Medical devices formed from high purity polyurethane

Abstract

In some aspects, the present disclosure relates to a medical device, at least a portion of which comprises a polymeric region comprising a poly (urethane amide), the poly (urethane amide) comprising a urethane group (-O-CO-NH-) and an amide group (-CO-NH-). In other aspects, the present disclosure relates to a 3-D printing method comprising reacting (a) a urethane-based acrylamide reactant with (b) a multi-arm polymer, the present invention relates to a urethane-based acrylamide reactant comprising a residue of a C4-C10 hydroxyalkyl acrylamide and a diisocyanate residue selected from the group consisting of a residue of a C6-C20 aromatic diisocyanate, a residue of a C4-C20 aliphatic diisocyanate, and a residue of a C6-C20 cycloaliphatic diisocyanate, the urethane-based acrylamide reactant comprising a residue of a C4-C10 hydroxyalkyl acrylamide and a residue of a diisocyanate selected from the group consisting of a residue of a C6-C20 aliphatic diisocyanate, the multi-arm polymer comprises 3 or more polymer arms and 3 or more end groups selected from the group consisting of thiol groups, amino groups, and hydroxyl groups.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 428,008, filed on November 25, 2022, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to medical devices formed using novel polyurethane compositions and precursors thereof. Background Art

[0004] The medical device industry uses medical-grade polyurethanes extensively in the manufacture of long-term implantable devices, including catheters, artificial polymer discs, and coatings. Polyurethanes are prepared by reacting polyols (e.g., short-chain and polymeric diols, triols, and higher polyols) having two or more reactive hydroxyl groups per molecule with polyisocyanates (e.g., aliphatic, alicyclic, or aromatic diisocyanates, triisocyanates, and polyisocyanates) having two or more isocyanate groups per molecule in the presence of a tin catalyst. For example, a diisocyanate is reacted with a diol according to the following scheme:

[0005]

[0006] Where n is an integer, R is an organic moiety such as an aliphatic, alicyclic, or aromatic moiety, and R' is also an organic moiety such as an aliphatic or polymeric moiety. The mechanical properties of the polyurethane, such as hardness and stretchability, can be widely adjusted by varying the weight percentages of the hard segment (e.g., aromatic diisocyanate) and the soft segment (e.g., hydroxyl-terminated polymer).

[0007] However, isocyanate (-N=C=O) is an extremely water-sensitive functional group. In the presence of water, it can be converted into a primary amine, which further reacts with the free isocyanate to form a urea (-NH-CO-NH-) linkage. Furthermore, current polyurethane formulations use a slight excess of diisocyanate to reduce water content, which results in urea linkage formation, leading to unpredictable variations in molecular weight, thermal properties, and mechanical properties. This issue poses particular challenges to quality control associated with the extrusion process in medical device manufacturing.

[0008] For these reasons, there is a need for a new high-purity polyurethane formulation that is free of side reactions leading to the formation of undesirable species (such as urea groups), is biocompatible, easily scalable, has similar thermal and mechanical properties to current polyurethanes, and can serve as an alternative in medical devices (such as guide wires and catheters) that have problems with cracking after implantation. Summary of the Invention

[0009] In various embodiments, the present disclosure is directed to a medical device, at least a portion of which comprises a polymer region comprising a poly(urethane amide) comprising urethane groups (—O—CO—NH—) and amide groups (—CO—NH—).

[0010] In some embodiments applicable to any of the preceding embodiments, the poly(urethane amide) further comprises amine (—NH—) linkages.

[0011] In some embodiments applicable to any of the preceding embodiments, the poly(urethane amide) further comprises thioether (—S—) linkages.

[0012] In some embodiments applicable to any of the preceding embodiments, the poly(urethane amide) further comprises ether (—O—) linkages.

[0013] In some embodiments applicable to any of the preceding embodiments, the poly(urethane amide) comprises (a) a poly(urethane amide) selected from the group consisting of C6-C 20 Aromatic diisocyanate residue, C4-C 20 Aliphatic diisocyanate residues and C6-C 20 One or more diisocyanate residues of alicyclic diisocyanate residues, (b) C4-C 10 residues of hydroxyalkylacrylamides, and (c) residues of polythiols, polyamines or polyols.

[0014] For example, the one or more diisocyanate residues may be selected from the group consisting of residues of toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), naphthalene diisocyanate (NDI), toluidine diisocyanates including 1,6-hexamethylene diisocyanate (HDI), tetramethylene diisocyanate, 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane (isophorone diisocyanate), and 4,4′-diisocyanatodicyclohexylmethane (HDI). 12 MDI).

[0015] For example, the polythiol may be selected from thiol-terminated C2-C 20 Aliphatic molecules, thiol-terminated polyethers, thiol-terminated polycarbonates, thiol-terminated poly-ε-caprolactones, thiol-terminated polyolefins, thiol-terminated polyesters, thiol-terminated polyoxazolines, and thiol-terminated polyvinylpyrrolidone.

[0016] For example, the polyol may be selected from hydroxyl terminated C2-C20 Aliphatic molecules, hydroxyl-terminated polyethers, hydroxyl-terminated polycarbonates, hydroxyl-terminated poly-ε-caprolactones, hydroxyl-terminated polyolefins, hydroxyl-terminated polyesters, hydroxyl-terminated polyoxazolines, and hydroxyl-terminated polyvinylpyrrolidone.

