Coating for medical devices

Abstract

A coating for a medical device is described. The coating comprises: a surface layer; and optionally a substrate layer; wherein the surface layer comprises polymer chains attached to an anticoagulant group, wherein the anticoagulant group is selected from a sulfonic acid group, a sulfonamide group, a sulfamic acid group, a bisulfate group, and a conjugate base thereof. Also described are medical devices comprising the coating, as well as uses and methods involving the coating and the medical devices.

Description

Technical Field

[0001] This invention relates to coatings for medical devices. The invention also relates to medical devices comprising the coating, and to uses and methods involving the coating or medical devices comprising the coating. Furthermore, the invention relates to methods for manufacturing the coating and kits for coating medical devices. Background Technology

[0002] The formation of blood clots within organs or tissues can pose a potential life-threatening risk. When using medical devices, blood may come into contact with the foreign surface of the device, which can trigger clot formation. Therefore, anticoagulants may be administered to patients before the use of medical devices to inhibit blood clotting and clot formation. However, the considerable side effects associated with the administration of anticoagulants must be considered. The use of such anticoagulants may not be safe for some patients.

[0003] Some medical devices, such as stents, are coated with heparin, an anticoagulant that prevents blood clots from forming. Heparin is a glycosaminoglycan. It is difficult to coat medical devices 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 of heparin use include heparin-induced thrombocytopenia. Heparin is contraindicated in several situations, including brain surgery, spinal surgery, eye surgery, hemophilia, lack of anticoagulants, severe uncontrolled hypertension, subacute infection of heart valves, cerebral hemorrhage, bulging and tearing of the aortic wall, stomach or intestinal ulcers, ulcerative colitis, intestinal inflammation, diverticulitis, severe liver disease, gallbladder and biliary problems, osteoporosis, and chronic kidney disease (stage 4 (severe) or stage 5 (failure)).

[0004] Other types of coatings have been applied to medical devices. These coatings typically contain multifunctional polymerizable compounds. One problem with this type of coating is that they may exhibit poor coating performance and may degrade within a relatively short time. When the coating lacks mechanical robustness, degradation byproducts can seep into the patient's body, which can be undesirable for some types of coatings. Summary of the Invention

[0005] The present invention provides a coating for a medical device comprising: a surface layer; and optionally a base layer; wherein the surface layer comprises polymer chains connected to or bonded to anticoagulant groups.

[0006] The coating of this invention does not form blood clots and is blood-compatible. This coating has a preventative effect because it can prevent or inhibit the formation of blood clots, thereby preventing or inhibiting the onset, progression, or recurrence of diseases and conditions associated with blood clots.

[0007] The inventors have discovered a polymer material (e.g., a polymer chain) that possesses advantageous properties for use as a coating for medical devices, particularly when it is attached to an anticoagulant group. The anticoagulant group can also be referred to as a blood-compatible group (i.e., the terms "anticoagulant group" and "blood-compatible group" are synonymous). The blood-compatible group contributes to the overall blood compatibility of the coating.

[0008] Typically, anticoagulant groups are sulfonic acid groups, sulfonamide groups, aminosulfonic acid groups, hydrogen sulfate groups, or their conjugate bases. Without being bound by theory, it is believed that when these groups in the coating are ionized, the negatively charged conjugate bases (e.g., sulfonate groups) repel platelet adhesion, thereby inhibiting or preventing the formation of blood clots on the coating surface.

[0009] The present invention also provides a medical device. This medical device has a surface coated with the coating of the present invention. The presence of the surface coating of the medical device prevents or inhibits the formation of blood clots on the device during use.

[0010] The present invention also provides a polymer compound. The polymer compound is represented by formula (C-2):

[0011]

[0012] in:

[0013] Each Y 1 Selected from O - OH, NH - and NH2, preferably selected from O - and OH;

[0014] Y 2 Selected from O - and OH;

[0015] Each L 1 It is C 2-5 Alkylene;

[0016] L 2 It is C 2-5 Alkylene;

[0017] R A Selected from H and C 1-6 alkyl;

[0018] n 1 It is an integer; and

[0019] n 2 It is an integer.

[0020] The present invention also provides a method for manufacturing a coating for medical devices. The method may include using a coupling agent to link or bond a compound containing an anticoagulant to a polymer. The anticoagulant may also be referred to as a blood compatibility agent (i.e., the terms "anticoagulant" and "blood compatibility agent" are synonymous). The method may produce polymer compounds, such as those represented by the above formula (C-2).

[0021] The present invention may further provide a method for coating the surface of a medical device. This method may include: optionally applying a substrate layer to the surface of the medical device, and applying a coating to the surface of the medical device.

[0022] Another aspect of the invention relates to a kit for coating medical devices. The kit comprises: (a) a polymer, (b) a compound containing an anticoagulant group, (c) a coupling agent, and optionally (d) a coating for forming a base layer.

[0023] The present invention also relates to the use of the coating and the medical device.

[0024] The coating of the present invention or the medical device of the present invention can be used for treatment of a human or animal body by surgical procedures or therapies and / or for diagnostic methods performed on a human or animal body. Diagnostic methods performed on a human or animal body are typically in vivo diagnostic methods.

[0025] The coating of the present invention or the medical device of the present invention is used to reduce or prevent blood clotting.

[0026] The present invention also provides a method for reducing or preventing blood clotting. This method involves bringing the medical device of the present invention into contact with blood.

[0027] One aspect of the method of the present invention can be an in vitro method for reducing or preventing blood clotting, for example, when processing blood. The method may include contacting a medical device with blood, wherein the blood has been removed from a human or animal body. The blood may be contacted with the medical device to process the blood. The processed blood may not be returned to the human or animal body, preferably the human or animal from which the blood was removed.

[0028] Another aspect of the method of the present invention is a method for reducing or preventing blood clotting during the diagnostic process. This method may include bringing a medical device into contact with blood to obtain diagnostic information. Attached Figure Description

[0029] The invention will be further described below with reference to the accompanying drawings.

[0030] Figure 1 It is a histogram showing the clot weight of a sample obtained from a whole blood assay.

[0031] Figure 2These are a series of photographs showing clots on samples from whole blood assays after a 12-hour incubation period.

[0032] Figure 3 It is a box plot showing the clot weight (g) of the sample obtained from the second whole blood assay.

[0033] Figure 4 These are a series of photographs showing clots on samples from a second whole blood test.

[0034] Figure 5 It is a graph showing the average clot weight of samples obtained from human whole blood assays.

[0035] Figure 6 These are a series of photographs showing clots on samples from human whole blood assays after overnight incubation.

[0036] Figure 7 This is a histogram showing the blood concentration levels of the coagulation factor thrombin-antithrombin complex (TAT) in donor blood at baseline and during / after a 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bars represent the mean and standard deviation.

[0037] Figure 8 This is a histogram showing the mean platelet count in donor blood during and after the 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bars represent the mean and standard deviation.

[0038] Figure 9 This 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 tubes and test items). Bars represent the mean and standard deviation.

[0039] Figure 10 This is a histogram showing the mean red blood cell count in donor blood during and after the 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bars represent the mean and standard deviation.

[0040] Figure 11 This is a histogram showing the mean white blood cell count in donor blood during and after the 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bars represent the mean and standard deviation.

[0041] Figure 12This is a histogram showing the mean hemolysis concentration in donor blood during and after the 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bars represent the mean and standard deviation.

[0042] Figure 13 This is a histogram showing the mean hemoglobin concentration in donor blood during and after the 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bars represent the mean and standard deviation.

[0043] Figure 14 This is a histogram showing the mean hematocrit concentration in donor blood during and after the 60-minute perfusion period (control tube and test item) in the Chandler-Loop model. Bar represents the mean and standard deviation. Detailed Implementation

[0044] definition

[0045] As used herein, the term "biocompatible," particularly in the context of coatings or components thereof, refers to the ability of a medical device or material to respond appropriately to a host in a particular application (e.g., as described in ISO 10993-1 (2018)). The definition of "biocompatibility," its related terminology, and the tests for its evaluation in ISO 10993-1 (2018) are incorporated herein by reference. Generally, biocompatibility means that a medical device or material is able to perform its desired function in a medical treatment without causing any adverse local or systemic effects in the recipient or beneficiary of that treatment, but rather to produce the most suitable beneficial cellular or tissue response in a particular situation and optimize the clinically relevant performance of that treatment.

[0046] For convenience, this article uses the term "sulfonic acid group". Generally, the term "sulfonic acid group" refers to a sulfonic acid group (-SO3H) or a sulfonate group (-SO3). - The plural term "sulfonic acid group" includes sulfonic acid groups (-SO3H) and sulfonate groups (-SO3). - or at least one sulfonic acid group (-SO3H) and at least one sulfonate group (-SO3) - The combination of sulfonic acid groups (-SO3H) is used unless the context otherwise requires. It should be understood that in certain environments, such as physiological environments, the sulfonic acid group (-SO3H) can dissociate into a sulfonate group (-SO3). - Or there may be a balance between them.

[0047] Generally, the term "sulfonic acid precursor" as used herein refers to a precursor group that can be hydrolyzed into a sulfonic acid group as defined herein. The precursor group may be a sulfonamide group (e.g., -SO2NH2, -SO2NHR). a or -SO2NR a R b ) or sulfonate group (-SO3R) a R a and R b Each can be independently selected from C1-C6 alkyl, phenyl, and benzyl groups.

[0048] As used in this article, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting of carbon and hydrogen atoms and containing no unsaturation. 1-6 "Alkyl" contains one to six carbon atoms. Unless otherwise specified in the specification, alkyl is unsubstituted or may be selected from one or more carbon atoms selected from hydroxyl, C10, C20, C30, C40, C50, C60, C7 ... 1-6 Alkyl groups and halogen (preferably fluorine) substituents are used. Preferably, the alkyl group is unsubstituted.

[0049] As used in this article, the term "olefin" refers to a straight-chain or branched hydrocarbon chain group consisting of carbon and hydrogen atoms and containing at least one carbon-carbon double bond.

[0050] As used herein, the term "alkoxy" refers to a group bonded by an oxygen atom of the formula -O-alkyl, where the alkyl group is as defined above. The term "aryloxy" as used herein refers to a group bonded by an oxygen atom of the formula -O-aryl, where the aryl group is as defined above.

[0051] As used herein, the term "aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms, wherein at least one ring in the ring system is completely unsaturated (i.e., according to Hückel theory, it contains a cyclic delocalized [4n+2]π electron system). Ring systems from which aryl groups can be derived include, for example, benzene, indane, indene, tetrahydronaphthalene, and naphthalene.

