxy and halo (preferably fluoro). Preferably, the alkyl group is unsubstituted.

[0026]

[0039] As used herein, the term "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.

[0027]

[0040] The term "alkoxy" as used herein refers to a radical attached through an oxygen atom of the formula -O-alkyl, where the alkyl group is defined above. The term "aryloxy" as used herein refers to a radical attached through an oxygen atom of the formula -O-aryl, where the aryl group is defined above.

[0028]

[0041] As used herein, the term "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 and carbon atoms, and at least one of the rings in the ring system is fully unsaturated (i.e., contains a delocalized [4n+2] π-electron system in accordance with Hückel theory). Ring systems from which aryl groups can be derived include, for example, benzene, indane, indene, tetralin, and naphthalene.

[0029]

[0042] The term "aryl-alkyl," as used herein, refers to a radical attached to an alkyl group, as defined above, which is further substituted with (or attached to) an aryl group, as defined above. Examples of aryl-alkyl groups include benzyl (PhCH2-) and phenylethyl.

[0030]

[0043] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain consisting of carbon and hydrogen atoms and containing no unsaturation. Examples of preferred alkylene groups include -CH-, -CH-CH-, -CH-CH-CH-, -CH(CH)-, and -C(CH)-CH-. 1-10 An alkylene group contains 1 to 10 carbon atoms. The alkylene is preferably straight-chain (e.g., unbranched).

[0031]

[0044] The term "alkenylene," as used herein, refers to a straight or branched divalent hydrocarbon chain consisting of carbon and hydrogen atoms and containing at least one double bond. The alkene group can have a cis or trans configuration. Examples of alkenylene groups include -CH=CH-, -CH2-CH=CH-, -C(CH3)=CH-CH2-, -CH2-C(CH3)=CH-CH2-, and -CH2-CH=C=CH-CH2-. "C 2-10 An alkenylene group contains 2 to 10 carbon atoms. When the alkenylene contains multiple double bonds, the double bonds can be conjugated or non-conjugated. It is preferred that the alkenylene group does not contain an allene group. More preferably, it is preferred that the alkenylene group contains a single double bond.

[0032]

[0045] The term "alkynylene," as used herein, refers to a straight or branched divalent hydrocarbon chain consisting of carbon and hydrogen atoms and containing at least a triple double bond. Examples of alkylene groups include -C≡C-, -CH2-C≡C-, CH(CH3)C≡C-CH2-, and -CH2-C≡CC≡CC(CH3)=CH-CH2-. 2-10 An alkynylene group contains 2 to 10 carbon atoms. When the alkynylene group contains multiple triple bonds, the triple bonds can be conjugated or non-conjugated. Preferably, the alkynylene group does not contain a double bond (e.g., a carbon-carbon double bond). More preferably, the alkynylene group comprises a single triple bond.

[0033]

[0046] As used herein, the term "phenylene" refers to a divalent radical derived from benzene (e.g., -CH-). A divalent radical (e.g., a disubstituted benzene ring) can have ortho-, meta-, or para-configuration of the substituents.

[0034]

[0047] Unless otherwise stated in the specification, each of the above groups (eg, alkyl, alkene, alkoxy, aryl, aryl-alkyl, alkylene, alkenylene, alkynylene, phenylene) is unsubstituted.

[0035] Detailed Description

[0048] The present invention provides a coating for a medical device. The coating reduces or prevents blood clotting. 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.

[0036]

[0049] As used herein, any reference to "blood" generally refers to the blood of a human or a non-human animal, such as a mammal. The present invention can be used in veterinary applications. The term "blood" preferably refers to human blood.

[0037]

[0050] Typically, the coating is biocompatible, preferably biocompatible and / or hemocompatible.

[0038]

[0051] The coating can comprise or consist essentially of a surface layer. The surface layer is the top layer of the coating. Thus, the surface layer can be the outer surface of the coated or coated medical device. During use, the surface layer of the coating comes into contact with blood.

[0039]

[0052] The surface layer or coating (e.g., as a whole) can be in the form of a gel, preferably a hydrogel. The hydrogel can provide a smooth surface to the medical device. When the surface layer or coating is in the form of a gel, it can be easily applied to the medical device.

[0040]

[0053] The surface layer may comprise or consist essentially of polymer chains bound or attached (eg, covalently bonded) to anticoagulant groups.

[0041]

[0054] Anticoagulant groups are typically selected from sulfonic acid groups, sulfonamide groups, sulfamic acid groups, hydrogen sulfate groups, and their conjugate bases. The structures of each group are shown below, where the wavy line indicates the point at which the group is directly or indirectly attached to the polymer chain. [ka]

[0042]

[0055] In general, it is preferred that the anticoagulant group be selected from sulfonic acid groups, sulfamic acid groups, hydrogen sulfate groups and their conjugate bases.

[0043]

[0056] The conjugate base of each group is shown below: The conjugate base of each group is a sulfonate group, a sulfonamide anion group, a sulfamate group, or a sulfate group, respectively. [ka]

[0044]

[0057] In general, it is preferred that the anticoagulant group is the conjugate base of a sulfonic acid group, a sulfamic acid group, or a hydrogen sulfate group. Thus, the anticoagulant group is preferably a sulfonate group, a sulfamate group, or a sulfate group, as described above.

[0045]

[0058] The polymer chain is preferably attached or linked to a plurality of anticoagulant groups, each of which is typically selected from sulfonic acid groups, sulfamic acid groups, hydrogen sulfate groups, and their conjugate bases, as defined above.

[0046]

[0059] Generally, the anticoagulant group is attached or bonded to the polymer chain by a linker group. In principle, any linker group can be used to connect the polymer chain to the anticoagulant group. However, certain linker groups may provide or contribute to advantageous properties of the coating.

[0047]

[0060] The linker group covalently attaches at least one anticoagulant group to the polymer chain, and thus may have a first end covalently attached to the polymer chain and a second end covalently attached to at least one anticoagulant group.

[0048]

[0061] A single anticoagulant group can be attached or linked to the polymer chain by a linker group (e.g., a single linker group), or multiple anticoagulant groups, such as two or three anticoagulant groups, can be linked to the polymer chain by linker groups (e.g., a single linker group).

[0049]

[0062] The polymer chain may be a linear polymer chain or a branched polymer chain, preferably a linear polymer chain.

[0050]

[0063] Generally, the surface layer is biocompatible. It is even more preferred that the polymer chains are biocompatible.

[0051]

[0064] The polymer chains typically have a number average (e.g., mean) molecular weight (Mn) of at least 300 g / mol, such as, for example, 300 to 50,000 g / mol, preferably 500 to 30,000 g / mol, and more preferably 1,000 to 10,000 g / mol. The number average (e.g., mean) molecular weight (Mn) can be determined by light scattering.

[0052]

[0065] Typically, the anticoagulant group is a sulfonic acid group or a sulfonate group. Preferably, each anticoagulant group of the plurality of anticoagulant groups is a sulfonic acid group or a sulfonate group.

[0053]

[0066] As noted above, the term "sulfonic acid group" as used herein refers to a sulfonic acid group (-SO3H) or a sulfonate group (-SO3 - ), as used herein, the term "sulfonic acid group" refers to a sulfonic acid group (-SO3H), a sulfonate group (-SO3 - ), or at least one sulfonic acid group (-SO3H) and at least one sulfonate group (-SO3 - ) combination.

[0054]

[0067] Thus, the surface layer may comprise or consist essentially of polymer chains attached or bonded to a plurality of sulfonic acid groups.

[0055]

[0068] In a first aspect of the invention, anticoagulant groups, particularly sulfonic acid groups, can be attached to the polymer chain after it has been formed by polymerization, instead of polymerizing monomers containing the anticoagulant group. In this context, a polymer chain attached or attached to an anticoagulant group or groups may be referred to herein as a polymer chain linked or attached to an anticoagulant group or groups, particularly when the or each anticoagulant group is a sulfonic acid group.

[0056]

[0069] Each sulfonic acid group may be linked or attached to a polymer chain by a linker group.

[0057]

[0070] To ensure that the surface of the coating exhibits a high negative charge density relative to platelets, the linker group must be relatively short (e.g., 1-3 atoms in length). If a longer linker group is used, the conformational flexibility of the linker group may result in the surface of the coating exhibiting a disordered arrangement of anticoagulant groups, particularly sulfonate groups. This can reduce the negative charge density provided by the surface of the coating.

[0058]

[0071] In general, it is preferred that the linker group be biocompatible.

[0059]

[0072] The polymer chain has the formula (A-0): [ka] [In formula (AO), each G 1 are the same or different and may be O, NH, or NR 1A are independently selected from Each R 1A are independently, C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl] The compound may comprise a repeat unit comprising a moiety such as represented by:

[0060]

[0073] each G 1 are preferably the same.

[0061]

[0074] The polymer chain has the following formula (A-1): [ka] The compound may include a repeat unit represented by:

[0062]

[0075] In the above formula (A-1), X 1A O - , OH, OR 1A , NH2, NHR 1A , and A 1A is selected from X 1B O - , OH, OR 1B , NH2, NHR 1B , and A 1B is selected from R 1A and R 1B Each of the following is independently 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, A 1A and A 1B Each of the independently represents the formula (S-1): [ka] [In formula (S-1), Z 1 O, NH, and NR 1 is selected from R 1 is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, Y 1 O - and OH, L 1 is expressed as equation (L-1): [ka] {In formula (L-1), P 1 is a single bond, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 alkynylene, and phenylene; Q 1 is a single bond, O, NH, NR 1Cand phenylene; W 1 is a single bond, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 alkynylene, and phenylene; R 1C is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl} represented by] It is expressed by:

[0063]

[0076] When formula (L-1) is combined with formula (S-1), A 1A and A 1B Each of the formula (S-1A): [ka] It is expressed by:

[0064]

[0077] The repeating unit represented by the above formula (A-1) can be obtained, for example, from a maleic acid monomer or a maleimide monomer.

