Novel antibacterial and antithrombotic medical devices

Abstract

A medical device comprising one or more polyhydroxyurethanes (PHUs) and a method for producing the same. The use of the medical device for loading and releasing or grafting biologically active molecules, in particular antimicrobial, antithrombotic and anticalcification molecules.

Description

[Technical Field]

[0001] The present invention relates to novel medical devices, particularly catheters or prosthetic heart valves, comprising polyhydroxyurethane, and methods for their manufacture.

[0002] The present invention also relates to the use of medical devices to load and release bioactive molecules, particularly antibacterial or antithrombotic molecules. [Background technology]

[0003] Medical devices that are implanted or inserted into a patient's body are commonly used in the medical field. Catheters and indwelling tubes or artificial valves have become important market-wide medical devices.

[0004] Medical devices such as indwelling devices are necessary for the treatment of patients, but the use of such indwelling devices or the procedures for placing the indwelling devices in the body may pose a risk of inflammation or infection by microorganisms.

[0005] Medical devices that are implanted or inserted into a patient's body may also be subject to calcification, degradation, and thrombosis in vivo.

[0006] Inflammation or infection of an indwelling device begins with bacterial colonization of the surface of the indwelling device or the surrounding area, or the formation of a biofilm on the surface of the indwelling device.

[0007] To minimize the risk of inflammation or infection, it is becoming more common for medical devices to have antibacterial coatings.

[0008] Several methods have been used to prevent microbial colonization of catheters, the most common of which involve the use of antimicrobial loaded or coated catheters.

[0009] However, coating strategies often result in rapid release of the antimicrobial agent. Other coatings use traditional antibiotics, which raises concerns about resistance with long-term use.

[0010] Non-Patent Document 1 describes the use of auranofin-releasing antibacterial and antibiofilm polyurethane (PU) coating for intravascular catheters. Catheters coated with PU and auranofin can inhibit biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA).

[0011] However, polyurethane compounds present some serious problems: Polyurethanes are based on isocyanate chemistry, which involves the reaction of a diol with an isocyanate to form a linear polyurethane.

[0012] Isocyanate-based materials are toxic because they are synthesized from toxic and harmful phosgene. Polyurethane-based isocyanates are also sensitive to moisture, which can cause the formation of unstable monosubstituted carbamic acids, which decompose in a highly exothermic reaction to produce urea and carbon dioxide.

[0013] Furthermore, in vitro and in vivo evaluation of polyurethane (PU) implants has revealed problems associated with long-term implantation: degradation affecting the surface structure of the PU has been observed. Accelerated mineralization due to infiltration of the PU by mineralized host material is likely the cause of premature failure of implants.

[0014] Therefore, there is a need for new, affordable, safe and effective medical devices, particularly catheters and prosthetic valves. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Frontiers in Cellular and infectious microbiology 9, art 37 of February 2019 Summary of the Invention [Problem to be solved by the invention]

[0016] The present inventors have now discovered novel non-isocyanate polyurethanes (NIPUs), also known as polyhydroxyurethanes (PHUs), for use in the manufacture of or coating medical devices. Novel medical devices comprising one or more polyhydroxyurethanes (PHUs) are capable of loading and releasing, or grafting onto, biologically active molecules, particularly antibacterial, antithrombotic, or anticalcification agents.

[0017] The use of non-isocyanate polyurethanes offers many attractive features for biomedical applications, including low cost, excellent biocompatibility, low toxicity, and a variety of mechanical properties that allow for their use in multiple manufacturing methods, such as extrusion, co-extrusion, casting, or 3D printing.

[0018] The object of the present invention is to provide novel medical devices comprising non-isocyanate polyurethanes, namely polyhydroxyurethanes (PHUs). [Means for solving the problem]

[0019] The term implantable medical device, as used herein, refers to all implantable foreign materials for clinical use in a host mammal, such as artificial joints, pacemakers, implantable cardioverter-defibrillators, catheters, e.g., intravascular or urinary catheters, stents, including coronary stents, prosthetic heart valves, intraocular lenses, dental implants, breast implants, endotracheal tubes, gastrostomy tubes, and the like.

[0020] In particular, an implantable medical device comprising polyhydroxyurethane (PHU) is a catheter that can be introduced into a host mammal to deliver fluids, such as blood products, glucose solutions, drugs, diagnostic agents, etc. Catheters can also be used, for example, to withdraw blood from the vasculature for blood processing purposes, or to drain urine from the bladder, or to collect samples.

[0021] The term "catheter" refers in accordance with the present invention to urinary catheters, central venous catheters, cardiovascular catheters, neurovascular catheters, intravenous catheters, and specialty catheters, but also to endotracheal tubes, cannulae, ophthalmic catheters, and the like.

[0022] The catheter according to the invention comprises one or more polyhydroxyurethanes (PHU). The catheter according to the invention can be made partly or entirely of one or more polyhydroxyurethanes (PHU).

[0023] Additionally or alternatively, catheters according to the present invention may be partially or completely coated with one or more polyhydroxyurethanes (PHUs).

[0024] In particular, the medical device comprising one or more polyhydroxyurethanes (PHU) is a prosthetic heart valve, such as a polymeric valve, a mechanical valve, or a biological valve.

[0025] Prosthetic heart valves that include one or more polyhydroxyurethanes (PHUs) can be made partially or entirely from one or more polyhydroxyurethanes (PHUs).

[0026] Alternatively, a prosthetic heart valve comprising one or more polyhydroxyurethanes (PHU) can be partially or completely coated with one or more polyhydroxyurethanes (PHU).

[0027] In certain embodiments, the valve is a mechanical valve, which can be a monoleaflet or bileaflet heart valve made of either pyrolytic carbon or pyrolytic carbon coated titanium, and can be further coated with one or more polyhydroxyurethanes (PHUs).

[0028] In certain embodiments, the valve is a biological valve, also called a tissue valve, which may be a bileaflet or trileaflet heart valve having tissue components provided by a donor animal, and may be further coated with one or more polyhydroxyurethanes (PHUs).

[0029] In certain embodiments, the valve is a polymeric valve. The polymeric valve can be a bileaflet or trileaflet heart valve made in whole or in part from one or more polyhydroxyurethanes (PHUs). If the polymeric valve is made from another polymeric composition, it can also be coated in whole or in part with a PHU.

[0030] The term "host mammal" as used herein refers to a human, but can also refer to an animal.

[0031] Novel medical devices comprising one or more of the non-isocyanate polyurethanes, i.e., polyhydroxyurethanes (PHUs), as a surface coating and / or as a major component of the bulk composition of the medical device, advantageously have greater hemocompatibility, induce less clotting, and induce less platelet adhesion than medical devices comprising isocyanate-based polyurethanes.

[0032] Novel medical devices comprising one or more non-isocyanate polyurethanes, ie, polyhydroxyurethanes (PHUs), can advantageously be loaded with and release one or more bioactive molecules for localized therapeutic treatment.

[0033] In a first aspect, the present invention provides a medical device comprising one or more polyhydroxyurethanes (PHUs) according to formula (1), optionally obtained by thermal polymerization, wherein n is an integer equal to or greater than 1 (n≧1), preferably n is 1 to 100, more preferably 1 to 20. The polyhydroxyurethanes obtained by thermal polymerization have either a linear structure or a network structure, [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 60 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein R2 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, preferably 2 to 60 carbon atoms, more preferably 2 to 20 carbon atoms, even more preferably 2 to 15 carbon atoms, or a mixture thereof; R2 is preferably alkylene, such as methylene, ethylene, methylenebis-cyclohexyl, heptamethylene, etc.; In the formula, R3 and R4 are the same or different and are selected from the group consisting of a hydrogen atom (H), a C 1~6Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl, etc.; C having 1 to 6 carbon atoms; 1~6 alkoxyalkyl, for example, methyloxy, ethyloxy, propoxy, isopropoxy, butoxy, pentoxy, etc.; R3 and R4 are preferably identical and equal to a hydrogen atom; However, as an exception, when R3 and / or R4 represent a hydrogen atom, R1 is [ka] Instead, and, as an exception, when R3 and / or R4 represent a hydrogen atom, R2 is [ka] isn't it.

[0034] In some embodiments, when R3 and R4 represent hydrogen atoms, R1 is [ka] Instead, When R3 and R4 represent a hydrogen atom, R2 is [ka] isn't it.

[0035] In some embodiments, the medical device according to the present invention is characterized in that the one or more polyhydroxyurethanes (PHU) are based on formula (1): [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 60 carbon atoms; wherein R2 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, preferably 2 to 60 carbon atoms, more preferably 2 to 20 carbon atoms, even more preferably 2 to 15 carbon atoms, or a mixture thereof; preferably, R2 is alkylene; where R3 and R4 are the same or different and are selected from H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. 1~6 Alkyl; C having 1 to 6 carbon atoms 1~6 represents alkoxyalkyl, In the formula, n is an integer of ≧1, preferably 1-100, more preferably 1-20.

[0036] In some embodiments of the medical device according to the present invention, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof, and R2 is alkylene.

[0037] In some embodiments of the medical device according to the present invention, the polyhydroxyurethane according to formula (1) is Polycyclocarbonate of formula (2) [ka] wherein R1 is a carbon bond between cyclic carbonate rings or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 40 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; Polyamines of formula (3) [ka] (wherein z is an integer of 2 to 6, wherein R2 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, in particular 2 to 60 carbon atoms, more in particular 2 to 20 carbon atoms, and even more in particular 2 to 15 carbon atoms; wherein R5 and R6 are the same or different and are selected from H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. 1~6 Preferably, R5 and R6 are hydrogen.

[0038] In some embodiments, the medical device according to the present invention comprises a polycyclocarbonate of formula (2) which is poly(propylene glycol)-bis-cyclocarbonate (PPGbisCC) of formula (5), wherein m is an integer ≧1, preferably 1-100, and most preferably 1-10; [ka] The polyamine is 4,4'-methylene-bis-(cyclohexylamine) (MBCHA) of formula (4) [ka] It is characterized in that:

[0039] In some embodiments, the medical device of the present invention comprises a polyamine selected from the group consisting of 4,4'-methylene-bis-(cyclohexylamine) of formula (4) and tris(2-aminoethyl)amine (TAEA) of formula (6). [ka] It is characterized by being a combination of the above.

[0040] In some embodiments, the medical device according to the present invention comprises a polytetrahydrofuran biscyclocarbonate having the formula (8), wherein p is an integer ≧1, preferably 1-100, and most preferably 1-10; [ka] The polyamine is 4,4'-methylene-bis-(cyclohexylamine) (MBCHA) of formula (4) [ka] It is characterized in that:

[0041] In some embodiments, the medical device according to the present invention is characterized in that the polyamine is 4,4'-methylene-bis-(cyclohexylamine) of formula (4) in combination with tris(2-aminoethyl)amine (TAEA) of formula (6). [ka]

[0042] In some embodiments, the polyhydroxyurethane (PHU) of the medical device according to the present invention is based on formula (9): [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 60 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein R8 is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, one or several hydrocarbon groups of which can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, the hydrocarbon chain having at least 2 carbon atoms, in particular 2 to 60 carbon atoms, more in particular 2 to 20 carbon atoms, even more in particular 2 to 15 carbon atoms, or a mixture thereof; preferably, R8 is alkylene; and In the formula, u is an integer of ≧1, preferably 1-10, and more preferably 1-5.

[0043] In some embodiments, the polyhydroxyurethane (PHU) of the medical device according to the present invention is based on formula (9), and is obtained by UV polyaddition of a polyallylcarbamate hydroxy derivative of formula (10) with a dithiol of formula (11) and a photoinitiator: [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 60 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; [ka] wherein R8 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or more hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, particularly 2 to 60 carbon atoms, more particularly 2 to 20 carbon atoms, even more particularly 2 to 15 carbon atoms, or a mixture thereof; preferably, R8 is alkylene.

[0044] In some embodiments, the medical device according to the present invention is characterized in that the polyallylcarbamate hydroxy derivative is polyallylcarbamate hydroxypropylene oxide of formula (14): [ka] In the formula, t≧1, preferably t is 1 to 1000, and most preferably 1 to 20.

[0045] In some embodiments, the medical device of the present invention is a catheter or a prosthetic heart valve.

[0046] The present invention also encompasses a method for producing a medical device comprising a polyhydroxyurethane as described herein, characterized in that the method comprises a mixing step (a) or a mixing step (b), where step (a) or step (b) corresponds to thermal polymerization or UV polymerization, respectively: a) mixing a polycyclocarbonate of formula (2) with a polyamine of formula (3), optionally with a catalyst, and thermally polymerizing the mixture to obtain a polyhydroxyurethane based on formula (1); [ka] wherein R1 is a carbon bond between cyclic carbonate rings or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 40 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein R2 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, preferably 2 to 60 carbon atoms, more preferably 2 to 20 carbon atoms, and even more preferably 2 to 15 carbon atoms; wherein R5 and R6 are the same or different and are selected from H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. 1~6 alkyl, preferably R5 and R6 are hydrogen; where R3 and R4 are the same or different and are selected from H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. 1~6Alkyl; C having 1 to 6 carbon atoms 1~6 represents alkoxyalkyl, and in the formula, n is an integer of ≧1, preferably n is 1 to 100, more preferably 1 to 20), b) mixing the polyvinyl carbamate hydroxy derivative of formula (10) with the dithiol of formula (11) and a photopolymerization initiator, and obtaining a polyhydroxyurethane based on formula (9) by UV polymerization; [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 60 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein R8 is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, one or several hydrocarbon groups of which can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, the hydrocarbon chain having at least 2 carbon atoms, in particular 2 to 60 carbon atoms, more in particular 2 to 20 carbon atoms, even more in particular 2 to 15 carbon atoms, or a mixture thereof; preferably, R8 is alkylene; and In the formula, u is an integer of ≧1, preferably 1 to 10, more preferably 1 to 5).

