JP2019010535A - Coating for substrate - Google Patents

Abstract

To provide a hydrophilic coating for substrate including a medical device, an analysis device, and a separation device, and a manufacturing method of the coating.SOLUTION: There is provided a substrate having a surface having a hydrophilic coating containing a crosslinked copolymer of components A and B, and optionally-selected components C and D, in which the component A contains one or more kind of hydrophilic monomers containing one or more alkene and/or alkyne groups respectively, the component B contains one or more kinds of hydrophilic monomers containing 2 or more alkene and/or alkyne groups respectively, the component C contains one or more kinds of useful compounds containing one or more alkene or alkyne groups respectively, and the component D contains one or more kinds of low molecular weight crosslinking agents containing 2 or more functional groups respectively independently selected from thiol, alkene and alkyne group, and contains a component E containing one or more kinds of chemical materials, and the hydrophilic coating covalently bind to a surface of the substrate.SELECTED DRAWING: Figure 1

Description

  The present invention relates to hydrophilic coatings for substrates such as medical devices, analytical devices, separation devices, and other industrial articles including membranes and fabrics, and methods for producing such coatings.

  Medical devices such as catheters, guidewires, retractable sheaths and stents generally have a surface coating that is intended to increase the physical performance of the device and extend its life. Of particular interest are hydrophilic coatings that can also provide lubricity to the coated device.

  Lubricity describes the property of “slippery” or “smoothness”. Lubricious coatings are particularly useful for intracorporeal devices, where the lubricity results in reduced frictional forces as the device is introduced and moved into the body, resulting in increased patient comfort, as well as inflammation and tissue Reduce damage. Lubricious coatings differ in composition, but for use in an in vivo aqueous environment, such coatings are usually hydrophilic and soluble. In addition to reducing friction, hydrophilic coatings also tend to be resistant to protein adhesion so that they have the potential to result in reduction or elimination of thrombosis. Examples of hydrophilic coating materials include coatings based on polyvinylpyrrolidone, poly (ethylene oxide) and polyurethane, as described in US Pat. No. 4,642,267 and US Pat. No. 6,461,311.

  The production of hydrophilic, lubricious coatings for in vivo use will present various difficulties. Such coatings are often prepared using organic solvents, and the excess amount needs to be removed below the limit of toxicity according to current guidance and practice. The coated medical device must also be able to withstand sterilization without chemically and / or physically modifying the coating or peeling off the device.

  One approach to forming a hydrophilic coating is to physically entrap the functional hydrophilic polymer within a network of supported polymers that provides the necessary adhesion to the surface of the substrate. These coatings are often referred to as interpenetrating networks (IPNs), and generally a first functional polymer that imparts the desired properties to the coating (in this case hydrophilic), and a crosslinked polymeric network. It consists of a supported polymer that is chemically cross-linked to form. International Publication No. 2008/130604 sprinkles ionic monomers such as acrylic acid into a hydrophilic polymer network such as polyethylene glycol, and then forms a coating with high compressive strength and lubricity when expanded by sucking water. An IPN formed by polymerizing an ionic monomer to form an IPN said to be disclosed is disclosed.

  However, the disadvantage of having a hydrophilic polymer entrapped within the IPN rather than chemically bonding to the coating is that the hydrophilic polymer may gradually migrate out of the IPN. For this reason, the coating will gradually lose hydrophilicity. More importantly, however, the release of such particulates from the coating of the device in the body may pose a health risk to the patient. Thus, minimizing granulation is important for many medical devices. Note that granulation is not only a concern for IPNs-it is possible that all polymer coatings may form granules on the surface that can be released in vivo.

  In vivo release of particles / aggregates from the surface of the coating (known as granulation) can be difficult in design and coating manufacture, removal of the coating itself via delamination or separation from the substrate. While sometimes present, there is also the possibility of both the above mentioned health risks and coating durability issues.

  Considering durability, the coating can be removed from the substrate either by stepwise erosion of the substrate of the coating and / or separation of the coating from the surface of the substrate. Thus, one way to improve the durability of the coating is to strengthen the bond between the coating and the surface of the substrate. This can be achieved, inter alia, by treating the surface and coating it with a primer in order to achieve better adhesion between the coating and the surface.

An ideal primer is one that can be universally applied to any substrate. In this regard, the use of polydopamine as a primer since the discovery that simple immersion of the substrate in a dilute aqueous solution of dopamine buffered to alkaline pH results in spontaneous deposition of the polydopamine thin film on the substrate has been Has attracted a lot of attention. Messersmith et al. (Science, 2007, 318, pp. 426-430) describes polydopamine coatings, including metals, metal oxides, ceramics, synthetic polymers, and a wide range of other hydrophilic and hydrophobic materials. It has been shown that it can be formed on any type of substrate surface. As shown in WO 2011/005258, which discloses the attachment of amine functional polyethylene glycol (“PEG-NH ₂ ”) to polydopamine coatings, polydopamine coatings can be applied to synthetic polymers or biomolecules on surfaces. By using it as a platform for binding, it has provided a hydrophilic outer layer to prevent biofilm formation.

  Hydrophilic, and preferably lubricious, coatings can advantageously be modified to include pharmacologically active chemicals such as anticoagulants to impart further beneficial properties to the coating. . US 2003/0135195 describes a highly lubricious formed from a mixture of aliphatic polyurethane colloidal polymer, (N-vinylpyrrolidone methacrylate / dimethylaminoethyl copolymer) -PVP water dilution and dendrimer. Medical devices such as catheters having a hydrophilic, hydrophilic coating are taught. The literature is aliphatic in a solution of (N-vinylpyrrolidone methacrylate / dimethylaminoethyl copolymer) -PVP and active agent (eg heparin) in a mixture of dendrimer, water, N-methyl-2-pyrrolidone and triethylamine. It teaches that a coating can be applied to a device by immersing the device in a colloidal dispersion of polyurethane polymer. The literature also teaches that heparin can be included in the voids within the dendrimer and that the incorporated heparin will elute from the hydrophilic polymer material at a predetermined rate.

  WO 2004/020012 (Surmodics) discloses coating compositions used to increase the static friction of the surface of delivery devices, including medical devices. As an example, the polyether monomer component is considered to have methoxy poly (ethylene glycol) methacrylate that contains only one alkene group and cannot be crosslinked.

  In summary, there remains a need for improved hydrophilic coatings for surfaces, particularly the surfaces of devices that are inserted into the body. Preferably, such coatings are lubricious, durable, non-toxic, low granulating, sterilizable, biocompatible and easily applied to surfaces.

In one aspect, the invention is a substrate having a surface with a hydrophilic coating comprising components A and B, and optionally a crosslinked copolymer of components C and D, comprising:
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers each containing an alkyne group,
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups,
Component C, if present, contains one or more beneficial chemicals each containing one or more alkene or alkyne groups, and Component D, if present, from thiol, alkene and alkyne groups Comprising one or more low molecular weight crosslinkers each comprising two or more independently selected functional groups;
The crosslinked copolymer is formed by radical polymerization involving the alkene and / or alkyne groups of components A, B and C (if present) and the functional groups of component D (if present);
The hydrophilic coating optionally includes a component E that contains one or more beneficial chemicals, where component E includes components A, B, C (if present) and D (if present); Does not form a copolymer,
As well as providing a substrate in which the hydrophilic coating is covalently bonded to the surface of the substrate.

  As illustrated in the examples, in at least some embodiments, the coating of the present invention is highly lubricious and durable while being non-toxic, stable against sterilization and aging, and biocompatible. And it has been found that it is easy to apply to the surface of the substrate required in surface independent procedures.

FIG. 1 illustrates an embodiment of the present invention where the covalent bond between the surface of the substrate and the hydrophilic coating is formed via reaction of surface-bound radicals on the surface of the substrate. FIG. 2 illustrates an embodiment of the present invention where radicals are formed in the liquid phase and polymerization is initiated in the liquid phase and on the surface of the substrate to produce a covalently bonded hydrophilic coating of components A and B. . FIG. 3 shows various proposed structures for polydopamine. FIG. 4 shows a schematic representation of an embodiment of the present invention. FIG. 5 shows the contact angle measurement of a polydopamine primer coating on a glass slide pretreated using Method A or Method B (see Example 1a). FIG. 6 shows the UV absorbance of benzophenone as a function of concentration (see Example 2). FIG. 7 shows an FTIR analysis of a hydrophilic coating prepared according to Example 3.3. FIG. 8 shows the lubricity values over 15 cycles for a hydrophilic coating prepared according to Example 3.3.15. FIG. 9 shows the lubricity values over 15 cycles for a hydrophilic coating prepared according to Example 3.3.19. FIG. 10 shows the lubricity values over 15 cycles for a hydrophilic coating prepared according to Example 3.5. FIG. 11 shows the lubricity values over 15 cycles for a hydrophilic coating prepared according to Example 3.6. FIG. 12 shows an overlaid schematic spectrum of UV / visible absorption for benzophenone and thioxanthone.

Substrates Using the method of the present invention, any substrate may be coated with the hydrophilic coating of the present invention, but such coatings may be medical devices, analytical devices, separation devices, or membranes and fabrics. Is particularly useful for other industrial articles, including

  For the purposes of this patent application, the term “medical device” refers to a device within or outside the body, but more generally refers to a medical device within the body.

  Thus, in one embodiment, the substrate is a medical device. In another embodiment, the substrate is an internal medical device. In a further embodiment, the substrate is an extracorporeal medical device.

  Examples of intracorporeal medical devices that can be permanent or temporary intracorporeal medical devices include bifurcated stents, balloon expandable stents, stents including self-expanding stents, stent grafts including bifurcated stent grafts, vascular grafts Grafts including bifurcated grafts, dilators, vascular occluders, embolic filters, embolus removal devices, artificial blood vessels, endovascular monitoring devices, artificial heart valves, pacemaker electrodes, guide wires, cardiac leads, cardiopulmonary bypass circuits, cannulas, Plugs, drug delivery devices, balloons, tissue patch devices, blood pumps, patches, cardiac leads, continuous infusion lines, arterial lines, devices for continuous sub-membrane injection, feeding tubes, CNS shunts (eg brain Pleural shunt, VA shunt, or VP shunt), ventricular peritoneal shunts, ventricular atrial shunts, shunts and the like for portosystemic shunt and ascites.

  A further example of a medical device in the body that can be permanent or temporary is a catheter. Examples of catheters include central venous catheters, peripheral venous catheters, hemodialysis catheters, eg, implantable venous catheters useful for angiography, angioplasty, or ultrasound chaining in the heart or peripheral veins and arteries Venous catheter, coated catheter including coronary artery catheter, hepatic artery injection catheter, CVC (central venous catheter), peripheral venous catheter, peripherally inserted central venous catheter (PIC line), pulmonary artery catheter with flow direct balloon at the tip, Complete parenteral feeding catheters, home continuous catheters (eg home continuous intestinal catheters and home continuous urogenital catheters), peritoneal dialysis catheters, CPB catheters (cardiopulmonary bypass), urinary catheters and microcatheters (eg intracranial applications) ® emission) are catheters, such as including but is not limited.