[0065]

[0078] In formula (A-1), part -L 1 - represents a linker group.

[0066]

[0079] The polymer chain linked or bonded to the multiple sulfonic acid groups may include a repeat unit represented by any one of formulas (A-1) to (A-3) described herein.

[0067]

[0080] In the polymer chain, each unit in the repeating unit represented by formula (A-1) may be the same or different.

[0068]

[0081] Typically, the surface layer comprises a plurality of polymer compounds (e.g., a distribution), each polymer compound comprising a polymer chain including a repeating unit represented by any one of formulas (A-1) to (A-3) described herein.

[0069]

[0082] After polymerization of an appropriate monomer, such as maleic acid or maleimide, a linker group and a sulfonic acid group are attached to the polymer chain. The linker group and the sulfonic acid group are introduced into the repeat unit, such as by reaction at the carbonyl group. This can be accomplished by reacting a compound comprising an anticoagulant with the polymer using a coupling agent, as described below. Some carbonyl groups may not undergo reaction (i.e., not 100% conversion) and may contain a linker group and a sulfonic acid group. When this occurs, (a)X 1A O - , OH, OR 1A , NH2, or NHR 1A and / or (b) X 1B O - , OH, OR 1B , NH2, or NHR 1B It could be.

[0070]

[0083] Generally, for example, when the surface layer comprises a plurality of polymer compounds, at least 90% of the units represented by formula (A-1) are A as defined above. 1A and / or A 1B (i.e., X 1A is A 1A and / or X 1B is A 1B It is preferable that the polymer contains at least 95% of the units represented by formula (A-1) 1A and / or A 1B and even more preferably at least 99% of the units represented by formula (A-1) are A 1A and / or A 1B Includes.

[0071]

[0084] Typically, each unit of the repeating unit represented by formula (A-1) is A as defined above. 1A or A 1B (i.e., X 1A is A 1A or X 1B is A 1B More preferably, each repeating unit represented by formula (A-1) is 1A and A 1B (i.e., X 1A is A 1A and X 1B is A 1B Therefore, X 1A is A 1A and X 1B is A 1B is.

[0072]

[0085] It is preferred that each unit in the repeating unit represented by formula (A-1) is the same.

[0073]

[0086] The polymer chain may include a repeat unit represented by the following formula (A-2): [ka]

[0074]

[0087] In formula (A-2), X 1A , X 1B , R 1A , R 1B , A 1A , A 1B , Z 1 , R 1 , Y 1 , L 1 , P 1 , Q 1 , W 1 and R 1C are as defined above, where at least one X 1A is A 1Aor X 1B is A 1B and n 1 is an integer.

[0075]

[0088] In formula (A-1) or formula (A-2), X 1A O - , OH, OR 1A and A 1A Selected from X 1B O - , OH, OR 1B , and A 1B Preferably, X is selected from 1A O - , O-H and A 1A Selected from X 1B O - , O.H., and A. 1B Even more preferably, it is selected from the following formula (A-3): [ka] It is represented by X 1A is A 1A and X 1B is A 1B is.

[0076]

[0089] In formula (A-1) or formula (A-2), X 1A OR 1A or NHR 1A When R 1A is C 1-6 Preferably, X is alkyl, particularly methyl or ethyl. Alternatively or additionally, X 1B OR 1B or NHR 1B When R 1B C 1-6 Alkyl, especially methyl or ethyl, is preferred.

[0077]

[0090] In formula (A-1) or formula (A-2), A 1A and A 1Bmay be the same or different. In general, A 1A and A 1B are preferably the same.

[0078]

[0091] In the above formulas (A-1) to (A-3), Z 1 NR 1 When R 1 is C 1-6 Alkyl, especially methyl or ethyl, is preferred.

[0079]

[0092] Typically, each Z in the above formulas (A-1) to (A-3) 1 is preferably selected from O and NH. 1 may be O. More preferably, each Z 1 can be NH. Z 1 When is O or NH, the linker group is attached to the polymer chain by an ester or amide group, which are typical biocompatible groups. Amide groups, in particular, are biocompatible, as they are present in peptides, for example.

[0080]

[0093] Generally, in formulas (A-1) to (A-3), each L 1 may be the same or different. 1 are preferably the same.

[0081]

[0094] Each P 1 is typically a single bond, C 1-10 alkylene and phenylene, each W1 being a single bond, C 1-10 More preferably, each P 1 is a single bond and C 1-10 alkylene; and each W 1 is a single bond and C 1-10 It may be selected from alkylene.

[0082]

[0095] Alternatively, each P 1 is C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 alkynylene, and each Q 1 are O, NH, NR 1C Each W 1 is a single bond. More preferably, each Q 1 is selected from O and NH. In this configuration, the anticoagulant group is a sulfamate group, a sulfate group, or their conjugate bases.

[0083]

[0096] Typically, each L 1 About P 1 , Q 1 and W 1 It is preferred that at least one of the groups is not a single bond.

[0084]

[0097] Q 1 When is O, P 1 It is generally preferred that Q is not a single bond. 1 When is O, P 1 is C 1-10 It is preferably alkylene, and more preferably P 1 is C 2-4 It is alkylene.

[0085]

[0098] Q 1 is O and P 1 When is not a single bond, W 1 It may be preferred that Q is not a single bond. More preferably, when Q is O, P 1 is C 1-10 alkylene, W 1 is C 1-10 alkylene, more preferably P 1 is C 2-4 alkylene, W 1 is C 2-4 It is alkylene.

[0086]

[0099] Q 1 When is phenylene, P 1 is a single bond or C 1-10 alkylene, W 1 is a single bond or C 1-10 It is generally preferred that Q is alkylene. 1 When is phenylene, P 1 is a single bond or C 1-3 alkylene, W 1 is a single bond or C 1-3 It is preferably alkylene.

[0087]

[0100] In general, each P 1 is C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 alkynylene, and each Q 1 is a single bond, and each W 1 is preferably a single bond. More preferably, each P 1 is C 1-10 Alkylene, especially C 2-5 C such as alkylene 2-6 Even more preferably, each P 1 is butylene, propylene or ethylene, preferably ethylene. 1 is ethylene, and Q 1 and W 1 When both are single bonds, the moiety represented by (S-1) can be formed from taurine, which is found naturally in the human body and can be formed when polymeric compounds are broken down.

[0088]

[0101] Typically, n 1 is at least 5, preferably at least 10. For example, n 1 may be 5-500, such as 10-300, more preferably 15-100.

[0089]

[0102] The polymer chain is X 1A , X 1Bor Y 1 O - When the polymer chain is anionic, Na + or K + may be present as a counter cation.

[0090]

[0103] For convenience, the repeat units represented by formulae (A-0) to (A-3) will be referred to herein using the label "first repeat unit." The label "first" in this context is used to distinguish this repeat unit from other types of repeat units. When referring to a "second repeat unit," a "third repeat unit," etc., there need not be a "first repeat unit."

[0091]

[0104] In addition to or as an alternative to the repeating units represented by the above formulae (A-0) to (A-3), the polymer chain may contain repeating units represented by the formula (B-0): [ka] [In formula (B-0), G 2 O, NH, and NR 2A is selected from R 2A are independently, C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, R A is H and C 1-6 alkyl] The compound may comprise a repeat unit comprising a moiety represented by:

[0092]

[0105] The polymer chain has the formula (B-1): [ka] The compound may include a repeat unit represented by:

[0093]

[0106] In the above formula (B-1), R A H and C 1-6 alkyl, X 2 O - , OH, OR 2A , NH2, NHR 2A , and A 2 is selected from R 2A is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, A 2 is the formula (S-2): [ka] [In formula (S-2), Z 2 O, NH, and NR 2 is selected from R 2 is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, Y 2 is selected from O and OH, L 2 is expressed as equation (L-2): [ka] {In formula (L-2), P 2 is a single bond, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 selected from alkynylene and phenylene; Q 2 is a single bond, O, NH, NR 2C and phenylene; W 2 is a single bond, C 1-10 Alkylene, C 2-10Alkenylene, C 2-10 alkynylene, and phenylene; R 2C is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl} represented by] It is expressed by:

[0094]

[0107] When formula (L-2) is combined with formula (S-2), A 2 is the formula (S-2A): [ka] It is expressed by:

[0095]

[0108] The repeating unit represented by the above formula (B-1) may be derived from, for example, an acrylic acid monomer, a methacrylic acid monomer, an acrylamide monomer, or a methacrylamide monomer.

[0096]

[0109] In formula (B-1), part -L 2 - represents a linker group.

[0097]

[0110] The polymer chain linked or bonded to the multiple sulfonic acid groups may include a repeat unit represented by any one of formulas (B-1) to (B-3) described herein.

[0098]

[0111] In the polymer chain, each repeating unit represented by formula (B-1) may be the same or different.

[0099]

[0112] Typically, the surface layer comprises a plurality of polymer compounds (e.g., a distribution), each of which comprises a polymer chain including a repeating unit represented by any one of formulas (B-1) to (B-3) described herein.

[0100]

[0113] The linker group and sulfonic acid group are attached to the polymer chain after polymerization of an appropriate monomer, such as acrylic acid or methacrylic acid. The linker group and sulfonic acid group are introduced into the repeat unit by reaction with a carbonyl group, for example. Some carbonyl groups may not undergo reaction (i.e., there is not 100% conversion) and may contain a linker group and a sulfonic acid group. When this occurs, X 2 O - , OH, OR 2A , NH2, or NHR 2A It could be.