[0047] The present invention also encompasses a method of coating a medical device comprising a polyhydroxyurethane as described herein, the method comprising depositing on a surface of the medical device at least one layer of a polyhydroxyurethane according to Formula (1) or Formula (9): [ka] wherein R1 is a carbon bond between cyclic carbonate rings or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has 2 to 40 carbon atoms; preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein R2 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, preferably 2 to 60 carbon atoms, more preferably 2 to 20 carbon atoms, and even more preferably 2 to 15 carbon atoms; where R3 and R4 are the same or different and are selected from H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. 1~6 Alkyl; C having 1 to 6 carbon atoms 1~6 represents alkoxyalkyl, wherein R8 is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, each of which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, in particular 2 to 60 carbon atoms, more in particular 2 to 20 carbon atoms, even more in particular 2 to 15 carbon atoms, or a mixture thereof; preferably R8 is alkylene; In the formula, u is an integer of ≧1, preferably 1 to 10, more preferably 1 to 5; In the formula, n is an integer of ≧1, preferably 1-100, more preferably 1-20.

[0048] In some embodiments, the medical device according to the present invention further comprises a bioactive molecule, preferably an antibacterial or antithrombotic agent.

[0049] PHUs based on formula (1) with a linear structure, such as those where R3 and R4 represent hydrogen atoms, can be advantageously used in fused filament fabrication (FFF) or fused deposition modeling (FDM), also known as 3D printing.

[0050] In some embodiments, the polyhydroxyurethane (PHU) of formula (1) is obtained by thermal polyaddition of a polyamine of formula (3) with a polycyclocarbonate of formula (2), [ka] wherein R1 is a carbon bond between cyclic carbonate rings or a straight or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 60 carbon atoms; Preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; In the formula, y is an integer of 2 or more, preferably 2 to 6, and more preferably 2 or 3; and where x is an integer from 1 to 4, which represents the number of methylene groups. When x is assumed to have a value of 1 to 4 according to the present invention, the resulting cyclic carbonate group is made up of 5, 6, 7, and / or 8 atoms, Preferably, the integer x is 1, resulting in a five-membered carbonate ring group.

[0051] Examples of polycyclocarbonates that can be used in the present invention are: [ka] In the formula, X is an oxygen atom (O) or a nitrogen atom (N), wherein R is one of the groups selected from: [ka]

[0052] Polycyclocarbonates can be prepared by any method known in the art, such as from a polyol by converting all or part of the alcohol functional groups of the polyol to glycidyl ether functional groups, followed by carbonation of the glycidyl ether functional groups, as described in EP 3199569, or by epoxidizing a molecule having at least two external double bonds, followed by an (organo)catalyzed carbon dioxide coupling reaction, as described in L.-N. He & al., "One-pot stepwise synthesis of cyclic carbonates directly from olefins with CO promoted by KSO / NaBr", J. CO Util., 2016, 16, 313-317, and R. Wang & al., "Direct Synthetic Processes for Cyclic Carbonates from Olefins and CO", Catal. Surv. from Asia, 2011, 15, 49-54, and C. Detrembleur & al., "Organocatalyzed coupling of carbon dioxide with epoxides for the synthesis of cyclic carbonates: catalyst design and mechanistic studies", Catal. Sci. Technol., 2017, 7, 2651.

[0053] In the polyamine of formula (3), [ka] z is an integer equal to or greater than 2, preferably equal to 2 to 6, most preferably equal to 2 or 3; R2 is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, one or several hydrocarbon groups of the hydrocarbon chain may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, the hydrocarbon chain having at least 2 carbon atoms, preferably 2 to 60 carbon atoms, more preferably 2 to 20 carbon atoms, and even more preferably 2 to 15 carbon atoms; preferably, R2 is an alkylene group, such as methylene, ethylene, methylene-bis-cyclohexyl, heptamethylene, etc.; polyether, preferably having a molecular weight in the range of 300 g / mol to 10,000 g / mol; polyester, preferably having a molecular weight in the range of 300 g / mol to 10,000 g / mol; polysiloxane, preferably having a molecular weight in the range of 300 g / mol to 10,000 g / mol; or a mixture thereof; R5 and R6 are the same or different and are selected from H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. 1~6 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl, etc., or C 3-8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R5 and R6 are preferably hydrogen, with the exception that when R5 and / or R6 are hydrogen, R2 is [ka] isn't it.

[0054] The polyamine of formula (3) can be a primary polyamine, a secondary polyamine, or a tertiary polyamine.

[0055] The polyamine of formula (3) is, for example, a diamine, in particular a linear aliphatic diamine such as 1,2-diaminoethane, 1,3-diaminopropane, butane-1,4-diamine, pentane-1,5-diamine, 1,6-diaminohexane, or 1,12-diaminododecane, hexamethylenediamine, 4,9-dioxa-1,12-dodecanediamine, 2,2'-(ethane-1,2-diylbis(oxy))diethanamine, or a cyclic aliphatic diamine such as isophoronediamine (IPDA), a triamine such as tris(2-aminoethyl)amine (TAEA), or any other polyamine such as polyethyleneimine or a dimeric fatty acid diamine, or an aromatic diamine such as o-xylylenediamine, m-xylylenediamine, p-xylylenediamine, or 1,2-diphenylethylenediamine. The use of polyamines with long chain portions and / or low -NH2 functionality can result in linear, flexible structures, while the use of polyamines with short chain portions and high -NH2 functionality can result in crosslinked, more rigid network structures.

[0056] Preferably, the polyamine of formula (3) is a primary polydiamine, most preferably 4,4'-methylenebis(cyclohexylamine) (MBCHA) of formula (4): [ka] This results in polyhydroxyurethane PHU of formula (1) where R2 is a methylenebis(cyclohexyl) group.

[0057] Alternatively, a primary polyamine can be used in combination with another primary polyamine, or in combination with a secondary or tertiary polyamine.

[0058] The term "primary polyamine," as used herein, refers to a polyamine of formula (3) where R5 and R6 are hydrogen.

[0059] The term "secondary polyamine," as used herein, refers to a polyamine of formula (3) where either R5 or R6 is hydrogen.

[0060] The term "tertiary polyamine," as used herein, refers to a polyamine of formula (3) in which R5 and R6 are not both hydrogen.

[0061] Thermal polyaddition is a reaction in which the polycyclocarbonate of formula (2) is ring-opened using the polyamine of formula (3) at a temperature of 10°C to 100°C, preferably 65°C to 80°C.

[0062] The polycyclocarbonate of formula (2) reacts with a polyamine, which is used as the nucleophile (Nu).

[0063] The thermal polyaddition is preferably carried out using a catalyst, which is used to increase the rate of the carbonate / amine reaction and allow decarboxylation of the cyclic carbonate. A wide range of catalysts can be used (see, for example, Blain et al., Green Chemistry 2014, 16, 4286). The selection of the appropriate catalyst depends on the specific formulation used, but also on the temperature used to form the polyhydroxyurethane. By way of non-limiting example, the catalyst can be selected from amine catalysts such as triazabicyclodecene (TBD), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), or other guanidines and amidines, trimethylhydroxyethylethylenediamine, trimethylaminopropylethanolamine, dimethylethanolamine, bis(2-dimethylaminoethyl)ether, triethylenediamine, dimethylaminocyclohexane, N-methylmorpholine, dimethylaminopyridine (DMAP), trimethylamine (NEt), trimethylamine, phosphazenes, phosphines (triarylphosphines and trialkylphosphines).

[0064] The catalyst may also be selected from ionic salts or ionic liquids composed of a combination of cations and anions. The cations may be alkali metals, such as Na, as described in WO 2021 / 004993. + , Li + , K. + , Cs + etc., or other metals, e.g., Mg 2+ , Ca 2+ etc., or other organic cations including ammonium, phosphonium, imidazolium, pyrazolium, triazolium, tetrazolium, pyridinium, piperidinium, pyrrolidinium, guanidinium, or amidinium.

[0065] The term "polyether," as used herein, refers to a linear or branched, aliphatic or aromatic, polymeric chain having two or more ether (-O-) linkages.

[0066] The term polyether refers in particular to polyalkylene oxides C 2n H 4n O n+1 , for example, polypropylene oxide, also known as polypropylene glycol, polyethylene oxide, also known as polyethylene glycol, polybutylene oxide, also known as polybutylene glycol, or mixtures thereof.

[0067] The term polyethylene oxide refers to: [ka] In the formula, n is an integer large enough to have a molecular weight of about 300 g / mol to about 10,000 g / mol.

[0068] The term polypropylene oxide refers to: [ka] In the formula, n is an integer large enough to have a molecular weight of about 300 g / mol to about 10,000 g / mol.

[0069] The term polybutylene oxide refers to: [ka] In the formula, n is an integer large enough to have a molecular weight of about 300 g / mol to about 10,000 g / mol.

[0070] The term "polyester," as used herein, refers to a linear or branched, aliphatic or aromatic, polymeric chain having two or more carboxyl (-COO-) linkages.

[0071] The term "polyol," as used herein, refers to a linear or branched, aliphatic or aromatic, polymeric chain having two or more alcohol groups.

[0072] The term "polysiloxane," or silicone, as used herein refers to a polymer consisting of a silicon-oxygen backbone of formula (18): [ka] In the formula, n is an integer large enough to have a molecular weight of about 300 g / mol to about 10,000 g / mol.

[0073] "C 1~6 The term "alkyl," as used herein, alone or in combination, refers to a straight or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and 1,2,2-trimethylpropyl.

[0074] "C 1~6 The term "alkoxy," as used herein, alone or in combination, refers to a straight or branched chain monovalent substituent attached through an ether oxygen. 1~6 It refers to alkyl groups having a free valence bond derived from this ether oxygen and having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy.

[0075] The term "ketone," as used herein, refers to a C=O group.

[0076] The term "heteroatom," as used herein, refers to an atom selected from N, O, S, Si, and S(O)n (where n is 0, 1, or 2), SiO.

[0077] The term "cycloalkyl," as used herein, refers to a monovalent or divalent 3- to 8-membered carbocyclic ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0078] The term "heterocycle", as used herein, refers to a monovalent or divalent non-aromatic monocyclic or bicyclic radical having 4 to 9 ring atoms, of which 1 to 3 ring atoms are heteroatoms independently selected from N, O, and S(O)n, where n is 0, 1, or 2, and the remaining ring atoms are C. Particularly piperidyl or cyclic carbonate.

[0079] The term "aryl," as used herein, refers to a monovalent or divalent aromatic carbocyclic group containing 6 to 14, especially 6 to 10, carbon atoms and having at least one aromatic ring or multiple fused rings, at least one of which is aromatic. Examples include phenyl, benzyl, naphthyl, biphenyl, anthryl, azulenyl, or indanyl.

[0080] The term "heteroaryl," as used herein, refers to a monovalent or divalent cyclic aromatic group containing one, two, or three heteroatoms and having at least one aromatic ring or multiple fused rings, at least one of which is aromatic. The aromatic ring can be a six-membered ring, such as pyridinyl, or a five-membered ring, such as thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, imidazolyl, triazolyl, or thiadiazolyl.

[0081] The term "allyl," as used herein, refers to the group CH2=CH-CH2-.

[0082] In one particular embodiment, the present invention provides a medical device comprising one or more polyhydroxyurethanes (PHUs) according to formula (7): [ka] In the formula, r is an integer of 1 or greater (r≧1), and s is an integer of 1 or greater (s≧1). Preferably, r is 1 to 100, more preferably 1 to 10. Preferably, s is 1 to 500, more preferably 1 to 20, and most preferably 1 to 6.

[0083] Polyhydroxyurethanes (PHUs) based on formula (7), also known as polypropylene glycol-based PHUs, are derived from polypropylene glycol bis(cyclocarbonate) (PPG biscc) of formula (5): [ka] (wherein m is an integer of 1 or more (m≧1), preferably m is 1 to 1000, more preferably 1 to 20), 4,4'-methylene-bis-(cyclohexylamine) (MBCHA) of formula (4) [ka] It can be obtained by thermal polyaddition between

[0084] The advantages of the polypropylene glycol-based PHU as described herein are that it is more hemocompatible than the corresponding polyurethane (PU) or polypropylene glycol-based PU of formula (17), which induces less blood clotting and platelet adhesion, and is less susceptible to bacterial infection. The corresponding polyurethane (PU) or polypropylene glycol-based PU of formula (17) can be obtained by the reaction shown in Figure 1, where m and q are 1 or greater (m≧1) and (q≧1). [ka] (PPG type PU)(17)

[0085] In a preferred embodiment, the present invention provides a medical device comprising one or more polyhydroxyurethanes (PHU) obtained by polyaddition of polypropylene glycol bis(cyclocarbonate) (PPG bisCC) of formula (5) with a diamine, preferably 4,4'-methylene-bis-(cyclohexylamine) (MBCHA) of formula (4), and a triamine, preferably tris(2-aminoethyl)amine (TAEA) of formula (6). [ka]

[0086] Thanks to the addition of triamine, the resulting PHU becomes an interconnected 3D network with better mechanical properties.