  Medical devices include intravascular device delivery systems such as stents, occluders, valves, diagnostic or diagnostic catheters including spectroscopic or imaging functions, placement wires, catheters or sheaths.

  In certain embodiments, the substrate is a bifurcated stent, a stent including a balloon expandable stent and a self-expanding stent, a stent graft including a bifurcated stent graft, a graft including a vascular graft and a bifurcated graft, a dilator, a vascular occluder. Emboli filters, emboli removal devices, microcatheters, central venous catheters, catheters including peripheral venous catheters and hemodialysis catheters, artificial blood vessels, sheaths including retractable sheaths, vascular intrinsic monitoring devices, artificial heart valves, pacemaker electrodes, A medical device selected from the group consisting of a guide wire, cardiac lead, cardiopulmonary bypass circuit, cannula, plug, drug delivery device, balloon, tissue patch device and blood pump That.

  Examples of extracorporeal medical devices are non-implantable devices such as extracorporeal blood treatment devices and transfusion devices. The device may have, inter alia, neural, peripheral, cardiac, orthopedal, dermal and gynecological applications.

  In another embodiment, the stent described above can be used in cardiac, peripheral or neural applications. In another embodiment, the stent graft can be used in cardiac, peripheral or neurological applications.

  In another embodiment, the sheaths described above are insertion diagnostic and therapeutic sheaths, large and standard caliber intravascular delivery sheaths, arterial introducer sheaths with and without hemostasis control and with and without steering, microintroducer sheaths, It can be a dialysis access sheath, a guide sheath, and a percutaneous sheath, all of which may be for access to the carotid artery, kidney, forearm, transseptal, pediatric and micro-applications.

  In another embodiment, the medical device can be used for nerve, peripheral, cardiac, orthopedic, skin or gynecological applications.

  The analytical device can be a solid support for performing analytical processes such as, for example, chromatography or immunoassays, active chemical species or catalysts. Examples of such devices include slides, beads, well plates and membranes. The separation device can be a solid support for performing a separation process such as, for example, protein purification, affinity chromatography or ion exchange. Examples of such devices include filters and columns.

  The surface to be coated can be the entire surface of the substrate or only a part of the surface of the substrate. Certain substrates may have an outer surface and an inner surface that can be coated either or both. For example, a tubular substrate such as an artificial blood vessel has an inner surface or lumen that can be coated independently of the outer surface. Surfaces including internal and external surfaces may require a coating of only the internal surface. Conversely, only the outer surface may require a coating. With the method of the invention it is possible to apply different coatings, for example on the outer and inner surfaces of the substrate.

  In one embodiment, up to 99% of the surface of the substrate, for example up to 95%, 90%, 75%, 50% or 25%, is coated with a hydrophilic coating. In one embodiment, both the exterior and interior surfaces of the substrate are coated. In another embodiment, only the outer surface of the substrate is coated. In one embodiment, the substrate to be coated is tubular in shape and has an internal surface or lumen that can be coated independently of the external surface. The surface of the substrate can be porous or non-porous.

  In another embodiment, a portion of the substrate surface can be selectively coated by adjusting the composition of the substrate surface. For example, the surface of a substrate containing abstractable hydrogen can be coated, but the portion of the surface of the substrate that does not contain abstractable hydrogen atoms will not be coated with a hydrophilic coating within this invention. .

Substrate materials useful within the present invention Substrates may comprise and be formed from, inter alia, metals or synthetic or naturally occurring organic or inorganic polymers or ceramic materials.

  Thus, for example, polyolefin, polyester, polyurethane, polyamide, polyether block amide, polyimide, polycarbonate, polyphenylene sulfide, polyphenylene oxide, polyether, silicone, polycarbonate, polyhydroxyethyl methacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, rubber, silicone rubber, Synthetic or naturally occurring such as polyhydroxy acids, polyallylamines, polyallyl alcohols, polyacrylamides, and polyacrylic acids, styrenic polymers, polytetrafluoroethylene, and copolymers thereof, derivatives thereof and mixtures thereof, It can be formed from organic or inorganic polymers or materials. Some of these classes are available as both thermosetting polymers and thermoplastic polymers. In this disclosure, the term “copolymer” shall be used to refer to any polymer formed from two or more monomers, such as 2, 3, 4, 5, etc. Bioabsorbable materials such as poly (D, L-lactide) and polyglycolide and copolymers thereof are also useful. Useful polyamides include, but are not limited to, nylon 12, nylon 11, nylon 9, nylon 6/9 and nylon 6/6. Examples of some copolymers of such materials include polyether-block-amides available from Elf Atochem North America, Philadelphia, Pennsylvania under the trade name PEBAX®. Another suitable copolymer is a polyetheresteramide. Suitable polyester copolymers include, for example, polyethylene terephthalate and polybutylene terephthalate, polyester ethers and HYTREL.RTM. From Dupont, Wilmington, Delaware. Polyester elastomer copolymers such as those available under the RTM trade name. Block copolymer elastomers such as copolymers having styrene end blocks and intermediate blocks formed from butadiene, isoprene, ethylene / butylene, ethylene / propene, and the like may be used in the present disclosure. Other styrenic block copolymers include acrylonitrile-styrene and acrylonitrile-butadiene-styrene block copolymers. Also, block copolymers that are specific block copolymer thermoplastic elastomers that are block copolymers, wherein the block copolymer is composed of polyester or polyamide hard segments and polyether soft segments may be used in the present disclosure. Other useful substrates are chlorine-containing polymers such as polystyrene, poly (methyl) methacrylate, polyacrylonitrile, poly (vinyl acetate), poly (vinyl alcohol), polyvinyl chloride, polyoxymethylene, polycarbonate, polyamide, polyimide, Polyurethanes, phenolic resins, aminoepoxy resins, polyesters, silicones, cellulose-based plastics, and rubbery plastics.

  Combinations of these materials can be used with and without crosslinking.

  The polymer substrate may optionally be blended with fillers and / or colorants. Accordingly, suitable materials include colored materials such as colored polymer materials.

  In one embodiment, the biocompatible material is a polyether block copolymer such as PEBAX®.

  Fluorinated polymers such as fluoropolymers such as expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluorocarbon copolymers (e.g. tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymers), copolymers of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE), and combinations of the above with and without cross-linking between polymer chains, drawn polyethylene, polyvinyl chloride, polyurethane, silicone, polyethylene , Polypropylene, polyurethane, polyglycolic acid, polyester, polyamide, elastomers and mixtures, blends and copolymers or derivatives thereof There is a possibility that.

  Other suitable substrates include proteins such as silk and wool, agarose and alginate. Certain metals and ceramics may also be used as the substrate according to the present invention. Suitable metals include, but are not limited to, biocompatible metals, titanium, stainless steel, high nitrogen stainless steel, gold, silver, rhodium, zinc, platinum, rubidium, copper, and magnesium, and mixtures thereof. There is nothing. Suitable alloys include cobalt-chromium alloys such as L-605, MP35N, and Elgiloy, nickel-titanium (such as nitinol) alloys, tantalum, and niobium alloys such as Nb-1% Zr. Ceramic substrates may include, but are not limited to, silicone oxide, aluminum oxide, alumina, silica, hydroxyapatite, glass, calcium oxide, polysilanol, and phosphorous oxide.

  In one embodiment, the biocompatible metal is a nickel-titanium alloy such as nitinol.

Hydrophilic Coating The hydrophilic coating of the present invention comprises components A and B and optional components C, D and E as described below.

Component A
Component A contains one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers, each containing an alkyne group, also now become the suitably. The alkene and / or alkyne group of component A participates in the radical polymerization reaction to form a copolymer. Preferably, component A comprises one or more C ₂ -C ₁₆ hydrophilic monomers each containing one or more alkene groups, also now become more suitably.

Carbon atoms of an alkene and / or alkyne groups, it should be noted that should be included within the limits of C ₂ -C _16. The term “hydrophilic monomer” is well known to those skilled in the art and broadly encompasses monomers that have an affinity for water and tend to be soluble in water and polar solvents. Polar solvents include, but are not limited to, alcohols (methanol, ethanol, propanol, isopropanol, etc.), tetrahydrofuran, DMF, DMSO, ethyl acetate and dioxane, and all aqueous solutions of the aforementioned solvents.

In one embodiment, component A comprises one or more C ₂ -C ₁₆ hydrophilic monomers each containing one alkene group or one alkyne group, also now become the suitably. In another embodiment, component A comprises one or more C ₂ -C ₁₆ hydrophilic monomers each containing one alkene group, also now become the suitably. The alkene and / or alkyne group can be a terminal group or a non-terminal group.

  Component A typically serves as a structural monomer that will polymerize to form a polymer with good structural stability and durability. Thus, the higher the proportion of component A in components A, B and optional C and / or D copolymer, the more durable the copolymer may be than expected. However, if the proportion of component A is too high, the resulting copolymer and coating may lose flexibility.

The hydrophilic nature of the monomer may be derived from the functional group it has (other than alkene or alkyne). Such functional groups may be in terminal or pendant positions or can form intramolecular bonds. In this disclosure, the term “hydrophilic monomer comprising a functional group” is understood to mean a hydrophilic monomer comprising a functional group and / or a pendant or terminal functional group that may be essential to the composition of the monomer (ie, an intra-monomer linker). I want. Thus, in one embodiment, the one or more components A comprise, preferably consist of, and consist of one or more C ₂ -C ₁₆ hydrophilic monomers each containing an alkene and / or alkyne group. One or more are selected from ester, ether, carboxyl, hydroxyl, thiol, sulfonic acid, sulfate, amino, amide, phosphate, keto and aldehyde groups. Like the alkene and / or alkyne groups, it is noted that it is preferable contained within the limits of the additional group C ₂ -C _16. The functional group can be neutral or charged. For example, the amino group can be neutral or can form a quaternary ammonium compound by protonation or another substitution. Similarly, carboxyl and phosphate groups can exist in a deprotonated form and can therefore be changed to negative. Also contemplated are zwitterionic hydrophilic monomers such as zwitterionic hydrophilic monomers having a betaine or phosphorylcholine moiety. In another embodiment, component A comprises one or more alkenes and / or alkyne groups, one or more further C ₂ of 1 or more, each containing carboxyl groups -C ₁₆ hydrophilic monomers, also preferably from now Become. In a further embodiment, component A comprises one or more C ₂ -C ₁₆ hydrophilic monomers each containing one alkene group and one carboxyl group, also now become the suitably.