[0052] As used herein, the term "aryl-alkyl" refers to a group bonded to an alkyl group as defined above, which is further substituted (or bonded to) an aryl group as defined above. Examples of aryl-alkyl groups include benzyl (PhCH2-) and phenethyl.

[0053] As used herein, the term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain consisting of carbon and hydrogen atoms and free from unsaturation. Preferred examples of alkylenes include -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-, and -C(CH3)2-CH2-. 1-10The "alkylene" group contains 1 to 10 carbon atoms. Preferably, the alkylene group is straight-chain (e.g., unbranched).

[0054] As used herein, the term "alkenyl" refers to a straight-chain or branched divalent hydrocarbon chain consisting of carbon and hydrogen atoms and containing at least one double bond. Alkenyl groups can be arranged in either cis or trans configurations. Examples of alkenyl groups include -CH=CH-, -CH2-CH=CH-, -C(CH3)=CH-CH2-, -CH2-C(CH3)=CH-CH2-, and -CH2-CH=C=CH-CH2-. 2-10 The "alkenyl" group contains 2 to 10 carbon atoms. When the alkenyl group contains more than one double bond, the double bonds can be conjugated or non-conjugated. Preferably, the alkenyl group does not contain a propadienyl group. More preferably, the alkenyl group contains a single double bond.

[0055] As used herein, the term "alkylene" refers to a straight-chain 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 The "ynyneyl" group contains 2 to 10 carbon atoms. When the ynyneyl group contains more than one triple bond, the triple bond can be conjugated or non-conjugated. Preferably, the ynyneyl group does not include a double bond (e.g., a carbon-carbon double bond). More preferably, the ynyneyl group contains a single triple bond.

[0056] As used herein, the term "phenylene" refers to a divalent group (e.g., -C6H4-) derived from benzene. The divalent group (e.g., a disubstituted benzene ring) may have substituents arranged in ortho, meta, or para positions.

[0057] Unless otherwise specified in the specification, each of the above groups (e.g., alkyl, olefin, alkoxy, aryl, aryl-alkyl, alkylene, alkenyl, ynylene, phenylene) is unsubstituted.

[0058] Detailed description

[0059] This invention provides a coating for use in medical devices. 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 blood-compatible coating.

[0060] As used herein, any reference to “blood” generally refers to the blood of humans or non-human animals, such as mammals. This invention can be used in veterinary applications. The term “blood” preferably refers to human blood.

[0061] Typically, the coating is biocompatible, preferably biocompatible and / or blood-compatible.

[0062] A coating includes, or may consist primarily of, a surface layer. The surface layer is the top layer of the coating. Therefore, a surface layer can be a coating or the outer surface layer of a coated medical device. During use, the surface layer of the coating comes into contact with blood.

[0063] Surface layers or coatings (e.g., as a whole) can be in the form of gels, preferably hydrogels. Hydrogels can provide a smooth surface for medical devices. When a surface layer or coating is in gel form, it can be easily applied to a medical device.

[0064] The surface layer comprises or may consist substantially of polymer chains connected to or bonded (e.g., covalently bonded) to anticoagulant groups.

[0065] Anticoagulant groups are typically selected from sulfonic acid groups, sulfonamide groups, aminosulfonic acid groups, hydrogen sulfate groups, and their conjugate bases. The structure of each group is shown below, where the wavy line indicates the direct or indirect connection point between the group and the polymer chain.

[0066]

[0067] Typically, the preferred anticoagulant group is selected from sulfonic acid groups, aminosulfonic acid groups, hydrogen sulfate groups, and their conjugate bases.

[0068] The conjugate bases for each group are shown below. The conjugate bases for each group refer to sulfonate groups, sulfonamide anionic groups, aminosulfonate groups, or sulfate groups, respectively.

[0069]

[0070] Typically, the preferred anticoagulant group is a conjugate base of a sulfonic acid group, an aminosulfonic acid group, or a hydrogen sulfate group. Therefore, the preferred anticoagulant group is a sulfonate group, an aminosulfonate group, or a sulfate group as shown above.

[0071] Preferably, the polymer chain is linked or bonded to multiple anticoagulant groups. Each of the multiple anticoagulant groups is typically selected from sulfonic acid groups, aminosulfonic acid groups, hydrogen sulfate groups, and their conjugate bases as defined above.

[0072] Typically, anticoagulant groups are linked or bonded to the polymer chain via linking groups. In principle, any linking group can be used to attach the polymer chain to the anticoagulant group. However, certain linking groups can provide or contribute to advantageous properties of the coating.

[0073] The linking group covalently bonds at least one anticoagulant group to the polymer chain. Therefore, the linking group may have a first end covalently bonded to the polymer chain and a second end covalently bonded to at least one anticoagulant group.

[0074] A single anticoagulant group can be linked or bonded to a polymer chain via a linker group (e.g., a single linker group). Alternatively, multiple anticoagulant groups, such as two or three anticoagulant groups, can be bonded to a polymer chain via a linker group (e.g., a single linker group).

[0075] The polymer chain can be a linear polymer chain or a branched polymer chain. Preferably, the polymer chain is a linear polymer chain.

[0076] Generally, the surface layer is biocompatible. More preferably, the polymer chains are biocompatible.

[0077] The polymer chains typically have a number-average (e.g., average) molecular weight (M0.05) of at least 300 g / mol, 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 Number-average (e.g., average) molecular weight (M) n It can be determined by light scattering.

[0078] Typically, the anticoagulant group is a sulfonic acid group or a sulfonate group. Preferably, each of the plurality of anticoagulant groups is a sulfonic acid group or a sulfonate group.

[0079] As stated above, the term "sulfonic acid group" is used herein to refer to either a sulfonic acid group (-SO3H) or a sulfonate group (-SO3). - The abbreviation for ) is used here. The plural term "sulfonic acid group" as used in this article refers to the sulfonic acid group (-SO3H) and the sulfonate group (-SO3). - or at least one sulfonic acid group (-SO3H) and at least one sulfonate group (-SO3) - () combinations, unless the context otherwise indicates.

[0080] Therefore, the surface layer comprises or may consist essentially of polymer chains connected to or bonded to multiple sulfonic acid groups.

[0081] In a first aspect of the invention, the anticoagulant group, particularly a sulfonic acid group, can be attached to the polymer chain after polymerization, rather than polymerizing a monomer containing the anticoagulant group. Hereinafter, the polymer chain attached or bonded to the anticoagulant group or multiple anticoagulant groups may be referred to as a polymer chain attached or coupled to the anticoagulant group or multiple anticoagulant groups, particularly when the anticoagulant group or each anticoagulant group is a sulfonic acid group.

[0082] Each sulfonic acid group can be linked or coupled to the polymer chain via a linker group.

[0083] It is believed that linker groups should be relatively short (e.g., 1 to 3 atoms in length) to ensure a high negative charge density on the coating surface for platelets. When longer linker groups are used, the coating surface may exhibit a disordered arrangement of anticoagulant groups (especially sulfonic acid groups) due to the conformational flexibility of the linker groups. This can reduce the negative charge density provided by the coating surface.

[0084] Typically, the preferred linker group is biocompatible.

[0085] The polymer chain may include repeating units, which include portions represented by formula (A-0):

[0086]

[0087] in:

[0088] Each G 1 Same or different, and independently selected from O, NH and NR. 1A ;and

[0089] Each R 1A Selected independently from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl.

[0090] Preferred for each G 1 They are the same.

[0091] The polymer chain may include repeating units represented by the following formula (A-1).

[0092]

[0093] In the formula (A-1) above:

[0094] X 1A Selected from O - OH, OR 1A NH2, NHR 1A and A 1A ;

[0095] X 1B Selected from O - OH, OR 1B NH2, NHR 1B and A 1B ;

[0096] R 1A and R1B Each was independently selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl;

[0097] A 1A and A 1B Each can be independently represented by equation (S-1):

[0098] -Z 1 -L 1 -SO2-Y 1

[0099] (S-1)

[0100] in:

[0101] Z1 is selected from O, NH and NR1;

[0102] R1 is selected from C1-6 alkyl, C6-10 aryl, and C6-10 aryl-C1-6 alkyl;

[0103] Y1 is selected from O- and OH;

[0104] L1 is represented by equation (L-1):

[0105] -P 1 -Q 1 -W 1 -

[0106] (L-1)

[0107] in:

[0108] P 1 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene;

[0109] Q 1 Selected from single bonds, O, NH, NR 1C and phenylene;

[0110] W 1 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; and

[0111] R 1C Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl.

[0112] When equation (L-1) is combined with equation (S-1), then A 1A and A 1B Each can be represented independently by equation (S-1A):

[0113] -Z 1 -P 1 -Q 1 -W 1 -SO2-Y 1

[0114] (S-1A).

[0115] The repeating unit represented by the above formula (A-1) can be obtained, for example, from maleic acid monomers or maleimide monomers.

[0116] In equation (A-1), part -L 1 - represents a linking group.

[0117] Polymer chains connected or coupled to multiple sulfonic acid groups may include repeating units represented by any one of the formulas (A-1) to (A-3) described herein.

[0118] In a polymer chain, each unit in the repeating unit represented by formula (A-1) may be the same or different.

[0119] Typically, the surface layer comprises a variety of polymer compounds (e.g., distributed), wherein each polymer compound comprises a polymer chain containing repeating units represented by any one of the formulas (A-1) to (A-3) described herein.

[0120] After polymerization of suitable monomers such as maleic acid or maleimide, linking groups and sulfonic acid groups are attached to the polymer chain. Linking groups and sulfonic acid groups are introduced into repeating units, for example, through reactions on carbonyl groups. This can be achieved by reacting a compound containing an anticoagulant with the polymer using a coupling agent, as described below. Some carbonyl groups may not undergo reactions involving both linking groups and sulfonic acid groups (i.e., no 100% conversion). When this occurs, then (a)X 1A It can be O-, OH, or OR 1A NH2 or NHR 1A and / or (b)X 1B It can be O - OH, OR 1B NH2 or NHR 1B .

[0121] Typically, for example when the surface layer contains multiple polymer compounds, preferably at least 90% of the units represented by formula (A-1) contain A as defined above. 1A and / or A 1B(i.e. X) 1A It is A 1A and / or X 1B It is A 1B More preferably, at least 95% of the units represented by formula (A-1) contain A. 1A and / or A 1B Even more preferably, at least 99% of the units represented by formula (A-1) contain A. 1A and / or A 1B .