[0087] In another specific embodiment, the present invention provides polytetrahydrofuran biscyclocarbonate (PTHF bisCC) of formula (8): [ka] (wherein p is an integer of 1 or more (≧1), preferably p is 1 to 100, most preferably 1 to 10), A diamine, preferably 4,4'-methylenebis(cyclohexylamine) of formula (4): [ka] The present invention provides a medical device comprising one or more polyhydroxyurethanes (PHUs) obtained by thermal polyaddition of

[0088] The advantages of polytetrahydrofuran-based PHUs obtained by thermal polyaddition are that they are more hemocompatible than the corresponding polyurethanes (PTHF-based PUs), which induce less blood clotting and platelet adhesion, and are less susceptible to bacterial infection.

[0089] In another preferred embodiment, the present invention provides a medical device comprising one or more polyhydroxyurethanes (PHU) obtained by thermal polyaddition of polytetrahydrofuran biscyclocarbonate of formula (8) with a diamine, preferably 4,4'-methylenebis(cyclohexylamine) of formula (4), and with a triamine, preferably tris(2-aminoethyl)amine (TAEA) of formula (6): [ka]

[0090] In a second aspect, the present invention provides a medical device comprising one or more polyhydroxyurethanes (PHU) obtained by UV polymerization according to formula (9).

[0091] When UV polymerization is used, the resulting polyhydroxyurethane based on formula (9) has a network structure, [ka] In the formula, u is an integer of 1 or more (n≧1), and n is preferably 1 to 100, more preferably 1 to 20. wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 60 carbon atoms; Preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein R8 is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, in particular 2 to 60 carbon atoms, more in particular 2 to 20 carbon atoms, even more in particular 2 to 15 carbon atoms, or a mixture thereof; R8 is preferably alkylene.

[0092] Polyhydroxyurethane (PHU) based on formula (9) can be obtained by UV polymerization in a two-step reaction.

[0093] The first step is to prepare a polycarbonate of formula (2) [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 60 carbon atoms; Preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; wherein x is an integer of 1 to 4, preferably equal to 1, and y is an integer of 2 or more, preferably 2 to 6, Polyamines of formula (15) [ka] (wherein R2 is a linear or branched unsaturated hydrocarbon chain having 2 to 40 carbon atoms, the linear or branched unsaturated hydrocarbon chain having at least a photoresponsive group; wherein R5 is hydrogen, R6 is hydrogen, a C6 having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain; 1~6 alkyl, and wherein z is an integer of ≧1, preferably 1 to 6), to obtain a polycarbamate hydroxy derivative having a photoresponsive group; Preferably, an amine having one or more olefins, such as allylamine, is used to obtain a polyallylcarbamate hydroxy derivative having a photoresponsive group on the linear or branched hydrocarbon chain, particularly at the end of the main chain.

[0094] In a preferred embodiment, the first step of aminolysis of the polycarbonate of formula (2) is carried out with allylamine to give the polyallylcarbamate hydroxy derivative of formula (10): [ka] wherein R1 is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 60 carbon atoms; Preferably, R1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof.

[0095] The polyallylcarbamate hydroxy derivative of formula (10) has a vinyl photoresponsive group at the end of the main straight or branched hydrocarbon chain, but can also have a vinyl photoresponsive group in the main chain.

[0096] The aminolysis can be carried out at a temperature between 20°C and 100°C, preferably between 40°C and 60°C, most preferably at 40°C.

[0097] Aminolysis can be catalyzed by DBU, DMAP, DABCO, TBD, MTBD, and DBN as exemplified herein below: [ka]

[0098] The aminolysis is preferably carried out using a DBU catalyst, ie, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU).

[0099] In the second step, the resulting polyallylcarbamate hydroxy derivative of formula (10) is then UV polymerized in the presence of a thiol of formula (16), preferably a thiol of formula (11), as a crosslinking agent and a photopolymerization initiator; R8-(SH) k (16) [ka] In the formula, k is an integer of ≧2, preferably 2 to 6, wherein R8 is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and the hydrocarbon chain has at least 2 carbon atoms, in particular 2 to 60 carbon atoms, more in particular 2 to 20 carbon atoms, even more in particular 2 to 15 carbon atoms, or a mixture thereof; R8 is preferably alkylene.

[0100] The term thiol, as used herein, refers to bithiol, trithiol, tetrathiol, or hexathiol, preferably pentaerythrityl tetrathiol, thiol trimethylolpropane, pentaerythritol tetra(3-mercaptopropionate), trimethylolpropane tri(3-mercaptopropionate), pentaerythritol tetrathioglycolate, and / or trimethylolpropane thioglycolate, tris[2-(3-mercaptopropionyloxy)ethyl]isocyanurate. The term also refers to telechelic, branched, or multiarm polymers having a thiol group at each chain end (e.g., polyethylene glycol dithiol or polypropylene glycol dithiol), or polymers having thiol groups as pendant groups along the polymer backbone, or peptides or proteins having at least two thiols.

[0101] Suitable dithiols and trithiols are, for example, 2,2'-(ethylenedioxy)diethanethiol of formula (12) and 2,2-bis(3-sulfanylpropanoyloxymethyl)butyl-sulfanylpropanoate of formula (13). [ka]

[0102] The term "photoinitiator" as used herein refers to, for example, bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide, also known as Irgacure 819; bis-(4-methoxybenzoyl)diethylgermanium, also known as Ivocerin; 2,3-bornanedione, also known as camphorquinone; and lithium phenyl-2,4,6-trimethylbenzoylphosphinate, also known as LAP, riboflavin-5-phosphate. Preferably, the photoinitiator is Irgacure 819.

[0103] The photopolymerization initiator can be used at a low concentration of 0% to 0.1%, preferably less than 0.1%.

[0104] According to some embodiments, UV polymerization occurs at wavelengths between 300 nm and 400 nm, preferably 365 nm. Optionally, UV polymerization can be combined with additional heating to enhance crosslinking and evaporate traces of solvent. Such additional heating can be performed at temperatures between 40°C and 100°C, preferably 70°C.

[0105] The resulting polyhydroxyurethane of formula (9) contains hydroxyl groups and other groups that can be advantageously used to load and release bioactive molecules for topical pharmaceutical treatment.

[0106] In one particular embodiment, the first step is the aminolysis of polypropylene oxide bicyclocarbonate, also known as PPGbisCC, of ​​formula (5): [ka] In the formula, m is an integer of 1 or more, preferably 1 to 1000, and more preferably 1 to 20.

[0107] In some embodiments, the bicyclocarbonate of formula (5) is first reacted with allylamine to give polyallylcarbamate hydroxypropylene oxide, also known as PPG-allyl, of formula (14): [ka] In the formula, t is an integer of 1 or more, preferably 1 to 1000, and more preferably 1 to 20.

[0108] In the second step, the polyallylcarbamate hydroxypropylene oxide of formula (14) is then crosslinked with the dithiol of formula (13) in the presence of a photoinitiator, such as bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide, under UV irradiation, preferably at 300 nm to 400 nm, most preferably at 365 nm. [ka]

[0109] In certain embodiments, the medical device is made of or partially made of one or more polyhydroxyurethanes (PHUs), particularly PHUs based on Formula (1) or PHUs based on Formula (9). Medical devices made of or partially made of polyhydroxyurethanes (PHUs) can optionally be reinforced with high surface area particles or fibers to improve mechanical properties, such as tensile strength, elongation at break, modulus, and shear modulus.

[0110] The structure of polyhydroxyurethane (PHU) based on formula (1) can be optionally reinforced by the addition of high surface area particles or fibers, such as silica, functionalized silica, polypropylene terephthalate mesh, or polyethylene mesh, or mixtures thereof, which are added to the mixture of polycarbonate of formula (2) and polyamine of formula (3) prior to thermal polymerization.

[0111] The polyhydroxyurethane (PHU) structure based on formula (9) can be optionally reinforced by the addition of high surface area particles or fibers, such as silica, functionalized silica, polypropylene terephthalate mesh, or polyethylene mesh, or mixtures thereof, which are added to a mixture of polyallylcarbamate hydroxy derivative of formula (10) and thiol of formula (11) prior to UV polymerization.

[0112] Medical devices made or partially made of one or more polyhydroxyurethanes (PHU), optionally with high surface area particles, can be obtained by casting, injection molding, extrusion, co-extrusion, jetting, 3D printing, coating, or by subjecting to additional manufacturing steps to produce a medical device according to the invention.

[0113] Medical devices made partially or entirely of one or more PHUs advantageously have higher hemocompatibility than comparable medical devices containing polyurethane (PU), which induces less blood clotting and platelet adhesion, and is less susceptible to bacterial infection.

[0114] Medical devices made in part or in whole of one or more PHUs can advantageously be loaded with and release bioactive molecules, thereby providing localized pharmaceutical treatment.

[0115] In another particular embodiment of the present invention, the medical device comprises one or more polyhydroxyurethanes (PHUs), in particular PHUs based on formula (1) or PHUs based on formula (9), which at least partially or entirely coat the surface of the medical device, for example, the surface of a catheter or a prosthetic heart valve.

[0116] The polyhydroxyurethane (PHU) used to at least partially or completely coat the surface of a medical device can be anchored or attached to the surface of the medical device using a variety of physical or chemical methods, such as surface irradiation, layer-by-layer (LbL) deposition, spin coating, plasma deposition, etc.

[0117] Medical devices partially or fully coated with one or more PHUs advantageously have higher hemocompatibility than comparable medical devices coated with polyurethane (PU), which induces less blood clotting and platelet adhesion, and is less susceptible to bacterial infection.

[0118] Medical devices that are at least partially or entirely PHU coated can advantageously be loaded with and release bioactive molecules, or bioactive molecules can be grafted onto the medical device, thereby providing localized pharmaceutical treatment.

[0119] In certain embodiments, the medical device is a catheter having a shaft made of one or more polyhydroxyurethanes (PHUs) or a catheter coated with one or more polyhydroxyurethanes (PHUs). The shaft can be a single-lumen shaft or a multi-lumen shaft, e.g., a shaft having two, three, four, or more lumens. The shaft is prepared by extrusion of one or more polyhydroxyurethanes (PHUs) during a single-layer or multi-layer co-extrusion process according to methods known in the art.

[0120] In another specific embodiment, the medical device is a prosthetic valve made or partially made of one or more polyhydroxyurethanes (PHUs), which can be synthesized directly in a mold designed to mimic a native valve with a symmetrical tri-leaflet design as reproduced in Figure 2.

[0121] In order to match the properties of the native valve, polyhydroxyurethane (PHU) must have sufficiently strong mechanical properties, such as a Young's modulus of around 2 MPa to 3 MPa, a tensile strength of more than 1.5 MPa, and an elastic deformation of more than 35%.

[0122] Such properties are met by polyhydroxyurethane (PHU), but can be improved by incorporating reinforcing particles such as silica to form crosslinked nodes to which the polyhydroxyurethane can attach with its OH groups, or by incorporating a reinforcing polyester mesh to improve tensile strength. Examples of reinforcing meshes include polyethylene or polypropylene terephthalate meshes.

[0123] Prosthetic heart valves can be made by 3D printing using computer programs optimized for valve design to satisfy computational fluid dynamics.

[0124] Indeed, experience has taught us that not only is the choice of artificial material important, but the design must also provide flow that is as laminar and reduced turbulence as possible and incorporate sufficient diastolic washing of the valve elements to minimize microthrombi.

[0125] Novel medical devices made of or coated with one or more PHUs can advantageously contain bioactive molecules that are further gradually released over time, thereby improving medical therapy, e.g., anti-infective or anti-thrombotic effects. In certain embodiments, the PHUs are impregnated with one or more bioactive molecules. Thus, in certain embodiments, medical devices comprise one or more PHUs impregnated with bioactive molecules. In other specific embodiments, medical devices comprise one or more PHUs grafted with bioactive molecules. Furthermore, novel medical devices comprising one or more PHUs impregnated with bioactive molecules advantageously provide local delivery, providing rapid therapeutic activity while minimizing off-site toxicity and reducing susceptibility to resistance.

[0126] In fact, the polyhydroxyurethane (PHU) according to the invention can be loaded with bioactive molecules by immersion in a solvent containing the bioactive molecules.

[0127] The polyhydroxyurethane (PHU) of the present invention swells upon contact with a solvent, allowing it to be loaded with bioactive molecules. The immersion solvent can be alcohol, water, THF, CHCl, or a mixture thereof, or any other solvent mixture that can dissolve bioactive molecules and swell the PHU. The loading of bioactive molecules occurs through H-bonding with the OH groups of the PHU.

[0128] After removal of the solvent, the polyhydroxyurethane (PHU) of the present invention is capable of releasing bioactive molecules over time when placed in the human body.

[0129] Alternatively, the polyhydroxyurethanes (PHUs) of the present invention can be grafted with bioactive molecules by methods known in the art.