The hydrophilic monomer can be linear, cyclic or branched. In one embodiment, component A is one or more alkenes and / or one or more C each containing an alkyne group _{2 ~C 16, C 2 ~C 15} , C 2 ~C 14, C 2 ~C 13, _{C 2 ~C 12, C 2 ~C} 11, C 2 ~C 10, C 2 ~C 9, C 2 ~C 8, C 2 ~C 7, C 2 ~C 6, C 2 ~C 5, C 2 _{~C 4, C 2 ~C 3,} C 3 ~C 16, C 3 ~C 15, C 3 ~C 14, C 3 ~C 13, C 3 ~C 12, C 3 ~C 11, C 3 ~C ₁₀ , C _{3 to} C ₉ , C _{3 to} C ₈ , C _{3 to} C ₇ , C _{3 to} C ₆ , C _{3 to} C ₅ , C _{3 to} C ₄ , C ₂ , C ₃ , C ₄ , C ₅ , _{C 6, C 7, C 8} , C 9, C 10, C 11, C 12, C 13, C 14, C 15, or comprises a C ₁₆ hydrophilic monomers, also now become the suitably. In one embodiment, the hydrophilic monomer of component A each contains one or more alkene groups. In another embodiment, the hydrophilic monomer of component A each contains one or more alkyne groups. Preferably, the hydrophilic monomer of component A contains an alkene group.

In one embodiment, component A comprises one or more alkene and or one or more C ₂ -C ₁₆ hydrophilic monomers containing an alkyne group respectively, also now happens Preferably, the one or more hydrophilic Mw of a sex monomer is 40-500 Da, for example, 40-100 Da, 40-90 Da, or 70-90 Da.

  Preferably component A contains only one alkene or alkyne group. Thus, no crosslinks will form within the copolymer of components A, B and optional C and / or D.

  In an embodiment, component A contains a carboxylate group.

  Specific examples of component A include acrylic acid, methacrylic acid, vinyl alcohol, allyl alcohol, vinylamine, allylamine, polyethylene glycol acrylate, oligoethylene glycol acrylate, 2-hydroxyethyl methacrylate (HEMA), acrylamide, methacrylamide, N-vinyl. Examples include, but are not limited to, pyrrolidone, glycidyl acrylate, glycidyl methacrylate, and 4-styrene sulfonate. In one embodiment, component A is acrylic acid. In another embodiment, component A is methacrylic acid. In a further embodiment, component A comprises and preferably consists of acrylic acid and / or methacrylic acid.

Examples of C ₂ -C ₉ hydrophilic monomers are shown below. The following charged hydrophilic polymer salts are also useful within the present invention.

Examples of C ₂ hydrophilic monomers

Examples of C ₃ hydrophilic monomers

Examples of C ₄ hydrophilic monomers

Examples of C ₅ hydrophilic monomer

Examples of C ₆ hydrophilic monomers

Examples of C ₇ hydrophilic monomer

Examples of C ₈ hydrophilic monomer

Examples of C ₉ hydrophilic monomer

Component B
Component B comprises and preferably consists of one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups. The alkene and / or alkyne group of component B participates in the radical polymerization reaction to form a copolymer. In an embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each containing two or more alkene groups.

  The term “hydrophilic polymer” is well known to those skilled in the art and broadly encompasses polymers that have an affinity for water and tend to be soluble in water and polar solvents. Polar solvents include, but are not limited to, alcohols (methanol, ethanol, propanol, isopropanol, etc.), tetrahydrofuran, DMF, DMSO, ethyl acetate and dioxane, and all aqueous solutions of the aforementioned solvents.

  Component B has hydrophilic properties. It will also typically provide lubricity to components A, B and optional C and / or D copolymers. Thus, the higher the proportion of component B in components A, B and optional C and / or D copolymers, the more lubricious the coating will be.

  In one embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each containing two alkene and / or alkyne groups. In another embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each containing two alkene groups.

  In one embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, said alkene and / or alkyne group being terminal Alkene and / or alkyne groups. It should be noted that component B may independently contain alkene or alkyne groups and can be both alkene functionalized and alkyne functionalized. Accordingly, a hydrophilic polymer “comprising two or more alkene and / or alkyne groups” is intended to include hydrophilic polymers comprising one alkene group and one alkyne group.

  Hydrophilic polymers each containing two or more alkenes and / or alkyne groups can be formed by functionalizing preformed hydrophilic polymers having alkene or alkyne groups. Such preformed polymers must have suitable reactive groups such as hydroxyl, amino, thiol, azide, oxirane, alkoxyamine and / or carboxyl groups. Such reactive groups can be at the ends of the hydrophilic polymer, along the backbone of the hydrophilic polymer, or at both positions. The preformed polymer with reactive groups can then be reacted with an alkene or alkyne functionalized material with complementary reactive groups such as carboxylic acids, activated esters or acid chlorides, amines or alcohols.

  In one embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is hyaluronic acid, a hyaluronic acid derivative , Poly-N-vinylpyrrolidone, poly-N-vinylpyrrolidone derivatives, polyethylene oxide, polyethylene oxide derivatives, polyalkylene glycols, polyether derivatives (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG ) Or polypropylene glycol (PPG) derivatives), polyglycidol, polyvinyl alcohol, polyvinyl alcohol derivatives, polyacrylic acid, polyacrylic acid derivatives, silicone, silicone derivatives, polysaccharides, polysaccharides Conductors, polysulfobetaines, polysulfobetaine derivatives, polycarboxybetaines, polycarboxybetaine derivatives, polyalcohols such as polyHEMA, polyacids such as alginate, dextran, agarose, poly-lysine, polymethacrylic acid, polymethacrylic acid derivatives, Polymethacrylamide, polymethacrylamide derivative, polyacrylamide, polyacrylamide derivative, polysulfone, polysulfone derivative, sulfonated polystyrene, sulfonated polystyrene derivative, polyallylamine, polyallylamine derivative, polyethyleneimine, polyethyleneimine derivative, polyoxazoline, polyoxazoline derivative , Independently selected from the group consisting of polyamines and polyamine derivatives. Block polymers of the above mentioned polymers are also useful, such as poly (vinyl alcohol-co-ethylene), poly (ethylene glycol-co-propylene glycol), poly (vinyl acetate-co-vinyl alcohol), poly (tetrafluoroethylene -Co-vinyl alcohol), poly (acrylonitrile-co-acrylamide), poly (acrylonitrile-co-acrylic acid-co-acrylamide).

  In another embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is hyaluronic acid, a hyaluronic acid derivative , Poly-N-vinylpyrrolidone, poly-N-vinylpyrrolidone derivatives, polyether derivatives (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG) or polypropylene glycol (PPG) derivatives, polyvinyl alcohol And independently selected from the group consisting of polyvinyl alcohol derivatives.

  When a hydrophilic polymer is said to be a derivative, eg a “polyamine derivative”, it is not intended to encompass alkene or alkyne derivatives—this refers to additional derivatization. Thus, a “polyamine derivative” may include, for example, a polyamine functionalized with a thiol, hydroxyl or azide group and then modified to include an alkene and / or alkyne group.

  In a further embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is polyethylene glycol (PEG), It is independently selected from the group consisting of polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG) and polypropylene glycol (PPG) derivatives. These copolymers (eg, copolymers of ethylene glycol and propylene glycol), these terpolymers, and mixtures thereof are also contemplated.

  In one embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each containing two alkene groups. In another embodiment, Component B comprises one or more polyether hydrophilic polymers (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycols) each containing two or more alkene and / or alkyne groups. (PPG) or polypropylene glycol (PPG) derivatives). In a preferred embodiment, component B comprises and preferably consists of one or more PEG polymers each containing two alkene groups. In another embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, said alkene and / or alkyne group being terminal Alkene and / or alkyne groups.

  When component B comprises and preferably consists of a polyether hydrophilic polymer, generally the polymer will be alkene and / or alkyne functionalized via its end groups. Polyether polymers are most often terminated with hydroxyl groups. However, other end groups include but are not limited to amino and thiol. Any of these groups can be functionalized with the required alkene and / or alkyne functionality. Suitable reagents for introducing alkene functional groups include alkene functionalizing reagents including leaving groups (eg, halogens), alkene functionalized carboxylic acids, acid chlorides and activated esters, or acrylate compounds. Suitable reagents for introducing alkyne functional groups include alkyne functionalized reagents including leaving groups (eg, halogens), alkyne functionalized carboxylic acids, acid chlorides and activated esters. Thus, polyether polymers can be independently alkene or alkyne functionalized through at least two bonds including but not limited to ether, thioether, amine, ester, thioester, amide and carbamate linkages. it can. By changing the bonds used in component B, the properties of the resulting copolymer can be changed. In one embodiment, the linkage is an ester linkage (see, eg, Structural Formula (I) below). In another embodiment, the bond is an amide bond (see, eg, Structural Formula (II) below). Component B can be either biodegradable or biologically stable.

  Those skilled in the art will appreciate that technical grades of bifunctional polymers (such as dihydroxyl PEG) may contain small amounts of the corresponding monofunctional (eg, monohydroxyl) polymers and are monofunctional when functionalized with alkene or alkyne groups. It will be appreciated that an alkene or monoalkyne functionalized polymer will be formed. Accordingly, component B is defined as consisting of one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups. However, small (not functionally important) amounts of monoalkene or monoalkyne functionalized hydrophilic polymer would be acceptable. This is also included within the definition of component B.

In one embodiment, Component B comprises and preferably consists of one or more polyethylene glycol (PEG) polymers each containing two or more alkene and / or alkyne groups. Preferably, each PEG polymer contains two alkene groups. PEG is a polyether compound that is linear and has the general formula H— [O—CH ₂ —CH ₂ ] _n —OH. Branch and dendritic types including hyperbranches are also contemplated and are generally known in the art. Typically, the branch polymer has a central branch core portion, and the majority of the linear polymer chains are attached to the central branch core. PEG is commonly used in branched form and can be prepared by the addition of ethylene oxide to various polyols such as glycerol, glycerol oligomers, pentaerythritol and sorbitol. The central branch can also be derived from several amino acids such as lysine. Branched poly (ethylene glycol) is commonly referred to as R (-PEG-OH) _{m where} R is derived from a core moiety such as glycerol, glycerol oligomer, or pentaerythritol, and m represents the number of arms. It can be expressed by a formula. US Pat. No. 5,932,462, US Pat. No. 5,643,575, US Pat. No. 5,229,490, US Pat. No. 4,289,872, US Application Publication No. 2003/0143596, WO 96/21469 And multi-arm PEG molecules as described in WO 93/21259 may also be used.

  Component B comprises one or more polyethylene glycol (PEG) polymers each containing two or more alkene and / or alkyne groups, and preferably when comprised, preferably the PEG polymer is a diacrylate functionalized PEG polymer It is.

  In one embodiment, the one or more diacrylate functionalized PEG polymers are of structural formula (I).