[0017] For example, the polyamine can be selected from amino-terminated C2-C 20 Aliphatic molecules, amino-terminated polyethers, amino-terminated polycarbonates, amino-terminated poly-ε-caprolactones, amino-terminated polyesters, amino-terminated polyoxazolines and amino-terminated polyvinylpyrrolidone, amino-terminated polyolefins, amino-terminated polyesters, amino-terminated polyoxazolines and amino-terminated polyvinylpyrrolidone.

[0018] In some embodiments applicable to any of the preceding embodiments, the poly(urethane amide) has one of the following formulas (I), (II), or (III):

[0019] wherein m is an integer from 1 to 20, n is an integer from 1 to 1000, and R is selected from C1-C 20 Aliphatic part, C6-C 20 Aromatic part and C6-C 20 alicyclic moiety, and wherein R' is selected from C1-C 20 aliphatic portion, polyether portion, polycarbonate portion, polyε-caprolactone portion, polyolefin portion, polyester portion, polyoxazoline portion and polyvinylpyrrolidone portion.

[0020] In some embodiments, the poly(urethane amide) of formula (I) is synthesized by H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m The reaction between -NH-CO-C=CH2 and HS-R'-SH forms.

[0021] In some embodiments, the poly(urethane amide) of formula (II) is synthesized by H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m The reaction between -NH-CO-C=CH2 and H2N-R'-NH2 forms.

[0022] In some embodiments, the poly(urethane amide) of formula (III) is synthesized by H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m The reaction between -NH-CO-C=CH2 and HO-R'-OH forms.

[0023] In some embodiments applicable to any of the preceding embodiments, R is selected from the group consisting of benzene, toluene, diphenylmethylene, naphthalene, hexamethylene, tetramethylene, isophorone, and dicyclohexylmethylene moieties.

[0024] In some embodiments applicable to any of the preceding embodiments, the polymeric region corresponds to an entire medical device, a medical device coating, or a medical device component.

[0025] In some embodiments applicable to any of the preceding embodiments, the polymeric region further comprises a therapeutic agent.

[0026] In some embodiments applicable to any of the preceding embodiments, the polymeric region further comprises an additive.

[0027] Other embodiments of the present disclosure are directed to methods of manufacturing a medical device, comprising:

[0028] (a) In H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m A Michael addition reaction occurs between -NH-CO-C=CH2 and HS-R'-SH to form a poly(urethane amide) of formula (I):

[0029]

[0030] (b) In H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m A Michael addition reaction occurs between -NH-CO-C=CH2 and H2N-R'-NH2 to form a poly(urethane amide) of formula (II):

[0031] or

[0032] (c) In H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m A Michael addition reaction occurs between -NH-CO-C=CH2 and HO-R'-OH to form a poly(urethane amide) of formula (III):

[0033] wherein m is an integer from 1 to 20, n is an integer from 1 to 1000, and R is selected from C2-C 20 Aliphatic part, C6-C 20 Aromatic part and C6-C 20alicyclic moiety, and wherein R' is selected from C2-C 20 aliphatic portion, polyether portion, polycarbonate portion, polyε-caprolactone portion, polyolefin portion, polyester portion, polyoxazoline portion and polyvinylpyrrolidone portion.

[0034] Other embodiments of the present disclosure relate to a 3-D printing method for forming a medical device or medical device component, comprising reacting (a) a urethane-based acrylamide reactant comprising C4-C 10 The residue of hydroxyalkyl acrylamide and the residue of 20 Aromatic diisocyanate residue, C3-C 20 Aliphatic diisocyanate residues and C6-C 20 The multi-arm polymer comprises three or more polymer arms and three or more terminal groups selected from the group consisting of thiol, amino and hydroxyl groups.

[0035] The above and other aspects, embodiments, features and advantages of the present disclosure will become apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is a schematic diagram of a method of forming a poly(urethaneamide) according to three embodiments of the present disclosure.

[0037] Figure 2 is a schematic diagram of a method of forming a poly(urethaneamide) according to three additional embodiments of the present disclosure.

[0038] Figure 3 is a schematic diagram of a method of forming a poly(urethane amide) used in conjunction with a 3-D printing process according to other embodiments of the present disclosure.

[0039] Figure 4 is a schematic diagram of a method of forming another poly(urethaneamide) according to one embodiment of the present disclosure. DETAILED DESCRIPTION

[0040] In the present disclosure, instead of making polyurethane by using diisocyanate, short chain diol and polyether diol in combination with tin catalyst, hydroxyalkyl acrylamide molecules H2C=C-CO-NH-(CH2) are used. m-OH (wherein m is 1 to 20 (i.e., m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) reacts with a diisocyanate O=C=NRN=C=O (wherein R is an organic moiety, such as an aliphatic, alicyclic, or aromatic moiety) to produce a urethane-based acrylamide H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m -NH-CO-C=CH2.

[0041] Specific examples of diisocyanates used to form such urethane-based acrylamides include aromatic diisocyanates such as toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), naphthalene diisocyanate (NDI), and toluidine diisocyanate, and aliphatic and alicyclic diisocyanates such as 1,6-hexamethylene diisocyanate (HDI), tetramethylene diisocyanate, 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane (isophorone diisocyanate, IPDI), and 4,4′-diisocyanatodicyclohexylmethane (HDI). 12 MDI or hydrogenated MDI).