[0130] The term "bioactive molecule" as used herein refers to, for example, antibacterial agents, anti-biofilm formation agents, antiplatelet agents, anticoagulants, antithrombotic agents, and anticalcification agents. Bioactive molecules can be incorporated into the bulk of medical devices made from one or more polyhydroxyurethanes (PHUs) or onto the surface of medical devices coated with one or more polyhydroxyurethanes.

[0131] Bioactive molecules can include any agent that is desired to be delivered to a cell, tissue, or organ to regulate or otherwise modify cellular function, including for therapeutic purposes. Bioactive molecules include, but are not limited to, pharmaceutically active compounds or diagnostic compounds.Bioactive molecules include, but are not limited to, nucleotides (aptamers, RNAi, antisense oligonucleotides), peptides, oligopeptides, proteins, apoproteins, glycoproteins, antigens and antibodies or antibody fragments thereof, receptors and other membrane proteins, retro-inverso oligopeptides, protein analogs in which a peptide bond is replaced by at least one non-peptide bond, enzymes, coenzymes, enzyme inhibitors, amino acids and their derivatives, hormones, lipids, phospholipids. substances, liposomes, ricin or ricin fragments; toxins such as aflatoxin, digoxin, xanthotoxin, rubratoxin, etc.; analgesics such as aspirin, ibuprofen, and acetaminophen, etc.; bronchodilators such as theophylline and albuterol, etc.; beta-blockers such as propranolol, metoprolol, atenolol, labetalol, timolol, penbutolol, and pindolol, etc.; antibacterial agents such as those listed above, as well as ciprofloxacin, cinoxacin, and norfloxacin, etc.; antihypertensive agents such as for example, clonidine, methyldopa, prazosin, verapamil, nifedipine, captopril, and enalapril; cardiovascular drugs, including antiarrhythmics, cardiac glycosides, antianginals, and vasodilators; central nervous system drugs, including stimulants, psychotropic drugs, antimanic drugs, and depressants; antiviral drugs; antihistamines, such as chlorpheniramine and brompheniramine; cancer treatment drugs, including chemotherapy drugs, such as chlorambucil, carboplatin, busulfan derivatives, doxorubicin, etoposide, topotecan (TPT), and the like; psychiatric drugs Tranquilizers such as diazepam, chlordiazepoxide, oxazepam, alprazolam, and triazolam; antidepressants such as fluoxetine, amitriptyline, nortriptyline, and imipramine; H-2 antagonists such as nizatidine, cimetidine, famotidine, and ranitidine; anticonvulsants; antiemetics; prostaglandins; muscle relaxants; anti-inflammatory substances; stimulants; decongestants; antiemetics; diuretics; antispasmodics; antiasthmatics; antiparkinsonian drugs; expectorants; antitussives; mucolytics; vitamins; and minerals and nutritional additives.Other molecules include: nucleotides; oligonucleotides; polynucleotides; and their art-recognized biologically functional analogs and derivatives, including, for example, methylated polynucleotides and nucleotide analogs with phosphorothioate linkages; plasmids, cosmids, artificial chromosomes, and other nucleic acid vectors; antisense polynucleotides, including those that are substantially complementary to at least one endogenous nucleic acid or have a sequence of the opposite sense to at least a portion of a selected viral or retroviral genome; promoters; enhancers; inhibitors; and other ligands that regulate gene transcription and translation.

[0132] The bioactive molecule can be an anti-infective agent, such as an antibiotic, for example, amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem / cilastatin, meropenem, cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, or cefdinir. , cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline, fosamil, ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin, oritavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam Onam, furazolidone, nitrofurantoin, linezolid, amoxicillin, ampicillin, piperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfa have antibacterial activity and are also referred to as antibacterial agents, including, but not limited to, anilamide, sulfisoxazole, trimethoprim-sulfamethoxazole, sulfamidochrysoidine, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, rifampicin, rifabutin, arsphenamine, chloramphenicol, fosfomycin, metronidazole, thiamphenicol, tigecycline, tinidazole, trimethoprim,Mention may also be made of pyrimidine derivatives as defined in WO 2019 / 158655 or triazolo(4,5-d)pyrimidine derivatives as defined in EP 3292867.

[0133] Biofilm formation inhibitors include naturally occurring peptides, such as human cathelicidin LL-37 or bovine peptide indolicidin, or synthetic peptides, such as 1018, natural compounds with a 2-aminoimidazole moiety, 2-aminoimidazole inhibitors, benzimidazole analogs, indole-triazo-amide analogs, plant-derived biofilm inhibitors, such as emodin, phloretin, and casbane diterpene. diterpene), resveratrol and its oligomers, sulfur derivatives, bromine-added furanone analogues, bromopyrrole alkaloids, skyllamycin and (-)-ageloxime D structure, cembranoids, N-acyl homoserine lactone analogues, caprolactone, molecules that interfere with the formation of amyloid-like fibers, fatty acids, nitric oxide donors, ionic liquids, such as 1-alkyl-3-methylimidazolium chlorides, 1-alkylquinolinium bromides, etc., all of which can be used in combination with traditional antibiotics or with pyrimidine derivatives as defined in WO 2019 / 158655 or triazolo(4,5-d)pyrimidine derivatives as defined in EP 3292867, which have antibacterial activity and are also referred to as antibacterial agents.

[0134] Antiplatelet agents include irreversible cyclooxygenase inhibitors, such as aspirin and triflusal (Disgren), adenosine diphosphate (ADP) receptor inhibitors, such as clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), ticlopidine (Ticlid), phosphodiesterase inhibitors, such as cilostazol (Pletal), protease-activated receptor 1 (PAR-1) antagonists, such as vorapaxar (Zontivity), and glycoprotein IIB / IIIA inhibitors. agents (for intravenous use only), such as abciximab (ReoPro), eptifibatide (Integrilin), tirofiban (Aggrastat), and the like; adenosine reuptake inhibitors, such as dipyridamole (Persantine), and the like; thromboxane inhibitors, thromboxane synthase inhibitors, and thromboxane receptor antagonists, such as terutroban, glycoprotein VI inhibitors, such as revacept, glycoprotein Ib inhibitors, and von Willebrand factor inhibitors, but are not limited to these.

[0135] Anticoagulants include, but are not limited to, acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumarate, phenprocoumon, warfarin, chlorindione, diphenadione, phenindione, thiochromarol, bemiparin, certoparin, ardeparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, dabigatran, apixaban, betrixaban, darexaban, edoxaban, otamixaban, rivaroxaban, alteplase, danaparoid, tinzaparin, and fondaparinux.

[0136] Thrombolytic agents include, but are not limited to, alteplase, reteplase, tenecteplase, saruplase, urokinase, anistreplase, monteplase, streptokinase, ancrod, brinase, and fibrinolysin.

[0137] Antithrombotic agents include anticoagulants and antiplatelet agents.

[0138] Anti-calcification agents include, but are not limited to, bisphosphonates, aluminum salts, glutaraldehyde, aminooleic acid, and metalloproteinase inhibitors.

[0139] Another object of the present invention is to provide a method for producing a medical device comprising one or more polyhydroxyurethanes (PHU), the method comprising step (a) or step (b) corresponding to thermal polymerization or UV polymerization, respectively, or a combination thereof: a) mixing a polycyclocarbonate of formula (2) with a polyamine of formula (3) and, optionally, a catalyst, and thermally polymerizing the mixture to obtain a polyhydroxyurethane based on formula (1); [ka] (wherein n, R1, R2 are as defined above), or b) mixing a polycarbamate hydroxyl derivative having two or more photoresponsive groups at the end or as pendant groups on the main hydrocarbon chain, a dithiol as a crosslinker, and a photopolymerization initiator, and then UV-polymerizing the resulting polyhydroxyurethane based on formula (9) [ka] (wherein u and R8 are as defined above).

[0140] The method of making a medical device comprising one or more polyhydroxyurethanes (PHUs) can optionally further comprise the addition of reinforcing particles or fibers in the mixing step (a) or the mixing step (b).

[0141] The mixture obtained in step (a) or step (b) can then be further processed by either casting, extrusion, co-extrusion, or 3D printing to obtain a medical device comprising polyhydroxyurethane according to formula (1) or formula (9), respectively, by thermal polymerization or UV polymerization, respectively.

[0142] The term "photoresponsive group," as used herein, refers to one or more vinyl or allyl groups.

[0143] The invention will now be described with reference to the following drawings, which are not intended to limit the scope of the invention as claimed. [Brief explanation of the drawings]

[0144] [Figure 1] FIG. 1 illustrates the synthesis of polypropylene glycol-based polyurethane. [Figure 2] FIG. 2 shows a tri-leaflet valve made by casting polyhydroxyurethane according to Example 22. [Figure 3a] FIG. 1 shows the synthesis of poly(ethylene glycol) bicyclocarbonate (PEGbisCC) in Example 1. [Figure 3b] FIG. 1 shows the thermal polymerization of PPGbisCC728 or PHU1 according to Example 2. [Figure 4] FIG. 1 shows UV synthesis of polyhydroxyurethane according to Example 5. [Figure 5] FIG. 1 shows PHU characterization by 1H NMR and FTIR-ATR spectra. [Figure 5a] FIG. 1 shows 1H NMR spectra of PPGDE and PPG bisCC. [Figure 5b] FIG. 1 shows FTIR-ATR spectra of PPGDE and bisCC PPG. [Figure 5c] FIG. 1 shows FTIR-ATR spectra of bisCC PPG and PHU. [Figure 5d] FIG. 1 shows the H NMR spectra of PTHFDE and PTHF bisCC. [Figure 5e] FIG. 1 shows FTIR-ATR spectra of PTHF and PTHFDE. [Figure 5f] FIG. 1 shows FTIR-ATR spectra of PTHFDE and PTHF bisCC. [Figure 5g] FIG. 1 shows FTIR-ATR spectra of PTHF bisCC and PHU. [Figure 5h] FIG. 1 shows 1H NMR spectra of PPG bisCC and PPG-allyl. [Figure 5i] FIG. 1 shows FTIR-ATR spectra of PPG-allyl and PHU A6b. [Figure 6] FIG. 1 shows a comparison of minocycline release over time between PTHF PHU, PPG PHU, PTHF-PU, and PPG-PU. [Figure 7] Figure 1 shows a comparison of the hemolysis % of PU and PPG-PHU: PPG-PHU and PTFH-PHU do not cause hemolysis. Medical-grade PU was used as a reference control. A hemolysis rate of less than 2% is considered non-hemolytic (dashed line). [Figure 8] Figure 1 shows a comparison of PU and PPG-PHU in a complement activation test: PPG-PHU does not activate the complement cascade in human whole blood. Medical-grade PU was used as a reference control, and zymosan was used as a positive control. [Figure 9] Figure 1 shows a comparison of PU, PPG-PHU, and PTHF-PHU in a contact-phase coagulation activation test: PPG-PHU and PTHF-PHU induce less contact-phase coagulation activation than medical-grade PU. Kaolin was used as a positive control. [Figure 10] Comparison of human platelet adhesion (UV absorption test) between PU and PPG-PHU. Human platelets do not adhere to PPG-PHU. Medical-grade PU was used as a reference control, and fibrinogen-coated polystyrene was used as a positive control. [Figure 11] This figure shows a comparison of PU and PPG-PHU in human plasma protein adsorption: PPG-PHU adsorbs less plasma proteins than medical-grade PU. [Figure 12]Figure 10: Dynamic rheology: storage and loss modulus of UV-cured PHU1 (bis CC PPG468) and PHU2 (bis CC PPG728). DETAILED DESCRIPTION OF THE INVENTION [Example]

[0145] Example 1: Synthesis of poly(ethylene glycol) bicyclocarbonate (PEGbisCC), 588 g / mole Poly(ethylene glycol) biscyclocarbonate was synthesized by coupling CO with PEG diglycidyl ether 500 g / mol (0.06 mol, 30 g, 1 equiv.) (Sigma Aldrich) using a two-component organocatalysis in combination with tetrabutylammonium iodide (TBAI, 0.03 mol, 0.05 equiv.) (Sigma Aldrich) as the catalyst in an 80 ml high-pressure cell (Autoclave, Top Industrie) equipped with a mechanical stirrer. The coupling reaction, shown in Figure 3, was carried out at 80 °C and 100 bar using 5 mol% of the catalyst ([TBAI]). These conditions ensured complete conversion of the terminal epoxy rings to the corresponding cyclic carbonates within 24 h.

[0146] After depressurizing the reactor, poly(ethylene glycol) biscyclocarbonate was collected and TBAI was removed by liquid-liquid extraction. First, poly(ethylene glycol) biscyclocarbonate was dissolved in 400 mL of chloroform and washed four times with 400 mL of Milli-Q water, and finally with 400 mL of Milli-Q water containing ammonium sulfate (10 g / L). The organic fraction was collected and rotavaped.

[0147] The same procedure can be used to prepare poly(propylene glycol) biscyclocarbonate using 380 g / mol (0.079 moles) of PPG diglycidyl ether (Sigma Aldrich) and 0.004 moles of tetrabutylammonium iodide (Sigma Aldrich).