[0101]

[0114] Generally, for example, when the surface layer comprises a plurality of polymer compounds, at least 90% of the units represented by formula (B-1) are A as defined above. 2 (i.e., X 2 is A 2 It is preferable that at least 95% of the units represented by formula (B-1) are A 2 and even more preferably, at least 99% of the units represented by formula (B-1) are A 2 Includes.

[0102]

[0115] Typically, each unit in the repeating unit represented by formula (B-1) is A 2 (i.e., X 2 is A 2 (It is).

[0103]

[0116] It is preferred that each unit in the repeating unit represented by formula (B-1) is the same.

[0104]

[0117] The polymer chain has the following formula (B-2): [ka] The compound may include a repeat unit represented by:

[0105]

[0118] In formula (B-2), 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 Each of the is as defined above, and n 2 is an integer.

[0106]

[0119] In formula (B-1) or formula (B-2), X 2 O - , OH, OR 2A and A 2 Preferably, X is selected from 2 O - , O-H and A 2 Even more preferably, X 2 is expressed by the following formula (B-3): [ka] A as represented by 2 is.

[0107]

[0120] Typically, in the above formulas (B-1) to (B-3), R A H and C 1-3 alkyl, preferably R A is selected from H and methyl. Even more preferably, R A is H.

[0108]

[0121] In formula (B-1) or formula (B-2), X 2 OR 2A or NHR 2A When R 2A C 1-6 Alkyl, especially methyl or ethyl, is preferred.

[0109]

[0122] In the above formulas (B-1) to (B-3), Z 2 NR 2 If R 2 is C 1-6 Alkyl, especially methyl or ethyl, is preferred.

[0110]

[0123] Typically, in the above formulas (B-1) to (B-3), Z 2 is preferably selected from O and NH. 2 can be O. More preferably, Z 2 can be NH. Z 2 When is O or NH, the linker group is attached to the polymer chain by an ester or amide group, which are typical biocompatible groups. Amide groups are biocompatible, especially as they are present in peptides.

[0111]

[0124] P 2 is typically a single bond, C 1-10 alkylene and phenylene; W 2 is a single bond, C 1-10 It may be selected from alkylene and phenylene. More preferably, P 2 is a single bond and C 1-10 alkylene; W 2 is a single bond and C 1-10 It may be selected from alkylene.

[0112]

[0125] Or P 2 is C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 alkynylene, and Q2 are O, NH, and NR 2C Selected from W 2 is a single bond. More preferably, Q 2 is selected from O and NH. In this configuration, the anticoagulant group is a sulfamate group, a sulfate group, or their conjugate bases.

[0113]

[0126] Typically, L 2 In the case of P 2 , Q 2 and W 2 It is preferred that at least one of the groups is not a single bond.

[0114]

[0127] Q 2 When is O, P 2 It is generally preferred that Q is not a single bond. 2 When is O, P 2 is C 1-10 It is preferably alkylene, and more preferably P 2 is C 2-4 It is alkylene.

[0115]

[0128] Q 2 is O and P 2 When is not a single bond, W 2 It may be preferred that Q is not a single bond. 2 When is O, P 2 is C 1-10 alkylene, W 2 is C 1-10 alkylene, more preferably P 2 is C 2-4 alkylene, W 2 is C 2-4 It is alkylene.

[0116]

[0129] Q 2 When is phenylene, P 2 is a single bond or C 1-10 alkylene, W 2is a single bond or C 1-10 It is generally preferred that Q is alkylene. 2 When is phenylene, P 2 is a single bond or C 1-3 alkylene, W 2 is a single bond or C 1-3 It is preferably alkylene.

[0117]

[0130] In general, P 2 is C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 alkynylene, and Q 2 is a single bond, and W 2 is preferably a single bond. 2 is C 1-10 Alkylene, especially C 2-5 C such as alkylene 2-6 Even more preferably, P is alkylene. 2 is butylene, propylene or ethylene, preferably ethylene. 2 is ethylene, and Q 2 and W 2 are single bonds, the moiety represented by (S-2) can be formed from taurine. As mentioned above, taurine can be formed when degradation of the polymer compound occurs.

[0118]

[0131] Typically, n 2 The integer represented by is at least 5, preferably at least 10. For example, n 2 can be 5-500, such as 10-300, more preferably 15-100.

[0119]

[0132] The polymer chain is X 2 or Y 2 When the polymer chain is anionic, Na + or K + may be present as a counter cation.

[0120]

[0133] For convenience, the repeat units represented by formulae (B-0) to (B-3) will be referred to herein using the label "second repeat unit." The label "second" in this context is used to distinguish this repeat unit from the "first repeat unit." As noted above, this label does not require that a "first repeat unit" must be present in addition to the "second repeat unit."

[0121]

[0134] A polymer chain linked or bonded to multiple sulfonic acid groups can be a copolymer.

[0122]

[0135] The copolymer may be an alternating copolymer (or interpolymer) comprising a first repeating unit represented by any one of formulas (A-0) to (A-3) and a second repeating unit represented by any one of formulas (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.

[0123]

[0136] The alternating copolymer may, for example, be of the formula: [ka] [wherein n is an integer] It can be expressed as:

[0124]

[0137] Typically, n is at least 5, preferably at least 10. For example, n may be 5-500, such as 10-300, more preferably 15-100.

[0125]

[0138] The copolymer has the following formula (C-1): [ka] The copolymer may be a block copolymer, such as a block copolymer represented by:

[0126]

[0139] In formula (C-1), X 1A , X 1B , R 1A , R 1B , A 1A , A 1B , Z 1 , R 1 , Y 1 , L 1 , P 1 , Q 1 , W 1 , R 1C and n 1 is as defined above for any of formulas (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 is as defined above for any of formulas (B-1) to (B-3).

[0127]

[0140] X 1A A 1A and / or X 1B A 1B and / or X 2 A 2 Therefore, X 1A , X 1B , and X 2 At least one of each is A 1A , A 1B , and A 2 More preferably, X 2 is A 2 and X1A and X 1B At least one of each is A 1A and A 1B Even more preferably, the compound represented by the following formula (C-2): [ka] As shown in the figure, X 1A is A 1A and X 1B is A 1B and X 2 is A 2 is.

[0128]

[0141] In the above formula (C-1) and formula (C-2), R A H and C 1-3 alkyl, preferably R A is selected from H and methyl. Even more preferably, R A is H.

[0129]

[0142] In formula (C-1), X 1A OR 1A or NHR 1A When R 1A is C 1-6 Preferably, X is alkyl, particularly methyl or ethyl; 1B OR 1B or NHR 1B When R 1B is C 1-6 Preferably, X is alkyl, particularly methyl or ethyl; 2 OR 2A or NHR 2A When R 2A is C 1-6 Alkyl, especially methyl or ethyl, is preferred.

[0130]

[0143] In formula (C-1), A 1A and A 1B may be the same or different. In general, A 1Aand A 1B are preferably the same.

[0131]

[0144] In the above formula (C-1), Z 1 NR 1 When R 1 is C 1-6 Alkyl, particularly methyl or ethyl, is preferred; Z 2 NR 2 When R 2 is C 1-6 Alkyl, especially methyl or ethyl, is preferred.

[0132]

[0145] Typically, in the above formulas (C-1) and (C-2), each Z 1 is preferably selected from O and NH, Z 2 is preferably selected from O and NH. 2 and each Z 1 can be O. More preferably, Z 2 and each Z 1 is NH.

[0133]

[0146] Generally, in formulas (C-1) and (C-2), each L 1 may be the same or different. 1 are preferably the same.

[0134]

[0147] Each P 1 is a single bond, C 1-10 alkylene and phenylene; W 1 is a single bond, C 1-10 alkylene and phenylene; P 2 is a single bond, C 1-10 alkylene and phenylene, and each W 2 is a single bond, C 1-10 More preferably, each P 1 is a single bond and C 1-10alkylene, and each W 1 is a single bond and C 1-10 alkylene; P 2 is a single bond and C 1-10 alkylene; W 2 is a single bond and C 1-10 It may be selected from alkylene.

[0135]

[0148] Typically, each L 1 In the case of P 1 , Q 1 and W 1 Preferably, at least one of L is not a single bond; 2 In the case of P 2 , Q 2 , and W 2 It is preferred that at least one of is not a single bond.

[0136]

[0149] Q 1 When is O, P 1 It is generally preferred that Q is not a single bond. 2 When is O, P 2 It is generally preferred that Q is not a single bond. 1 When is O, P 1 is C 1-10 Preferably, Q is alkylene. 2 When is O, P 2 is C 1-10 It is preferably alkylene. More preferably, P 1 is C 2-4 alkylene, and P 2 is C 2-4 It is alkylene.

[0137]

[0150] Q 1 is O and P 1 When is not a single bond, W 1 It may be preferable that Q is not a single bond. 2 is O and P 2 When is not a single bond, W 2It may be desirable that Q is not a single bond. 1 When is O, P 1 is C 1-10 alkylene, W 1 is C 1-10 It is preferably alkylene, and when Q2 is O, P 2 is C 1-10 alkylene, W 2 is C 1-10 It is preferably alkylene, and more preferably P 1 is C 2-4 alkylene, W 1 is C 2-4 alkylene, and P 2 is C 2-4 Alkylene, W 2 is C 2-4 It is alkylene.