[0042] For example, in one specific embodiment, N-hydroxyethyl acrylamide (CAS#7646-67-5) is reacted with 1,6-hexamethylene diisocyanate (CAS#822-06-0) to form a urethane-based acrylamide as follows:

[0043]

[0044] Other options for forming urethane-based acrylamides are those using different diisocyanates, including 4′-methylenebis(cyclohexyl isocyanate) and 4,4′-methylenebis(phenyl isocyanate) for producing urethane-based acrylamides, such as Figure 2 The reaction is shown in Figure 2. Although acrylamide with a carbon-carbon double bond was used in the above reaction, other unsaturated substances with carbon-carbon triple bonds (such as propiolamido) can also be used. The terminal unsaturated groups of urethane-based acrylamides then provide a platform for making polyurethanes in an open system without worrying about any possible side reactions such as urea formation. In particular, using urethane-based acrylamides as building blocks, it can be polymerized with three different functional groups: thiol, amine, and hydroxyl groups.

[0045] For example, the terminal alkylene group of a urethane-based acrylamide can participate in various reactions, including various Michael addition reactions, including thiol-ene Michael addition reactions, amino-ene Michael addition reactions, and hydroxy-ene Michael addition reactions.

[0046] For example, a urethane-based acrylamide precursor can react with a polythiol precursor, HS-R'-SH, in a thiol-ene Michael addition reaction as shown below:

[0047]

[0048] Where n is 1 to 100.

[0049] In the presence of a suitable catalyst, the reaction can be accelerated. Different catalysts can be used for this purpose, including base catalysts (such as pentylamine and hexylamine (primary amines), triethylamine (tertiary amine)), phosphines (such as dimethylphenylphosphine (DMPP) and tris (2-carboxyethyl) phosphine (TCEP)), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). The reaction temperature can be, for example, in the range of room temperature to 50 ° C.

[0050] In an amino-ene Michael addition reaction (also known as an amino-ene click reaction), a urethane-based acrylamide precursor can react with a polyamine precursor, H2N-R'-NH2, to provide a polyamine urethane, as shown below:

[0051]

[0052] wherein n is 1 to 100. The reaction temperature can be in the range of, for example, room temperature to 50°C.

[0053] Urethane-based acrylamide precursors can react with polyols HO-R'-OH in a hydroxy-ene Michael addition reaction as shown below:

[0054]

[0055] wherein n is 1 to 100. The reaction temperature can be in the range of, for example, room temperature to 50°C.

[0056] In the above reaction, R' is an organic moiety, such as an aliphatic moiety or a polymeric moiety. For example, R' can be C1-C 20As another example, R' can be a polymeric moiety selected from various synthetic, natural, or synthetic-natural hybrid polymer moieties, including, for example, polyether moieties, including poly(alkylene oxides) such as (ethylene oxide) (PEO) (also known as polyethylene glycol or PEG) moieties, poly(propylene oxide) moieties, or poly(ethylene oxide-co-propylene oxide) moieties, polyphenylene ether moieties, poly(N-vinyl pyrrolidone) moieties, vinyl alcohol polymer and copolymer moieties such as poly(vinyl alcohol) moieties, ethylene-vinyl alcohol copolymer moieties, polyoxazolines, including poly(2-alkyl-2-oxazoline) moieties such as poly(2-methyl-2-oxazoline) moieties, poly(2-ethyl-2-oxazoline) moieties, oxazoline) moieties and poly(2-propyl-2-oxazoline) moieties, acrylic polymer moieties, polymethyl methacrylate moieties, poly(hydroxyethyl methacrylate) moieties, poly(hydroxyethyl acrylate) moieties, acrylic copolymer moieties such as 2-hydroxyethyl methacrylate and methyl methacrylate copolymer moieties, poly(allyl alcohol) moieties, PEG methyl ether acrylate moieties, PEG methyl ether methacrylate moieties, PNIPAAM moieties, polysaccharide moieties, polyetherimide moieties, polyolefin moieties, including polyethylene moieties, polypropylene moieties, polyisobutylene moieties, polybutadiene moieties, poly(4-methyl-1-pentene) moieties, and ethylene / propylene copolymers moiety, a cyclic olefin copolymer moiety, a halogenated polymer moiety such as a polyvinyl chloride moiety and a fluorine-containing polymer moiety such as a polytetrafluoroethylene moiety, a polyvinylidene fluoride moiety, a polyamide moiety such as a nylon moiety and a polyphthalamide moiety, a styrene polymer and copolymer moiety such as a polystyrene moiety and an acrylonitrile butadiene styrene polymer moiety, a copolymer moiety of styrene with an olefin monomer such as isobutylene, isoprene and butadiene, for example, a polystyrene-polyisobutylene-polystyrene (SIBS) moiety, a polystyrene-polyisoprene-polystyrene (SIS) moiety, a polystyrene-polybutadiene-polystyrene (SBS) moiety, a polycarbonate moiety, a polyester such as poly polyethylene terephthalate portion, polybutylene terephthalate portion, polyoxymethylene (polyacetal) portion, aliphatic polyketone portion, aromatic polyketone portion such as polyetheretherketone (PEEK) portion, siloxane polymer portion, including poly(dimethylsiloxane) and dimethylsiloxane copolymer portion, sulfone polymer portion such as polysulfone portion, polyethersulfone portion and polyphenylsulfone portion, polyphenylene sulfide portion, polyacrylonitrile portion, polyimide portion, polyetherimide portion, bioabsorbable polymer portion such as poly(lactic acid) portion, poly(glycolic acid) portion, poly(ε-caprolactone) portion, polyhydroxybutyrate valerate portion and bioabsorbable copolymer portion such as poly(lactic-co-glycolic acid) portion, etc.