[0148] Example 2: Polyhydroxyurethane (PHU) from polypropylene glycol biscyclocarbonate PPG bisCC (728 and 468) 728 and PHU 468 Thermal synthesis of ANPIA1bL6 and ANPIA1bL7 ANPIA1bL6:PPG bisCC 728 g / mol (1.92 mmol, 1.40 g, 1 equiv., prepared from PPGDE 640 g / mol (see Example 1)), 4-((4-aminocyclohexyl)methyl)cyclohexanamine (MBCHA, 0.38 mmol, 0.08 g, 0.2 equiv.) (Sigma Aldrich), and tris(2-aminoethyl)amine (TAEA, 1.02 mmol, 0.15 g, 0.53 equiv.) (Sigma Aldrich) were placed in a vial and magnetically stirred at 40° C. for 10 min. The resulting mixture was poured into a flat Teflon mold (5 × 2.5 × 0.1 cm) and placed in an oven at 70° C. for 24 h.

[0149] The same procedure was used with ANPIA1bL7:PPG bisCC 468 g / mol (prepared from PPGDE 380 g / mol) and by adjusting the amounts of the other reagents to maintain the same molar ratio (PPGDE / MBCHA / TAEA: 1 / 0.2 / 0.53).

[0150] Example 3: Thermal synthesis of polypropylene glycol-based polyurethane PU (L25C). A round-bottom flask equipped with a dry N2 purge was charged with 4,4'-methylenebis(cyclohexyl isocyanate) (1.08 g, 4.12 mmol) (Sigma Aldrich), triethanolamine (0.16 g, 1.07 mmol), and polypropylene glycol (1 g, 2.5 mmol) (Sigma Aldrich) and stirred to form a homogeneous solution. After 10 min, dibutyltin dilaurate (5 mg) was added, and the round-bottom flask was placed in an oil bath at 30 °C under vacuum. The reaction was allowed to proceed for 5 min, and the resulting melt was poured onto Kapton oil paper and pressed between two aluminum plates with 1 mm spacers at 80 °C and 5 psi for 3 h. After demolding, the sample was post-cured at 100 °C for 24 h.

[0151] Example 4: Thermal synthesis of polypropylene glycol-based polyurethane PU (L25D), also known as PPG-based PU. The PPG-based PU (L25D) was prepared by mixing 4,4′-methylenebis(cyclohexyl isocyanate) (0.82 g, 3.13 mmol) (Sigma Aldrich), triethanolamine (0.062 g, 0.41 mmol) (Sigma Aldrich), and polypropylene glycol (1 g, 2.5 mmol) (Sigma Aldrich) following the same procedure as in the synthesis of L25C in Example 3, except that a different ratio between 4,4′-methylenebis(cyclohexyl isocyanate) and PPG (1 / 0.8) was used.

[0152] Example 5: UV synthesis of PHU. A second route to obtain PHU networks is UV crosslinking. In this example, UV-PHU was synthesized in two steps according to the chemical reaction scheme shown in Figure 4.

[0153] The first step is the grafting of allyl functional groups onto the ends of the PPG bisCC chains. To obtain quantitative functionalization, allylamine was added in excess, and the reaction was catalyzed using 2,3,4,7,8,9-octahydropyrimido(1,2-a)azepine (DBU). The first step is also described in more detail in Example 16. The conversion of PPG bisCC to PPG-allyl is carried out by: 1 This was checked by H NMR spectroscopy (Figure 5h). The disappearance of the peaks at 4.8 and 4.5 ppm, which are assigned to the cyclocarbonate of PPG bisCC 468, was observed, as was the appearance of peaks corresponding to PPG-allyl (5.9–5.8 ppm and 5.2–5.1 ppm).

[0154] In the second step, the PPG-allyl obtained in the first step was reacted with the thiol group of 2,2-bis(3-sulfanylpropanoyloxymethyl)butyl 3-sulfanylpropanoate as a crosslinker and Irgacure 819 (BASF) as a photoinitiator under UV irradiation (365 nm). Thus, this step resulted in a PHU network. The second step is also described in more detail in Example 17.

[0155] Each PHU solution was prepared and poured into a flat Teflon mold, placed under a UV lamp for 15 min, and then placed in an oven at 70 °C overnight. After removing the mold, the product was analyzed by FTIP-ATR spectroscopy to identify the -OH and -NH groups (at 3200 cm), as shown in Figure 5i. -1 ~3500cm -1 ), and the CO (1711 cm -1 ), NH(1535cm -1 ), N-CO-O and COC (1256 cm -1 ) was characterized.

[0156] Example 6: Mechanical Properties - Comparison of Polypropylene Glycol-Based PU and Polypropylene Glycol-Based PHU Mechanical properties were measured at room temperature under dry conditions according to ASTM D638. The tensile strength and elongation of the HPU film were measured and compared with those of the PU film using a tester (Instron 5566, USA) at a speed of 10 mm / min, a pressure of 2.7 bar, and a static load cell of 10 N. The test involved placing a sample 1 cm wide and 3 cm long between two clamps and stretching the film until it broke.

[0157] The results are shown in Table 1. Other mechanical tests such as swelling and contact angle were also performed.

[0158] The swelling ratio of the dried networks was measured after immersion in phosphate buffered saline (PBS, pH = 7.2) for 24 hours. This solution was chosen because its pH (= 7.2) is close to physiological pH. The swelling ratio was determined using the following equation: Swelling = (W s,w -W i ) / W i ×100% In the formula, W s,w is the weight of the sample swollen with PBS, and W i is the weight of the dry sample.

[0159] Contact angles were measured using a contact angle meter DGD Fast / 60 and the software WINDROP (GBX Instruments) in surface energy mode. For each measurement, a 15 μl droplet of Milli-Q water was placed on the surface of the material. The contact angle was then determined after 180 seconds. Measurements were repeated three times at three different locations.

[0160] The results are also shown in Table 1.

[0161] [Table 1]

[0162] Example 7: Synthesis of polyhydroxyurethane as a crosslinked network First step: Synthesis of bis(cyclocarbonate) poly(propylene glycol) (PPG bisCC) 728 g / mol: An 80 ml high-pressure autoclave (Top Industrie) was charged with poly(propylene glycol) diglycidyl ether (PPGDE) 640 g / mol (0.047 mol, 30 g, 1 eq) (Sigma Aldrich) and tetrabutylammonium iodide (TBAI, 0.047 mol, 1.73 g, 0.05 eq) (Sigma Aldrich). The stainless steel reactor was then filled with 100 bar of CO2 (Air Liquide) and heated to 80 °C for 24 hours. After depressurizing the reactor, the resulting product was collected and TBAI was removed by liquid-liquid extraction. First, PPG bisCC was dissolved in 400 ml of chloroform and washed four times with 400 ml of Milli-Q water, and finally with 400 ml of Milli-Q water containing ammonium sulfate (10 g / l) (Sigma Aldrich). The organic fraction was collected and the solvent was removed by rotary evaporation. The same procedure was used with PPGDE 380 g / mol (0.079 mol) (Sigma Aldrich) and 0.079 mol of tetrabutylammonium iodide (Sigma Aldrich).

[0163] Figure 5a shows the results of PPGDE 640 g / mol and PPG bisCC after catalyst purification. 1 The H NMR spectra are shown in Figure 5b. The conversion of PPGDE to PPG bisCC is clearly demonstrated by the complete disappearance of the peaks corresponding to the epoxy groups in the range of 2.6 ppm to 3.2 ppm in the PPG bisCC spectrum, while the peaks assigned to the cyclocarbonate of PPG bisCC appear at 4.5 ppm and 4.8 ppm. As further evidence of the conversion, the FTR-ATR spectra of PPGDE and PPG bisCC are also shown in Figure 5b. The peak at 1250 cm assigned to the epoxy groups of PPGDE is -1 and 907 cm -1 The overall disappearance of the peak at 1797 cm -1 and 1162 cm -1 It is visible to the naked eye.

[0164] Second step: Synthesis of crosslinked poly(hydroxyurethane) networks: Bis(cyclocarbonate)poly(propylene glycol) (PPG bisCC) 728 g / mol (1.92 mmol, 1.40 g, 1 equiv., prepared from 640 g / mol of PPGDE), 4-((4-aminocyclohexyl)methyl)cyclohexanamine (MBCHA, 0.38 mmol, 0.08 g, 0.2 equiv.), and N′,N′-bis(2-aminoethyl)ethane-1,2-diamine (TAEA, 1.02 mmol, 0.15 g, 0.53 equiv.) were placed in a vial and magnetically stirred for 10 min at 40° C. The solution was then poured into a flat Teflon mold (5 × 2.5 × 0.1 cm) and left in an oven at 70° C. for 24 h before being characterized by FTIR-ATR spectroscopy.

[0165] The conversion of cyclocarbonate to PHU was checked and confirmed by IR spectroscopy. Figure 5c shows the FTIR-ATR spectra of bisCC PPG and PHU, which show a peak at 1797 cm corresponding to the cyclocarbonate functional group of PTHF bisCC. -1 and 1166 cm -1 The peak of -OH group and -NH group (3340 cm) completely disappeared. -1 ) and urethane group CO (1698cm -1 ), NH(1552cm -1 ), N-CO-O, and COC (1342 cm -1 ) is visible.

[0166] The peak assigned to the remaining unreacted cyclocarbonate was also at 1797 cm -1 It is visible to the naked eye.

[0167] The same procedure was used with 468 g / mol of PPG bisCC (prepared from 380 g / mol of PPGDE) and by adjusting the amounts of the other reagents to maintain the same molar ratios (2.99 mmol, 1.40 g, and 1 equivalent of BisCC PPG, 0.60 mmol, 0.13 g, and 0.2 equivalents of MBCHA, and 1.58 mmol, 0.23 g, and 0.53 equivalents of TAEA). The amines used were sometimes varied but used in the same molar ratios.

[0168] Example 8: Thermal synthesis of polytetrahydrofuran-based PHU First step: Synthesis of diepoxypolytetrahydrofuran (DEPTHF) with a molecular weight of 760 g / mol. [ka] Polytetrahydrofuran (PTHF) (20 g, 650 g / mol, 30 mmol) (Sigma-Aldrich) was dissolved in 250 mL of anhydrous toluene (Sigma-Aldrich) and dried by azeotropic distillation with toluene three times. The O-hydroxy end groups of PTHF were then converted to sodium alkoxide by reaction with sodium hydride (4 g) at 30 °C for 2 h. Eight equivalents of epichlorohydrin (ECH) (19 mL, 92.5 g / mol) were added to the solution, and the reaction was continued at 40 °C for 12 h. The excess ECH was then evaporated under vacuum to recover DEPTHF, which was then redissolved in dichloromethane (200 mL) (Sigma-Aldrich). The CHCl solution was extracted twice with water, followed by drying over anhydrous magnesium sulfate and filtration to remove the dichloromethane.

[0169] Figure 5d shows the results of PTHF and PTHF bisCC. 1 The H NMR spectra show that the conversion of PTHF to DEPTHF is confirmed by the appearance of peaks in the range of 2.6 ppm to 3.2 ppm, corresponding to epoxy groups. After 12 hours of reaction at 40 °C, near quantitative yields (91% to 97%) were observed.

[0170] Figure 5e shows the FTIR-ATR spectra of PTHF and PTHFDE. The functionalization of PTHF is indicated by the peak at 1250 cm, which corresponds to the epoxy group. -1 and 910cm -1 The appearance of a new peak at 3400 cm, which is attributed to the -OH group of PTHF, -1 This was confirmed by the disappearance of the peak.

[0171] Step 2: Synthesis of polytetrahydrofuran bis(cyclocarbonate) (PTHF bisCC) 850 g / mol: An 80 ml high-pressure autoclave was charged with 760 g / mol (25 g, 1 equivalent) of DEPTHF and 0.6 g (0.05 equivalent) of tetrabutylammonium iodide (TBAI). The stainless steel reactor was then filled with 100 bar of CO (Air Liquide) and heated to 80 °C for 24 hours. After depressurizing the reactor, the resulting product was collected and TBAI was removed from it by liquid-liquid extraction. Thus, PTHF bisCC was first dissolved in 400 ml of chloroform and washed four times with 400 ml of Milli-Q water, and finally with 400 ml of Milli-Q water containing ammonium sulfate (10 g / l) (Sigma-Aldrich). The organic fraction was collected and rotary evaporated.

[0172] Figure 5d shows the NMR analysis of PTHF and PTHF bisCC, which clearly confirms the complete conversion of PTHFDE to PTHF bisCC, as the peaks in the range of 2.6 ppm to 3.2 ppm corresponding to the epoxy groups completely disappear, while the peaks assigned to the cyclocarbonate of PTHF bisCC appear at 4.5 ppm and 4.8 ppm.

[0173] Figure 5f shows the FTR-ATR spectra of PTHFDE and PTHF bisCC. The peaks attributable to the cyclocarbonate group of PTHF bisCC appear at 1797 cm -1 and 1166 cm -1 It is recorded in.

[0174] Third step: Synthesis of linear poly(hydroxyurethane): PTHF bisCC 850 g / mol (1 equiv.) and 1,12-diaminododecane (1 equiv.) (Sigma Aldrich) were placed in a vial and magnetically stirred for 10 min at 120° C. The resulting solution was then poured into a flat Teflon mold (5 × 2.5 × 0.1 cm) and left in an oven at 40° C. for 24 h before being characterized by differential scanning calorimetry (DSC).