[0138]

[0151] Q 1 When is phenylene, P 1 is a single bond or C 1-10 alkylene, W 1 is a single bond or C 1-10 It is generally preferred that Q is alkylene. 1 When is phenylene, P 1 is a single bond or C 1-3 alkylene, W 1 is a single bond or C 1-3 It is preferably alkylene.

[0139]

[0152] Q 2 is phenylene, generally, P 2 is a single bond or C 1-10 alkylene, W 2 is a single bond or C 1-10 It is preferably alkylene. More preferably, Q 2 When is phenylene, P 2 is a single bond or C 1-3 alkylene, and W2 is a single bond or C 1-3 It is preferably alkylene.

[0140]

[0153] In general, each P 1 is C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 alkynylene, and each Q 1 is a single bond, and each W 1 is a single bond, and P 2 is C 1-10 Alkylene, C 2-10 Alkenylene, and C 2-10 alkynylene, and Q 2 is a single bond, and W 2 is preferably a single bond. More preferably, each P 1 is C 1-10 Alkylene, especially C 2-5 C such as alkylene 2-6 alkylene, and P2 is C 1-10 Alkylene, especially C 2-5 C such as alkylene 2-6 Even more preferably, each P 1 is ethylene, and P 2 is ethylene.

[0141]

[0154] In formula (C-2), each Y 1 O - and OH, and Y 2 is selected from O and OH. 1 is C 2-5 alkylene, and L 2 is C 2-5 alkylene, and n 1 is an integer. 2 is preferably an integer. More preferably, L 1 is ethylene and L 2 is ethylene, and n 1 is an integer equal to or greater than 5, and n 2 is an integer greater than or equal to 5.

[0142]

[0155] Typically, in the above formula (C-1) or (C-2), n 1 The integer represented by is at least 5, preferably at least 10. For example, n 1 can be 5-500, such as 10-300, more preferably 15-100.

[0143]

[0156] n 2 The integer represented by is typically at least 5, preferably at least 10. For example, n 2 can be 5-500, such as 10-300, more preferably 15-100.

[0144]

[0157] The polymer chain is X 1A , X 1B , X 2 , Y 1 or Y 2 When the polymer chain is anionic, Na + or K + may be present as a counter cation.

[0145]

[0158] When the polymer chain is linked or attached to multiple sulfonic acid groups, the polymer chain (e.g., before being linked or attached to multiple sulfonic acid groups) has a number average (e.g., mean) molecular weight (Mn) of at least 300 g / mol, such as, for example, 300 to 50,000 g / mol, preferably 500 to 30,000 g / mol, and more preferably 1,000 to 10,000 g / mol. n )).

[0146]

[0159] In the first embodiment described above, the polymer chains linked or bonded to the anticoagulant groups have advantageous properties, particularly when they contain a repeating unit represented by any one of formulas (A-0) to (A-3), especially when they are represented by formula (C-1) or (C-2). The surface layer or coating can be a hydrogel. The coating can also be biodegradable, since degradation of the polymer chains linked or bonded to the anticoagulant groups can result in the formation of biocompatible by-products. In addition to reducing or preventing blood clotting, the anticoagulant component of the surface layer can also have excellent stability and be relatively inexpensive, especially when compared to other anticoagulant components in the art, such as heparin.

[0147]

[0160] In a second embodiment, polymerization of monomers comprising anticoagulant groups, such as sulfonic acid groups, can provide polymer chains attached or bound to anticoagulant groups. The monomers themselves, for example, comprise sulfonic acid groups or sulfonic acid group precursors. In this context, a polymer chain attached or bound to an anticoagulant group or groups may be referred to herein as a polymer comprising an anticoagulant group or groups, particularly when each anticoagulant group is a sulfonic acid group.

[0148]

[0161] The monomer comprising a sulfonic acid group can be a compound comprising an alkene group and a sulfonic acid group, such as vinyl sulfonic acid, styrene sulfonic acid (e.g., 4-styrene sulfonic acid), 2-acrylamido-2-methylpropane sulfonic acid, or their conjugate bases (e.g., sulfonates).

[0149]

[0162] The monomer comprising a sulfonic acid precursor group can be a compound comprising an alkene group and a sulfonic acid precursor group.

[0150]

[0163] The polymer comprising sulfonic acid groups may be a homopolymer, so the polymer is a homopolymer comprising sulfonic acid groups.

[0151]

[0164] Examples of homopolymers containing sulfonic acid groups include polyvinyl sulfonic acid, polystyrene sulfonic acid, poly(2-acrylamido-2-methylpropanesulfonic acid), and their conjugate bases. The homopolymer containing sulfonic acid groups is preferably poly(2-acrylamido-2-methylpropanesulfonic acid).

[0152]

[0165] The polymer comprising sulfonic acid groups can be a copolymer (e.g., a copolymer comprising sulfonic acid groups). The copolymer comprising sulfonic acid groups can be an alternating copolymer or a block copolymer.

[0153]

[0166] The copolymer comprising sulfonic acid groups can be obtained from at least two monomers or from only two monomers.

[0154]

[0167] The copolymer comprising sulfonic acid groups can be obtained from a first monomer and a second monomer, the first monomer being different from the second monomer. The copolymer can be obtained by copolymerization of the first monomer and the second monomer.

[0155]

[0168] The first monomer comprises a sulfonic acid group or a sulfonic acid group precursor. The monomer comprising a sulfonic acid group may be a compound comprising an alkene group and a sulfonic acid 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 their conjugate bases (e.g., sulfonates). Preferably, the first monomer is 2-acrylamido-2-methylpropane sulfonic acid or its conjugate base.

[0156]

[0169] Similarly, the monomer comprising a sulfonic acid precursor group can be a compound comprising an alkene group and a sulfonic acid precursor group.

[0157]

[0170] The second monomer comprises an alkene group. The second monomer may be selected from acrylic acid, itaconic acid, vinyl acetate, and maleic acid. Preferably, the second monomer is maleic acid.

[0158]

[0171] The copolymer comprising sulfonic acid groups can be, for example, 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).

[0159]

[0172] When the polymer comprises sulfonic acid groups, the polymer (e.g., containing sulfonic acid groups) has a number average (e.g., average) molecular weight (Mn) of at least 300 g / mol, such as 300 to 50,000 g / mol, preferably 500 to 30,000 g / mol, and more preferably 1,000 to 10,000 g / mol.

[0160]

[0173] Generally, 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 components of the surface or base layer.

[0161]

[0174] The antimicrobial agent may comprise silver.

[0162]

[0175] The coating of the present invention is typically disposed on the surface of a medical device. The surface of the medical device can be the interior or internal surface of the medical device (e.g., the interior surface of a catheter) or the exterior surface of the medical device. The coating can be disposed on the surface of a medical device that receives blood or a blood product comprising platelets.

[0163]

[0176] The coating may provide complete or partial coverage of the surface of the medical device.

[0164]

[0177] In the coating of the present invention, a surface layer is disposed on the surface of the medical device.

[0165]

[0178] In some cases, the surface layer may be disposed directly on the surface of the medical device, such that the surface layer is in direct contact with the surface of the medical device.

[0166]

[0179] The surface layer may be applied directly to the surface of the medical device, particularly if it is capable of adhering or bonding to this surface.

[0167]

[0180] The surface of the medical device can be functionalized with groups that can be attached to the polymer chains, such as by applying a base coating. The surface of the medical device can have amine groups that can react with carbonyl groups in the polymer chains to form amide groups, thereby attaching a surface layer of the coating to the surface of the medical device.

[0168]

[0181] Multiple layers can be disposed on the surface of the medical device, each layer can comprise polymer chains attached or bonded to an anticoagulant, as defined above, with the top or outermost layer being the surface layer.

[0169]

[0182] Generally, the coating may also comprise a base layer. The base layer is typically disposed below the surface layer. One or more layers may be present between the base layer and the surface layer, with each layer comprising polymer chains attached or bonded to the anticoagulant groups described above. Alternatively, the surface layer may be disposed directly on the base layer.

[0170]

[0183] The surface layer is preferably disposed directly on the base layer, and thus is typically coated onto the base layer.

[0171]

[0184] The base layer can be disposed on a surface of the medical device. The base layer is typically disposed directly on the surface of the medical device, such that the base layer is in direct contact with the surface.

[0172]

[0185] It is generally preferred that the base layer adhere or bond, preferably adhere, to the surface of the medical device.

[0173]

[0186] Typically, the base layer is biocompatible.

[0174]

[0187] The base layer may comprise or consist essentially of a protein, preferably a human protein.

[0175]

[0188] The protein may be albumin. Preferably, the albumin is human albumin, preferably recombinant human albumin.

[0176]

[0189] Albumin, particularly recombinant human albumin, mimics the albumin found in the human circulatory system. It can adhere to a wide variety of surfaces, particularly those of medical devices, by static attraction. It also provides a bio-passive surface that can protect against platelet activation.

[0177]

[0190] Generally, the surface layer of the coating is bonded to the base layer. The surface layer can be adhesively bonded to the base layer or covalently bonded to the base layer. Base layer When comprises albumin, the albumin may be covalently attached to the polymer chain.

[0178]

[0191] The present invention also provides a medical device that can be used in a location that comes into contact with blood or a blood product containing platelets.

[0179]

[0192] The coating is disposed on a surface of a medical device. Thus, the medical device has a surface coated with a coating of the present invention. For convenience, a surface coated with a coating of the present invention will be referred to as a "coated surface." The coated surface is intended for use in contact with blood or a blood product containing platelets, preferably blood.

[0180]

[0193] Typically, the coating has a thickness of 0.05 μm to 300 μm, preferably 0.1 μm to 200 μm, and more preferably 1 μm to 100 μm. Generally, the coating thickness is selected so as not to significantly increase the profile of the medical device for use in a patient.