[0057] In a thiol-ene Michael addition reaction according to the present disclosure, a urethane-based acrylamide precursor as described herein can be reacted with a polythiol precursor (e.g., a dithiol precursor, a trithiol precursor, or a higher polythiol precursor), for example, an aliphatic dithiol, a trithiol, or a higher polythiol precursor, such as a C1-C 20Alkyl dithiols, trithiols or higher polythiol precursors, and / or can be reacted with any of a variety of synthetic, natural or synthetic-natural hybrid polymeric dithiols, trithiols or polythiol precursors, including, for example, thiol-terminated polyethers, including thiol-terminated poly(alkylene oxides) such as thiol-terminated poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG), thiol-terminated poly(propylene oxide), thiol-terminated poly(tetramethylene oxide) (PEO), thiol-terminated poly(tetramethylene oxide) (PEO), thiol-terminated poly(propylene oxide), thiol-terminated poly(tetramethylene oxide) (PEO), thiol-terminated poly( ...ethylene oxide) (PEO), thiol-terminated poly(propylene oxide), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(propylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide) (PEO), thiol-terminated poly(ethylene oxide oxide)) or thiol-terminated poly(ethylene oxide-co-propylene oxide), and thiol-terminated polyphenylene ethers, thiol-terminated poly(N-vinyl pyrrolidone), thiol-terminated vinyl alcohol polymers and copolymers such as thiol-terminated poly(vinyl alcohol) and thiol-terminated ethylene-vinyl alcohol copolymers, thiol-terminated polyoxazolines, including thiol-terminated poly(2-alkyl-2-oxazolines) such as thiol-terminated poly(2-methyl-2-oxazoline), thiol-terminated poly(2-ethyl-2-oxazoline) and thiol-terminated poly(2-propyl-2-oxazoline), thiol-terminated acrylic polymers such as thiol-terminated alcohol-terminated polymethyl methacrylate, thiol-terminated poly(hydroxyethyl methacrylate), thiol-terminated poly(hydroxyethyl acrylate), thiol-terminated acrylic copolymers such as thiol-terminated copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate, thiol-terminated poly(allyl alcohol), thiol-terminated PEG methyl ether acrylate, thiol-terminated PEG methyl ether methacrylate, thiol-terminated PNIPAAM, thiol-terminated polysaccharides, thiol-terminated polyetherimides, thiol-terminated polyolefins including polyethylene, thiol-terminated polypropylene, thiol-terminated polyisobutylene, thiol-terminated thiol-terminated polybutadiene, thiol-terminated poly(4-methyl-1-pentene) and thiol-terminated ethylene / propylene copolymers, thiol-terminated cyclic olefin copolymers, thiol-terminated halogenated polymers such as thiol-terminated polyvinyl chloride and thiol-terminated fluoropolymers such as thiol-terminated polytetrafluoroethylene, thiol-terminated polyvinylidene fluoride, thiol-terminated polyamides such as thiol-terminated nylon and thiol-terminated polyphthalamide, thiol-terminated styrene polymers and copolymers such as thiol-terminated polystyrene and thiol-terminated acrylonitrile butadiene styrene polymers, styrene and olefin monomers such as isobutylene, isoprene and butadiene thiol-terminated copolymers of thiol-terminated olefins, for example thiol-terminated styrene-isobutylene-styrene (SIBS), thiol-terminated styrene-isoprene-styrene (SIS) copolymers, thiol-terminated styrene-butadiene-styrene (SBS) copolymers, thiol-terminated polycarbonates, thiol-terminated polyesters such as thiol-terminated polyethylene terephthalate, thiol-terminated polybutylene terephthalate, thiol-terminated polyoxymethylene (polyacetal), thiol-terminated aliphatic polyketones, thiol-terminated aromatic polyketones such as thiol-terminated polyetheretherketone (PEEK), thiol-terminated siloxane polymers,Including thiol-terminated poly (dimethylsiloxane) and thiol-terminated dimethylsiloxane copolymers, thiol-terminated sulfone polymers such as thiol-terminated polysulfone, thiol-terminated polyethersulfone and thiol-terminated polyphenylsulfone, thiol-terminated polyphenylene sulfide, thiol-terminated polyacrylonitrile, thiol-terminated polyimide, thiol-terminated polyetherimide, thiol-terminated bioabsorbable polymers such as thiol-terminated poly (lactic acid), thiol-terminated poly (glycolic acid), thiol-terminated poly (ε-caprolactone), thiol-terminated polyhydroxybutyrate valerate, thiol-terminated copolymers such as thiol-terminated poly (lactic-co-glycolic acid), etc.