[0175] The glass transition temperature (Tg) and melting temperature (Tm) were determined by differential scanning calorimetry using an indium-calibrated TA Instruments DSC Q100 thermal analyzer. Curves were analyzed using TA Instruments Universal Analysis 2000 software. The procedure after sample insertion was as follows: equilibration at -80°C and a 2-minute isothermal step to 100°C with a 10°C / min ramp (first heating cycle), followed by a 2-minute isothermal step to -80°C with a 10°C / min ramp (first cooling cycle), followed by a 2-minute isothermal step to 150°C with a 10°C / min ramp (second heating cycle), followed by a 2-minute isothermal step to -80°C with a 10°C / min ramp (second cooling cycle), followed by a 2-minute isothermal step to 150°C with a 10°C / min ramp (third heating cycle), followed by a 2-minute isothermal step.

[0176] DSC analysis shows a Tg of around -61°C and a Tm in the range of about 8°C to about 14°C, which are characteristic of a semi-crystalline polymer.

[0177] Third step: Synthesis of crosslinked poly(hydroxyurethane) networks: PTHF bisCC 850 g / mol (1 g, 1 equiv.), 4-((4-aminocyclohexyl)methyl)cyclohexanamine (MBCHA, 0.05 g, 0.2 equiv.) (Sigma Aldrich), and N′,N′-bis(2-aminoethyl)ethane-1,2-diamine (TAEA, 0.09 g, 0.53 equiv.) (Sigma Aldrich) were placed in a vial and magnetically stirred for 10 min at 40° C. The solution was then poured into a flat Teflon mold (5 × 2.5 × 0.1 cm) and left in an oven at 70° C. for 24 h before being characterized by IR spectroscopy.

[0178] The conversion of cyclocarbonate to PHU was checked and confirmed by IR spectroscopy.

[0179] Figure 5f shows the FTIR-ATR spectra of PTHF bisCC and PHU, showing the peak at 1797 cm corresponding to the cyclocarbonate functional group of PTHF bisCC. -1 and 1166 cm -1 The peak of -OH group and -NH group (3340 cm) completely disappeared. -1 ) and urethane group CO (1698cm -1 ), NH(1552cm -1 ), N-CO-O, and COC (1342 cm -1 ) is visible.

[0180] Example 9: Loading and release of minocycline over time - Comparison of polypropylene glycol-based PU / polypropylene glycol-based PHU and polytetrahydrofuran-based PU / polytetrahydrofuran-based PHU Polypropylene glycol-based PU (380 g / mol), polytetrahydrofuran-based PU (650 g / mol), polypropylene glycol-based PHU (468 g / mol), and polytetrahydrofuran-based PHU (850 g / mol) were immersed in 1 mL of a 5 mg / mL minocycline solution in CH2Cl2 / C2H5OH (1:1) for 25 min.

[0181] A PHU disk (7 mm) was immersed in 1 mL of a 5 mg / mL minocycline solution in CH2Cl2 / C2H5OH (1:1) for 25 minutes.

[0182] The swollen disks (7 mm) were wiped with filter paper and dried in a vacuum oven at room temperature for 2 hours. For static release, the film was immersed in PBS buffer (1 mL) to determine the amount of minocycline loaded on the PHU disks. The released solution was collected and completely replaced with fresh medium. The minocycline content was then quantified and analyzed by HPLC spectrometry and compared with a standard concentration curve of minocycline in a 1:1 solution of CHCl / CHOH.

[0183] FIG. 6 shows that PTHF PHU and PPG PHU released 1 mg and 0.6 mg, respectively, after 6000 minutes, which was very good compared to PTHF-based PU and PPG-based PPU, which released 0.01 mg and no release, respectively, after 6000 minutes.

[0184] Example 10: Hemocompatibility test, coagulation test, and platelet adhesion test—Comparison of polypropylene glycol-based PU (PPG-PU) / polypropylene glycol-based PHU (PPG-PHU) and polytetrahydrofuran-based PU (PTHF-PU) / polytetrahydrofuran-based PHU (PTHF-PHU). This example describes five protocols for testing polymer blood compatibility, and further illustrates in Examples 11 to 15 that medical devices containing polyhydroxyurethane according to the present invention have higher blood compatibility than medical devices containing medical-grade polyurethane used as a reference, which induces less blood clotting and platelet adhesion.

[0185] Test materials used in the following tests: Polyurethane (PU) (medical grade urinary catheters, SpeediCath™, Coloplast and Carbothane™, ref PC3585A, Lubrizol), and 0.5 cm of PHU (PPG-PHU, PTHF-PHU) 2Polymer patch.

[0186] Before use, the UV-sterilized patches were washed with sterile saline under shaking for 3 days, with the washing solution changed daily.

[0187] a. Hemolysis test using washed red blood cells (RBC): direct contact material: Calculation of surface area to volume ratio and hemolysis rate follows standards ISO 10993-12, ISO 10993-4, and ASTM standard F756-13 Blood collection tube: sodium citrate vacutainer tube (3.2% citrate, BD Biosciences) Non-binding 48-well and 96-well plates for suspension cultures (polystyrene, Greiner Bio-One) Spectrophotometer Spectra max PLUS 384 (Molecular Devices).

[0188] protocol: 1. Blood is collected from healthy volunteers by venipuncture into citrated tubes. Blood is collected using a 21G needle. The first 2 ml is discarded. Blood samples are used within 1 hour of collection. 2. Centrifuge the whole blood at 100 x g for 15 minutes at room temperature (RT). 3. Remove the upper layer (platelet-rich plasma and white blood cell layer) 4. Resuspend the lower layer containing red blood cells in 2 volumes of phosphate-buffered saline (PBS) and mix by inverting the tube. 5. Centrifuge (Jouan B4i Series, S-40 High Throughput Swing-Out Rotor) at 900 × g for 10 min at room temperature (RT) for 15 min and discard the supernatant. 6. Repeat steps 7 and 8 twice for a total of three washes or until the supernatant is clear. 7. Remove the supernatant completely and use the red blood cells (RBC) for hemolysis test. 8. Resuspend 1 mL of RBC concentrate (cut off the tip of the tip) in 7 mL of PBS and mix by inverting the tube upside down. 9. Add 300 μl (microliters) of mixed RBC / PBS to wells containing PU or PHU patches and to empty wells (negative control) of a 48-well plate. For the positive control, resuspend 1 mL of RBC concentrate in 7 mL of distilled HO, using 300 μL per well. 10. Incubate for 1 or 3 hours at 37°C with gentle agitation at 100 rpm on an orbital shaker. 11. After the 3 hour incubation, transfer the sample to a test tube and centrifuge at 900 x g for 15 minutes at room temperature (Eppendorf benchtop centrifuge). 12. Transfer the supernatant to a new tube, avoiding any solid impurities while aspirating. Pipette 100 μl into a 96-well polystyrene plate. 13. Measure the absorbance at 545 nm in a multiwell plate reader according to ISO 10993-4 (optical hemoglobin detection method). 14. Calculate the percent hemolysis using the following formula: Hemolysis (%)=(OD 試料 -OD 陰性対照 ) / (OD 陽性対照 -OD 陰性対照 ) x 100

[0189] Materials with hemolysis greater than 5% are classified as hemolytic, between 5% and 2% as slightly hemolytic, and less than 2% as non-hemolytic (Totea G et al. Cent. Eur. J. Chem. 12(7) 2014 796-803).

[0190] b. Plasma protein adsorption assay material: Micro BCA Protein Assay Kit, ThermoFisher Ref 23235 Citrated plasma: Pooled normal human plasma, Cryopep (CCN-10) Polymer patch, PU (medical grade urinary catheters, SpeediCath™, Coloplast and Carbothane™, ref PC3585A, Lubrizol) and test PHU (PPG-PHU, PTHF-PHU), area 0.5 cm 2 Non-binding 48-well plates for suspension cultures (polystyrene, Greiner Bio-One) Spectrophotometer Spectra max PLUS 384 (Molecular Devices).

[0191] Conditions: Negative control: empty well; Positive control: cover glass

[0192] protocol: 1. Incubate an aliquot of plasma with the polymer patch in a 1.5 mL Eppendorf for 2 hours and 15 minutes at 37° C., ensuring that the patch is completely immersed in the plasma. 2. Transfer the polymer patches to a 48-well plate. 3. Wash gently with 300 μl of PBS. Proteins are extracted using 350 μl of 4.1% SDS in PBS at 4°C for 1 hour. The microBCA (bicinchoninic acid) assay is a highly sensitive method, detecting proteins down to 5 ng / ml. Bicinchoninic acid is a soluble form of Cu. + It binds ions with a 2:1 stoichiometry, resulting in high sensitivity. 5. Determine protein concentration by measuring absorbance at 562 nm in a spectrophotometer according to the manufacturer's instructions.

[0193] c. Contact phase coagulation assay (NaPTT test) material: 5-CLOT NAPTT Reagent, 5-Diagnostics (5D-51426) Kaolin (aluminum silicate hydroxide) (Sigma-Aldrich 1332-58-7) Stago STart(TM)4 Hemostasis Analyzer Citrated plasma: Pooled normal human plasma, Cryopep (CCN-10) CaCl2 solution

[0194] protocol The NaPTT reagent is a synthetic phospholipid platelet substitute intended to test activation of contact phase coagulation. The Stago Analyzer is a semi-automated system incorporating an electromechanical clot detection method (a viscosity-based detection system). Clot formation in citrated human standard plasma is measured by Ca 2+ It is catalyzed by the addition of ions as well as by phospholipids. Kaolin was used as a positive control for contact phase activation.

[0195] Conditions: Negative control: plasma alone; Positive control: 100 mg / mL kaolin

[0196] 1. Thaw an aliquot of plasma in a water bath at 37°C. 2. An aliquot of plasma is incubated with a polymer patch in a 1.5 mL Eppendorf tube, ensuring that the patch is completely immersed in the plasma, for 10 minutes at 37° C. As a positive control, 100 μl of plasma is incubated with 100 mg / mL kaolin in a 1.5 mL Eppendorf tube for 10 minutes at 37° C. 3. The plasma is then flash frozen in a dry ice / acetone bath (-78°C) and stored at -80°C until analysis. 4. On the day of the test, thaw the plasma at 37°C and immediately process it in the Stago STart™ 4 instrument. 5. Add 100 μl of pre-warmed plasma in the cuvette containing the coated metal beads to 37° C. pre-warmed Nodia reagent, then initiate clotting by adding pre-warmed calcium solution (8.3 mM). 6. The clotting end point is measured by the pendulum motion of beads aligned by an electromagnetic field. Such motion is affected by the viscosity of the plasma and stops when the viscosity is at its maximum, i.e., when plasma clotting occurs.

[0197] d. Platelet adhesion assay material Blood collection tube: sodium citrate vacutainer tube (3.2% citrate, BD Biosciences) Non-binding 24-well and 96-well plates for suspension cultures (polystyrene, Greiner Bio-One) Spectrophotometer Spectra max PLUS 384 (Molecular Devices) Human fibrinogen ref 341576 (Calbiochem) 2x pNPP buffer (0.1 M citrate buffer pH 5.4, 10 mM p-nitrophenyl phosphate, 2% Triton X-100)

[0198] protocol Conditions: Negative control: BSA-coated wells; Positive control: Fibrinogen-coated wells Platelet adhesion to surfaces is analyzed using the p-nitrophenyl phosphate (pNPP) test. The value obtained from this test is directly proportional to the number of platelets attached to the surface. The pNPP test measures the levels of alkaline phosphatase and acid phosphatase released during platelet lysis. Hydrolysis of pNPP, a substrate for these phosphatases, produces p-nitrophenol, which has an absorbance maximum at 405 nm and is proportional to the amount of platelets bound to the surface.

[0199] 1. Blood is collected from healthy volunteers by venipuncture using a 21 gauge needle into citrated tubes. The first 2 ml is discarded. Blood samples are used within 1 hour of collection. 2. Prepare platelet-rich plasma (PRP) by centrifugation at 100 x g. 3. Adjust the platelet density to 250,000 platelets / μl using autologous platelet-poor plasma (PPP). 4. Add the polymer patches to the BSA-coated wells of a 24-well plate. 5. 350 μl (microliters) of platelet-rich plasma (PRP) or PPP is incubated with the PU or PHU polymer patches or in empty BSA- or fibrinogen-coated wells under shaking conditions (100 rpm) at 37° C. for 45 minutes. 6. Wash the surface three times with saline. 7. Add 200 μL of pNPP buffer and incubate for 1 hour under shaking and light-protected conditions to achieve lysis of adherent platelets. 8. Add 140 μl of 2M NaOH solution to each well. 9. Transfer 100 μl to a 96-well plate and measure the absorbance at 405 nm in a spectrophotometer. 10. Subtract the background reading from the PPP incubation from the PRP reading. 11. Determine platelet count from a calibration curve performed with increasing platelet density.