[0181]

[0194] A medical device can be coated with a single layer of the coating of the present invention. Alternatively, the medical device can be coated with multiple layers of the coating of the present invention. Thus, the surface of the medical device can be coated with several alternating layers of a base layer and a layer comprising polymer chains attached to anticoagulant groups.

[0182]

[0195] The medical device can be an implantable medical device or an extracorporeal medical device. The implantable medical device can be a permanently implanted medical device or a temporarily implanted medical device.

[0183]

[0196] The medical device may be a transient blood-contacting device, which may not be, for example, implantable or extracorporeal.

[0184]

[0197] The medical device may be for in vivo or in vitro use. The medical device is preferably for in vivo use.

[0185]

[0198] The medical device may have a component for use in vivo, preferably at least a surface of which is coated with the coating of the present invention.

[0186]

[0199] The coated surface of the medical device or a component of the medical device can be inserted into a region of the body, such as an affected area of ​​the body, which can be, for example, an 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, an aorta, a vena cava, or a peripheral artery or vein.

[0187]

[0200] Once in place, the coated surface prevents blood clotting on and around the medical device or components of the medical device, thereby inhibiting thrombosis, particularly subacute device thrombosis.

[0188]

[0201] A medical device or component thereof may be a needle, catheter, stent, graft, shunt, dressing, surgical staple, guidewire, cannula, surgical instrument, endoscope, prosthesis or organoid (e.g., insulin secretion device), implantable monitor or sensor, defibrillator, ventricular assist device, pacemaker (e.g., cardiac pacemaker), implantable pump (e.g., intra-aortic balloon pump or ventricular assist pump), cell reservoir (e.g., for stem cell placement), prosthesis (e.g., prosthetic heart valve), orthopedic device, electrical stimulation lead or may be a lead tip, an implantable vascular access port, a blood storage bag, a blood tube, 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 neuroaneurysm treatment device, a heart valve repair device, an intravitreal drug delivery device, a joint replacement, an intraocular implant, a blood oxygenator, a blood filter, a septal defect device, a hemodialysis unit, a hemoperfusion unit, or a plasmapheresis unit or an anastomosis device.

[0189]

[0202] Examples of catheters include balloon or inflation catheters, injection catheters, central venous catheters, arterial catheters, and suction catheters. It may be preferred that the medical device is a central venous catheter or a suction catheter.

[0190]

[0203] Examples of grafts include vascular grafts, stent grafts or bypass grafts. It may be preferred that the medical device is a bypass graft.

[0191]

[0204] Examples of stents include vascular stents, urethral stents, biliary stents, biliary stents, esophageal stents, and tracheal or bronchial stents.

[0192]

[0205] Generally, it may be preferred that the medical device be selected from central venous catheters, suction catheters, bypass grafts, perfusion lines, cardiac bypass machines, and extracorporeal oxygenation and heat exchange circuits.

[0193]

[0206] The medical device or component thereof may comprise a metal, a polymeric material, a glass, or a ceramic. Thus, the coating of the present invention can be applied to a surface comprising a metal, a plastic, or a ceramic.

[0194]

[0207] The metal can be, for example, 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), an iron alloy, a palladium alloy, a rhenium alloy, or a magnesium alloy.

[0195]

[0208] The polymeric material can be, for example, cellulose acetate, cellulose nitrate, silicone, polyethylene terephthalate, polyurethane, polyamide, polyester (e.g., nylon), polyorthoester, polyanhydride, polyethersulfone, polycarbonate, polypropylene, polyethylene, or polytetrafluoroethylene.

[0196]

[0209] The ceramic may include, for example, oxides, carbides, or nitrides of transition metals such as titanium oxide, hafnium oxide, iridium oxide, chromium oxide, aluminum oxide, and zirconium oxide.

[0197]

[0210] The present invention also provides a polymer compound having the formula (C-2): [ka] [In formula (C-2), Each Y 1 O - and OH, Y 2 O - and OH, Each L 1 is C 2-5 is alkylene, L 2 is C 2-5 is alkylene, R A H and C 1-6 alkyl, preferably H and methyl; n 1 is an integer, n 2 is an integer] It is expressed as:

[0198]

[0211] Each L 1 is ethylene and L 2 is preferably ethylene.

[0199]

[0212] R A is preferably selected from H and methyl. More preferably, R A is H.

[0200]

[0213] n 1 The integer represented by is at least 5, preferably at least 10. For example, n 1 can be 5-500, such as 10-300, more preferably 15-100.

[0201]

[0214] n 2 The integer represented by is typically at least 5, preferably at least 10. For example, n 2 can be 5-500, such as 10-300, more preferably 15-100.

[0202]

[0215] Also provided by the present invention are coatings and uses in medical devices.

[0203]

[0216] The coating or medical device comprising the coating may be used in the treatment of the human or animal body by surgery or therapy and / or in diagnostic procedures performed on the human or animal body.

[0204]

[0217] Diagnostic methods carried out in the human or animal body are typically in vivo diagnostic methods.

[0205]

[0218] Surgical or therapeutic diagnostic methods or treatments typically involve contacting the coating, or a medical device comprising the coating, with blood.

[0206]

[0219] The coating or medical device comprising the coating is for use in reducing or preventing blood clotting, preferably for reducing or preventing blood clotting on the coated surface of the medical device.

[0207]

[0220] The present invention also provides a method for reducing or preventing blood clotting, comprising contacting a medical device of the present invention with blood, the medical device being used in the normal manner, except that the presence of the coating inhibits or prevents the formation of blood clots, particularly on the coated surface of the medical device.

[0208]

[0221] One aspect of this method is an in vitro method. For example, the method can be an in vitro method of reducing or preventing blood clotting when processing blood. The blood can be processed to produce a blood product, such as processed blood or a blood product for storage.

[0209]

[0222] The method can comprise contacting a medical device with blood, wherein the blood has been removed from a human or animal body. The blood can be contacted with the medical device to treat the blood.

[0210]

[0223] The method may not include administering the treated blood or blood product to the human or animal body. The blood product or treated blood may not be returned to the human or animal body, preferably the human or animal body from which the blood was removed.

[0211]

[0224] A further aspect of this method is a diagnostic method, in particular an in vitro and / or ex vivo diagnostic method.

[0212]

[0225] The method may relate to a method of reducing or preventing blood clotting in a diagnostic procedure. The method may comprise contacting a medical device with blood to obtain diagnostic information. The medical device may be contacted with pre-obtained or pre-delivered blood.

[0213]

[0226] The diagnostic procedure is not performed on a human or animal body, or the diagnostic procedure is performed on a non-living (e.g., dead) human or animal body, and thus the diagnostic method may not include the step of removing blood from a human or animal body, particularly a living human or animal body.

[0214]

[0227] The present invention also provides a method for producing a coating for a medical device, in particular a coating comprising a surface layer comprising polymer chains attached or bound to anticoagulant groups according to the first aspect.

[0215]

[0228] The method involves attaching or binding (e.g., by a coupling reaction) a compound comprising an anticoagulant to a polymer using a coupling agent. The compound comprising an anticoagulant can be attached or bound to the polymer by forming an amide group.

[0216]

[0229] The present invention further provides a kit for coating a medical device, particularly when the coating has a surface layer comprising polymer chains attached or bound to anticoagulant groups according to the first aspect.

[0217]

[0230] The kit comprises (a) a polymer, (b) a compound comprising an anticoagulant group, (c) a coupling agent, and optionally (d) a coating to form a base layer.

[0218]

[0231] The polymer may be dispersed, for example, in a solution or gel.

[0219]

[0232] In the method or kit of manufacture, the polymer forms a polymer chain that is attached or bound to an anticoagulant group.

[0220]

[0233] Typically, the polymer has the following formula (D-1): [ka] The repeating unit includes a repeating unit represented by:

[0221]

[0234] In the above formula (D-1), X 3 OH, OR 3A , N.H. 2 and NHR 3A Selected from R 3A is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6alkyl.

[0222]

[0235] X 3 is preferably selected from OH and NH, more preferably X 3 is OH.

[0223]

[0236] The repeating unit represented by the above formula (D-1) can be obtained, for example, from a maleic acid monomer or a maleimide monomer.

[0224]

[0237] The polymer has the following formula (D-2): [ka] The compound may include a repeat unit represented by:

[0225]

[0238] In formula (D-2), 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 can be 5-500, such as 10-300, more preferably 15-100.

[0226]

[0239] The polymer may be a copolymer. The copolymer typically has the following formula (D-3): [ka] and the block copolymers are those represented by:

[0227]

[0240] In formula (D-3), X 3 and n 1 is as defined above for formula (D-1) or (D-2), and R A H and C 1-6alkyl; and X 4 OH, OR 4 , NH2, and NHR 4 Selected from R 4 is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, and n2 is an integer.

[0228] R A is preferably H and C 1-3 alkyl. More preferably, R A is selected from H and methyl. Even more preferably, R A is H.

[0229]

[0242] X 4 is preferably selected from OH and NH, more preferably X 4 is OH.

[0230]

[0243] Typically, n 2 The integer represented by is at least 5, preferably at least 10. For example, n 2 can be 5-500, such as 10-300, more preferably 15-100.

[0231]

[0244] The compound comprising an anticoagulant group has the formula (E-1): [ka] [In formula (E-1), Z 3 are OH, NH2, and NHR 3 is selected from R 3 is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl, L 3is expressed as equation (L-3): [ka] {In formula (L-3), P 3 is a single bond, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 selected from alkynylene and phenylene; Q 3 is a single bond, O, NH, NR 3C and phenylene; W 3 is a single bond, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 selected from alkynylene and phenylene; R 3C is C 1-6 Alkyl, C 6-10 Aryl, and C 6-10 Aryl-C 1-6 alkyl} represented by] It can be represented by:

[0232]

[0245] Z 3 is preferably NH2.