[0058] A specific thiol-ene Michael addition reaction according to the present disclosure is shown in Figure 1 wherein the aliphatic dithiol precursor (specifically, C1-C 20 Alkyldithiol, more specifically 1,6-hexanedithiol) with urethane-based acrylamide precursors (specifically, It can be formed by reacting N-hydroxyethyl acrylamide and 1,6-diaminohexane as described above. Instead of or in addition to the aliphatic diol precursor, the reaction can also be performed using a polymer thiol precursor, such as one of those described above. By reacting with polymers of varying molecular weights, a range of properties can be imparted to the final product.

[0059] In the amino-ene Michael addition reaction according to the present disclosure, the urethane-based acrylamide precursor as described herein can be reacted with a polyamine precursor (e.g., a diamine precursor, a triamine precursor, or a higher polyamine precursor), for example, an aliphatic diamine, triamine, or a higher polyamine precursor, such as a C1-C 20alkyl diamines, triamines or higher polyamine precursors, and / or can be reacted with any of a variety of synthetic, natural or synthetic-natural hybrid polymeric diamines, triamines or higher polyamine precursors, including, for example, amino-terminated polyethers, including amino-terminated poly(alkylene oxides) such as amino-terminated poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG), amino-terminated poly(propylene oxide), amino-terminated poly(tetramethylene oxide) or amino-terminated poly(ethylene oxide-co-propylene oxide), and amino-terminated polyphenylene ethers, amino-terminated poly(N-vinyl pyrrolidone), amino-terminated vinyl alcohol polymers and copolymers such as amino-terminated poly(vinyl alcohol) and amino-terminated ethylene-vinyl alcohol copolymers, Amino-terminated polyoxazolines, including amino-terminated poly(2-alkyl-2-oxazolines) such as amino-terminated poly(2-methyl-2-oxazoline), amino-terminated poly(2-ethyl-2-oxazoline) and amino-terminated poly(2-propyl-2-oxazoline), amino-terminated acrylic polymers such as amino-terminated polymethyl methacrylate, amino-terminated poly(hydroxyethyl methacrylate), amino-terminated poly(hydroxyethyl acrylate), amino-terminated acrylic copolymers such as amino-terminated copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate, amino-terminated poly(allyl alcohol), amino-terminated PEG methyl ether acrylate, amino-terminated PEG methyl ether methacrylate, amino-terminated PNIPAAM, amino-terminated polysaccharides, amino-terminated polyetherimides, amino-terminated polyolefins, including polyethylene, amino-terminated polypropylene, amino-terminated polyisobutylene, amino-terminated polybutadiene, amino-terminated poly(4-methyl-1-pentene) and amino-terminated ethylene / propylene copolymers, amino-terminated cyclic olefin copolymers, amino-terminated halogenated polymers such as amino-terminated polyvinyl chloride and amino-terminated fluoropolymers such as amino-terminated polytetrafluoroethylene, amino-terminated polyvinylidene fluoride, amino-terminated polyamides such as amino-terminated nylon and amino-terminated polyphthalamide, amino-terminated styrene polymers and copolymers such as amino-terminated polystyrene and amino-terminated acrylonitrile butadiene styrene polymers, styrene and olefin monomers, amino-terminated copolymers of amino-terminated monomers such as isobutylene, isoprene and butadiene, for example amino-terminated styrene-isobutylene-styrene (SIBS), amino-terminated styrene-isoprene-styrene (SIS) copolymers, amino-terminated styrene-butadiene-styrene (SBS) copolymers, amino-terminated polycarbonates, amino-terminated polyesters such as amino-terminated polyethylene terephthalate, amino-terminated polybutylene terephthalate, amino-terminated polyoxymethylene (polyacetal), amino-terminated aliphatic polyketones, amino-terminated aromatic polyketones such as amino-terminated polyetheretherketone (PEEK), amino-terminated silicone polymers, including amino-terminated poly(dimethylsiloxane) and amino-terminated dimethylsiloxane copolymers,amino-terminated sulfone polymers such as amino-terminated polysulfone, amino-terminated polyethersulfone and amino-terminated polyphenylsulfone, amino-terminated polyphenylene sulfide, amino-terminated polyacrylonitrile, amino-terminated polyimide, amino-terminated polyetherimide, amino-terminated bioabsorbable polymers such as amino-terminated poly(lactic acid), amino-terminated poly(glycolic acid), amino-terminated poly(ε-caprolactone), amino-terminated polyhydroxybutyrate valerate, amino-terminated copolymers such as amino-terminated poly(lactic acid-co-glycolic acid), and the like.

[0060] A specific amino-ene Michael addition reaction according to the present disclosure is shown in Figure 1 wherein the aliphatic diamine precursor (specifically, C1-C 20 Alkyl diamine precursor, more specifically 1,6-hexanediamine) and urethane-based acrylamide (specifically, It can be formed by reacting N-hydroxyethyl acrylamide and 1,6-diaminohexane as described above. Instead of or in addition to the aliphatic diamine precursor, the reaction can also be carried out using a polymeric amine precursor, such as one of those described above. By reacting with polymers of varying molecular weights, a range of properties can be imparted to the final product.