[0200] e. Complement activation assay material: Blood collection tube: sodium citrate vacutainer tube (3.2% citrate, BD Biosciences) Zymosan (Merck ref 58856-93-2) Anti-C5a ELISA kit (ThermoFisher Scientific ref BMS2088) Non-binding 24-well plates for suspension cultures (polystyrene, Greiner Bio-One)

[0201] Conditions: Negative control: blood incubated in empty wells; Positive control: blood incubated with 10 μg / ml zymosan

[0202] protocol: 1. Add polymer patches to BSA-coated wells of a 24-well plate. 2. 400 μL of blood is incubated with the test polymer or zymosan for 30 minutes at 37° C. with shaking at 100 rpm. 3. Centrifuge the blood at 900 x g for 15 minutes at room temperature. Transfer the plasma to a new tube and centrifuge again for 15 minutes at 900 x g. Aliquot the plasma sample and keep frozen at -80°C until analysis. 4. Plasma levels of activated complement (C5a) are determined by ELISA according to the manufacturer's instructions.

[0203] Example 11: Comparison of % hemolysis of PU, PPG-PHU, and PTHF-PHU: Direct contact of human red blood cells with PPG-PHU or PTHF-PHU does not cause hemolysis.

[0204] 0.5cm made of polyurethane (PU) (medical grade urinary catheter, SpeediCath™, Coloplast) or polyhydroxyurethane (PHU): PPG (468g / mL)-PHU or PTHF (850g / mL)-PHU 2 The polymer patches were incubated with 300 μl of human red blood cell (RBC) concentrate for 1 or 3 hours at 37° C. under shaking (100 rpm).

[0205] The hemolysis rate was determined as described in step a of the test protocol in Example 10.

[0206] As shown in Figure 7, all of the hemolysis rates were below 2%, which is considered non-hemolytic. That is, neither the PPG-PHU polymer nor the PTHF-PHU polymer caused hemolysis. The hemolysis rates were similar to those obtained by direct contact with medical-grade PU, which was used as a reference control.

[0207] Example 12: Comparison of complement activation tests of PU and PPG-PHU: Complement activation is the immune system's response to inflammation and bacterial infection.

[0208] Direct contact of PPG-PHU with anticoagulated human whole blood does not activate the complement cascade.

[0209] 0.5cm made of polyurethane (PU) (medical grade urinary catheter, SpeediCath™, Coloplast) or polyhydroxyurethane (PHU):PPG (468g / mL)-PHU 2 The polymer patches were incubated with 400 μL of citrated human whole blood for 5, 15, and 30 minutes at 37° C. under 100 rpm shaking. Zymosan (1 mg / mL) was used as a positive control.

[0210] Plasma was separated and levels of activated complement 5 (C5a) were determined by ELISA as described in step e of the test protocol in Example 10.

[0211] As shown in Figure 8, PPG-PHU, like medical-grade PU, did not activate the complement cascade, in contrast to zymosan, which induced a clear increase in plasma C5a levels.

[0212] Example 13: Comparison of contact phase activation clotting tests of PU, PPG-PHU, and PTHF-PHU: The contact phase coagulation activation upon direct contact with human plasma is lower for PPG-PHU or PTHF-PHU than for medical grade PU.

[0213] 0.5 cm made of polyurethane (PU) (medical grade urinary catheter, SpeediCath™, Coloplast) or polyhydroxyurethane (PHU): PPG (468 g / mL)-PHU, PPG (728 g / mL)-PHU, or PTHF (850 g / mL)-PHU 2 The polymer patches were immersed in human citrated plasma for 10 minutes at 37° C. Kaolin (100 mg / mL) was used as a clot-activating stimulus (positive control).

[0214] Clot activation was assessed in a coagulometer during plasma recalcification using NaPTT reagent as described in step c of the test protocol in Example 10. As shown in Figure 9, PPG-PHU (made of two different molecular weights of PPG) induced less clot activation than medical-grade PU, as indicated by longer clotting times. The positive control, kaolin, led to significantly shorter clotting times than the polymer. The baseline corresponds to plasma not contacted with the polymer.

[0215] Example 14: Comparison of human platelet adhesion between PU and PPG-PHU (absorbance test): Human platelets do not adhere to PPG-PHU.

[0216] 0.5 cm made of polyurethane (PU) (medical grade Carbothane™, ref. PC3585A, Lubrizol) or polyhydroxyurethane (PHU): PPG (468 g / mL)-PHU or PPG (728 g / mL)-PHU 2 The polymer patches were immersed in human citrated platelet-rich plasma (PRP) for 45 minutes at 37° C. As a positive control for platelet adhesion, PRP was added to fibrinogen-coated polystyrene wells under shaking conditions (100 rpm) at 37° C. for 45 minutes.

[0217] Platelet adhesion was analyzed using the p-nitrophenyl phosphate (pNPP) assay as described in step b of the test protocol in Example 10.

[0218] As shown in Figure 10, human platelets did not adhere to either PPG-PHU or medical grade PU, whereas adhesion was observed with fibrinogen.

[0219] Example 15: Comparison of human protein absorption between PU and PPG-PHU: The adsorption of human plasma proteins was lower with PPG-PHU than with medical-grade PU.

[0220] 0.5 cm made of polyurethane (PU) (medical grade Carbothane™ ref. PC3585A, Lubrizol) or polyhydroxyurethane (PHU): PPG (468 g / mL)-PHU or PPG (728 g / mL)-PHU 2 The polymer patches were immersed in human citrated plasma at 37°C for 2 hours.

[0221] Protein adsorption was analyzed using the MicroBCA (bicinchoninic acid) assay as described in step b) of the test protocol in Example 10.

[0222] As shown in Figure 11, PPG-PHU (made of two different molecular weights of PPG) adsorbed less protein than medical-grade PU.

[0223] Example 16: Synthesis of allyl polypropylene glycol biscyclocarbonate PPG bisCC Mw 728 and 468 Allyl functional groups were grafted onto PPG bisCC 728 g / mol by mixing PPG bisCC 728 (1.30 mmol, 1 g, 1 equiv.), allylamine (3.25 mmol, 0.19 g, 2.5 equiv.), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU, 0.13 mmol, 0.02 g, 0.1 equiv.) in a vial at 40 °C for 3–4 days. The mixture was then pumped under vacuum for several hours to remove excess allylamine, yielding PPG with allyl groups at both ends of the PPG chain.

[0224] The same procedure was used with PPG bisCC 468 g / mol, keeping the same molar ratio.

[0225] Example 17: UV synthesis of polyhydroxyurethane (PHU): polypropylene glycol biscyclocarbonate PPG bisCC 728 PPG-allyl (1.19 mmol, 1 g, 1 equiv.), 2,2-bis(3-sulfanylpropanoyloxymethyl)butyl 3-sulfanylpropanoate (0.79 mmol, 0.31 g, 0.67 equiv.), and Irgacure 819 (0.19 mmol, 0.05 g, 0.1 equiv., predissolved in a few drops of chloroform) were mixed together and homogenized, then poured into a flat Teflon mold (5 × 2.5 × 0.1 cm) and placed under a UV lamp (Omnicure Series 2000, 200 W, Hg, wavelength = 365 nm) for 15 minutes. The mold was then placed in an oven at 70 °C for 24 hours. The same procedure was used with 468 g / mol of PPG bisCC, adjusting the amounts of the other reagents to maintain the same molar ratio. (PPG-allyl (1.72 mmol, 1 g, 1 equiv.), 2,2-bis(3-sulfanylpropanoyloxymethyl)butyl 3-sulfanylpropanoate (1.15 mmol, 0.45 g, 0.67 equiv.), and Irgacure 819 (0.115 mmol, 0.048 g, 0.1 equiv.)

[0226] PPGbisCC728 and PPGbisCC468 were then de-templated and characterized by various techniques. The conversion of bisCC PPG to PPG-PHU-allyl was 1 The conversion of PPG-PHU-allyl into a UV-cured PPG-PHU network was then checked and confirmed by IR spectroscopy. The FTIR-ATR spectra of the PPG-PHU-allyl and UV-cured networks are shown in Figure 5i. The disappearance of the peaks at 4.8 and 4.5 ppm, which are assigned to the cyclocarbonate of bisCC PPG, was visually observed, as was the appearance of peaks at 5.9–5.8 ppm and 5.2–5.1 ppm, which correspond to PPG-PHU-allyl. -1 (C=C), 991 cm -1 (CH), and 909 cm -1As further evidence of the conversion of bisCC PPG during the preceding step, peaks corresponding to the functional groups of PPG-PHU, i.e., -OH and -NH groups (3200 cm -1 ~3500cm -1 ), and the CO (1711 cm -1 ), NH(1535cm -1 ), N-CO-O, and COC (1256 cm -1 ) is also shown.

[0227] Example 18: Glass transition temperature - Comparison of thermally and UV cured PPGbisCC728 (PHU1) and PGbisCC468 (PHU2). Glass transition temperatures were determined by differential scanning calorimetry using a TA Instruments DSC Q100 thermal analyzer calibrated with indium. Curves were analyzed using TA Instruments Universal Analysis 2000 software. After sample insertion, the procedure was as follows: equilibration and isothermal step at -60°C for 2 minutes (cycle 1), heating to 120°C at a ramp of 10°C / min, followed by a 2-minute isothermal step (cycle 2), equilibration and isothermal step at -60°C for 2 minutes (cycle 3), and finally heating to 200°C at a ramp of 10°C / min (cycle 4). Thermograms were recorded during the fourth cycle.

[0228] Differential scanning calorimetry and thermogravimetric analysis were performed on UV-cured and heat-cured PHUs. The glass transition temperatures of UV-PHU1 and UV-PHU2 were found to be similar to those of heat-cured PHUs. In fact, as shown in Table 3, UV-PHU1 and UV-PHU2 had T g were −23.1°C and −4.7°C, while PHU1 and PHU2 were −23.1°C and −4.7°C, respectively, as shown in Table 2. g The TGA curves of UV-PHU1 and UV-PHU2 were similar to those of PHU1 and PHU2, i.e., showed thermal decomposition at 300-350°C.

[0229] Example 19: Equilibrium water absorption - comparison of thermally and UV cured PPGbisCC728 (PHU1) and PGbisCC468 (PHU2). The weight gain of the dried PHU networks was measured after immersion for 4, 8, and 24 hours in phosphate-buffered saline solution (PBS, pH = 7.2), which was chosen because its pH (= 7.2) is close to physiological pH (important when considering pharmaceutical applications).

[0230] The equilibrium water absorption (EWA) was determined using the following formula: EWA=(W s,w -W i ) / Wi×100% In the formula, W s,w is the weight of the sample swollen in PBS, and W i is the weight of the dry sample.

[0231] The EWA of thermally and UV-cured PPGbisCC728 (PHU1) and PGbisCC468 (PHU2) are reported in Tables 4 and 5, respectively.

[0232] Example 20: Rheological properties: Comparison of thermally and UV-cured PPGbisCC728 (PHU1) and PGbisCC468 (PHU2). Rheological properties were measured using two strain-controlled rheometers: one (ARES, Rheometric Scientific) was used for thermal dynamic rheology at 70 °C with the software TA Orchestrator, and the other (ARES G2, TA Instruments) was used for UV dynamic rheology at room temperature with the program TRIOS. The UV lamp was the same as that used for UV synthesis, i.e., an Omnicure Series 2000, 200 W, 365 nm.

[0233] Following crosslinking of both UV-cured PHUs prepared according to Example 17, rheological experiments were performed under UV conditions. The storage and loss moduli of UV-cured high-mass PHUs (UV-PH728 or UV-PHU1) and low-mass PHUs (UV-PH468 or UV-PHU2) are shown in Figure 12. The corresponding gel points for both UV-PHU1 and UV-PHU2 occurred after only 4 minutes, which is earlier than the corresponding thermally cured PHUs, i.e., 23 and 16 minutes for PHU1 and PHU2, respectively. Thus, crosslinked networks formed more rapidly under UV conditions than under thermal conditions, likely due to the higher reactivity of thiols toward the allyl functional groups. However, just as in the thermal approach, the gel point of UV-PHU1 (GP1) was lower than that of PHU2 (GP2), indicating that crosslinked networks formed more quickly with the lower-mass polymer. The higher storage modulus of PHU2 than that of PHU1 also indicates its higher degree of cross-linking, which is due to the smaller molar mass of the cross-linked internodes of PHU2.

[0234] Mechanical properties, such as Young's modulus, stress at break, and elongation at break, were measured under dry and hydrated conditions. Under dry conditions, UV-PHU1 was virtually identical to PHU1, and similar PHUs were obtained by the thermal crosslinking route (Note, Tables 2 and 3). However, this was not the case for UV-PHU2 and PHU2. In fact, PHU2 had a Young's modulus of 15.62 MPa, while UV-PHU2 exhibited a modulus of only 1.53 MPa. Its stress at break and elongation at break were also lower than those of PHU2.

[0235] As shown in Table 5, UV-PHU2 exhibited a higher T than UV-PHU1 in the hydrated state. gThe UV-cured PHU exhibits higher values ​​of Young's modulus as well as higher stress at break and elongation at break. The difference between the Young's modulus values ​​obtained under dry and wet conditions is also much smaller than that observed for the heat-cured PHU. This can be explained by the higher hydrophobic group content of the UV-cured PHU due to the insertion of allyl groups and 2,2-bis(3-sulfanylpropanoyloxymethyl)butyl 3-sulfanylpropanoate. In fact, the UV-cured PHU has as many -OH groups as the heat-cured PHU. However, the ratio between polar and nonpolar groups is significantly lower in the UV-cured PHU. This hypothesis, that the high hydrophobic group content prevents the interaction of water with the hydroxyl groups along the chain, is supported by the low EWA (equilibrium water absorption) obtained with the UV-cured PHU (around 10%, see Note, Table 5).