[0233]

[0246] P 3 is typically a single bond, C 1-10 alkylene and phenylene; W 3 is a single bond, C 1-10 It may be selected from alkylene and phenylene. More preferably, P 3 is a single bond and C 1-10 alkylene; W 3 is a single bond and C 1-10 It may be selected from alkylene.

[0234]

[0247] Or P 3 is C 1-10 Alkylene, C2-10 Alkenylene and C 2-10 alkynylene, and Q 3 are O, NH, and NR 3C Selected from W 3 is a single bond. More preferably, Q 3 is selected from O and NH.

[0235]

[0248] Typically, L 3 In the case of P 3 , Q 3 and W 3 It is preferred that at least one of the groups is not a single bond.

[0236]

[0249] Q 3 When is O, P 3 It is generally preferred that Q is not a single bond. 3 When is O, P 3 is C 1-10 It is preferably alkylene, and more preferably P 3 is C 2-4 It is alkylene.

[0237]

[0250] Q 3 is O and P 3 When is not a single bond, W 3 It may be preferable that Q is not a single bond. 3 When is O, P 3 is C 1-10 alkylene, W 3 is C 1-10 It is preferably alkylene, and more preferably P 3 is C 2-4 alkylene, W 3 is C 2-4 It is alkylene.

[0238]

[0251] Q 3 When is phenylene, P 3 is a single bond or C 1-10alkylene, W 3 is a single bond or C 1-10 It is generally preferred that Q is alkylene. 3 When is phenylene, P 3 is a single bond or C 1-3 alkylene, W 3 is a single bond or C 1-3 It is preferably alkylene.

[0239]

[0252] In general, P 3 is C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 alkynylene, and Q 3 is a single bond, and W 3 is preferably a single bond. 3 is C 1-10 Alkylene, especially C 2-5 C such as alkylene 2-6 Even more preferably, P is alkylene. 3 is butylene, propylene or ethylene, preferably ethylene.

[0240]

[0253] The compound represented by formula (E-1) can be taurine.

[0241]

[0254] The coupling agent can be a carbodiimide coupling agent. Examples of carbodiimide coupling agents include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). Preferably, the coupling agent is EDC.

[0242]

[0255] In the kit of the present invention, the coupling agent may be a powder.

[0243]

[0256] The coating for forming the base layer can be a solution, suspension, or gel comprising a protein, preferably a human protein. Preferably, the coating for forming the base layer is a solution, such as a stabilized solution. As mentioned above, the protein can be albumin. Preferably, the albumin is human albumin, preferably recombinant human albumin.

[0244]

[0257] The manufacturing method of the present invention involves coupling a carboxylic acid or amide group of the polymer to a hydroxy or amino group of the compound, including the anticoagulant, using a coupling agent. Such coupling reactions are known in the art.

[0245]

[0258] The coupling reaction produces polymer chains attached or bound to anticoagulant groups. Any remaining coupling agent can be removed, such as by rinsing with water, to form a coating.

[0246]

[0259] The coating can be applied to the surface of the medical device by, for example, dip coating, spraying, washing, brushing, roller, or spin coating, or the coating can be pumped through the medical device, such as to coat the interior surface of the medical device.

[0247]

[0260] The thickness of the coating can be controlled by varying the immersion time, flow rate, etc., and the number of coating steps. Each coating can be provided to the surface of the medical device as described herein in a series of applications. The number of applications can be selected to provide individual coated layers of appropriate thickness, as well as the desired total number of coatings, as needed.

[0248]

[0261] When the coating includes a base layer, the base layer can be applied to the surface of the medical device before the surface layer. The surface of the medical device can be coated with a solution, suspension, or gel comprising a protein, preferably a human protein. The protein can be albumin. Preferably, the albumin is human albumin, preferably recombinant human albumin.

[0249]

[0262] The present invention may also provide a method of coating the surface of a medical device, the method comprising applying a coating as described above to the surface of the medical device. The coating is applied to form a surface layer, and may be applied, for example, as described above.

[0250]

[0263] The surface layer coating may be pre-formed, and thus the polymer chains attached or bonded to anticoagulant groups in accordance with the present invention may be applied directly to the surface of the medical device or to the base layer of the surface of the medical device, if present.

[0251]

[0264] Alternatively, the polymer chains attached or bound to the anticoagulant groups can be formed on the surface of the medical device (e.g., in situ), or can be formed in a base layer, if present, on the surface of the medical device. Thus, the coating can be preferably prepared on the surface or base layer of the medical device according to a method for preparing a coating for a medical device. Thus, a compound comprising an anticoagulant, a polymer, and a coupling agent can be applied to the surface of the medical device, or to the base layer, if present. The compound comprising the anticoagulant can be attached or bound to the polymer (e.g., attached or bound to form a coating) using a coupling agent, as described in the method for preparing a coating for a medical device.

[0252]

[0265] The method can include attaching or binding a compound comprising an anticoagulant to the polymer using a coupling agent. Anticoagulants are sometimes referred to as hemocompatible agents (i.e., the term "anticoagulant" is synonymous with the term "hemocompatible agent").

[0253]

[0266] The surface of the medical device may already be coated with a base layer. Thus, the method may also include applying (or coating) a base layer to the surface of the medical device, or applying a coating to the medical device to form such a base layer. A coating in this context is a coating to form a base layer.

[0254]

[0267] When a base layer has already been applied to the surface of the medical device, the coating applied to form the surface layer may be applied to the base layer on the surface of the medical device. [Example]

[0255] Example

[0268] The invention is illustrated by the following non-limiting examples.

[0256] Example 1 Bovine serum albumin coating

[0269] Bovine serum albumin solution was prepared in distilled water buffer at pH 4.5 (by HCl and NaOH titration) and a concentration of approximately 25 mg / 100 mL.

[0257]

[0270] The PVC tubing samples were incubated in this solution at room temperature for 0-1 hour with gentle rotation to produce bovine serum albumin-coated samples.

[0258]

[0271] All albumin-coated samples were then immersed in DI water for 15 minutes and allowed to dry.

[0259] Poly(maleic acid-co-acrylic acid) coating

[0272] A 1 mL / 200 mL solution of poly(maleic acid-co-acrylic acid) polymer at pH 4.5 was prepared. The samples were incubated in this solution at room temperature for 0-1 h with gentle rotation. Subsequently, all samples were immersed in deionized (DI) water for 15 min and then dried.

[0260]

[0273] To crosslink albumin and poly(maleic acid-co-acrylic acid), 500 mg of EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in distilled water at pH 4.5 was used. Samples coated with both albumin and poly(maleic acid-co-acrylic acid) were incubated in this solution for 15 minutes to 1 hour. The coated samples were then removed, rinsed with deionized water, and dried.

[0261]

[0274] Sulfonic acid group modified coating The samples were then treated to crosslink the poly(maleic acid-co-acrylic acid) polymer with taurine. A pH 8.3 distilled water solution was prepared by titration with HCl and NaOH. 500 mg of EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 500 mg of taurine (2-aminosulfonic acid) were added to the coated sample in 100 mL of pH 8.3 solution. The coated sample was incubated for 3 to 24 hours to allow crosslinking to occur. The coated sample was then rinsed with deionized water and dried.

[0262]

[0275] The coated samples were treated with toluidine blue, which has a high affinity for acidic groups, such as sulfonic acid groups, present in the coating. After treatment, the coated samples exhibited a blue / purple color, confirming the presence of sulfonic acid groups.

[0263] Heparin coating (comparison)

[0276] The commercial coating was obtained from Coatings2Go™ and applied to the substrate using the provided instructions. The coating was hydrophilic and contained acrylate-derived polymer repeat units. Heparin was attached to the coated substrate by chemical crosslinking using EDC as described above.

[0264] Research and Results Whole Blood Assay

[0277] To measure the anticoagulant activity of the coatings, whole blood assay experiments were performed.

[0265] Experiment 1 - Sheep whole blood Experiments were performed using citrated whole sheep blood within 24 hours after phlebotomy. Immediately before the start of the experiment (T0), the blood was recalcified using calcium chloride 0.025 M (Hemosil) at a ratio of 9:1. Experiments were performed using the following PVC tubing samples: [Table 1]

[0266]

[0279] Before measurements were performed, triplicates of each sample were incubated with 1 mL of blood at 37°C under static conditions (T3, T6, and T12 hours). An uncoated 2 mL tube (sample C) was used as a control, as shown in Table 1. The tubes were weighed before and after incubation. Subsequently, the tubes were inverted onto a weighing boat, and excess liquid was absorbed using tissue paper without touching the clot. The weight of each clot was measured using a microbalance and obtained by subtracting the weight of the weighing boat. The results are shown in Table 2 and the histogram in Figure 1. [Table 2]

[0267]

[0280] Each clot was also photographed (see Figure 2). The photograph on the left (labeled (E)) corresponds to the control. The photographs on the right (labeled (A)-(D) and corresponding to the samples in Table 2 above) show the triplicate structure of each type of sample. The difference in clot formation between the uncoated sample (C) and the other samples (A, B, and D) can be seen in the photographs.