[0061] In a hydroxy-ene Michael addition reaction according to the present disclosure, a urethane-based acrylamide precursor as described herein can be reacted with a polyol precursor (e.g., a diol precursor, a triol precursor, or a higher polyol precursor), for example, an aliphatic diol, triol, or a higher polyol precursor, such as a C1-C 20Alkyl diols, triols or higher polyol precursors, and / or can be reacted with any of a variety of synthetic, natural or synthetic-natural mixed polymer diols, triols or higher polyol precursors, including, for example, hydroxyl-terminated polyethers, including hydroxyl-terminated poly(alkylene oxides) such as hydroxyl-terminated poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG), hydroxyl-terminated poly(propylene oxide), hydroxyl-terminated poly(tetramethylene oxide) or hydroxyl-terminated poly(ethylene oxide-co-propylene oxide), and hydroxyl-terminated polyphenylene ethers, hydroxyl-terminated poly(N-vinyl pyrrolidone), hydroxyl-terminated vinyl alcohol polymers and copolymers such as hydroxyl-terminated poly(vinyl alcohol) and hydroxyl-terminated ethylene-vinyl alcohol copolymers. compounds, hydroxyl-terminated polyoxazolines, including hydroxyl-terminated poly(2-alkyl-2-oxazolines) such as hydroxyl-terminated poly(2-methyl-2-oxazoline), hydroxyl-terminated poly(2-ethyl-2-oxazoline) and hydroxyl-terminated poly(2-propyl-2-oxazoline), hydroxyl-terminated acrylic polymers such as hydroxyl-terminated polymethyl methacrylate, hydroxyl-terminated poly(hydroxyethyl methacrylate), hydroxyl-terminated poly(hydroxyethyl acrylate), hydroxyl-terminated acrylic copolymers such as hydroxyl-terminated copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate, hydroxyl-terminated poly(allyl alcohol), hydroxyl-terminated PEG methyl ether acrylate, hydroxyl-terminated PEG methyl ether methacrylate, hydroxyl-terminated PNIPAAM , hydroxy-terminated polysaccharides, hydroxy-terminated polyetherimides, hydroxy-terminated polyolefins including polyethylene, hydroxy-terminated polypropylene, hydroxy-terminated polyisobutylene, hydroxy-terminated polybutadiene, hydroxy-terminated poly(4-methyl-1-pentene) and hydroxy-terminated ethylene / propylene copolymers, hydroxy-terminated cyclic olefin copolymers, hydroxy-terminated halogenated polymers such as hydroxy-terminated polyvinyl chloride and hydroxy-terminated fluoropolymers such as hydroxy-terminated polytetrafluoroethylene, hydroxy-terminated polyvinylidene fluoride, hydroxy-terminated polyamides such as hydroxy-terminated nylon and hydroxy-terminated polyphthalamide, hydroxy-terminated styrene polymers and copolymers such as hydroxy-terminated polystyrene and hydroxy-terminated acrylonitrile butadiene styrene polymers, styrene and olefin monomers and copolymers. hydroxy-terminated copolymers of isobutylene, isoprene and butadiene, for example hydroxy-terminated styrene-isobutylene-styrene (SIBS), hydroxy-terminated styrene-isoprene-styrene (SIS) copolymers, hydroxy-terminated styrene-butadiene-styrene (SBS) copolymers, hydroxy-terminated polycarbonates, hydroxy-terminated polyesters such as hydroxy-terminated polyethylene terephthalate, hydroxy-terminated polybutylene terephthalate, hydroxy-terminated polyoxymethylene (polyacetal), hydroxy-terminated aliphatic polyketones, hydroxy-terminated aromatic polyketones such as hydroxy-terminated polyetheretherketone (PEEK), hydroxy-terminated siloxane polymers, including hydroxy-terminated poly(dimethylsiloxane) and hydroxy-terminated dimethylsiloxane copolymers,Hydroxy-terminated sulfone polymers such as hydroxy-terminated polysulfone, hydroxy-terminated polyethersulfone and hydroxy-terminated polyphenylsulfone, hydroxy-terminated polyphenylene sulfide, hydroxy-terminated polyacrylonitrile, hydroxy-terminated polyimide, hydroxy-terminated polyetherimide, hydroxy-terminated bioabsorbable polymers such as hydroxy-terminated poly(lactic acid), hydroxy-terminated poly(glycolic acid), hydroxy-terminated poly(ε-caprolactone), hydroxy-terminated polyhydroxybutyrate valerate, hydroxy-terminated copolymers such as hydroxy-terminated poly(lactic-co-glycolic acid), and the like.

[0062] The specific hydroxy-ene Michael addition reaction according to the present disclosure is shown in Figure 1 wherein a diol polymer precursor (specifically, a hydroxyl-terminated PEG precursor) is reacted with a urethane-based acrylamide precursor (specifically, It can be formed by reacting N-hydroxyethyl acrylamide and 1,6-diaminohexane as described above. By reacting with polymers of different molecular weights, a range of properties can be provided to the final product. For example, reacting with hydroxyl-terminated polyethylene glycols of different molecular weights can provide a range of hardness to the product. Instead of or in addition to the diol polymer precursor, the reaction can also be carried out with aliphatic diols such as C1-C 20 Alkyl glycol.