(In the formula, n is 10 to 50,000, for example, 15 to 5,000, for example, 100 to 400, preferably 150 to 260.)

  In another embodiment, the one or more diacrylate functionalized PEG polymers are of structural formula (II).

(In the formula, n is 10 to 50,000, for example, 15 to 5,000, for example, 100 to 400, preferably 150 to 260.)
When component B comprises and preferably consists of one or more PEG polymers each containing two or more alkene or alkyne groups, the average molecular weight of the PEG polymer is, for example, 600-2000000 Da, 60000-2000000 Da, It is 40000-200000 Da, 400000-1600,000 Da, 800-1200000 Da, 600-40000 Da, 600-20000 Da, 4000-16000 Da, or 8000-12000 Da.

  In one embodiment, component B comprises and preferably consists of one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the molecular weight of each hydrophilic polymer is independently 600 to 40000 Da, 600 to 20000 Da, 4000 to 16000 Da, or 8000 to 12000 Da.

  Component B may consist of two or more (eg, two) different hydrophilic polymers each containing two or more alkene and / or alkyne groups. For example, component B may consist of two different polyether polymers each having a different molecular weight. Thus, in one embodiment, component B comprises and preferably consists of two different hydrophilic polymers each containing two or more alkene and / or alkyne groups. In another embodiment, component B comprises and preferably consists of two different polyether polymers each containing two or more alkene and / or alkyne groups. In a further embodiment, component B comprises and preferably consists of two different molecular weight PEG polymers each containing two or more alkene and / or alkyne groups. In one embodiment, component B comprises a first PEG polymer comprising two alkene groups (average molecular weight is 600-40000 Da, 600-20000 Da, 4000-16000 Da or 8000-12000 Da), and two alkene groups A second PEG polymer comprising, wherein the second PEG polymer has an average molecular weight of 60000-2000000 Da, 40000-2000000 Da, 400000-1600000 Da, or 800000-1200000 Da, and preferably consists of this.

  Suitably, the second, higher average molecular weight PEG polymer will be present in a lower weight percent (% by weight) than that of the first, lower average molecular weight. For example, when Component B comprises and preferably consists of two different molecular weight PEG polymers, at least 99% (by weight) of Component B is a lower average molecular weight PEG polymer, such as at least 98%, 97 %, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85% or 80% (by weight). The addition of a much higher molecular weight PEG polymer tends to have the effect of increasing the lubricity of the final hydrophilic coating. However, if the proportion of higher molecular weight PEG polymer is made too high, the amount of crosslinking in components A, B and optionally the copolymer of C and / or D is reduced, which is the durability of the hydrophilic coating. May be affected.

Component C
Component C is an optional component in the hydrophilic coating of the present invention. When present, Component C contains and preferably consists of one or more beneficial chemicals each containing one or more alkene or alkyne groups (preferably one alkene or alkyne group). The alkene or alkyne group of component C participates in the radical polymerization reaction to form a copolymer.

  The term “beneficial chemical” encompasses any chemical that imparts a particular desired effect when included in the hydrophilic coating of the present invention. Examples of beneficial chemicals include chemicals with pharmacological activity, conductive agents, lubricants or adhesives. For example, the beneficial chemical may be a chemical with pharmacological activity, a conductive agent or an adhesive. A “chemical substance having pharmacological activity” in the present disclosure is a chemical substance that induces a biological response that is used interchangeably with the term “drug”.

  Examples of chemical substances having pharmacological activity include, but are not limited to, antithrombotic agents, hemostatic agents, angiogenesis inhibitors, angiogenesis agents, antibacterial agents, antiproliferative agents, proliferative agents and anti-inflammatory agents. Absent.

Chemical anti-thrombotic agents with pharmacological activity The use of anti-thrombotic agents may prevent or reduce the significant adverse effects of blood clotting that can occur when a medical device is inserted into the body. Examples of antithrombotic agents include heparin, heparin derivatives, hirudin, eptifibatide, tirofiban, urokinase, D-Phe-Pro-Arg chloromethyl ketone, RGD peptide-containing compound, AZX100 cell peptide that mimics HSP20 (Capstone Therapeutics Inc., USA), thrombin inhibitors, platelet receptor antagonists, antithrombin antibodies, antiplatelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors (clopidogrel and abciximab) and antiplatelet peptides, such as coumadin (warfarin) 4-hydroxycoumarins such as vitamin K antagonists), argatroban, thrombomodulin and anticoagulant proteins. Examples of the antithrombotic agent may include enzymes such as apyrase. Such a substrate may be charged (eg anionic) or uncharged. Other examples are glycosaminoglycans, dermatan disulfate, dermatan disulfate analogs, and derivatives thereof.

  The term “heparin” refers to a fragment of a heparin molecule, heparin molecule or heparin derivative. A heparin derivative can be any functional or structural variation of heparin. Typical variations include heparin sodium (eg, hepsal or praline), heparin potassium (eg, clarine), heparin lithium, heparin calcium (eg, calcipaline), magnesium heparin (eg, kuteparin), and low molecular weight heparin (eg, oxidative). Examples include alkali metal or alkaline earth metal salts of heparin, such as ardeparin sodium or dalteparin, prepared by depolymerization or deamination cleavage. Other examples include heparan sulfate, heparinoids, heparin based compounds and heparin with a hydrophobic counterion. Other desired anticoagulants include synthetic heparin compositions called “fondaparinux” compositions (eg, Glaxosmith Klein elixir) that are involved in the antithrombin mediated inhibition of factor Xa. Additional derivatives of heparin include, for example, mild nitrite degradation (US Pat. No. 4,613,665), or periodate oxidation (US Pat. No. 6,653,457) and the biological activity of the heparin moiety substantially retained. And heparin and heparin moieties modified by other modification reactions known in the art.

Hemostatic agents By using hemostatic agents, bleeding, major bleeding, or blood flowing through blood vessels or body parts may be stopped to prevent massive loss of blood. They can cause platelet aggregation and thrombus formation, and their use can stop bleeding in surgical procedures. Examples of hemostatic agents include fibrin sealants, absorbable hemostatic agents with and without thrombin, solutions of thrombin, collagen, microfibrous collagen, gelatin, gelatin sponge, regenerated oxidized cellulose, bone wax, glucosamine-containing polymers, Chitosan, plant extract, mineral, rFVIIa and antifibrinolytic agent.

Angiogenesis inhibitors Angiogenesis inhibitors inhibit tumor angiogenesis and also target vascular endothelial cells. Examples of angiogenesis inhibitors are sunitinib, bevacizumab, itraconazole, suramin, and tetrathiomolybdate.

Angiogenic agents Angiogenic agents can be used in applications where cell proliferation is desired. Examples of angiogenic agents include growth factors and RGD proteins.

Antibacterial agents Antibacterial agents are a general term for drugs, chemicals, or other drugs that either delay the killing or growth of pathogenic bacteria. Among antibacterial agents are antibacterial agents, antiviral agents, antifungal agents, and antiparasitic agents. Examples of antibacterial agents include diamidine, iodine and iodophor, peroxygen, phenols, bisphenols, halophenols, biguanides, silver compounds, triclosan, chlorhexidine, triclocarban, hexachlorophene, dibromopropamidine, chloroxylenol, phenol and cresol Or combinations thereof and salts and combinations thereof, antibiotics, erythromycin or vancomycin; dopamine, bromocriptine mesylate, pergolide mesylate or another dopamine agonist; or another radiotherapeutic agent; iodine containing which functions as a radiopaque substance Compounds, barium-containing compounds, gold, tantalum, platinum, tungsten or other heavy metals; peptides, proteins, enzymes, extracellular matrix components, cellular components or Other biological agents; captopril, enalapril, or other angiotensin converting enzyme (ACE) inhibitors; ascorbic acid, nitrofurazone, benzalkonium chloride such as rifampin, gentamicin cephalosporins, aminoglycosides, nitrofurantoin and Antibiotics such as minocycline, salicylic acid, alpha tocopherol, superoxide dismutase, deferoxamine, 21-aminosteroid (lasaroid), or another free radical scavenger, iron chelator or antioxidant; angiopeptin; 14C-3H A selected from the group consisting of-, 131I-, 32P, or 36S-radiolabeled form, or any other radiolabeled form described above; or any mixture thereof Thing, and the like. Other examples include cytotoxic drugs, cytostatics and cell growth factors; vasodilators; chemicals that interfere with endogenous vasoactive mechanisms; inhibitors of leukocyte recruitment such as monoclonal antibodies; cytokines; hormones or combinations thereof It is.

Proliferators Proliferators stimulate cell proliferation and are, by way of example, vascular cell growth promoters such as growth factors, transcription activators, and translational promoters.

Antiproliferative agents Antiproliferative agents are growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antigrowth factor antibodies, bifunctional molecules consisting of growth factors and cytotoxins, Vascular cell growth inhibitors such as bifunctional molecules consisting of antibodies and cytotoxins; protein kinases and tyrosine kinase inhibitors (eg tyrphostins, genisteins, quinoxalines); prostacyclin analogs, cholesterol-lowering drugs, angiopoietins, etc. A drug used for prevention or delay. The inclusion of chemicals also prevents restenosis by reducing or preventing cell proliferation when the device is inserted into the body, especially in smooth muscle cells. Examples of such chemicals include, but are not limited to, antiproliferative agents such as mycophenolate mofetil, azathioprine, paclitaxel and sirolimus. Other examples include cilostazol, everolimus, dicoumarol, zotarolimus, carvedilol, and major taxane domain binders such as paclitaxel and their analogs, epothilone, discodermolide, docetaxel, such as Abraxane RTM (Abraxane is ABRAXIS BIOSCIENCE, LLC Paclitaxel protein binding particles such as (registered trademark), suitable cyclodextrin (or cyclodextrin-like molecule), paclitaxel complexed with rapamycin and analogs thereof, rapamycin complexed with suitable cyclodextrin (or cyclodextrin-like molecule) (Or rapamycin analog), SiRNA, 17 beta-estradiol, 17 beta-estradio complexed with the appropriate cyclodextrin Dicoumarol, 5-Fluorouracil, Cisplatin, Vinblastine, Vincristine, Epothilone, Endostatin, Angiostatin, Angiopeptin, Smooth Muscle Cell Proliferation Complexed with Lu, Dicoumarol, Appropriate Cyclodextrin, Beta-lapachone and Analogs Monoclonal antibodies that can be blocked, as well as antitumor agents such as thymidine kinase inhibitors and anti-miotics; anesthetics such as lidocaine, bubivacine and ropivacaine.

Anti-inflammatory drugs Anti-inflammatory drugs are drugs that reduce inflammation. Many steroids, specifically glucocorticoids, reduce inflammation or swelling by binding to glucocorticoid receptors. These drugs are often called corticosteroids. Nonsteroidal anti-inflammatory drugs (NSAIDs) are active by inhibiting the cyclooxygenase (COX) enzyme. Some common examples of NSAIDs are, but are not limited to, aspirin, ibuprofen, and naproxen. Other specific COX-inhibitors will also be contemplated. Examples of anti-inflammatory drugs are steroids such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and mesalamine, sirolimus and everolimus (and related analogs).