[0268]

[0281] After 3 hours, no clotting was observed in the control tube (E) or any of the four samples (A)-(D). After 6 hours, very limited clotting was observed, but no actual solid clots formed. After 12 hours, clotting was clearly observed in samples (A), (B), and (D). Clot measurements were performed (see Table 2 and Figure 1). The following statistical analyses were then performed, followed by post-hoc tests:

[0269] statistical analysis

[0282] One-way ANOVA was performed on all four samples, followed by Tukey HSD test. [Table 3] [Table 4]

[0270]

[0283] The conclusion from the ANOVA analysis is that the p-values ​​in Table 4 corresponding to the F-statistics of the one-way ANOVA are less than 0.05, suggesting that one or more treatments are significantly different.

[0271]

[0284] Post-hoc tests are likely to identify which pairs of treatments are significantly different from each other (Tukey HSD test). [Table 5]

[0272]

[0285] In the Tukey HSD test, when the p-value corresponding to the F-statistic of one-way ANOVA is less than 0.01, the results strongly suggest that the effects associated with the pair of samples were significantly different.

[0273]

[0286] There was no statistically significant difference in clot formation between the coating of the present invention (D) and the heparin coating (A).

[0274] Experiment 2 - Sheep's whole blood

[0287] The experimental conditions described above for the whole blood assay in Experiment 1 were also used in this experiment. Briefly, samples were incubated overnight in triplicate with 1 mL of blood at 37°C under static conditions. Citrated whole blood was remineralized using 0.025 M calcium chloride (Hemosil) at a 9:1 ratio immediately prior to the start of the experiment (T0). The samples shown in Table 6 were prepared using the method described above. [Table 6]

[0275]

[0288] A triplicate control consisting of liquid heparin at a final concentration of 0.5 U / mL was included in the experiment (labeled "H").

[0276]

[0289] The clots were weighed on a fine balance as previously described (see Table 7 and Figure 3) and photographed (see Figure 4). [Table 7]

[0277]

[0290] Statistical analysis was performed in the form of an analysis of variance between the four sample types, followed by post-hoc tests. Since the Levene test assumed equal variances (p=391), an ANOVA was performed (see Table 8), followed by Tukey and Bonderroni tests (Table 3). [Table 8]

[0278]

[0291] The p-values ​​in Table 8, which correspond to the F-statistics of the one-way ANOVA, suggest that the samples show significant differences. The following post hoc tests show pairwise statistical comparisons between samples. [Table 9]

[0279]

[0292] Both post hoc tests showed similar results (see Table 9, especially with ptukey and pbonf). Sample B3 shows significant differences from all other samples, namely B4, B5, and control H. Sample B4 is significantly different from control H, but different from sample B5. Sample B5 and control H do not show significant differences.

[0280] Experiment 3 - Human Whole Blood

[0293] The experimental conditions for the whole blood assay described above were also used for this experiment, except that human blood was used, but with additional replicates (six instead of three), a saline rinse of the tubes before the experiment (PBS 0.1 M), and a clot spinning step (0.1 g, 1 min) before the measurement.

[0281]

[0294] Human whole blood was collected the previous day (at 4:00 PM) by phlebotomy into sodium citrate buffer (3.2%) and stored overnight at 4°C before the experiment. Immediately before the start of the experiment, blood was recalcified using calcium chloride (2.06%) at a 9:1 ratio. Samples (six replicates of each) were incubated overnight with 1 mL of blood at 37°C under static conditions. 2 mL polypropylene Eppendorf tubes were coated as described above. The samples tested were heparin-coated tubes (H), albumin-coated tubes (A), sulfonate-modified coatings of the present invention (S), PEG-coated tubes (P), and uncoated tubes (U). An additional control (L) consisting of liquid heparin at a final concentration of 0.5 U / mL was included in the experiment. The clots were weighed on a fine balance. The results are shown in Table 10 and graphically in Figure 5. Photographs of the samples are shown in Figure 6. The mass from the clots of whole blood after overnight incubation in tubes coated with various compounds was compared (weight and photograph). [Table 10]

[0282]

[0295] Statistical analysis in the form of an analysis of variance (Table 11) between the six sample types was performed, followed by post-hoc tests (Table 4). [Table 11] [Table 12]

[0283]

[0297] Regarding the coating, clot S was the lightest and clot U had the highest mass. Sample L, from the incubation of whole blood with liquid heparin, was the lightest, as expected. Visually, clot samples L and H, both in contact with heparin, appeared more liquid, in contrast to all other clots, and resembled those obtained in uncoated tubes (negative control).

[0284]

[0298] Statistical analysis in the form of analysis of variance (ANOVA) showed significant differences between the six types of samples. Tukey's post-hoc test identified differences between sample L and all other samples, as expected. Differences were also significant between samples U and S, but not between S and H.

[0285] Experiment 2

[0299] The coating of the present invention was compared to a commercially available coating using an in vitro Chandler Loop System™.

[0286] coating

[0300] The coatings tested are shown in Table 13 below. Each coating was tested by applying the coating to a tube. Commercially available reference coatings are numbered R1 through R4. Coating number 5 is a coating of the present invention (a sulfonate group-modified coating) and was prepared as described in Example 1. The length of each coated sample was 47 cm, where "n" is the number of blood donors. [Table 13]

[0287]

[0301] As controls, both blood sample controls were used to provide a baseline and an uncoated tube was used as a reference.

[0288] Chandler Loop Model

[0302] Before using coatings in a clinical setting, it is essential to test the hemocompatibility of medical devices that come into contact with blood under standardized conditions. The in vitro Chandler loop model is a closed system that allows for the investigation of the effect of artificial surfaces on initiating different cascade reactions of the human hemostatic system (coagulation, cellular changes, complement, and inflammation). In the Chandler loop system, a polymer tube partially filled with blood is formed into a reclosable loop and rotated at rotational speeds of 10–40 RPM in a temperature-controlled water bath to simulate arterial flow conditions. A multiparametric approach was used to evaluate the surface, which not only assessed thrombosis but also measured phenotypic markers of central importance within the hemostatic system. The coated tubes were tested for hemocompatibility using an in vivo Chandler loop model with fresh human whole blood.

[0289]

[0303] The control (baseline) had no blood loop contact, but each coated tube was subjected to 60 minutes of hemoperfusion within the loop. Blood was obtained from five healthy volunteers. The quality of the blood used in these experiments is crucial. The following exclusion criteria for blood donors must be strictly met: taking any medication affecting hemostasis in the past two weeks. [Table 14]

[0290] thrombogenicity

[0304] SEM (LEO 1430, Zeiss) analysis of two experiments (donors 1 and 2) showed no signs of actual thrombus formation in all groups. Low platelet adhesion was observed on the surface of uncoated tubes and on coating numbers R1, R4, and R5.

[0291] coagulation

[0305] Contact of blood with a substance initiates intrinsic coagulation via factors XII, XI, and an additional factor X, which regulates prothrombin conversion. During the thrombin formation reaction, the prothrombin fragment F 1+2 is released. The generated thrombin is inactivated by complex formation with antithrombin, forming the so-called TAT complex. Plasma concentrations of TAT, a marker for detecting coagulation activation, were measured immunochemically using a Siemens™ automated immunoassay analyzer equipped with ELISA.

[0292]

[0306] The results are shown in Figure 7, where the coatings on the x-axis use the numbering set forth in Table 13 above, with "B" representing the baseline and "C" representing the control. In this study, the coatings of the present invention were found to be comparable to the commercially available coatings numbered R1, R2, and R4. Decreased TAT concentrations were measured only for coating number R3.

[0293] platelet

[0307] Contact between blood and artificial surfaces leads to platelet activation and alterations, resulting in a continuous loss of platelet function. When platelets come into contact with an artificial surface, they begin to adhere to this surface. They then begin to stick to each other and form aggregates. The resulting drop in platelet count is an important marker of the hemocompatibility of blood-contacting devices. Platelets were counted using a cell counter (Micros 60, ABX Hematology, Montpellier, France).

[0294]

[0308] The results are shown in Figure 8. During the 60-minute test period, the platelet count decreased moderately in the control group (C). Similar values ​​were detected for coating numbers R1 to R4 and 5.

[0295] β-thromboglobulin (β-TG)

[0309] Platelet activation occurs in four steps: shape change with pseudopodia formation, adhesion, aggregation, and release of platelet factors (e.g., platelet factor 4, β-TG) from α-granules. The concentration of β-thromboglobulin (β-TG) in plasma corresponds to the degree of platelet activation. β-TG concentration was measured immunochemically (ELISA, Diagnostica Stago SAS, Asnières-sur-Seine, France).

[0296]

[0310] Due to the circulation, the concentration of β-TG increased in the control tube, indicating a mild increase in platelet activation. See the results shown in Figure 9. Similar levels were measured in coating numbers R4 and 5. Coating numbers R1-R3 showed a decrease in β-TG concentration compared to these groups.

[0297] Hematological parameters

[0311] The numbers of red blood cells, white blood cells, hemolysis, HGB, and HCT (see below), respectively, were measured using a cell counter (Micros 60, ABX Hematology, Montpellier, France).

[0298] Red blood cells (RBCs) and white blood cells (WBCs)

[0312] WBCs in contact with any artificial surface may attach to this surface and attempt to fight off potential pathological invaders. This reaction leads to a drop in WBC count, which is an important marker of hemocompatibility of blood-contacting devices. When RBC membranes are disrupted by high shear forces, this reaction leads to a drop in RBCs.

[0299]

[0313] See results in Figures 10 and 11. Red and white blood cell counts remained stable over the 60 minute perfusion period.

[0300] hemolysis

[0314] Erythrocyte destruction was quantified by measuring free plasma hemoglobin, and the results are shown in Figure 12. No significant differences were detected between the test groups.

[0301] Hemoglobin (HGB) and hematocrit (HCT)

[0315] The results are shown in Figures 13 and 14. HGB and HCT concentrations were very stable during the 60-minute perfusion period.