[0063] Other options for the reaction to form the urethane-based acrylamide precursor include those using different diisocyanates, including 4′-methylenebis(cyclohexyl isocyanate) (H12MDI) and 4,4′-methylenebis(phenyl isocyanate) (MDI), such as Figure 2 In addition, various polythiols, polyamines, and polyols can be used in the above-mentioned reaction to form urethane-based acrylamides, including thiol-terminated polyethers, thiol-terminated polycarbonates, thiol-terminated polyε-caprolactones, thiol-terminated polyisobutylenes, amino-terminated polyethers, amino-terminated polycarbonates, amino-terminated polyε-caprolactones, amino-terminated polyisobutylenes, other hydroxyl-terminated polyethers other than PEG (e.g., Figure 4 hydroxy-terminated poly(tetramethylene oxide) shown), hydroxy-terminated polycarbonate, hydroxy-terminated polyε-caprolactone, hydroxy-terminated polyisobutylene, and others as described above.

[0064] The novel polyurethanes described herein can be used to form a variety of polymeric regions for use in medical devices. These include polymeric regions corresponding to entire medical devices, polymeric regions corresponding to coatings on medical devices, and polymeric regions corresponding to components of medical devices.

[0065] Such medical devices include the following: guidewires, catheters such as balloon catheters, guide catheters, drug delivery catheters, guidewires such as percutaneous nephrolithotomy (PCNL) guidewires, occlusion devices such as (mesh on nitinol), prosthetic heart valves, endoscopes, anchors, embolic coils, stent paste, ports, pumps, tubes, ventricular assist devices, filters, baskets, or drug delivery devices.

[0066] Depending on the specific polyurethane and application, processing techniques that can be used include melt processing, solvent processing, and thermal processing (e.g., where a crosslinked network is formed). A crosslinked network is formed when the urethane-based acrylamide reactant has three, four, or more reactive unsaturated groups and / or when the other Michael addition reactant (e.g., an aliphatic-based reactant or a polymer-based reactant, particularly a multi-arm polymer-based reactant) has three, four, or more thiol groups, three, four, or more amino groups, or three or more hydroxyl groups.

[0067] Thus, a variety of techniques can be used to form poly(urethaneamide)-containing polymer regions according to the present invention.

[0068] For example, in some embodiments, thermoplastic processing techniques are used to form polymer regions of various shapes and sizes. Using these techniques, it is possible to form polymer regions by first providing a polymer melt comprising one or more poly(urethane amides) according to the present disclosure and one or more optional additives (as required), and then cooling the melt. The example of thermoplastic technology includes compression molding, injection molding, blow molding, spinning, vacuum forming and calendering, and is extruded into sheets, fibers, rods, pipes and other cross-sectional profiles of various lengths. Using these and other thermoplastic processing techniques, various polymer regions can be formed.

[0069] In some embodiments, solvent-based techniques are used to form polymer regions of various shapes and sizes. Using these techniques, polymer regions can be formed by first providing a polymer solution comprising a solvent, one or more poly(urethane amides) according to the present disclosure, and one or more optional additives (as needed), and then removing the solvent. The solvent ultimately selected will contain one or more solvent species, which are typically selected based on their ability to dissolve the one or more poly(urethane amides) and any optional additives, as well as other factors (including drying rate, surface tension, etc.). Examples of solvent-based techniques include solvent casting techniques, spin coating techniques, web coating techniques, solvent spraying techniques, dipping techniques, techniques involving coating via mechanical suspension (including air suspension), inkjet techniques, electrostatic techniques, and combinations of these processes, etc.

[0070] In some embodiments, polymer domains of various shapes and sizes can be formed from a fluid containing a reactive precursor, the fluid containing (a) one or more urethane-based acrylamide precursors as described herein and (b) one or more Michael addition precursors selected from one or more dithiol, trithiol or higher polythiol precursors as described herein, one or more diamine, triamine or higher polyamine precursors as described herein, or one or more diol, triol or higher polyol precursors as described herein, (c) one or more suitable solvents as needed, and (d) one or more optional additives as needed. The polymer domains can be formed from such reactive liquids, for example, using molding techniques, fiber spinning techniques, extrusion techniques, casting techniques, coating techniques, spraying techniques, laser-based 3D printing techniques, photo-based 3D printing, and the like. In some embodiments, for example, where the precursors react relatively quickly, the urethane-based acrylamide precursor and the Michael addition precursor are mixed and then immediately molded, spun, extruded, cast, coated, or sprayed.

[0071] Thus, processing applications of the present technology include 3-D printing that can be used to form various structures for medical devices. For example, Figure 3 As shown, a cross-linked network can be formed by reacting one or more urethane-based acrylamide precursors as described herein with a Michael addition reactant (specifically, a multi-arm polymer having four thiol groups). 3-D printers suitable for performing this process include digital light processing (DLP).

[0072] In some embodiments of the present invention, a fluid (e.g., a polymer melt, a polymer solution, or a fluid containing a reactive precursor, as described above) is applied to a substrate to form the polymer region. For example, the substrate may correspond to all or a portion of an implantable or insertable medical device (e.g., one of those described above, etc.) to which the polymer region is applied. The substrate may also be, for example, a template, such as a mold, from which the polymer region is removed after solidification. In other embodiments, such as fiber spinning, extrusion and coextrusion techniques, or particle spraying techniques, one or more polymer regions are formed from a polymer melt, a polymer solution, or a fluid containing a reactive precursor without the aid of a substrate.

[0073] Various optional additives may be added to the polymer regions of the present disclosure.