[0236] [Table 2]

[0237] [Table 3]

[0238] [Table 4]

[0239] [Table 5]

[0240] Example 21: 3D printing of UV-PHU1 and UV-PHU2 Due to the fast crosslinking rate of the UV-cured PHUs, the solutions were prepared using the same protocol as UV-PHU1 and UV-PHU2 in Example 17, in order to maintain the same conditions.

[0241] Sheets of PHU were printed on the heated plate of a 3D printer. 3D printing parameters included a flow rate of 0.03 ml / min on the plate, a maximum heating temperature of 70°C, and a UV light exposure percentage of 50%. UV-PHU2 was selected for printing testing because it exhibited the best mechanical properties. After removing the printed PHU from the plate, it was placed in a UV oven at 60°C for 10 minutes. The 3D-printed PHU with the best results is shown in Table 6 (3D-PHU1). In the table, 3D-PHU1 is compared with UV-PHU2, which is the same polymer but crosslinked without being 3D printed (Note, Example 17). 3D-PHU1 exhibits the same EWA as UV-PHU2 (only 10%) and much higher mechanical properties in both the dry and hydrated states. Therefore, these results pave the way for the preparation of medical devices made from UV-PHU.

[0242] [Table 6]

[0243] Example 22: Preparation of PHU-based prosthetic heart valve. A polyhydroxyurethane-based trileaflet prosthetic heart valve prototype was prepared by compression molding. The valve, measuring 24 mm with a leaflet thickness of 0.5 mm, is reproduced in Figure 2.

[0244] Bis(cyclocarbonate)poly(propylene glycol) (bisCC PPG) 728 g / mol (1.92 mmol, 1.40 g, 1 equiv.), 4-((4-aminocyclohexyl)methyl)cyclohexanamine (MBCHA, 0.38 mmol, 0.08 g, 0.2 equiv.), and N′,N′-bis(2-aminoethyl)ethane-1,2-diamine (TAEA, 1.02 mmol, 0.15 g, 0.53 equiv.) were placed in a vial and magnetically stirred for 10 minutes at 40° C. The solution was then poured into a mold and placed in an oven at 70° C. for 24 hours.

[0245] This valve prototype was then tested for its hydraulic properties in a pulse duplicator (Vivitro Labs, product number 18363) according to the requirements of ISO 5840. Flow and pressure data were obtained under simulated cardiac conditions.

[0246] Data were obtained assuming a mean arterial pressure of 100 mmHg and a heart rate of 70 beats per minute. Effective valve area (EOA) and regurgitant fraction were determined and compared with commercially available bioprostheses (Avalus™, Medtronic's Mosaic™, and Abbott's Trifecta™). The ISO standard for EOA (ISO standard >1.25 cm) was used. 2 ) and regurgitation rate percentage (ISO standard <10%) are obtained.

[0247] The project leading to this application has received funding from Interreg Euregio Meuse-Rhine (grant agreement name EMR100 PolyValve).

Claims

1. 1. An implantable medical device comprising one or more polyhydroxyurethanes (PHUs), wherein the one or more polyhydroxyurethanes (PHUs) are represented by formula (1) or formula (9): 【Chemical 1】 (In the formula, R １ is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, wherein one or more hydrocarbon groups of said hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, said hydrocarbon chain having from 2 to 60 carbon atoms; In the formula, R ２ is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and in which the hydrocarbon chain has at least 2 carbon atoms or is a mixture thereof; In the formula, R ３ and R ４ are the same or different and are H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. １～６ Alkyl; C having 1 to 6 carbon atoms １～６ represents alkoxyalkyl, and wherein n is an integer ≧1; However, as an exception, ３ and / or R ４ When represents a hydrogen atom, R １ teeth, 【Chemistry 2】 Instead, and, with the exception of R ３ and / or R ４ When represents a hydrogen atom, R ２ teeth, 【Chemistry 3】 Instead, In the formula, R ８ is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, in which the hydrocarbon chain has at least two carbon atoms or is a mixture thereof; and wherein u is an integer ≧1.

2. R １ 2. The medical device of claim 1, wherein is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof.

3. Polyhydroxyurethane (PHU) based on formula (1), wherein R １ is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof; R ２ The medical device of claim 1 , wherein is alkylene.

4. The polyhydroxyurethane according to formula (1) is Polycyclocarbonate of formula (2) 【Chemistry 4】 (In the formula, R １ is a carbon bond between cyclic carbonate rings or a straight or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 40 carbon atoms; In the formula, x is an integer from 1 to 4; wherein y is an integer of 2 or greater; Polyamines of formula (3) 【Chemistry 5】 (wherein z is an integer from 2 to 6, In the formula, R ２ is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and in which the hydrocarbon chain has at least two carbon atoms; In the formula, R ５ and R ６ are the same or different and are H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. １～６ represents alkyl, However, as an exception, ５ and / or R ６ When is hydrogen, R ２ teeth, 【Chemistry 6】 Instead, However, as an exception, ５ and / or R ６ When is a hydrogen atom, R １ teeth, 【Chemistry 7】 The medical device according to any one of claims 1 to 3, which is obtained by thermal polyaddition with (not).

5. The medical device of claim 4, wherein R 5 and R 6 are hydrogen.

6. The medical device according to claim 4 or 5, wherein the polyhydroxyurethane based on formula (1) is obtained by thermal polyaddition of a polycyclocarbonate of formula (2), and R 1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof.

7. The polycyclocarbonate of formula (2) is poly(propylene glycol)-bis-cyclocarbonate (PPGbisCC) of formula (5), wherein m is an integer ≧1; 【Chemistry 8】 The polyamine is 4,4'-methylene-bis-(cyclohexylamine) (MBCHA) of formula (4): 【Chemistry 9】 The medical device according to any one of claims 4 to 6, characterized in that:

8. The polyamine is a mixture of 4,4'-methylene-bis-(cyclohexylamine) of formula (4) and tris(2-aminoethyl)amine (TAEA) of formula (6). 【Chemistry 10】 The medical device according to any one of claims 4 to 7, characterized in that it is a combination of the above.

9. The polycyclocarbonate is a polytetrahydrofuran biscyclocarbonate of formula (8), wherein p is an integer ≧1; 【Chemistry 11】 The polyamine is 4,4'-methylene-bis-(cyclohexylamine) (MBCHA) of formula (4): 【Chemistry 12】 The medical device according to any one of claims 4 to 8, characterized in that:

10. The medical device according to claim 9, characterized in that the polyamine is a combination of 4,4'-methylene-bis-(cyclohexylamine) of formula (4) and tris(2-aminoethyl)amine (TAEA) of formula (6). 【Chemistry 13】

11. The polyhydroxyurethane (PHU) based on formula (9) is Polycarbonate of formula (2) 【Chemistry 14】 (In the formula, R １ is a carbon bond between cyclic carbonate rings or a straight or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 60 carbon atoms; In the formula, y is an integer of 2 or more, wherein X is an integer from 1 to 4; Polyamines of formula (15) 【Chemistry 15】 (In the formula, R ２ is a linear or branched unsaturated hydrocarbon chain having 2 to 40 carbon atoms, the linear or branched unsaturated hydrocarbon chain having at least a photoresponsive group; In the formula, R ５ is hydrogen, and R ６ is hydrogen, a C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain １～６ alkyl, and wherein z is an integer ≧1; to obtain a polycarbamate hydroxy derivative having a photoresponsive group, The polycarbamate hydroxy derivative having a photoresponsive group, Thiol of formula (16) and a photopolymerization initiator R ８ -(H) ｋ (16) (In the formula, R ８ is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and in which the hydrocarbon chain has at least 2 carbon atoms or is a mixture thereof; The medical device according to any one of claims 1 to 4, which is obtained by further reacting by UV polyaddition using a compound represented by the formula (I) above, wherein k is an integer of 2 or more.

12. The medical device of claim 11, wherein the thiol is a dithiol of formula (11). 【Chemistry 16】

13. R ５ and R ６ The medical device according to claim 11 or 12, wherein is hydrogen.

14. the photoresponsive group is an allyl group, The polycarbamate hydroxy derivative having a photoresponsive group is a polyallylcarbamate hydroxy derivative represented by formula (10): 【Chemistry 17】 In the formula, R １ is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, wherein one or more hydrocarbon groups of said hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, said hydrocarbon chain having from 2 to 60 carbon atoms; and the thiol is a dithiol of formula (11): 【Chemistry 18】 In the formula, R ８ is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and in which the hydrocarbon chain has at least 2 carbon atoms or is a mixture thereof.

15. The polyallylcarbamate hydroxy derivative is a polyallylcarbamate hydroxypropylene oxide of formula (14): 【Chemistry 19】 12. The medical device according to claim 11, wherein t≧1.

16. The medical device according to any one of claims 1 to 15, which is a catheter or an artificial heart valve.

17. A method for producing an implantable medical device comprising the polyhydroxyurethane of any one of claims 1 to 16, comprising the steps of: Step (a) or step (b) corresponds to thermal polymerization or UV polymerization, respectively: a) mixing a polycyclocarbonate of formula (2), a polyamine of formula (3), and optionally a catalyst, and obtaining a polyhydroxyurethane based on formula (1) by thermal polymerization; 【Chemistry 20】 (In the formula, R １ is a carbon bond between cyclic carbonate rings or a straight or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 40 carbon atoms; In the formula, R ２ is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and in which the hydrocarbon chain has at least two carbon atoms; In the formula, R ５ and R ６ are the same or different and are H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. １～６ represents alkyl, with the exception of R ５ and / or R ６ When is hydrogen, R ２ teeth, 【Chemical 21】 Instead, and, with the exception of R ５ and / or R ６ When is hydrogen, R １ teeth, 【Chemical 22】 Instead, In the formula, R ３ and R ４ are the same or different and are H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. １～６ Alkyl; C having 1 to 6 carbon atoms １～６ represents alkoxyalkyl, and wherein n is an integer ≧1; However, as an exception, ３ and / or R ４ When represents a hydrogen atom, R １ teeth, 【Chemical 23】 isn't it), b) mixing a polyvinyl carbamate hydroxy derivative having a photoresponsive group, of formula (10), with a thiol of formula (16) and a photoinitiator to obtain a polyhydroxyurethane based on formula (9) by UV polymerization; 【Chemistry 24】 (In the formula, R １ is a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, wherein one or more hydrocarbon groups of said hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, said hydrocarbon chain having from 2 to 60 carbon atoms; In the formula, R ８ is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, in which the hydrocarbon chain has at least two carbon atoms or is a mixture thereof; and wherein k is an integer ≧2; wherein u is an integer ≧1. or a combination of both.

18. A method for producing an implantable medical device comprising the polyhydroxyurethane of claim 17, comprising: A method wherein R 1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof, R 5 and R 6 are hydrogen, the thiol is a dithiol of formula (11), and R 8 is alkylene. 【Chemistry 25】

19. 16. A method of coating an implantable medical device comprising the polyhydroxyurethane of any one of claims 1 to 15, comprising: The surface of the medical device is coated with a polyhydroxyurethane based on formula (1) and / or formula (9). 【Chemical 26】 (In the formula, R １ is a carbon bond between cyclic carbonate rings or a straight or branched hydrocarbon chain, which can be unsubstituted or substituted, and one or more hydrocarbon groups of the hydrocarbon chain can be replaced with a heteroatom, a ketone, a cycloalkyl, a heterocycle, an aryl, or a heteroaryl, each of which can be substituted or unsubstituted, and the hydrocarbon chain has from 2 to 40 carbon atoms; In the formula, R ２ is aryl or heteroaryl, each of which may be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which may be unsubstituted or substituted, in which one or several hydrocarbon groups may be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which may be unsubstituted or substituted, and in which the hydrocarbon chain has at least two carbon atoms; In the formula, R ３ and R ４ are the same or different and are H, C having 1 to 6 carbon atoms in a linear or branched saturated hydrocarbon chain. １～６ Alkyl; C having 1 to 6 carbon atoms １～６ represents alkoxyalkyl, However, as an exception, ３ and / or R ４ When represents a hydrogen atom, R １ teeth, 【Chemical 27】 rather than and, with the exception of R ３ and / or R ４ When represents a hydrogen atom, R ２ teeth, 【Chemical Formula 28】 Instead, In the formula, R ８ is aryl or heteroaryl, each of which can be unsubstituted or substituted, or a linear or branched hydrocarbon chain, which can be unsubstituted or substituted, in which one or several hydrocarbon groups can be replaced by a heteroatom, a cycloalkyl, or a heterocycle, each of which can be unsubstituted or substituted, and in which the hydrocarbon chain has at least 2 carbon atoms or is a mixture thereof; wherein u is an integer ≧1; and wherein n is an integer ≧1.

20. The method of claim 19, wherein R 1 is polypropylene oxide, polyethylene oxide, polybutylene oxide, polytetrahydrofuran, or a mixture thereof.

21. The medical device according to any one of claims 1 to 15, further comprising a biologically active molecule, an antibacterial agent or an antithrombotic agent.

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