[0302] conclusion

[0316] During the 60-minute incubation period, plasma concentrations of activation markers, blood cell changes, and platelet adhesion indicated that the tubing coated with the coating of the present invention (No. 5) had comparable effects on several hemostatic activation cascades when compared to all other tubing coated with commercially available coatings. Regarding TAT formation, an excellent marker for detecting coagulation activation, the measured TAT concentration induced by the coating of the present invention (No. 5) was very low. Overall, the results of the hemocompatibility test of the coating of the present invention indicate good hemocompatibility.

[0303] Example 3 Cytotoxicity Test Method

[0317] This method is designed to determine the biological responses of mammalian cells in vitro. Mouse fibroblast L929 cells were used, cultured in growth medium: Dulbecco's Modified Medium (MOD) supplemented with serum and Earle's salts.

[0304]

[0318] A sample of the coating of the present invention (sulfonic acid group modified coating) was prepared as described in Example 1. The required extraction ratio was 6 cm 2 / ml, respectively. 2Two samples representing the internal surface area of ​​the specimen were extracted separately with 47.7 ml of extraction medium (L929 cells in each tube) under agitation. After extraction, the extractants were pooled in a sterile glass bottle. The extractant was prepared from Minimum Essential Medium (Eagle's modified) with Earle's salts, supplemented with fetal bovine serum (5%) and penicillin and streptomycin (50001 U). The calculation considered the area of ​​all major surfaces, but did not take into account the edges or porosity of the specimen.

[0305]

[0319] The interfacial area of ​​the positive and negative control materials per milliliter of final extract volume was 0.5 cm per ml. 2 It was calculated to be more than that.

[0306]

[0320] Positive control strips (Hatano Laboratory product code: RM-B), polyurethane film containing 0.25% zinc dibutyldithiocarbamate (ZDBC), were used. The material was received non-sterile and pre-cut to the required size (1 cm x 1 cm). Since three pieces were required for each test run, all pieces were packaged in autoclave bags and sterilized at 121°C for 15 minutes (three pieces per bag). 6.6 cm 2 Three pieces, each 1.0 cm × 1.0 cm × 0.05 cm, representing a total surface area of ​​were extracted with 13.2 ml of extraction medium under agitation conditions.

[0307]

[0321] For the negative control, a piece of polyethylene tubing (Science Lab Supplies product code: TUB3708) known not to produce a cytotoxic response in this test was used. The negative control was 2.0 cm long, had an outer diameter of 0.6 cm, and an inner diameter of 0.4 mm, and had a total surface area of ​​6.3 cm2 extracted in 12.6 ml of extraction medium under agitated conditions. 2 It was.

[0308]

[0322] The test procedures were performed in accordance with ISO 19093-5 and MV033. Samples and controls were extracted for 24 hours at 37±1°C. The following concentrations of test article extract and positive control extract were used in the test: 100%, 50%, 25%, 13%, and 6%. Cell cultures were exposed to the extract for 24 hours at 37±1°C. Microscopic examination of the cell cultures was performed at the completion of exposure to the extract without fixation or staining. Determination of cytotoxicity was performed qualitatively, and observations were numerically graded. The degree of cytotoxicity observed in each culture was numerically graded as follows: [Table 15]

[0309] result

[0323] As can be seen from the results in Tables 16 and 17 for the cell control, the negative and positive controls demonstrate that the test was effective. As shown in Table 18, the test sample (invention) at 100% concentration had a reactivity rating of 0 under the test conditions used. The coating of the invention was non-reactive to cell culture.

[0310]

[0324] According to ISO 10993-5:2009, the achievement of a numerical rating greater than 2 based on Table 15 is considered a cytotoxic effect. [Table 16] [Table 17] [Table 18] The present invention further includes the following aspects. 1. A coating for a medical device, comprising: a surface layer and an optional base layer; A coating wherein the surface layer comprises polymer chains attached to anti-clotting groups, the anti-clotting groups being selected from sulfonic acid groups, sulfonamide groups, sulfamic acid groups, hydrogen sulfate groups, and their conjugate salts. 2. The polymer chain bound to the anti-coagulation group has the formula (C-2): [ka] [In formula (C-2), Each Y 1 O - , OH, NH - , and N.H. 2 is selected from, preferably O - and OH, Y 2 O - and OH, Each L 1 is C 2-5 an alkene, preferably ethylene; L 2 is C 2-5 an alkene, preferably ethylene; R A H and C 1-6 alkyl, preferably H and methyl; n 1 is an integer, preferably 5 or more n 2 is an integer, preferably 5 or greater] The coating according to item 1, represented by: 3. The coating of item 1 or 2, wherein the polymer chain is bound to a plurality of anti-coagulation groups, each anti-coagulation group being bound to the polymer chain by a linker group, and preferably the plurality of anti-coagulation groups is a plurality of sulfonic acid groups, sulfonate groups, or a combination thereof. 4. The polymer chain has the formula (A-1):

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Claims

1. 1. A coating for a medical device comprising: Surface layer; and a base layer, wherein the base layer is biocompatible and comprises a protein; The surface layer is Formula (B-1): 【Chemistry 1】 [In formula (B-1), R Ａ is H and C １－６ alkyl, X ２ A ２ and A ２ is the formula (S-2): 【Chemistry 2】 {In formula (S-2), Z ２ is O, NH and NR ２ is selected from R ２ is C １－６ Alkyl, C ６－１０ Aryl and C ６－１０ Aryl-C １－６ alkyl, Y ２ Yes, O － and OH, L ２ is represented by formula (L-2): 【Transformation 3】 [In formula (L-2), P ２ is a single bond, C １－１０ Alkylene, C ２－１０ Alkenylene, C ２－１０ selected from alkynylene and phenylene; Q ２ represents a single bond, O, NH, or NR ２Ｃ and phenylene; W ２ is a single bond, C １－１０ Alkene, C ２－１０ Alkenylene, C ２－１０ selected from alkynylene and phenylene; R ２Ｃ is C １－６ Alkyl, C ６－１０ Aryl and C ６－１０ Aryl-C １－６ alkyl] represented by is represented by] 10. The coating of claim 1, wherein the polymer chain comprises a repeating unit represented by:

2. R Ａ The coating of claim 1 , wherein is selected from H and methyl.

3. Z ２ The coating of claim 1 or 2, wherein is selected from O and NH.

4. P ２ is C １－１０ Alkylene, C ２－１０ Alkenylene and C ２－１０ alkynylene, Q ２ is a single bond, W ２ is a single bond, The coating according to any one of claims 1 to 3.

5. P ２ is C １－１０ Alkylene, C ２－１０ Alkenylene and C ２－１０ alkynylene, Q ２ is O, NH and NR ２Ｃ is selected from W ２ is a single bond, The coating according to any one of claims 1 to 3.

6. The coating of any one of claims 1 to 5, wherein the protein is a human protein.

7. The coating of claim 6 , wherein the protein is human albumin.

8. 8. The coating of claim 7, wherein the human albumin is recombinant human albumin.

9. The coating of any one of claims 1 to 8, wherein the surface layer is in the form of a hydrogel.

10. The coating of claim 7 , wherein the human albumin is covalently attached to the polymer chain.

11. The coating according to any one of the preceding claims, wherein the polymer chains have a number average molecular weight of 1,000 to 10,000 g / mol.

12. The polymer chain has the formula (A-1): 【Chemistry 4】 [In the formula (A-1), X １Ａ Yes, O － , OH, OR １Ａ , N.H. ２ , N.H.R. １Ａ and A １Ａ is selected from X １Ｂ Yes, O － , OH, OR １Ｂ , N.H. ２ , N.H.R. １Ｂ and A １Ｂ is selected from R １Ａ and R １Ｂ Each of the groups is independently C １－６ Alkyl, C ６－１０ Aryl and C ６－１０ Aryl-C １－６ alkyl, A １Ａ and A １Ｂ Each of the formulas (S-1): 【Transformation 5】 {In the formula (S-1), Z １ is O, NH and NR １ is selected from R １ is C １－６ Alkyl, C ６－１０ Aryl and C ６－１０ Aryl-C １－６ alkyl, Y １ Yes, O － and OH, L １ is represented by formula (L-1): 【Transformation 6】 [In the formula (L-1), P １ is a single bond, C １－１０ Alkene, C ２－１０ Alkenylene, C ２－１０ selected from alkynylene and phenylene; Q １ represents a single bond, O, NH, or NR １Ｃ and phenylene; W １ is a single bond, C １－１０ Alkene, C ２－１０ Alkenylene, C ２－１０ selected from alkynylene and phenylene; R １Ｃ is C １－６ Alkyl, C ６－１０ Aryl and C ６－１０ Aryl-C １－６ alkyl] represented by is represented by] The coating of any one of claims 1 to 11, comprising a repeat unit represented by:

13. Each Z １ The coating of claim 12, wherein is selected from O and NH.

14. Each P １ is C １－１０ Alkene, C ２－１０ Alkenylene and C ２－１０ alkynylene, Each Q １ is a single bond, Each W １ is a single bond, 14. The coating of claim 12 or 13.

15. Each P １ is C １－１０ Alkylene, C ２－１０ Alkenylene and C ２－１０ alkynylene, Each Q １ is O, NH and NR １Ｃ is selected from Each W １ The coating of claim 12 or 13, wherein is a single bond.

16. A medical device having a surface coated with the coating of any one of claims 1 to 15.

17. A coating according to any one of claims 1 to 15 for use in the treatment of the human or animal body by surgery or therapy and / or in diagnostic methods performed on the human or animal body.

18. A coating according to any one of claims 1 to 15 for use in reducing or preventing blood clotting.

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