[0122] Typically, each unit in the repeating unit represented by equation (A-1) includes A as defined above. 1A Or A 1B At least one of them (i.e., X) 1A It is A 1A , or X 1B It is A 1B More preferably, each of the repeating units represented by equation (A-1) includes A as defined above. 1A and A 1B (i.e. X) 1A It is A 1A And X 1B It is A 1B Therefore, X 1A It is A 1A X 1B It is A 1B .

[0123] Preferably, each unit in the repeating unit represented by equation (A-1) is identical.

[0124] The polymer chain may include repeating units represented by the following formula (A-2).

[0125]

[0126] In equation (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 Each of them is defined as above, and each of them conforms to X. 1A It is A 1A or X 1B It is A 1B At least one of them, and n 1It is an integer.

[0127] In formula (A-1) or formula (A-2), X is preferred. 1A Selected from O-, OH, OR 1A and A 1A And X 1B Selected from O-, OH, OR 1B and A 1B More preferably, X 1A Selected from O-, OH and A 1A And X 1B Selected from O - OH and A 1B Even more preferably, X 1A It is A 1A And X 1B It is A 1B As shown in equation (A-3) below.

[0128]

[0129] In equation (A-1) or equation (A-2), when X 1A Is it OR 1A or NHR 1A When, R is preferred 1A It is C 1-6 Alkyl groups, particularly methyl or ethyl. Optionally or additionally, when X 1B Is it OR 1B or NHR 1B When, R is preferred 1B It is C 1-6 Alkyl groups, especially methyl or ethyl groups.

[0130] In equation (A-1) or equation (A-2), A 1A and A 1B They can be the same or different. Generally, A is preferred. 1A and A 1B same.

[0131] In equations (A-1) to (A-3) above, when Z 1 It is NR 1 When, R is preferred 1 It is C 1-6 Alkyl groups, especially methyl or ethyl groups.

[0132] Typically, in equations (A-1) to (A-3) above, each Z 1 The preferred selection is from O and NH. Each Z 1 It can be O. More preferably, each Z 1 It is NH. When Z 1When the molecule is O or NH, the linking group is attached to the polymer chain via an ester or amide group, which is typically a biocompatible group. Amide groups, in particular, are biocompatible because they are present, for example, in peptides.

[0133] Typically, in equations (A-1) to (A-3), each L 1 They can be the same or different. Preferably each L 1 They are the same.

[0134] Each P 1 Usually selected from single bonds, C 1-10 Alkylenes and phenylenes; and each W 1 Can be selected from single key, C 1-10 Alkylenes and phenylenes. More preferably, each P 1 Can be selected from single bonds and C 1-10 Alkylene; and each W 1 Can be selected from single bonds and C 1-10 Alkylene.

[0135] Or, each P 1 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 etymynyl; each Q 1 Selected from O, NH and NR 1C And each W 1 It is a single bond. More preferably, each Q... 1 Selected from O and NH. In this arrangement, the anticoagulant group is an aminosulfonate group, a sulfate group, or its conjugate base.

[0136] Typically, for each L 1 P is preferred 1 Q 1 and W 1 At least one of them is not a single bond.

[0137] When Q 1 When it is O, P is usually preferred. 1 Not a single bond. More preferably, when Q 1 When it is O, P is preferred. 1 It is C 1-10 Alkylene, more preferably P 1 It is C 2-4 Alkylene.

[0138] When Q 1 When O is an O bond and P is not a single bond, W may be preferred. 1 Not a single bond. More preferably, when Q 1 When it is O, P is preferred. 1 It is C 1-10 Alkylene, and W1 It is C 1-10 Alkylene, more preferably P 1 It is C 2-4 Alkylene, and W 1 It is C 2-4 Alkylene.

[0139] When Q 1 When it is a phenylene oxide, P is generally preferred. 1 Is it a single key or C? 1-10 Alkylene, and W 1 Is it a single key or C? 1-10 Alkylene. More preferably, when Q 1 When it is phenylene, P is preferred. 1 Is it a single key or C? 1-3 Alkylene, and W 1 Is it a single key or C? 1-3 Alkylene.

[0140] Typically, each P is preferred 1 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 etymynyl; each Q 1 It is a single key, and each W 1 It is a single bond. More preferably, each P 1 It is C 1-10 Alkylenes, especially C 2-6 Alkylene, such as C 2-5 Alkylene. Even more preferably, each P 1 It is butylene, propyleneene, or ethylene, preferably ethylene. When P 1 It is ethylene and Q 1 and W 1 When all bonds are single bonds, the portion represented by (S-1) can be formed from taurine. Taurine is naturally present in the human body and can be formed if the polymer compound degrades.

[0141] Typically, n 1 The represented integer must be at least 5, preferably at least 10. For example, n 1 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0142] Polymer chains can be anionic, for example, when X... 1A X 1B Or Y 1 It is O - When the polymer chain is anionic, then Na + or K + It can exist as a counter cation.

[0143] For convenience, the repeating units represented by equations (A-0) to (A-3) are referred to as "first repeating unit" in this document. The label "first" is used to distinguish this repeating unit from other types of repeating units. When referring to "second repeating unit," "third repeating unit," etc., the existence of "first repeating unit" is not required.

[0144] In addition to or as a substitute for the repeating units represented by formulas (A-0) to (A-3) above, the polymer chain may include repeating units comprising the portion represented by formula (B-0):

[0145]

[0146] in:

[0147] G 2 Selected from O, NH and NR 2A ;

[0148] R 2A Selected independently from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 Alkyl groups; and

[0149] R A Selected from H and C 1-6 alkyl.

[0150] The polymer chain may include repeating units represented by formula (B-1).

[0151]

[0152] In the above equation (B-1):

[0153] R A Selected from H and C 1-6 alkyl;

[0154] X 2 Selected from O - OH, OR 2A NH2, NHR 2A and A 2 ;

[0155] R 2A Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl;

[0156] A 2 This can be expressed by equation (S-2):

[0157] -Z2 -L 2 -SO2-Y 2

[0158] (S-2)

[0159] in:

[0160] Z 2 Selected from O, NH and NR 2 ;

[0161] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl;

[0162] Y 2 Selected from O - and OH;

[0163] L 2 This can be expressed by equation (L-2):

[0164] -P 2 -Q 2 -W 2 -

[0165] (L-2)

[0166] in:

[0167] P 2 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene;

[0168] Q 2 Selected from single bonds, O, NH, NR 2C and phenylene;

[0169] W 2 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; and

[0170] R 2C Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl.

[0171] When equation (L-2) is combined with equation (S-2), then A 2 This can be expressed by equation (S-2A):

[0172] -Z 2 -P 2 -Q 2 -W 2 -SO2-Y 2

[0173] (S-2A).

[0174] The repeating unit represented by the above formula (B-1) can be obtained, for example, from acrylic acid monomer, methacrylic acid monomer, acrylamide monomer or methacrylamide monomer.

[0175] In equation (B-1), part -L 2 - represents a linking group.

[0176] Polymer chains connected or coupled to multiple sulfonic acid groups may include repeating units represented by any one of formulas (B-1) to (B-3) as described herein.

[0177] In a polymer chain, each unit in the repeating unit represented by formula (B-1) may be the same or different.

[0178] Typically, the surface layer comprises a variety of polymer compounds (e.g., distributed), wherein each polymer compound comprises a polymer chain containing repeating units represented by any one of the formulas (B-1) to (B-3) described herein.

[0179] After polymerization of suitable monomers such as acrylic acid or methacrylic acid, linking groups and sulfonic acid groups are attached to the polymer chain. These linking and sulfonic acid groups are introduced into repeating units, for example, through reactions on carbonyl groups. Some carbonyl groups may not undergo reactions involving both the linking and sulfonic acid groups (i.e., no 100% conversion). When this occurs, X... 2 It can be O - OH, OR 2A NH2 or NHR 2A .

[0180] Typically, for example when the surface layer comprises multiple polymer compounds, preferably at least 90% of the units represented by formula (B-1) include A as defined above. 2 (i.e. X) 2 It is A 2 More preferably, at least 95% of the units represented by formula (B-1) include A. 2 Even more preferably, at least 99% of the units represented by formula (B-1) include A. 2 .

[0181] Typically, each unit in the repeating unit represented by equation (B-1) includes A 2 (i.e. X) 2 It is A2 ).

[0182] Preferably, each unit in the repeating unit represented by equation (B-1) is identical.

[0183] The polymer chain may include repeating units represented by the following formula (B-2).

[0184]

[0185] In equation (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 is defined as above, and where n 2 It is an integer.

[0186] In formula (B-1) or formula (B-2), X is preferred. 2 Selected from O - OH, OR 2A and A 2 More preferably, X 2 Selected from O - OH and A 2 Even more preferably, X 2 It is A 2 As shown in equation (B-3).

[0187]

[0188] Typically, in equations (B-1) to (B-3) above, R A Selected from H and C 1-3 Alkyl group, preferably R A Selected from H and methyl. Even more preferably, R A It's H.

[0189] In equation (B-1) or equation (B-2), when X 2 Is it OR 2A or NHR 2A When, R is preferred. 2A It is C 1-6 Alkyl groups, especially methyl or ethyl groups.

[0190] In equations (B-1) to (B-3) above, when Z 2 It is NR 2 When, R is preferred.2 It is C 1-6 Alkyl groups, especially methyl or ethyl groups.

[0191] Typically, in equations (B-1) to (B-3) above, Z 2 The preferred components are O and NH. Z 2 It can be O. More preferably, Z. 2 It is NH. When Z 2 When the molecule is O or NH, the linking group is attached to the polymer chain via an ester or amide group, which is typically a biocompatible group. Amide groups, in particular, are biocompatible because they are present in peptides.

[0192] P 2 Usually selected from single bonds, C 1-10 Alkylenes and phenylenes; and W 2 Can be selected from single key, C 1-10 Alkylenes and phenylenes. More preferably, P 2 Can be selected from single bonds and C 1-10 Alkylene; and W 2 Can be selected from single bonds and C 1-10 Alkylene.

[0193] Or, P 2 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; Q 2 Selected from O, NH and NR 2C And W 2 It is a single bond. More preferably, Q 2 Selected from O and NH. In this arrangement, the anticoagulant group is an aminosulfonate group, a sulfate group, or its conjugate base.

[0194] Typically, for L 2 P is preferred 2 Q 2 and W 2 At least one of them is not a single bond.

[0195] When Q 2 When it is O, P is usually preferred. 2 Not a single bond. More preferably, when Q 2 When it is O, P is preferred. 2 It is C 1-10 Alkylene, more preferably P 2 It is C 2-4 Alkylene.