[0074] Such additives include one or more therapeutic agents, drug release modifiers, chemical stabilizers, leveling agents, colorants, plasticizers, wetting agents, catalysts, cross-linking agents, free radical initiators, lubricants, antioxidants, imaging agents (including radiopaque agents), MRI contrast agents, and echogenic agents.

[0075] Examples of therapeutic agents include, but are not limited to, antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, proliferation inhibitors, anti-restenotic agents, smooth muscle cell inhibitors, antibiotics, antimicrobial agents, analgesics, anesthetics, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, and drugs that can promote neointimal formation, such as endothelial cell growth.

[0076] Where a therapeutic agent is included, a wide range of therapeutic agent loadings may be used in conjunction with the medical devices of the present invention, with the therapeutically effective amount being readily determined by one of ordinary skill in the art and ultimately depending on factors such as the condition to be treated, the age, sex and condition of the subject, the nature of the therapeutic agent, the nature of the polymeric region, and the nature of the medical device.

Claims

1. A medical device comprising at least a portion thereof comprising a polymer region comprising a poly(urethane amide) comprising urethane groups (—O—CO—NH—) and amide groups (—CO—NH—).

2. The medical device of claim 1, wherein the poly(urethane amide) further comprises amine (-NH-) bonds.

3. The medical device of claim 1, wherein the poly(urethane amide) further comprises thioether (-S-) linkages.

4. The medical device of claim 1, wherein the poly(urethane amide) further comprises ether (-O-) linkages.

5. The medical device of any one of claims 1 to 4, wherein the poly(urethane amide) comprises (a) a poly(urethane amide) selected from the group consisting of C6-C 20 Aromatic diisocyanate residue, C4-C 20 Aliphatic diisocyanate residues and C6-C 20 One or more diisocyanate residues of alicyclic diisocyanate residues, (b) C4-C 10 residues of hydroxyalkylacrylamides, and (c) residues of polythiols, polyamines or polyols.

6. The medical device of claim 5, wherein the one or more diisocyanate residues are selected from the group consisting of residues of toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), naphthalene diisocyanate (NDI), toluidine diisocyanate, 1,6-hexamethylene diisocyanate (HDI), tetramethylene diisocyanate, 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane (isophorone diisocyanate), and 4,4′-diisocyanatodicyclohexylmethane (HDI). 12 MDI), wherein the polythiol is selected from the group consisting of thiol-terminated C2-C 20 aliphatic molecules, thiol-terminated polyethers, thiol-terminated polycarbonates, thiol-terminated poly-ε-caprolactones, thiol-terminated polyolefins, thiol-terminated polyesters, thiol-terminated polyoxazolines and thiol-terminated polyvinylpyrrolidones, wherein the polyol is selected from hydroxyl-terminated C2-C 20 aliphatic molecules, hydroxyl-terminated polyethers, hydroxyl-terminated polycarbonates, hydroxyl-terminated poly-ε-caprolactones, hydroxyl-terminated polyolefins, hydroxyl-terminated polyesters, hydroxyl-terminated polyoxazolines and hydroxyl-terminated polyvinylpyrrolidone, or wherein the polyamine is selected from amino-terminated C2-C 20 Aliphatic molecules, amino-terminated polyethers, amino-terminated polycarbonates, amino-terminated poly-ε-caprolactones, amino-terminated polyolefins, amino-terminated polyesters, amino-terminated polyoxazolines, and amino-terminated polyvinylpyrrolidone.

7. The medical device of any one of claims 1-6, wherein the poly(urethane amide) has one of the following formulas (I), (II), or (III): wherein m is an integer from 1 to 20, n is an integer from 1 to 1000, and R is selected from C2-C 20 Aliphatic part, C6-C 20 Aromatic part and C6-C 20 alicyclic moiety, and wherein R' is selected from C2-C 20 aliphatic portion, polyether portion, polycarbonate portion, polyε-caprolactone portion, polyolefin portion, polyester portion, polyoxazoline portion and polyvinylpyrrolidone portion.

8. The medical device of claim 7, wherein the poly(urethane amide) of formula (I) is H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m -NH-CO-C=CH2 and HS-R'-SH reaction between the poly (urethane amide) of formula (II) is formed by H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m -NH-CO-C=CH2 and H2N-R'-NH2, or wherein the formula (III) is formed by H2C=C-CO-NH-(CH2) m -O-CO-NH-R-NH-CO-O-(CH2) m -NH-CO-C=CH2 and The reaction between HO-R'-OH forms.

9. The medical device of any one of claims 7 or 8, wherein R is selected from benzene, toluene, diphenylmethylene, naphthalene, hexamethylene, tetramethylene, isophorone and dicyclohexylmethylene moieties.

10. The medical device of any one of claims 1-9, wherein the polymer region corresponds to the entire medical device.

11. The medical device of any one of claims 1-9, wherein the polymer region corresponds to a medical device coating.

12. The medical device of any one of claims 1-9, wherein the polymer region corresponds to a medical device component.

13. The medical device of any one of claims 1-9, wherein the polymeric region corresponds to an extruded medical device component.

14. The medical device of any one of claims 1-13, wherein the polymeric region further comprises a therapeutic agent.

15. The medical device of any one of claims 1-14, wherein the polymeric region further comprises an additive.

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