  Specific chemical substances having pharmacological activity that may be used in the present invention include heparin, heparin derivatives, thrombin, collagen, itraconazole, suramin, RGD protein, silver compound, triclosan, chlorhexidine, growth factor, paclitaxel, sirolimus, everolimus, Examples include but are not limited to dexamethasone and steroids.

Adhesive Adhesive is a compound used to increase surface tack or viscosity. These can be high molecular weight compounds or low molecular weight compounds. The tacky surface allows adhesion and makes the coating much more difficult to peel off. Adhesives include, but are not limited to, poorly cured systems, epoxide-containing systems, tackifiers and foams thereof. Many biopolymers—proteins, carbohydrates, glycoproteins, and mucopolysaccharides—may be used to form hydrogels that contribute to adhesion.

Lubricants Lubricants are compounds that can increase the hydrophilicity of the present invention when introduced. Examples of hydrophilic chemicals include hyaluronic acid, hyaluronic acid derivatives, poly-N-vinyl pyrrolidone, poly-N-vinyl pyrrolidone derivatives, polyethylene oxide, polyethylene oxide derivatives, polyalkylene glycols, polyether derivatives (eg, polyethylene glycol ( PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG) or polypropylene glycol (PPG) derivatives), polyglycidol, polyvinyl alcohol, polyvinyl alcohol derivatives, polyacrylic acid, polyacrylic acid derivatives, silicone, silicone derivatives, polysaccharides , Polysaccharide derivatives, polysulfobetaines, polysulfobetaine derivatives, polycarboxybetaines, polycarboxybetaine derivatives, polyalcohols such as polyHEMA Polyacids such as alginate, dextran, agarose, poly-lysine, polymethacrylic acid, polymethacrylic acid derivatives, polymethacrylamide, polymethacrylamide derivatives, polyacrylamide, polyacrylamide derivatives, polysulfone, polysulfone derivatives, sulfonated polystyrene, sulfonation It is a hydrophilic polymer independently selected from the group consisting of polystyrene derivatives, polyallylamine, polyallylamine derivatives, polyethyleneimine, polyethyleneimine derivatives, polyoxazolines, polyoxazoline derivatives, polyamines and polyamine derivatives. Block polymers of the above mentioned polymers are also useful, such as poly (vinyl alcohol-co-ethylene), poly (ethylene glycol-co-propylene glycol), poly (vinyl acetate-co-vinyl alcohol), poly (tetrafluoroethylene -Co-vinyl alcohol), poly (acrylonitrile-co-acrylamide), poly (acrylonitrile-co-acrylic acid-co-acrylamide).

Conductive Agents Incorporating conductive materials into the coatings of the present invention can provide a conductive surface for devices such as electrodes. Examples of the conductive agent include polyfluorene, polyphenylene, polypyrene, polyazulene, polynaphthalene, polypyrrole (PPY), polycarbazole, polyindole, polyazepine, polyaniline, polythiophene (PT), poly (3,4-ethylenedioxythiophene) (PEDOT), poly (p-phenylene sulfide), polyacetylene (PAC), poly (p-phenylene vinylene) (PPV), or derivatives thereof.

Molecular weight range of component C In one embodiment, the molecular weight of component C is 20000 Da or less. In another embodiment, the molecular weight of component C is between 100,000 Da and 1500,000 Da.

  In one embodiment, the molecular weight of component C is, for example, 100000 Da or less, such as 50000 Da or less (eg 50-3000 Da), such as 25000 Da or less (eg 9000-20000 Da, such as 9000-11000 Da), such as 1000 Da or less (eg 150-600 Da). It is.

  In another embodiment, component C is a protein having a molecular weight of 40,000 Da to 80,000 Da. In another embodiment, component C is a polymeric conductive agent having a molecular weight of 1000 Da to 30000 Da.

  In one embodiment, component C is present and comprises heparin or a heparin derivative comprising one or more (eg one) alkene or alkyne group, preferably one or more (eg one) alkene group, It preferably also consists of this. The heparin or heparin derivative described above can be modified by any suitable method involving an alkene or alkyne group. Example 6 describes a specific synthesis of terminal methacrylated heparin. Example 5.7 illustrates how a coating of the present invention comprising the heparin incorporated in a copolymer can be prepared.

Component D
Component D is an optional component in the hydrophilic coating of the present invention. When present, component D comprises, and preferably consists of, one or more low molecular weight crosslinkers each containing two or more functional groups independently selected from thiol, alkene and alkyne groups. The functional group of D participates in the radical polymerization reaction to form a copolymer. For example, component D includes and preferably consists of one or more low molecular weight crosslinkers each containing two or more thiol groups, eg, two thiol groups. The thiol group participates in a radical polymerization reaction via a thiol-ene / yne reaction to form a crosslinked copolymer.

  The presence of the optional component D may tend to improve the structural stability of the copolymer and thus the structural stability of the coating. The presence of optional component D may tend to improve the durability of the coating.

  Low molecular weight crosslinkers (including low molecular weight PEGs) will typically have a molecular weight of less than 1000 Da, such as less than 600 Da, such as 100-1000 Da, such as 100-600 Da.

  In one embodiment, the crosslinking agent is bisphenol A propoxylate diacrylate, 1,3-butanediol diacrylate, 1,4-butanediol diacrylate, 1,3-butanediol dimethacrylate, 1,4-butanediol diacrylate. Methacrylate, N, N '-(1,2-dihydroxyethylene) bisacrylamide, di (trimethylolpropane) tetraacrylate, diurethane dimethacrylate, N, N'-ethylenebis (acrylamide), glycerol 1,3-diglycero Rate diacrylate, glycerol dimethacrylate, glycerol propoxylate (1PO / OH) triacrylate, 1,6-hexanediol diacrylate, 1,6-hexanediol dimethacrylate, 1,6-hexanediol Toxylate diacrylate, 1,6-hexanediylbis [oxy (2-hydroxy-3,1-propanediyl)] bisacrylate, hydroxypivalylhydroxypivalate bis [6- (acryloyloxy) hexanoate], neopentyl glycol Diacrylate, pentaerythritol diacrylate monostearate, pentaerythritol propoxylate triacrylate, pentaerythritol triacrylate, poly (propylene glycol) diacrylate, poly (propylene glycol) dimethacrylate, 1,3,5-triacryloylhexahydro- 1,3,5-triazine, tricyclo [5.2.1.02,6] decandimethanol diacrylate, trimethylolpropane benzoate diacrylate , Trimethylolpropane ethoxylate triacrylate, trimethylolpropane propoxylate triacrylate, trimethylolpropane triacrylate, tri (propylene glycol) diacrylate or tris [2- (acryloyloxy) ethyl] isocyanurate, but limited It will never be done. Acrylated or methacrylated low molecular weight PEGs are also useful.

  In another embodiment, the cross-linking agent may be N, N′-methylenebisacrylamide, 3- (acryloyloxy) -2-hydroxypropyl methacrylate or bis [2- (methacryloyloxy) ethyl] phosphate, but is limited Never happen. Also useful are derivatized acrylamides and methacrylamides derived from low molecular weight PEGs.

  In another embodiment, the crosslinking agent is 2,4,6-triallyloxy-1,3,5-triazine, 1,3,5-triallyl-1,3,5-triazine-2,4,6 ( 1H, 3H, 5H) -trione, trimethylolpropane allyl ether, trimethylolpropane diallyl ether pentaerythritol allyl ether, diallyl carbonate, diallyl maleate and diallyl succinate and the like, but not limited . Allyl functionalized low molecular weight PEGs are also useful.

  In another embodiment, the crosslinking agent is hexa (ethylene glycol) dithiol, 1,2-ethanedithiol, 1,3-propanedithiol, 2,3-dimercapto-1-propanol and 1,3,5-triazine-2. Polyfunctional thiolated PEG such as, 4,6-trithiol may be used, but is not limited thereto.

  In another embodiment, the cross-linking agent may be, but is limited to, 1,6-heptadiyne, 3- (allyloxy) -1-propyne, propargyl ether and 2-methyl-1-buten-3-yne There is no. Alkyne functionalized low molecular weight PEGs are also useful.

  In a preferred embodiment, the crosslinker may be, but is not limited to, alkene and / or thiol and / or alkyne and / or functionalized low molecular weight PEG.

  A thiol containing component D may be advantageously included to reduce the sensitivity of the system to oxygen inhibition of the polymerization reaction.

Ingredient E
Component E, if present, contains and preferably consists of one or more beneficial chemicals, and Component E includes components A, B, C (if present) and D (present) In some cases) and do not form a copolymer. The presence of component E will tend to change the properties of the hydrophilic coating containing it.

  In one embodiment, component E is covalently bound to the copolymer. This embodiment is particularly suitable when it is desired to avoid any elution from the coating of component E.

  In one embodiment, component E is not covalently bonded to the copolymer. For example, component E is ionically bound to the copolymer. Alternatively, component E can be entrapped within the copolymer without chemically or ionic binding to the copolymer. For example, component E can be absorbed into the copolymer by a process that involves the swelling of the copolymer preformed on the surface of the substrate having a solution containing component E. Component E will be absorbed into the voids in the copolymer so that it swells.

  Thus, in certain embodiments, component E may gradually elute from the hydrophilic coating. This is particularly useful when component E is a drug, and systemic and local administration of the drug is advantageous. Distribution and elution over time may be controlled.

  Component E can be a mixture of subcomponents where (at least) one subcomponent is covalently bonded to the copolymer and (at least) one subcomponent is not covalently bonded to the copolymer.

  Useful chemicals include those listed under the heading “Component C”. Useful chemicals may be functionalized or non-functionalized-for example, they can be functionalized when it is to be covalently attached to a copolymer.

  Additional useful chemicals as component E include salts that will assist the conductivity of the hydrophilic coating when in contact with water. Such salts can be, but are not limited to, lithium, sodium or potassium chloride. Metals such as gold and silver may also be used as the conductive agent.

  Thus, for example, in a reaction following the polymerization reaction, component E can react with a copolymer of components A and B (and optionally other components C and D) already formed as a coating on the substrate.

  For example, if component A was acrylic acid and component B was a diacrylate functionalized PEG polymer, the resulting copolymer of components A and B would have pendant carboxylic acid groups. The carboxylic acid groups on the surface of the copolymer may then react with a suitably functionalized component E (eg, using a coupling agent such as carbodiimide and amine functionalized component E). Alternatively, component E can be functionalized with thiol groups and then on the surface of components A and B and optional C and / or D copolymers under UV irradiation via a thiol-ene or thiol-in reaction. To the remaining alkene or alkyne groups.