[0196] When Q 2 When O is an O bond and P is not a single bond, W may be preferred. 2 Not a single bond. More preferably, when Q2 When it is O, P is preferred. 2 It is C 1-10 Alkylene, and W 2 It is C 1-10 Alkylene, more preferably P 2 It is C 2-4 Alkylene, and W 2 It is C 2-4 Alkylene.

[0197] When Q 2 When it is a phenylene oxide, P is generally preferred. 2 Is it a single key or C? 1-10 Alkylene, and W 2 Is it a single key or C? 1-10 Alkylene. More preferably, when Q 2 When it is phenylene, P is preferred. 2 Is it a single key or C? 1-3 Alkylene, and W 2 Is it a single key or C? 1-3 Alkylene.

[0198] Typically, P is preferred. 2 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; Q 2 It is a single key, and W 2 It is a single bond. More preferably, P 2 It is C 1-10 Alkylenes, especially C 2-6 Alkylene, such as C 2-5 Alkylene. Even more preferably P 2 It is butylene, propyleneene, or ethylene, preferably ethylene. When P 2 It is ethylene and Q 2 and W 2 When all bonds are single bonds, the portion represented by (S-2) can be formed from taurine. As mentioned above, taurine can be formed if the polymer compound degrades.

[0199] Typically, n 2 The represented integer must be at least 5, preferably at least 10. For example, n 2 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0200] Polymer chains can be anionic, for example, when X... 2 Or Y 2 It is O - When the polymer chain is anionic, then Na + or K + It can exist as a counter cation.

[0201] For convenience, the repeating units represented by equations (B-0) to (B-3) are referred to herein by the label "second repeating unit". The label "second" is used to distinguish this repeating unit from the "first repeating unit". As mentioned above, this label does not require the existence of a "first repeating unit" in addition to the "second repeating unit".

[0202] Polymer chains connected or coupled to multiple sulfonic acid groups can be copolymers.

[0203] The copolymer may be an alternating copolymer 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.

[0204] For example, alternating copolymers can be represented by the following formula:

[0205] –[-(A-1)-(B-1)-] n -

[0206] Where n is an integer.

[0207] Typically, n is at least 5, preferably at least 10. For example, n can range from 5 to 500, for example from 10 to 300, and more preferably from 15 to 100.

[0208] The copolymer can be a block copolymer, such as a block copolymer represented by the following formula (C-1).

[0209]

[0210] In equation (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 As defined by any of the above equations (A-1) to (A-3), R A X 2 R 2A A 2Z 2 R 2 Y 2 L 2 P 2 Q 2 W 2 R 2C and n 2 As defined by any of the above equations (B-1) to (B-3).

[0211] Preferred X 1A It is A 1A and / or X 1B It is A 1B and / or X 2 It is A 2 Therefore, X 1A X 1B and X 2 At least one of them is A 1A A 1B and A 2 More preferably, X 2 It is A 2 And X 1A and X 1B At least one of them is A 1A and A 1B Even more preferably, X 1A It is A 1A X 1B It is A 1B X 2 It is A 2 As shown in equation (C-2).

[0212]

[0213] In equations (C-1) and (C-2) above, R A Selected from H and C 1-3 Alkyl group, preferably R A Selected from H and methyl. Even more preferably, R A It's H.

[0214] In equation (C-1), when X 1A Is it OR 1A or NHR 1A When, R is preferred. 1A It is C 1-6 Alkyl groups, especially methyl or ethyl; when X 1B Is it OR 1B or NHR 1B When, R is preferred. 1B It is C 1-6 Alkyl groups, especially methyl or ethyl; when X 2Is it OR 2A or NHR 2A When, R is preferred. 2A It is C 1-6 Alkyl groups, especially methyl or ethyl groups.

[0215] In equation (C-1), A 1A and A 1B They can be the same or different. Generally, A is preferred. 1A and A 1B same.

[0216] In the above equation (C-1), when Z 1 It is NR 1 When, R is preferred. 1 It is C 1-6 Alkyl groups, especially methyl or ethyl groups; and when Z 2 It is NR 2 When, R is preferred. 2 It is C 1-6 Alkyl groups, especially methyl or ethyl groups.

[0217] Typically, in equations (C-1) and (C-2) above, each Z 1 Preferred ingredients are O and NH; Z 2 The preferred components are O and NH. Z 2 and each Z 1 It can be O. More preferably, Z. 2 and each Z 1 It is NH.

[0218] Typically, in equations (C-1) and (C-2), each L 1 They can be the same or different. Preferably each L 1 They are the same.

[0219] Each P 1 Can be selected from single key, C 1-10 Alkylenes and phenylenes; W 1 Can be selected from single key, C 1-10 Alkylenes and phenylenes; P 2 Can be selected from single key, C 1-10 Alkylenes and phenylenes; and each W 2 Can be selected from single key, C 1-10 Alkylenes and phenylenes. More preferably, each P 1 Can be selected from single bonds and C 1-10 Alkylene; each W 1 Can be selected from single bonds and C 1-10 Alkylene; P 2 Can be selected from single bonds and C 1-10 Alkylene; and W 2 Can be selected from single bonds and C1-10 Alkylene.

[0220] Typically, for each L 1 P is preferred 1 Q 1 and W 1 At least one of them is not a single bond; and for L 2 P is preferred 2 Q 2 and W 2 At least one of them is not a single bond.

[0221] When Q 1 When it is O, P is usually preferred. 1 It's not a single key. When Q... 2 When it is O, P is usually preferred. 2 Not a single bond. More preferably, when Q 1 When it is O, P is preferred. 1 It is C 1-10 Alkylene; when Q 2 When it is O, P is preferred. 2 It is C 1-10 Alkylene; more preferably, P 1 It is C 2-4 Alkylene, and P 2 It is C 2-4 Alkylene.

[0222] When Q 1 It is O and P 1 When it is not a single bond, W may be preferred. 1 It's not a single key. When Q... 2 It is O and P 2 When it is not a single bond, W may be preferred. 2 Not a single bond. More preferably, when Q 1 When it is O, P is preferred. 1 It is C 1-10 Alkylene, and W 1 It is C 1-10 Alkylene; and when Q 2 When it is O, P is preferred. 2 It is C 1-10 Alkylene, and W 2 It is C 1-10 Alkylene; more preferably P 1 It is C 2-4 Alkylene; W 1 It is C 2-4 Alkylene; P 2 It is C 2-4 Alkylene, and W 2 It is C 2-4 Alkylene.

[0223] When Q1 When it is a phenylene oxide, P is generally preferred. 1 Is it a single key or C? 1-10 Alkylene, and W 1 Is it a single key or C? 1-10 Alkylene. More preferably, when Q 1 When it is phenylene, P is preferred. 1 Is it a single key or C? 1-3 Alkylene, and W 1 Is it a single key or C? 1-3 Alkylene.

[0224] When Q2 is phenylene, it is generally preferred that P2 is a single bond or C. 1-10 Alkylene, and W2 is a single bond or C 1-10 Alkylene. More preferably, when Q2 is phenylene, P2 is preferably a single bond or C. 1-3 Alkylene, and W2 is a single bond or C 1-3 Alkylene.

[0225] Typically, each P is preferred 1 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 etymynyl; each Q 1 It is a single key; each W 1 It is a single bond; P 2 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; Q 2 It is a single key, and W 2 It is a single bond. More preferably, each P 1 It is C 1-10 Alkylenes, especially C 2-6 Alkylene, such as C 2-5 Alkylene; P 2 It is C 1-10 Alkylenes, especially C 2-6 Alkylene, such as C 2-5 Alkylene. Even more preferably, each P 1 It is ethylene, and P 2 It is ethylene.

[0226] In equation (C-2), each Y is preferred. 1 Selected from O - and OH; Y 2 Selected from O - and OH; L 1 It is C 2-5 Alkylene; L 2 It is C 2-5 alkylene; n 1 It is an integer; and n is an integer.2 It is an integer. More preferably, L 1 It is ethylene, L 2 It is ethylene, n 1 It is an integer greater than or equal to 5, and n 2 It is an integer greater than or equal to 5.

[0227] Typically, in equation (C-1) or (C-2) above, n 1 The represented integer must be at least 5, preferably at least 10. For example, n 1 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0228] n 2 The represented integer is typically at least 5, preferably at least 10. For example, n 2 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0229] Polymer chains can be anionic, for example, when X... 1A X 1B X 2 Y 1 Or Y 2 It is O - When the polymer chain is anionic, then Na + or K + It can exist as a counter cation.

[0230] When the polymer chain is attached to or coupled to multiple sulfonic acid groups, the polymer chain (e.g., before it is attached to or coupled to the multiple sulfonic acid groups) has a number-average (e.g., average) molecular weight (M) of at least 300 g / mol, for example, 300 to 50,000 g / mol, preferably 500 to 30,000 g / mol, more preferably 1,000 to 10,000 g / mol. n ).

[0231] In the first aspect described above, polymer chains attached to or coupled to the anticoagulant group have advantageous properties, particularly when they comprise repeating units represented by any one of formulas (A-0) to (A-3), and especially when represented by formulas (C-1) or (C-2). The surface layer or coating can be a hydrogel. Furthermore, the coating can be biodegradable, as degradation of the polymer chains attached to or coupled to the anticoagulant group may lead to the formation of biocompatible byproducts. In addition to reducing or preventing blood clotting, the anticoagulant component of the surface layer can also exhibit excellent stability and relative inexpensiveness, particularly compared to other anticoagulant components in the art, such as heparin.

[0232] Secondly, polymerization of monomers containing anticoagulant groups such as sulfonic acid groups can provide polymer chains linked to or bonded to the anticoagulant groups. The monomers themselves contain, for example, sulfonic acid groups or sulfonic acid group precursors. Hereinafter, polymer chains linked to or bonded to anticoagulant groups or multiple anticoagulant groups may be referred to as polymers containing anticoagulant groups or multiple anticoagulant groups, particularly when the anticoagulant group or each anticoagulant group is a sulfonic acid group.

[0233] Monomers containing sulfonic acid groups can be compounds containing both olefinic and sulfonic acid groups. Examples of such compounds include vinylsulfonic acid, styrenesulfonic acid (e.g., 4-styrenesulfonic acid), 2-acrylamido-2-methylpropanesulfonic acid, or their conjugate bases (e.g., sulfonates).

[0234] Monomers containing sulfonic acid precursor groups can be compounds containing both olefinic and sulfonic acid precursor groups.