  Component E uses carbodiimide chemistry to form amide bonds, reductive amination reactions to form amine bonds, azide-alkyne reactions to form triazole bonds, and thiol-alkene / yne reactions to form thioether bonds. It can be introduced by covalent attachment of component E to the coating.

  The method described above is merely exemplary and one skilled in the art can apply any suitable coupling technique to component E that covalently bonds to the copolymer. In this aspect of the embodiment, component E will tend to be primarily present on the outer surface of the polymer coating on the substrate. In another aspect, component E can be dispersed throughout the coating.

  In one embodiment, component E is present and comprises and preferably consists of heparin or a heparin derivative that can be covalently bonded to the copolymer at an end point or a single point or multiple points as a coating on the substrate, or Including. In another embodiment, component E is present, and heparin that can be covalently attached to a polyamine, such as polyethyleneimine, which can be ionically attached to the copolymer as a coating on the substrate, either end-point or single-point or multi-point. Or a heparin derivative, and preferably consists of or comprises. The heparin or heparin derivative described above can be modified by any suitable method that promotes binding to the coating. Examples 5.2-5.4 and Example 5.8 describe how heparin can bind to the copolymers of the present invention.

Variation of the embodiment for the hydrophilic coating In one embodiment, component C is present and component D is not present. In one embodiment, component D is present and component C is not present. In one embodiment, components C and D are not present. In one embodiment, components C and D are present.

  In one embodiment, component E is present. In one embodiment, component E is absent.

Other aspects of the hydrophilic coating The relative ratio of component A and component B must be such that the coating has structural integrity while retaining its hydrophilicity. For example, if the relative ratio of component A is too high compared to the ratio of component B, the coating is less flexible and may be poorly hydrophilic. Conversely, if the relative ratio of component B is too high compared to the ratio of component A, the resulting coating may not have sufficient structural integrity to withstand delamination. When component C is present, the relative ratios of components A, B and C and optional D exhibit the beneficial properties that the coating binds to component C, but are still hydrophilic and structurally stable. There must be something.

  Exemplary (non-limiting) component ratios are shown in Tables A and B below.

  The ratios mentioned above refer to the mass ratio of components A, B, C and D (if necessary) present in the polymerization solution before polymerization takes place. Components A, B, C and D (or at least the relative proportions of the copolymers from components A, B, C and D) present in the resulting coating are the individual components in the polymerization solution before the coating is formed. It can be reasonably expected to be substantially equivalent to the mass ratio. In any subsequent step involved in the reaction or binding of the copolymers of compounds A, B, C and D and E, the ratio of E to the ratio of components A, B, C and D in the polymerization solution is in solution. Refers to the mass ratio of E.

  The dry thickness of the hydrophilic coating on the substrate can be determined by limiting the amount of components A, B and optional C and D in the polymerization solution and / or by limiting the polymerization time and / or present. In this case, it can be controlled by appropriately changing the built-in condition of E. Suitably, the hydrophilic coating has a dry thickness of at least 100 μm, such as at least 50 μm, 25 μm, 10 μm, 5 μm, 1 μm, 0.5 μm or 0.1 μm. In one embodiment, the thickness of the copolymer coating is 0.1-5 μm, such as 0.1-2.5 μm or 0.5-2.5 μm.

  The amount of solvent used in the polymerization solution can vary, which is a parameter that affects the coating properties with respect to lubricity, durability and granulation and can be varied by those skilled in the art. One skilled in the art can optimize this parameter. If a given ratio of PEG to acrylic acid (for example) results in poor coating properties at certain polymer solution concentrations, it may typically exhibit good coating properties if the concentration is changed. Exemplary amounts of solvent are shown in the examples.

The present invention relates to a method for forming a hydrophilic coating that is covalently bonded to the surface of a substrate, the method comprising:
(A) contacting the surface with a mixture comprising components A and B, optional component C, optional component D and a radical initiator,
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers, each containing an alkyne group, also now happens Preferably,
Component B comprises, and preferably consists of, one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups
Component C, if present, includes and preferably consists of one or more beneficial chemicals each containing one or more (eg, one) alkene or alkyne groups, and Component D is present The process comprising, and preferably consisting of, one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from thiol, alkene, and alkyne groups;
And (b) the alkene and / or alkyne groups of component A, B and C (if present) and component D to form a crosslinked copolymer of component A, component B, and optional components C and D. Initiating radical polymerization involving functional groups (if present), wherein the copolymer is covalently bonded to the surface, and (c) optionally, one or more beneficial chemicals A component E comprising, preferably consisting of, a hydrophilic coating, wherein component E comprises a copolymer with components A, B, C (if present) and D (if present). A method is provided that includes the step of not forming.

  The present invention also provides a substrate having a hydrophilic coating obtainable by the method described above.

  The present invention also provides a device obtainable by the method described above.

  It should be noted that all aspects of the present invention described above and in this disclosure equally refer to the substrate of the present invention and the method of the present invention.

  The hydrophilic coating of the present invention is formed by contacting the surface of a substrate with a solution (referred to in this disclosure as a polymerization solution) containing components A and B and optional components C and D and a radical initiator. Can do. Suitably, the reaction solvent is a polar solvent such as an alcohol (eg, methanol, ethanol, propanol, or isopropanol), THF or DMF, or an aqueous solution of any of the above solvents. Thus, in one embodiment, the polymerization solvent is selected from methanol, ethanol, propanol, isopropanol, THF or DMF. In another embodiment, the solvent is selected from ethanol, propanol or isopropanol, or an aqueous solution thereof. In another embodiment, the solvent is ethanol. In a further embodiment, the solvent is water itself. Thus, the coatings of the present invention can be prepared using Class 3 or Class 2 solvents, avoiding the use of organic solvents listed as Class 1 in USP chapters describing residual solvents. Preferably, the coatings of the present invention can be prepared using Class 3 solvents alone, thus avoiding the use of organic solvents listed as Class 2 and Class 1, and consequently the final hydrophilic properties. Avoiding the need for further purification steps to remove traces of residual solvent from the conductive coating.

  The method of the present invention results in the formation of a hydrophilic coating that is covalently bonded to the surface of the substrate. The covalent bond is a functional group of the group on the surface of the substrate with the alkene and / or alkyne groups on components A, B and C (if present) and on component D (if present). Is achieved through a reaction between.

  The hydrophilic coating of the present invention is formed by free radical polymerization of components A, B and optional C and D (referred to in this disclosure as radical polymerization) to form a copolymer that is covalently bonded to the surface. In an embodiment, radical polymerization may be carried out using a free radical initiator (referred to in this disclosure as a radical initiator), sometimes referred to as a “Norish type II” or “type II” radical initiator (on the surface of the substrate itself or It is initiated by abstracting hydrogen atoms from a surface containing abstractable hydrogen atoms (which can be a surface primer coating of a polymer containing abstractable hydrogen atoms). In another embodiment, radical polymerization is initiated by the generation of radicals in the bulk (radicals react with polymerizable groups in the bulk and at the surface). Initiators for such processes are thermal initiators and / or radical initiators. These radical initiators are sometimes referred to as “Norish Type I” or “Type I” radical initiators.

  Free radical initiators (“radical initiators”) readily rearrange / decompose to form free radical species (initiating species). This in turn reacts with components A, B and (optional) C and D (embodiment (i)) or with reactive groups on the surface of the substrate (embodiment (ii)) in turn. Form radical species. These two steps are collectively referred to as start. In the free radical polymerization reaction, the free radical species produced by the initiating species further react in components A, B and (optional) C and D addition chain reactions.

  Photoinitiators are compounds that generate free radicals when exposed to ultraviolet or visible light. Based on the mechanism of radical formation, photoinitiators are generally divided into two classes. Type I photoinitiators undergo free bond generation by unimolecular bond cleavage under irradiation. Type II photoinitiators undergo a bimolecular reaction, and the excited state of the photoinitiator interacts with a second molecule (co-initiator, usually H donor), thereby free radicals through a hydrogen abstraction mechanism. Is generated. Subsequent polymerization is usually initiated by radicals generated from the coinitiator. Ultraviolet photoinitiators are available in both Type I and Type II. However, visible light photoinitiators belong almost exclusively to the class II of photoinitiators.

  Suitable ultraviolet photoinitiators include benzophenone, xanthone, thioxanthone, benzoin ether, benzyl ketal, α-dialkoxyacetophenone, α-hydroxyalkylphenone, α-aminoalkylphenone and acylphosphine oxide. See the more detailed discussion in the section heading “Radical initiators capable of extracting hydrogen atoms from surfaces” below.

  Once the surface to be coated is in contact with the polymerization solution, the polymerization is initiated by any suitable means for the particular initiator used. For example, when the radical initiator is a photoinitiator, polymerization is initiated by exposure of the polymerization solution to ultraviolet light. When initiating polymerization with ultraviolet light, any suitable ultraviolet light source can be used, for example, a Fusion UV lamp or Oriel UV that provides UV-A and / or UV-B and / or UV-C radiation. It is a lamp. If a thermal initiator is used, the heat can be supplied by any suitable means such as an oven or a heating element. When the polymerization is initiated using a photoinitiator, the reaction is preferably allowed to proceed at room temperature.

  Inert curing conditions may be used to avoid oxygen inhibition problems that may result in poor curing.

  In one embodiment, the polymerization is conducted under an inert atmosphere (eg, polymerization under an argon atmosphere, eg, under a nitrogen atmosphere).

  In another embodiment, the polymerization solution may be purged with an inert gas prior to polymerization to increase polymerization kinetics and improve cure. The polymerization solution may be purged with, for example, argon gas or nitrogen gas.

Embodiment (i)
In a first embodiment, the covalent bond between the surface of the substrate and the hydrophilic coating is formed via reaction of surface-bonded radicals on the surface of the substrate having components of the hydrophilic coating. Surface-bonded radicals are generated through the extraction of hydrogen atoms from the surface of the substrate.

  As shown in FIG. 1, in this embodiment, polymerization is initiated when the radical initiator in the liquid phase in contact with the surface pulls out hydrogen atoms from the surface of the substrate to form surface-bound radicals. Surface bound radicals react with at least one of components A, B and C and D (if present and if such reaction is possible-only components A and B are shown in FIG. 1) The copolymer is covalently bound to. The copolymer is already present either via all components A, B and C and D (if present) (or either component A or component B or component C or component D (if present)). It can be covalently bound to the surface (at least through the components of the copolymer that had been used). The relative amount of each of the components will in part determine the proportion of covalent bonds through component A and / or component B and / or component C and / or component D (if present). However, the component that preferentially reacts with surface-bound radicals is also determined by the relative reactivity of the component, which depends on the reactivity of the component's alkene and / or alkyne functionality. When the proportions of components A and B (if present and capable of such a reaction and C and D) were equal, then the component with the most active alkene or alkyne group is preferred to the surface bound radical. Will be expected to react.