[0235] Polymers containing sulfonic acid groups can be homopolymers. Therefore, the polymer is a homopolymer containing sulfonic acid groups.

[0236] Examples of homopolymers containing sulfonic acid groups include polyethylene sulfonic acid, polystyrene sulfonic acid, poly(2-acrylamido-2-methylpropanesulfonic acid), or their conjugate bases. Preferred homopolymers containing sulfonic acid groups are poly(2-acrylamido-2-methylpropanesulfonic acid).

[0237] Polymers containing sulfonic acid groups can be copolymers (e.g., copolymers containing sulfonic acid groups). Copolymers containing sulfonic acid groups can be alternating copolymers or block copolymers.

[0238] Copolymers containing sulfonic acid groups can be obtained from at least two monomers or from only two monomers.

[0239] A copolymer containing sulfonic acid groups can be obtained from a first monomer and a second monomer, wherein the first monomer is different from the second monomer. This copolymer can be obtained by copolymerizing the first monomer and the second monomer.

[0240] The first monomer contains a sulfonic acid group or a sulfonic acid group precursor. The monomer containing the sulfonic acid group can be a compound containing both an olefinic 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-methylpropanesulfonic acid, or their conjugate bases (e.g., sulfonates). Preferably, the first monomer is 2-acrylamido-2-methylpropanesulfonic acid or its conjugate base.

[0241] Similarly, monomers containing sulfonic acid precursor groups can be compounds containing both olefinic and sulfonic acid precursor groups.

[0242] The second monomer contains an olefinic group. The second monomer may be selected from acrylic acid, itaconic acid, vinyl acetate, and maleic acid. Preferably, the second monomer is maleic acid.

[0243] The copolymer containing 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).

[0244] When the polymer contains sulfonic acid groups, the polymer (e.g., including sulfonic acid groups) has a number-average (e.g., average) molecular weight (M) of at least 300 g / mol, for example, 300 to 50,000 g / mol, preferably 500 to 30,000 g / mol, more preferably 1,000 to 10,000 g / mol. n ).

[0245] Typically, the coating may further contain an antimicrobial agent. The base layer and / or surface layer may contain the antimicrobial agent. The antimicrobial agent may, for example, be mixed with components of the surface layer or base layer.

[0246] Antimicrobial agents may include silver.

[0247] The coating of this invention is typically applied to the surface of a medical device. The surface of the medical device can be an inner or internal surface (e.g., the inner surface of a catheter) or an outer surface. The coating can be applied to the surface of a medical device that will come into contact with blood or blood products containing platelets.

[0248] The coating can completely or partially cover the surface of a medical device.

[0249] In the coating of the present invention, the surface layer is disposed on the surface of the medical device.

[0250] In some cases, the surface layer can be applied directly to the surface of the medical device. Therefore, the surface layer is in direct contact with the surface of the medical device.

[0251] Surface layers can be applied directly to the surface of a medical device, especially if they can adhere to or bond to that surface.

[0252] The surface of a medical device can be functionalized with groups that can bond to polymer chains, for example, by applying a base coating. The surface of a medical device can contain amine groups. These amine groups can react with carbonyl groups in the polymer chain to form amide groups, thereby bonding the surface layer of the coating to the surface of the medical device.

[0253] Multiple layers may be disposed on the surface of the medical device. Each layer may contain polymer chains attached to or bonded to an anticoagulant as defined above. The top or outermost layer will be the surface layer described above.

[0254] Generally, the coating may also include a base layer. The base layer is typically disposed below the surface layer. There may be one or more layers between the base layer and the surface layer, wherein this layer or each layer contains polymer chains linked or bonded to anticoagulant groups as described above. Alternatively, the surface layer may be disposed directly on the base layer.

[0255] Preferably, the surface layer is disposed directly on the substrate layer. Therefore, the surface layer is typically coated on the substrate layer.

[0256] The substrate layer can be disposed on the surface of the medical device. The substrate layer is typically disposed directly on the surface of the medical device. Therefore, the substrate layer is in direct contact with the surface.

[0257] It is generally preferred to adhere or bond the substrate layer, preferably to the surface of the medical device.

[0258] Normally, the basal layer is biocompatible.

[0259] The basal layer may contain proteins, preferably human proteins, or be composed primarily of them.

[0260] The protein can be albumin. Human albumin is preferred, and recombinant human albumin is even more preferred.

[0261] Albumin, particularly recombinant human albumin, can mimic the albumin found in the human circulatory system. It can adhere to various surfaces via electrostatic attraction, especially those of medical devices. It also provides a bio-passivated surface that can prevent platelet activation.

[0262] Generally, the surface layer of the coating is bonded to the substrate layer. The surface layer can be adhesively bonded to the substrate layer or covalently bonded to it. When the substrate layer contains albumin, the albumin can be covalently bonded to the polymer chains.

[0263] The present invention also provides a medical device. This medical device can be used in places where it comes into contact with blood or blood products containing platelets.

[0264] The coating is applied to the surface of a medical device. Therefore, the medical device has a surface coated with the coating of the present invention. For convenience, the surface coated with the coating of the present invention is referred to as the "coated surface". The coated surface is intended to come into contact with blood or blood products containing platelets (preferably blood).

[0265] Typically, the coating thickness ranges from 0.05 μm to 300 μm, preferably from 0.1 μm to 200 μm, and more preferably from 1 μm to 100 μm. The coating thickness is usually chosen such that it does not significantly increase the shape of the medical device used inside a patient.

[0266] The medical device may be coated with a single layer of the coating of the present invention. Alternatively, the medical device may be coated with multiple layers of the coating of the present invention. Thus, the surface of the medical device may be coated with several alternating layers of a base layer and a layer comprising polymer chains connected to anticoagulant groups.

[0267] The medical device can be an implantable medical device or an external medical device. An implantable medical device can be a permanently implantable medical device or a temporarily implantable medical device.

[0268] The medical device may be a momentary blood contact device, which may not be implantable or external.

[0269] This medical device can be used either internally or externally. Internal use is preferred.

[0270] The medical device may have components for in vivo use. Preferably, at least one surface of said component is coated with the coating of the present invention.

[0271] A medical device or a component of a medical device has a coated surface that can be inserted into an area of ​​the body, such as a diseased area of ​​the body. The body area 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 intracranial artery or vein; the aorta; the vena cava; or a peripheral artery or vein.

[0272] Once in place, the coating prevents blood from clotting on and around the medical device or its components, thereby inhibiting thrombosis, particularly subacute device thrombosis.

[0273] Medical devices or components thereof may be needles, catheters, stents, grafts, shunts, dressings, surgical staples, leads, cannulas, surgical instruments, endoscopes, artificial organs or organoids (e.g., insulin secretion devices), implantable monitors or sensors, defibrillators, ventricular assist devices, pacemakers (e.g., cardiac pacemakers), implantable pumps (e.g., intra-aortic balloon pumps or ventricular assist pumps), cell reservoirs (e.g., for stem cell placement), prosthetic devices (e.g., prosthetic heart valves), orthopedic devices, electrical stimulation leads or lead tips, implantable vascular access ports, blood storage bags, blood catheters, breast implants, pain control devices, prostate cancer treatment devices, dental implants, focal epilepsy treatment devices, nerve regeneration catheters, vena cava filters, spinal repair devices, spinal cord stimulators, internal hearing aids, nerve aneurysm treatment devices, heart valve repair devices, intravitreal drug delivery devices, joint replacements, ophthalmic implants, blood oxygenators, blood filters, dialysis devices, hemoperfusion devices, plasma exchange devices, or anastomotic devices.

[0274] Examples of catheters include balloon or inflatable catheters, injection catheters, central venous catheters, arterial catheters, and aspiration catheters. Preferably, the medical device is a central venous catheter or an aspiration catheter.

[0275] Examples of grafts include vascular grafts, stent grafts, or bypass grafts. Preferably, the medical device is a bypass graft.

[0276] Examples of stents include vascular stents, urethral stents, bile duct stents, biliary stents, esophageal stents, and tracheal or bronchial stents.

[0277] Typically, the medical device is preferably selected from central venous catheters, aspiration catheters, bypass grafts, perfusion lines, cardiac bypass machines, and extracorporeal oxygenation and heat exchange circuits.

[0278] Medical devices or their components may include metals, polymers, glass, or ceramics. Therefore, the coating of the present invention can be applied to surfaces containing metals, plastics, or ceramics.

[0279] The metal can be, for example, stainless steel, titanium, nickel, tantalum, cobalt, chromium, nickel, molybdenum, manganese, gold, platinum, iridium, silver, tungsten, titanium alloys (e.g., nickel-titanium), nickel-chromium alloys (e.g., Inconel), cobalt-chromium alloys (e.g., elgiloy), iron alloys, palladium alloys, rhenium alloys, or magnesium alloys.

[0280] The polymeric material can be, for example, cellulose acetate, cellulose nitrate, silicone resin, polyethylene terephthalate, polyurethane, polyamide, polyester (e.g., nylon), polyorthoester, polyanhydride, polyethersulfone, polycarbonate, polypropylene, polyethylene, or polytetrafluoroethylene.

[0281] Ceramics can 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.

[0282] The present invention also provides a polymer compound. The polymer compound is represented by formula (C-2):

[0283]

[0284] in:

[0285] Each Y 1 Selected from O - and OH;

[0286] Y 2 Selected from O - and OH;

[0287] Each L 1 It is C 2-5 Alkylene;

[0288] L2 It is C 2-5 Alkylene;

[0289] R A Selected from H and C 1-6 Alkyl groups, preferably selected from H and methyl groups;

[0290] n 1 It is an integer; and

[0291] n 2 It is an integer.

[0292] Preferred for each L 1 It is ethylene, L 2 It is ethylene.

[0293] R A Preferably selected from H and methyl. More preferably, R A It's H.

[0294] n 1 The represented integer must be at least 5, preferably at least 10. For example, n 1 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0295] n 2 The represented integer is typically at least 5, preferably at least 10. For example, n 2 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0296] The present invention also provides the use of the coating and the medical device.

[0297] The coating or medical device containing the coating may be used for treatment of a human or animal body by surgical procedures or therapies and / or for diagnostic methods performed on a human or animal body.

[0298] Diagnostic methods performed on humans or animals are typically in vivo diagnostic methods.

[0299] Diagnostic methods or treatments via surgery or therapy often involve contact between a coated or coated medical device and blood.

[0300] Coatings or medical devices containing coatings are used to reduce or prevent blood clotting, preferably to reduce or prevent blood clotting on the coated surface of the medical device.

[0301] The present invention also provides a method for reducing or preventing blood clotting. The method involves contacting the medical device of the present invention with blood. In addition to the presence of a coating that inhibits or prevents the formation of blood clots, particularly on the coated surface of the medical device, the medical device is used in its normal manner.

[0302] One aspect of this method is an in vitro method. For example, the method could be an in vitro method for reducing or preventing blood clotting during blood processing. Blood can be processed to produce processed blood or blood products, such as blood products for storage.

[0303] This method may include bringing a medical device into contact with blood, wherein the blood has been removed from a human or animal body. The blood may come into contact with the medical device to process the blood.

[0304] This method may not include the step of applying treated blood or blood products to a human or animal body. The blood products or treated blood may not be returned to the human or animal body; preferably, the blood is removed from the human or animal body.

[0305] Another aspect of this method is diagnostic methods, particularly in vitro and / or ex vivo diagnostic methods.

[0306] This method may involve reducing or preventing blood clotting during diagnostic procedures. The method may include contacting a medical device with blood to obtain diagnostic information. The medical device may contact pre-obtained or pre-delivered blood.

[0307] The diagnostic procedure is not performed on a human or animal body, or the diagnostic procedure is performed on a non-living (e.g., deceased) human or animal body. Therefore, the diagnostic method may not include the step of drawing blood from a human or animal body, particularly a living human or animal body.

[0308] The present invention also provides a method for manufacturing a coating for medical devices, particularly a coating comprising a surface layer containing polymer chains linked or bonded to anticoagulant groups according to the first aspect.

[0309] This method involves using a coupling agent to link or bond (e.g., via a coupling reaction) a compound containing an anticoagulant to a polymer. The compound containing the anticoagulant can be linked or bonded to the polymer by forming an amide group.

[0310] The present invention further provides a kit for coating medical devices, particularly when the coating has a surface layer comprising polymer chains linked or bonded to anticoagulant groups according to the first aspect.

[0311] The kit includes: (a) a polymer, (b) a compound containing an anticoagulant group, (c) a coupling agent, and optionally (d) a coating for forming a base layer.

[0312] For example, polymers can be dispersed in solutions or gels.

[0313] In the manufacturing method or the kit, the polymer forms polymer chains that are linked or bonded to anticoagulant groups.

[0314] Typically, the polymer comprises repeating units represented by the following formula (D-1).

[0315]

[0316] In the above equation (D-1), X 3 Selected from OH, OR 3A NH2 and NHR 3A And R 3A Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl.

[0317] Preferred X 3 Selected from OH and NH2, more preferably X 3 It is OH.

[0318] The repeating unit represented by the above formula (D-1) can be obtained, for example, from maleic acid monomers or maleimide monomers.

[0319] The polymer may include repeating units represented by the following formula (D-2).

[0320]

[0321] In equation (D-2), X 3 As defined above, and n 1 It is an integer. Typically, n 1 At least 5, preferably at least 10. For example, n 1 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0322] The polymer can be a copolymer. The copolymer is typically a block copolymer, such as a block copolymer represented by the following formula (D-3).

[0323]

[0324] In equation (D-3), X 3 and n 1 As defined in equation (D-1) or (D-2) above; R A Selected from H and C 1-6 Alkyl; X 4 Selected from OH, OR 4 NH2 and NHR 4 ;R 4 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C1-6 Alkyl; and n 2 It is an integer.

[0325] R A Preferably selected from H and C 1-3 Alkyl group. More preferably, R A Selected from H and methyl. Even more preferably, R A It's H.

[0326] Preferred X 4 Selected from OH and NH2, more preferably X 4 It is OH.

[0327] Typically, n 2 The represented integer must be at least 5, preferably at least 10. For example, n 2 The range can be from 5 to 500, for example from 10 to 300, more preferably from 15 to 100.

[0328] Compounds containing an anticoagulant group can be represented by formula (E-1):

[0329] Z 3 -L 3 -SO3H

[0330] (E-1)

[0331] in:

[0332] Z 3 Selected from OH, NH2 and NHR 3 ;

[0333] R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl;

[0334] L 3 This can be expressed by equation (L-3):

[0335] -P 3 -Q 3 -W 3 -

[0336] (L-3)

[0337] in:

[0338] P 3 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene;

[0339] Q 3Selected from single bonds, O, NH, NR 3C and phenylene;

[0340] W 3 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; and

[0341] R 3C Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl.

[0342] Z is preferred 3 It is NH2.

[0343] P 3 Usually selected from single bonds, C 1-10 Alkylenes and phenylenes; and W 3 Can be selected from single key, C 1-10 Alkylenes and phenylenes. More preferably, P 3 Can be selected from single bonds and C 1-10 Alkylene; and W 3 Can be selected from single bonds and C 1-10 Alkylene.

[0344] Or, P 3 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; Q 3 Selected from O, NH and NR 3C And W 3 It is a single bond. More preferably, Q 3 Selected from O and NH.

[0345] Typically, for L 3 P is preferred 3 Q 3 and W 3 At least one of them is not a single bond.

[0346] When Q 3 When it is O, P is usually preferred. 3 Not a single bond. More preferably, when Q 3 When it is O, P is preferred. 3 It is C 1-10 Alkylene, more preferably P 3 It is C 2-4 Alkylene.

[0347] When Q 3 When O is an O bond and P is not a single bond, W may be preferred.3 Not a single bond. More preferably, when Q 3 When it is O, P is preferred. 3 It is C 1-10 Alkylene, and W 3 It is C 1-10 Alkylene, more preferably P 3 It is C 2-4 Alkylene, and W 3 It is C 2-4 Alkylene.

[0348] When Q 3 When it is a phenylene oxide, P is generally preferred. 3 Is it a single key or C? 1-10 Alkylene, and W 3 Is it a single key or C? 1-10 Alkylene. More preferably, when Q 3 When it is phenylene, P is preferred. 3 Is it a single key or C? 1-3 Alkylene, and W 3 Is it a single key or C? 1-3 Alkylene.

[0349] Typically, P is preferred. 3 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; Q 3 It is a single key, and W 3 It is a single bond. More preferably, P 3 It is C 1-10 Alkylenes, especially C 2-6 Alkylene, such as C 2-5 Alkylene. Even more preferably P 3 It is butylene, propylene, or ethylene, preferably ethylene.

[0350] The compound represented by formula (E-1) can be taurine.

[0351] 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). EDC is the preferred coupling agent.

[0352] In the kit of the present invention, the coupling agent may be a powder.

[0353] The coating used to form the base layer can be a solution, suspension, or gel containing a protein, preferably a human protein. Preferably, the coating used to form the base layer is a solution, such as a stable solution. As mentioned above, the protein can be albumin. Preferably, the albumin is human albumin, and more preferably recombinant human albumin.

[0354] The manufacturing method of the present invention includes using a coupling agent to couple a carboxylic acid or amide group of a polymer to a hydroxyl or amino group of a compound containing an anticoagulant. Such coupling reactions are known in the art.

[0355] The coupling reaction produces polymer chains that are linked or bonded to the anticoagulant group. Any residual coupling agent can be removed to form a coating, for example, by rinsing with water.

[0356] The coating can be applied to the surface of a medical device by means of, for example, dip coating, spray coating, washing, brush coating, roller coating, or spin coating. Alternatively, the coating can be pumped through the medical device, for example, to coat the inner surface of the medical device.

[0357] The thickness of the coating can be controlled by varying the soaking time, flow rate, and the number of coating steps. As described in this document in a range of applications, each coating can be applied to the surface of a medical device. The number of applications can be selected to provide a single coating of appropriate thickness, as well as the total number of coatings required, depending on the need.

[0358] 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 containing a protein, preferably a human protein. The protein can be albumin. Preferably, the albumin is human albumin, and more preferably, recombinant human albumin.

[0359] The present invention may also provide a method for coating a surface of a medical device. The method includes applying a coating as described above to the surface of the medical device. The coating is applied to form a surface layer, and can be applied, for example, as described above.

[0360] The coating on the surface layer can be pre-formed. Therefore, according to the present invention, polymer chains linked or bonded to anticoagulant groups can be applied directly to the surface of the medical device, or applied to the base layer if a base layer is present on the surface of the medical device.

[0361] Alternatively, polymer chains linked or bonded to anticoagulant groups can be formed on the surface of the medical device (e.g., in situ formation), or on a substrate layer if present on the surface of the medical device. Thus, a coating can be manufactured on the surface of the medical device or the substrate layer, preferably according to a method for manufacturing a medical device coating. Therefore, a compound comprising an anticoagulant, a polymer, and a coupling agent can be applied to the surface of the medical device, or to the substrate layer if present. The compound comprising the anticoagulant can be linked or bonded to the polymer using a coupling agent (e.g., to form a coating), as described in the method for manufacturing a medical device coating.

[0362] This method may include using a coupling agent to link or bond a compound containing an anticoagulant to a polymer. Anticoagulants may also be referred to as blood compatibility agents (i.e., the terms "anticoagulant" and "blood compatibility agent" are synonymous).

[0363] The surface of the medical device may already be coated with a base layer. Therefore, the method may also include applying a base layer to the surface of the medical device, or applying a coating to the medical device to form a base layer, as described above. In this document, the coating is a coating used to form a base layer.

[0364] When the base layer has already been applied to the surface of a medical device, the coating applied to form the surface layer can be applied to the base layer on the surface of the medical device.

[0365] Example

[0366] The invention will now be illustrated by the following non-limiting embodiments.

[0367] Example 1

[0368] Bovine serum albumin coating

[0369] Bovine serum albumin solution was prepared in distilled water buffer at pH 4.5 (by titration with HCl and NaOH) with a concentration of approximately 25 mg / 100 mL.

[0370] The PVC pipe sample was incubated in the solution at room temperature for 0-1 hour and then gently rotated to produce a sample coated with bovine serum albumin.

[0371] All samples coated with albumin were then soaked in deionized water for 15 minutes and dried.

[0372] Poly(maleic acid-co-acrylic acid) coating

[0373] Prepare a 1 mL / 200 mL poly(maleic acid-co-acrylic acid) polymer solution at pH 4.5. Incubate the samples gently by rotating them in this solution at room temperature for 0–1 hour. All samples were then immersed in deionized (DI) water for 15 minutes and dried.

[0374] To crosslink albumin and poly(maleic acid-co-acrylic acid), 500 mg of EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) was used in distilled water at pH 4.5. Samples coated with 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.