  Preferably, the alkene and / or alkyne groups of components A, B, C and D (if present and capable of reacting) will react with surface bound radicals at a substantially equivalent rate. . Thus, either as component A, B, C and D (if present and capable of reacting) or as component A or component B or component C or component D (if present and capable of reacting) The proportion of copolymer bound to the surface, at least via the copolymer components already present, is directly related to the proportion of each component present in the polymerization solution. For example, if component A is acrylic acid and component B is a diacrylate functionalized PEG, the alkene group of each component reacts with surface bound radicals at essentially the same rate, and the copolymer is And B will bind to the surface.

Accordingly, in one embodiment, the present invention is a method of forming a hydrophilic coating that is covalently bonded to the surface of a substrate, wherein the substrate has a surface comprising abstractable hydrogen atoms, said method comprising:
(A) contacting the surface with a mixture comprising a component A and B, an optional component C, an optional component D and a radical initiator capable of generating surface-bound radicals by extracting hydrogen atoms from the surface. And
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers, each containing an alkyne group, also now happens Preferably,
Component B comprises, and preferably consists of, one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups
Component C, if present, includes and preferably consists of one or more beneficial chemicals each containing one or more (eg, one) alkene or alkyne groups, and Component D is present The process comprising, and preferably consisting of, one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from thiol, alkene, and alkyne groups;
And (b) the alkene and / or alkyne groups of component A, B and C (if present) and component D to form a crosslinked copolymer of component A, component B, and optional components C and D. Initiating radical polymerization involving functional groups (if present), wherein the copolymer is covalently bonded to the surface via reaction of surface-bonded radicals; and (c) optionally Incorporating component E, comprising and preferably consisting of one or more beneficial chemicals, into a hydrophilic coating, wherein component E is component A, B, C (if present) and D A method comprising the step of not forming a copolymer with (if present) is provided.

  As described above, in the present embodiment, a substrate having a surface containing a hydrogen atom that can be extracted is required.

  “Abstractable hydrogen atom” is defined as a covalently bonded hydrogen atom that can be withdrawn or removed by what is in an excited state, and as a result, free radicals in atoms that were originally covalently bonded to a hydrogen atom. Generate (at least first). The hydrogen atom that can be extracted usually desorbs after the stabilization radical when it is extracted. The stability of a radical depends on the nature of the atom containing the radical (eg its hybridization), the nature of the atom in proximity to the radical (eg unsaturation that would allow delocalization of the radical) and further reactions. Depends on a number of factors including steric hindrance that may interfere with the center.

  A substrate having a surface containing abstractable hydrogen atoms may have a “unique surface containing abstractable hydrogen atoms” which means a material containing abstractable hydrogen atoms, and the surface of the substrate is the material Made in (prior to any coating process).

  Thus, in one embodiment, the surface of the substrate itself contains (in the present disclosure) abstractable hydrogen atoms. A substrate having a unique surface containing abstractable hydrogen atoms is formed from the material of the substrate having abstractable hydrogen atoms (or at least a portion of the surface is formed therefrom). Examples of substrate materials that may be modified to have abstractable hydrogen atoms and / or have a unique surface containing abstractable hydrogen atoms include polyolefins, polyesters, polyurethanes, polyamides, poly Ether block amide, polyimide, polycarbonate, polyphenylene sulfide, polyphenylene oxide, polyether, silicone, polycarbonate, polyhydroxyethyl methacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, rubber, silicone rubber, polyhydroxy acid, polyallylamine, polyallyl alcohol, polyacrylamide And polyacrylic acid, styrenic polymers, polytetrafluoroethylene and copolymers thereof, derivatives thereof and mixtures thereof. Is is it is not. Some of these classes are available both as thermoset and thermoplastic polymers. In this disclosure, the term “copolymer” is used to refer to any polymer formed from two or more monomers, such as 2, 3, 4, 5, etc. Bioabsorbable materials such as poly (D, L-lactide) and polyglycolide and copolymers thereof are also useful. Useful polyamides include, but are not limited to, nylon 12, nylon 11, nylon 9, nylon 6/9 and nylon 6/6. Examples of some copolymers of such materials include polyether-block-amides available from Elf Atochem North America, Philadelphia, Pennsylvania under the trade name PEBAX®. Another suitable copolymer is a polyetheresteramide. Suitable polyester copolymers include, for example, HYTREL. Polyethylene terephthalate and polybutylene terephthalate, polyester ethers and polyester elastomer copolymers such as those available from DuPont, Wilmington, Del., Under the trade name RTM. Block copolymer elastomers such as styrene end blocks and copolymers thereof having mid blocks formed from butadiene, isoprene, ethylene / butylene, ethylene / propylene, and the like may be used in the present disclosure. Other styrenic block copolymers include acrylonitrile-styrene and acrylonitrile-butadiene-styrene block copolymers. Also, certain block copolymer thermoplastic elastomers that are block copolymers made of polyester or polyamide hard segments and polyether soft segments may be used in the present disclosure. Other useful substrates are chlorine-containing polymers such as polystyrene, poly (methyl) methacrylate, polyacrylonitrile, poly (vinyl acetate), poly (vinyl alcohol), polyvinyl chloride, polyoxymethylene, polycarbonate, polyamide, polyimide, Polyurethane, phenolic resin, amino epoxy resin, polyester, silicone, cellulose base plastic and rubbery plastic.

  Combinations of these materials can be used with and without crosslinking.

  The polymer substrate may optionally be blended with fillers and / or colorants. Accordingly, suitable base materials include pigmented materials such as colored polymer materials.

  In one embodiment, the biocompatible material having an abstractable hydrogen atom is a polyether block amide such as PEBAX®.

  In another embodiment, the material is a protein such as silk or wool, agarose or alginate. Also, certain metals and ceramics that can be modified to have abstractable hydrogen atoms may be used as the substrate according to the present invention. Suitable metals include, but are not limited to, biocompatible metals, titanium, stainless steel, high nitrogen stainless steel, gold, silver, rhodium, zinc, platinum, rubidium, copper, and magnesium, and combinations thereof. There is nothing. Suitable alloys include cobalt-chromium alloys such as L-605, MP35N, and Elgiloy, nickel-titanium alloys (such as nitinol), tantalum, and niobium alloys such as Nb-1% Zr. The ceramic substrate may include, but is not limited to, silicone oxide, aluminum oxide, alumina, silica, hydroxyapatite, glass, calcium oxide, polysilanol, and phosphorous oxide.

  In one embodiment, the biocompatible metal is a nickel-titanium alloy such as nitinol.

  In another embodiment, the substrate that may be modified to have abstractable hydrogen atoms and / or have a unique surface that includes abstractable hydrogen atoms includes fluorinated polymers such as fluoropolymers. Examples include, but are not limited to, expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluorocarbon copolymers such as tetrafluoroethylene perfluoroalkyl vinyl ether (TFE / PAVE) copolymers, copolymers of tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE), and combinations of the above with and without cross-linking between polymer chains, drawn polyethylene, polyvinyl chloride, poly Urethane, silicone, polyethylene, polypropylene, polyurethane, polyglycolic acid, polyesters, polyamides, elastomers and mixtures thereof, blends and copolymers or derivatives may be useful.

  Alternatively, the substrate can be coated with a surface coating of a polymer containing abstractable hydrogen atoms. Thus, in another embodiment, the surface of the substrate is a surface coating of a polymer containing abstractable hydrogen atoms. The surface coating of a polymer containing an abstractable hydrogen atom is also referred to as a “surface primer coating of a polymer containing an abstractable hydrogen atom” or a “surface primer coating of a (specific polymer containing an abstractable hydrogen atom)”. The disclosure mentions that the hydrophilic coating of the present invention is applied over a surface coating of a polymer containing abstractable hydrogen atoms. Application of polymers containing abstractable hydrogen atoms may result in a more uniformly applied components A, B and optional C and D copolymer backcoat coatings. A uniform coating with sufficient adhesion is desirable from a regulatory standpoint, and specific coating uniformity will be required to meet performance specifications. Further, in order to prevent delamination and granulation, strong adhesion between the undercoat layer and the substrate is also desired from the viewpoint of regulation.

  In this embodiment, preferably, the substrate to be coated does not have a unique surface containing abstractable hydrogen atoms, or the amount of abstractable hydrogen atoms is insufficient, and thus the polymer The surface subbing coating provides a surface containing the required abstractable hydrogen atoms. However, a substrate having a unique surface containing abstractable hydrogen atoms may also have a surface subbing coating of a polymer containing abstractable hydrogen atoms. Thus, in a further embodiment, a substrate having a surface containing abstractable hydrogen atoms is coated with a surface primer coating of a polymer containing abstractable hydrogen atoms. This has the further advantage of providing a more uniform distribution of abstractable hydrogen atoms on the surface.

  In at least some aspects of this embodiment, the application of the hydrophilic coating is an independent substrate, i.e., at least a portion of the substrate can be coated with a surface coating of a polymer containing hydrogen atoms that can be extracted. Then, (in principle) a part of the substrate can be provided with a hydrophilic coating. Thus, in this embodiment, the amount or type of abstractable hydrogen atoms on the surface of the substrate need not be evaluated prior to the application of the hydrophilic coating-the polymer surface coating is required for releasability New hydrogen atoms.

  A substrate having a surface subbing coating of a polymer containing abstractable hydrogen atoms is preferably made by applying the appropriate monomer to the surface of the substrate under polymerization conditions. Examples of polymers containing abstractable hydrogen atoms include polymers containing catechol functional groups and / or quinone functional groups and / or semiquinone functional groups. In one embodiment, the polymer containing an abstractable hydrogen atom is selected from the group consisting of a polymer containing a catechol functional group, a polymer containing a quinone functional group, and a polymer containing a semiquinone functional group.

  In one embodiment, the polymer containing an abstractable hydrogen atom contains a catechol functional group. The catechol functional group is shown in structural formula (III).

(Wherein at least one of R _a , R _b , R _c and R _d is attached to the polymer, and R _a , R _b , R _c or R _d is preferably still H).

  In one embodiment, the polymer containing an abstractable hydrogen atom contains a semiquinone functional group. The semiquinone functional group is represented by Structural Formula (IVa) or Structural Formula (IVb).

(Wherein at least one of R _a , R _b , R _c and R _d is attached to the polymer, and R _a , R _b , R _c or R _d is preferably still H).

  In one embodiment, the polymer containing an abstractable hydrogen atom contains a quinone functional group. The quinone functional group is represented by structural formula (Va) or structural formula (Vb).

(Wherein at least one of R _a , R _b , R _c and R _d is attached to the polymer, and R _a , R _b , R _c or R _d is preferably still H).