[0375] Sulfonic acid group modified coating

[0376] The samples were then processed to crosslink the poly(maleic acid-co-acrylic acid) polymer with taurine. A distilled aqueous solution at pH 8.3 was prepared by titration of HCl and NaOH. 500 mg EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 500 mg taurine (2-aminosulfonic acid) were added to 100 mL of the pH 8.3 solution to the coated sample. The coated sample was incubated for 3–24 hours to allow crosslinking to occur. The coated sample was then rinsed with deionized water and dried.

[0377] The coated samples were treated with toluidine blue. Toluidine blue has a high affinity for acidic groups, such as any sulfonic acid groups present in the coating. After treatment, the coated samples showed a blue / purple color, confirming the presence of sulfonic acid groups.

[0378] Heparin coating (comparison)

[0379] From Coatings2Go TM Obtain a commercially available coating and apply it to a substrate using the provided instructions. This coating is hydrophilic and contains repeating polymeric units derived from acrylates. As described above, heparin is chemically crosslinked to the coated substrate using EDC.

[0380] Research and Results

[0381] Whole blood testing methods

[0382] Whole blood assays were performed to measure the anticoagulant activity of the coating.

[0383] Experiment 1 – Whole Blood from Sheep

[0384] Within 24 hours of the venous incision, experiments were conducted using citric acid-treated sheep whole blood. Just before the start of the experiment (T0), the blood was recalcified with 0.025M calcium chloride (Hemosil) at a ratio of 9:1. The experiments were performed using the following PVC tube samples.

[0385] Table 1: Sample Types

[0386]

[0387] Before measurement, three copies of each sample were incubated with 1 mL of blood at 37°C (T3, T6, and T12 hours) under static conditions. An uncoated 2 mL tube (sample C) served as a control, as shown in Table 1. The tubes were weighed before and after incubation. Subsequently, the tubes were inverted on a weighing boat, and excess liquid was absorbed with thin paper without contact with the clot. The weight of each clot was measured using a precision balance, and the weight of each clot was obtained by subtracting the weight of the weighing boat. The results are shown in Table 2 and... Figure 1 In the histogram.

[0388] Table 2: Clot Weight (g)

[0389]

[0390]

[0391] 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) to (D) to correspond to the samples in Table 2 above) show triplicate of each type of sample. The differences in clot formation between the uncoated sample (C) and the other samples ((A), (B), and (D)) can be seen in the photographs.

[0392] After 3 hours, no coagulation was observed in the control tube (E) or any of the four samples (A) through (D). Very limited coagulation was observed after 6 hours, but no true solid agglomerates formed. After 12 hours, coagulation was clearly observed in samples (A), (B), and (D). Measurements of the agglomerates were taken (see Table 2 and...). Figure 1 Then, the following statistical analysis was performed, followed by post-hoc testing.

[0393] Statistical analysis

[0394] One-way ANOVA was performed on all four samples, followed by the Tukey HSD test.

[0395] Table 3: Descriptive Statistics

[0396] deal with A B C D Total Observation N 3 3 3 3 12 sum 1.162 1.203 1.879 1.081 5.325 average value 0.3873 0.401 0.6263 0.3603 0.4438 sum of squares 0.4531 0.4831 1.1776 0.3896 2.5034 Sample variance 0.0015 0.0003 0.0004 0.0001 0.0128 Sample standard deviation 0.0387 0.0182 0.019 0.0071 0.113 Standard deviation of the mean 0.0224 0.0105 0.011 0.0041 0.0326

[0397] Table 4: One-way ANOVA

[0398] source sum of squares Degrees of freedom Mean Square F-statistic p-value deal with 0.1359 3 0.0453 80.6864 2.54E-06 mistake 0.0045 8 0.0006 Total 0.1404 11

[0399] In the conclusions of the ANOVA analysis, the p-values ​​of the F-statistics corresponding to one-way ANOVA in Table 4 were less than 0.05, indicating that there were significant differences between one or more treatments.

[0400] Post-hoc tests may determine which treatments differed significantly from one another (Tukey HSD test).

[0401] Table 5: Tukey HSD Test

[0402] Processing Q statistic p-value inference A vs C 17.470 0.001 **p<0.01 A vs D 1.974 0.534 Not significant B vs C 16.471 0.001 **p<0.01 C vs D 19.443 0.001 **p<0.01

[0403] In the Tukey HSD test, when the p-value of the F-statistic corresponding to the one-way ANOVA is less than 0.01, the results strongly indicate that there is a significant difference in the effect associated with the sample pair.

[0404] There was no statistically significant difference in clot formation between the coating (D) and the heparin coating (A) of the present invention.

[0405] Experiment 2 – Whole Blood from Sheep

[0406] The experimental conditions for the whole blood assay in Experiment 1 above were also used in this experiment. In short, under static conditions, three aliquots of the sample were incubated overnight at 37°C with 1 mL of blood. Just before the start of the experiment (T0), the citric acidified whole blood was recalcified using 0.025M calcium chloride (Hemosil) at a ratio of 9:1. The samples shown in Table 6 were prepared using the above method.

[0407] Table 6: Sample Types

[0408]

[0409] The experiment included three control sets (labeled "H") consisting of liquid heparin at a final concentration of 0.5 U / mL.

[0410] As previously mentioned, the clots were weighed on a precision balance (see Table 7 and...). Figure 3 ), and also took photos (see Figure 4 ).

[0411] Table 7: Clot Weight (g)

[0412]

[0413]

[0414] Statistical analysis was performed using ANOVA among the four sample types, followed by post-hoc tests. The Levene test assumed equal variances (p = 391), so ANOVA was performed first (see Table 8), followed by the Tukey and Bonderroni tests (Table 3).

[0415] Table 8: One-way ANOVA

[0416] Case sum of squares Degrees of freedom Mean Square F-statistic p-value deal with 0.064 3 0.021 18.29 <0.001 mistake 0.009 8 0.001

[0417] The p-values ​​of the F-statistics corresponding to one-way ANOVA in Table 8 indicate that the samples show significant differences. The following post-hoc tests show paired statistical comparisons between samples.

[0418] Table 9: Post-event inspection

[0419]

[0420]

[0421] 1 p tukey The p-value corresponding to the Tukey HSD test; 2 p bonf The p-value corresponding to the Bonferroni test.

[0422] The two post-hoc tests showed similar results (see Table 9, especially p). tukey and p bonf Sample B3 showed significant differences from all other samples, namely B4, B5, and control H. Sample B4 showed a significant difference from control H, but not from sample B5. Sample B5 and control H did not show significant differences.

[0423] Experiment 3 – Human Whole Blood

[0424] The experimental conditions described above for whole blood assays were also used in this experiment, except that human blood was used, with additional replicates (six times instead of three), and the tubes were rinsed with saline (PBS 0.1M) before the experiment and the clot was rotated (0.1g, 1 minute) before measurement.

[0425] Human whole blood was collected the previous day (4 PM) via venipuncture in citrate buffer (3.2%) and stored overnight at 4°C prior to the experiment. Just before the experiment began, the blood was recalcified using calcium chloride (2.06%) at a ratio of 9:1. Samples (six replicates per sample) were incubated overnight at 37°C with 1 mL of blood 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), the sulfonic acid group-modified coating 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. Clots were weighed on a precision balance. The results are shown in Table 10 and... Figure 5 The image is represented graphically. A photograph of the sample is shown below. Figure 6 As shown. Comparison of whole blood clot mass (weight and photographs) after overnight incubation in tubes coated with various compounds.

[0426] Table 10: Clot Weight (mg)

[0427]

[0428]

[0429] Statistical analysis was performed using analysis of variance among the six sample types (Table 11), followed by post-hoc tests (Table 4).

[0430] Table 11: ANOVA - Clot Weight

[0431] Case Homogeneity correction sum of squares df Mean Square F P coating none 156797.222 5.000 31359.444 47.442 <0.001 coating Brown-Forsythe 156797.222 5.000 31359.444 47.442 <0.001 coating Welch 156797.222 5.000 31359.444 44.710 <0.001 Remaining none 19830.000 30.000 661.000 Remaining Brown-Forsythe 19830.000 12.623 1570.892 Remaining Welch 19830.000 13.554 1463.060

[0432] Note the third type of sum of squares.

[0433] Table 12: Post-examination results

[0434]

[0435]

[0436] For the coating, clot S was the lightest, and clot U was the heaviest. Sample L, from whole blood incubated with liquid heparin, was the lightest as expected. Visually, both clot samples L and H, which were in contact with heparin, looked more liquid than all other clots (similar to clots obtained in uncoated tubes (negative control)).

[0437] Statistical analysis in the form of analysis of variance (ANOVA) revealed significant differences among the six types of samples. Tukey's post-hoc test accurately identified the differences between sample L and all other samples, as expected. The difference between samples U and S was also significant, but the difference between S and H was not significant.

[0438] Example 2

[0439] Using the external Chandler Loop System TM The coating of the present invention is compared with commercially available coatings.

[0440] coating

[0441] The tested coatings are shown in Table 13 below. Each coating was tested by applying it to a tube. Commercially available reference coatings are numbered R1 to R4. Coating No. 5 is the coating of the present invention (a coating modified with sulfonic acid groups), prepared as described in Example 1. The length of each coated sample is 47 cm, and "n" is the number of blood donors.

[0442] Table 13: Tested Coatings

[0443]

[0444] As a control, blood samples were used to provide a baseline, and uncoated tubes were used as a reference.

[0445] Chandler-Loop model

[0446] Before coatings can be used in clinical settings, blood compatibility with blood-contacting medical devices must be tested under standardized conditions. The in vitro Chandler-Loop model is a closed system in which the effects of artificial surfaces on different cascades of responses (coagulation, cellular alterations, complement, and inflammation) in the human hemostatic system can be studied. In the Chandler Loop system, polymer tubes partially filled with blood form reclosable loops and are rotated in a temperature-controlled pool at 10–40 RPM to simulate arterial flow conditions. The surface is evaluated using a multiparametric approach that extends beyond thrombosis assessment to measure expression markers of critical importance in the hemostatic system. The blood compatibility of the coated tubes is tested using an in vitro Chandler-Loop model with fresh human whole blood.

[0447] The control (baseline) had no blood circuit contact, while each coated tube underwent 60 minutes of blood perfusion within the circuit. Blood was obtained from five healthy volunteers. The quality of the blood used in these experiments was critical. The following exclusion criteria for blood donors had to be strictly met: use of medications affecting hemostasis within the past two weeks.

[0448] Table 14: Parameters of the Chandler Loop Model

[0449]

[0450] thrombosis

[0451] SEM (LEO 1430, Zeiss) analysis of the two experiments (donor 1 and 2) showed no signs of true thrombosis in any group. Low platelet adhesion was observed on the uncoated tube surface and on coatings R1, R4, and R5.

[0452] Blood clotting

[0453] Blood-substance contact initiates intrinsic coagulation via factors XII, XI, and another factor X that regulates prothrombin conversion. During the thrombin formation reaction, the prothrombin fragment F1+2 is cleaved. The resulting thrombin is inactivated by forming a complex with antithrombin, forming the so-called TAT complex. Plasma TAT concentration is a marker used to detect coagulation activation, and is measured using Siemens. TM Automated immunoassay analyzers and ELISA are used for immunochemical measurements.

[0454] The results are as follows Figure 7 As shown, the coatings on the x-axis are numbered using the designations listed in Table 13 above, where "B" represents the baseline and "C" represents the control. In this study, we found that the coating of the present invention is comparable to commercially available coatings designated R1, R2, and R4. A reduced TAT concentration was measured only for coating designation R3.

[0455] platelets

[0456] Contact between blood and artificial surfaces leads to platelet activation and alteration, accompanied by a progressive loss of platelet function. If platelets come into contact with any artificial surface, they begin to adhere to it. Subsequently, they begin to clump together and form aggregates. The resulting decrease in platelet count is a key indicator of blood compatibility in blood-contact devices. Platelet counts were performed using a cell counter (Micros 60, ABX Hematology, Montpellier, France).

[0457] The results are as follows Figure 8 As shown. During the 60-minute test, the platelet count in the control group (C) decreased slightly. Similar values ​​were detected in coatings R1 through R4 and R5.

[0458] β-Thromboglobulin (β-TG)

[0459] Platelet activation occurs in four steps: shape change and pseudopodia formation, adhesion, aggregation, and release of platelet factors (platelet factor 4, β-TG, etc.) from α-granules. The concentration of β-thromboglobulin (β-TG) in plasma corresponds to the degree of platelet activation. The concentration of β-TG is determined using immunochemical methods (ELISA, Diagnostica Stago SAS, Asnières sur Seine, France).

[0460] Due to circulation, the concentration of β-TG in the control tube increased, indicating a slight increase in platelet activation. See also... Figure 9 The results are shown. Similar levels were measured in coatings R4 and 5. Compared to these groups, coatings R1 through R3 showed a decrease in β-TG concentration.

[0461] hematological parameters

[0462] The number of red blood cells, white blood cells, hemolyzed cells, HGB, and HCT (see below) were measured using a cell counter (Micros 60, ABX Hematology, Montpellier, France).

[0463] Red blood cells (RBCs) and white blood cells (WBCs)

[0464] WBCs in contact with any artificial surface may adhere to that surface and attempt to fight off the supposed pathological intruder. This reaction leads to a decrease in WBC count and is a key indicator of blood compatibility in blood-contact devices. This reaction can also cause a reduction in RBCs if the membrane of RBCs is damaged by high shear forces.

[0465] See Figure 10 and 11 The results showed that red blood cell and white blood cell counts remained stable during the 60-minute perfusion.

[0466] hemolysis

[0467] Red blood cell destruction was quantified by measuring free plasma hemoglobin. Results were as follows: Figure 12 As shown, no significant differences were detected between the test groups.

[0468] Hemoglobin (HGB) and hematocrit (HCT)

[0469] The results are as follows Figure 13 and 14 As shown, HGB and HCT concentrations remained very stable during the 60-minute perfusion period.

[0470] in conclusion

[0471] During a 60-minute incubation period, changes in plasma concentration of the activated marker, blood cell counts, and platelet adhesion indicated that the tube (No. 5) coated with the coating of this invention was equally effective for several hemostatic activation cascades compared to all other tubes coated with commercially available coatings. Regarding TAT formation, an excellent marker for detecting coagulation activation, the measured TAT concentration induced by the coating of this invention (No. 5) was very low. Overall, the blood compatibility test results of the coating of this invention demonstrate good blood compatibility.

[0472] Example 3

[0473] Cytotoxicity assay

[0474] This method was designed to assess the biological responses of mammalian cells in vitro. Mouse fibroblast L929 cells were cultured in L929 cell growth medium (Dulbecco's MOD medium (modified) containing Earle's salts supplemented with serum).

[0475] Samples of the coating (sulfonic acid group modified coating) of the present invention were prepared as described in Example 1. To achieve the desired extraction rate of 6 cm⁻¹... 2 / ml, two samples were extracted, each representing 285.89cm. 2 The internal surface area was calculated, and each sample was extracted in each tube with 47.7 ml of L929 cell extraction medium under stirred conditions. After extraction, the extract was collected in sterile glass vials. The extract was prepared from Eagle's (modified) minimum essential medium containing Earle's salts supplemented with fetal bovine serum (5%) and penicillin and streptomycin (5000 IU). The area of ​​all major surfaces was considered in the calculations, but the edges or any porosity of the test specimens were not taken into account.

[0476] The interfacial area of ​​the positive and negative control materials per milliliter of the final extract volume was calculated to be no less than 0.5 cm². 2 / ml.

[0477] A positive control strip (Hatano Institute product code: RM-B), a polyurethane membrane containing 0.25% zinc dibutyldithiocarbamate (ZDBC), was used. The received material was unsterilized. The material was pre-cut to the desired size (1cm × 1cm). Since three aliquots were required for each test run, all materials were packaged in autoclaved bags and sterilized at 121°C for 15 minutes (three aliquots per bag). Three aliquots were extracted in 13.2 mL of extraction medium under stirred conditions, each aliquot measuring 1.0cm × 1.0cm × 0.05cm, with a total surface area of ​​6.6cm². 2 .

[0478] For the negative control, a section of polyethylene tubing (Scientific Laboratory Supplies product code: TUB3708) known not to produce cytotoxicity in this assay was used. The negative control was 2.0 cm long, with an outer diameter of 0.6 cm, an inner diameter of 0.4 mm, and a total surface area of ​​6.3 cm². 2 It was extracted in 12.6 mL of extraction medium under stirring conditions.

[0479] The test procedure was performed according to ISO 10993-5 and MV033. Samples and controls were extracted at 37±1℃ for 24 hours. The following concentrations of the test extract and positive control extract were used in the experiment: 100%, 50%, 25%, 13%, and 6%. Cell cultures were exposed to the extract at 37±1℃ for 24 hours. Microscopic examination of the cell cultures was performed after exposure to the extract without fixation and staining. Cytotoxicity was qualitatively determined, and the observations were numerically graded. The degree of cytotoxicity observed in each culture is numerically graded as follows.

[0480] Table 15: Qualitative morphological classification of extract cytotoxicity

[0481]

[0482] result

[0483] As can be seen from the cell control results in Tables 16 and 17, the negative and positive controls demonstrate the effectiveness of the test. As shown in Table 18, under the test conditions used, the reactivity grade of the 100% concentration test sample (of this invention) was 0. The coating of this invention does not react with cell cultures.

[0484] According to ISO 10993-5:2009, based on Table 15, results with a numerical grade greater than 2 are considered to be cytotoxic effects.

[0485] Table 16: Results of the negative control

[0486]

[0487] Table 17: Results of Positive Controls

[0488]

[0489] Table 18: Test Extraction Results

[0490]

Claims

1. A coating for use in medical devices, comprising: Surface layer; and The basal layer, wherein the basal layer is biocompatible and contains human albumin; The surface layer comprises a copolymer consisting of polymer chains connected to a plurality of sulfonic acid groups or sulfonate groups via linker groups, wherein the polymer chains are obtained by polymerization of monomers selected from acrylic acid and methacrylic acid and optionally monomers selected from maleic acid and maleimide, wherein the polymer chains comprise repeating units represented by formula (B-1): ， in: R A Selected from H and C 1-6 alkyl; X 2 It is A 2 ; A 2 This can be expressed by equation (S-2): -Z 2 -L 2 -SO2-Y 2 (S-2) in: Z 2 Selected from O, NH and NR 2 ; R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl; Y 2 Selected from O - and OH; L 2 The linker group is represented by formula (L-2): -P 2 -Q 2 -W 2 - (L-2) in: P 2 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; Q 2 Selected from single bonds, O, NH, NR 2C and phenylene; W 2 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; R 2C Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 Alkyl groups; and The surface layer is disposed directly on the substrate layer and is bonded to the substrate layer.

2. The coating according to claim 1, wherein the copolymer is an alternating copolymer or a block copolymer.

3. The coating according to claim 1, wherein R A Selected from H and methyl.

4. The coating according to claim 1, wherein the human albumin is recombinant human albumin.

5. The coating according to claim 1, wherein the surface layer is in the form of a hydrogel.

6. The coating of claim 1, wherein the human albumin is covalently bonded to the polymer chain.

7. The coating according to claim 1, wherein the number average molecular weight of the polymer chains is from 1,000 to 10,000 g / mol.

8. The coating according to claim 1, wherein the polymer chain comprises repeating units represented by formula (A-1): ， in: X 1A Selected from O - OH, OR 1A NH2, NHR 1A and A 1A ; X 1B Selected from O - OH, OR 1B NH2, NHR 1B and A 1B ; R 1A and R 1B Each was independently selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl; A 1A and A 1B Each can be independently represented by equation (S-1): -Z 1 -L 1 -SO2-Y 1 (S-1) in: Z 1 Selected from O, NH and NR 1 ; R 1 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl; Y 1 Selected from O - and OH; L 1 This can be expressed by equation (L-1): -P 1 -Q 1 -W 1 - (L-1) in: P 1 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; Q 1 Selected from single bonds, O, NH, NR 1C and phenylene; W 1 Selected from single bond, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl and phenylene; and R 1C Selected from C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Aryl-C 1-6 alkyl.

9. The coating according to claim 8, wherein: (a) Conforms to X 1A It is A 1A or X 1B It is A 1B At least one of them, or (b) X 1A It is A 1A And X 1B It is A 1B .

10. The coating of claim 8, wherein each Z 1 Selected from O and NH.

11. The coating according to claim 8, wherein each P 1 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 etymynyl; each Q 1 It is a single key, and each W 1 It is a single key.

12. The coating according to claim 8, wherein each P 1 Selected from C 1-10 Alkylene, C 2-10 imide and C 2-10 etymynyl; each Q 1 Selected from O, NH and NR 1C And each W 1 It is a single key.

13. A medical device having a surface coated with a coating according to any one of claims 1 to 12.

14. An in vitro or ex vivo method for reducing or preventing blood clotting, the method comprising: The medical device comes into contact with blood, wherein the medical device is as defined in claim 13.

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