  In one embodiment, the polymer comprising an abstractable hydrogen atom comprises a structural formula (III) of a catechol functional group and / or a structural formula (IVa) and / or a structural formula (IVb) of a semiquinone functional group and / or a quinone functional group. The structural formula (Va) and / or (Vb) of the group.

Polydopamine In one embodiment, the polymer containing abstractable hydrogen atoms is polydopamine. Polydopamine is an example of a polymer containing catechol functional groups. In another embodiment, the polymer comprising abstractable hydrogen atoms comprises polydopamine. As discussed in the background of the present invention, polydopamine is formed by polymerization of monomeric dopamine. The exact structure of polydopamine is not well understood. Also, many structures have been proposed as shown in FIG.

  The polymerization of dopamine occurs under oxidative conditions and a slight exposure to air (ie oxygen) is sufficient for the initiation of the polymerization. It is generally known that the first oxidation of dopamine occurs at the catechol moiety, and then reacts with another part of dopamine or undergoes intermolecular cyclization (via a pendant primary amine) to nitrogen. A containing vehicle can be formed. The structure A of polydopamine (as described in WO 2010/006196) suggests polydopamine consisting of repeating 5,6-dihydroxy-3H-indole units and bridging at the 4 and 7 positions. Structure B (as described in Zhao et al., Polym. Chem., 2010, 1, pages 1430-1433) is a similar polymer, but every other 5,6-dihydroxy-3H-indole unit. Suggests polymers that are substituted with 5,6-dihydroxyindoline units. Structure C is similar to structure A as before, but another possible structure for polydopamine in which every other 5,6-dihydroxy-3H-indole unit is replaced with an acyclic dopamine molecule. As proposed by the present inventors. This structure of polydopamine thus contains primary amine functional groups. Structure D (described in Kang et al., Langmuir, 2009, 25, pp. 9656-9659) has also been proposed by the present inventors, and a bond between dopamine molecules and a bond between catechol rings in a nitrogen five-membered ring. To suggest. This structure also suggests that quinone and catechol rings are present in the polymer structure. Finally, structure E (described in Dreyer et al., Langmuir, 2012, 28, pages 6428-6435) is not covalently linked to polydopamine, but instead is based on 5,6-dihydroxyindoline and its dione derivative. It shows a completely different structure which is a supramolecular assembly of monomers.

  It should be noted that, in the context of the present invention, the structure representation of polydopamine is not critical to the effectiveness of the methods and coatings of the present invention, and the above discussion only includes background references.

In one aspect, the present invention is a substrate having a first coating and a second coating, wherein the first coating is a polydopamine surface primer coating, and the second coating comprises components A and A hydrophilic coating comprising B and a cross-linked copolymer of optional components C and D comprising:
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers, each containing an alkyne group, also now happens Preferably,
Component B comprises, and preferably consists of, one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups
Component C, if present, includes and preferably consists of one or more beneficial chemicals each containing one or more (eg, one) alkene or alkyne groups, and Component D is present And comprising one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from thiol, alkene and alkyne groups, and preferably consists of
The crosslinked copolymer is formed by radical polymerization involving the alkene and / or alkyne groups of components A, B and C (if present) and the functional groups of component D (if present);
The hydrophilic coating comprises one or more beneficial chemicals and preferably optionally comprises component E, wherein component E comprises components A, B, C (if present) and D A second coating that does not form a copolymer with (if present)
As well, the second coating provides a substrate that is covalently bonded to the first coating.

  “Substrate having a first coating and a second coating” shall not mean “a substrate consisting of a first coating and a second coating” (−one or more). Can be applied to the substrate prior to application of the first coating, and / or one or more additional coatings can be applied to the substrate after application of the second coating) Note that in general. For example, in the above aspects of the invention, one or more further coatings between the substrate and the polydopamine surface primer coating are possible and / or one or more on the second (hydrophilic) coating. Additional coatings can be applied.

The “polydopamine” referred to in this disclosure is preferably formed by polymerization of dopamine and / or dopamine analogs. Preferably, polydopamine is formed by polymerization of dopamine. Dopamine analogs include those that are similar in structure to dopamine, including molecules that have the same or similar biochemical pathway as dopamine, and oxidized derivatives of tyrosine. In one embodiment, the dopamine analog is a compound of structural formula (II), wherein one or more of R ¹ -R ⁹ is not H.

In another embodiment, the dopamine analog is a compound of structural formula (II), wherein R ¹ -R ⁹ are H, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C _{From the} group consisting of ₈ alkynyl, —OH, —CO ₂ H, —C (O) C ₁ -C ₈ alkyl, —C (O) C ₂ -C ₈ alkenyl, —C (O) C ₂ -C ₈ alkynyl. Selected independently). Suitably, the compound of structural formula (II) contains at least one abstractable hydrogen atom.

  Natural dopamine analogs include the following.

Methods for preparing polydopamine coatings As noted above, dopamine in an alkaline aqueous solution exposed to air (ie, oxygen) will polymerize to form polydopamine without additional reaction. However, the polymerization rate can be increased by adding an oxidizing agent to the dopamine-containing solution. Suitable oxidizing agents include but are not limited to ammonium persulfate and sodium persulfate. Thus, in one embodiment, the polydopamine surface coating is formed by contacting the surface of the substrate with a mixture comprising an oxidant and dopamine and / or dopamine analogs.

  Dopamine polymerization has also been observed faster in alkaline aqueous solutions, presumably due to activation of the catechol hydroxy group for deprotonation and oxidation. However, as shown in Example 1.8, we advantageously dopamine in which the use of an oxidizing agent proceeds in a controlled manner at a neutral or acidic pH within a reasonable time frame. It has been found that polymerization is possible. Suitable oxidizing agents include ammonium persulfate and sodium persulfate.

  Thus, in one embodiment, the polydopamine surface coating is formed by contacting the surface of the substrate with a mixture comprising an oxidizing agent and dopamine and / or dopamine analogs at pH 4-10, eg, pH 7. In another embodiment, the polydopamine surface coating is formed at pH <7, such as pH 4-7. In a further embodiment, the polydopamine surface coating is formed at a pH of 5 to 6.9, such as 5.5 to 6.5. The pH of the dopamine and / or dopamine analog solution can be adjusted with any suitable acid or base, such as HCl or NaOH, respectively.

  Coating a substrate with a polydopamine surface coating under acidic or neutral conditions over the basic conditions of the prior art advantageously coats a base sensitive substrate with the hydrophilic coating of the present invention. Make it possible. However, the inventors have found that the polymerization of dopamine (or dopamine analogs) under acidic or neutral conditions (ie, pH <7) is due to the formation of polydopamine formed in the bulk and on the surface of the polydopamine coating. It has been found that it has the further advantage of greatly reducing the precipitation of particles or aggregates.

  Based on the results described in the examples, the inventors have found that a pH of around 6 is necessary to allow a suitable polymerization time of dopamine to reach a suitable thickness of coating before a significant degree of granulation occurs. It was concluded that the value was optimal. Although the polymerization reaction at a more acidic pH is slower, we have determined that during a given time of polymerization, the reaction is highly controlled due to slower kinetics, and the precipitation of polydopamine particles and aggregates. It was observed that it can be minimized. As discussed in the context of the present invention, granulation on the surface of the coating can be a problem in certain applications. Further, as discussed in the examples, also Wei et al., Polym. Chem. 2010, 1, pages 1430-1433, confirming that the slower polymerization at acidic pH under oxidizing conditions is at least as good as that observed for polymerization under faster alkaline conditions. To produce a coating that is uniform. Coatings prepared at acidic pH under oxidizing conditions are more reproducible, thus extending the process time during which polydopamine granulation occurs. This is an advantage from a manufacturing point of view.

  As shown in Example 1.9 and discussed in Example 1a, the amount of oxidizer affects the polymerization rate and can also affect the amount of granulation. In an example, the amount of dopamine in the solution is 1 g / L to 5 g / L, and the amount of APS in the solution is 0.6 g / L to 3 g / L. In one embodiment, granulation appears to be lower with 1 g / L dopamine and 0.6 g / L APS due to acceptable reaction rates. The polymerization rate may be increased by increasing the concentration of dopamine and / or APS. The concentration of dopamine or analog may typically be 0.5-10 g / L, and the concentration of APS may typically be 0.1-5 g / L. One skilled in the art can adjust the concentration of dopamine and the concentration of oxidizing agent in solution to optimize the kinetics of the polymerization reaction.

  The polymerization of dopamine can be carried out in aqueous solution or in an aqueous / organic mixture such as a mixture of water and methanol, ethanol, propanol and / or isopropanol.

  The pH of the solution can be controlled with a buffer (e.g. http://www.sigmaaldrich.com/life-science/core-bioagents/biological-buffers/learning-center/buffer-reference.ref. checking).

  As discussed in Examples 1 and 1a, MES buffer was found to be suitable. Other possible buffers include ACES, PIPES, MOPSO, bis-trispropane, BES, MOPS, TES, and HEPES.

  The time required to form the polydopamine coating will vary depending on the specific reaction conditions used. For example, the addition of an oxidant may increase the rate of polymerization or may allow the use of neutral or acidic pH. The polydopamine coating is preferably formed during a time suitable for efficient manufacture. For example, the desired polydopamine coating can be formed within a range of 24 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour or 30 minutes. As a general principle, the longer the polymerization time, the thicker the polydopamine coating that forms. However, after a certain period of polymerization, polydopamine will precipitate from solution in a particulate form that causes the various problems described above. Thus, the optimal polymerization time for dopamine is long enough to obtain a sufficient coating of polydopamine, but not so long as to disable the control of granulated polydopamine that can form in solution. . Suitably, the polymerization time does not exceed 24 hours, for example up to 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour or 30 minutes.

  Suitably, the thickness of the polydopamine coating is 5 to 100 nm, for example 10 to 50 nm.

  Preferably, the polydopamine coating is formed at room temperature, but the polymerization can be carried out at higher / lower temperatures.

  A detailed method of forming a polydopamine coating on various substrates is shown in Examples 1.1 to 1.13 and an optimized procedure is shown in Example 1.11.

  A possible alternative approach to forming polydopamine using charge (voltage) is described by Kang et al., Angelwandte Chemie, 2012, vol. 124, pages 1-5.

Radical initiator capable of abstracting hydrogen atoms from the surface According to an embodiment, polymerization of components A, B and optional C and D abstracts hydrogen atoms from the surface of the substrate to produce surface-bound radicals Initiated by a radical initiator. A surface-bonded radical is a radical that binds to or remains in the range of a surface from which hydrogen atoms have been extracted. The surface bound radicals then react with components A, B and optionally at least one of C and D to form a copolymer of related components that are covalently bonded to the surface.

  Preferably, the radical initiator is not covalently bonded to the surface containing hydrogen atoms that can be withdrawn either before or after the polymerization reaction.

  Suitable type II photoinitiators based on benzophenone other than benzophenone include benzophenone-3,3'-4,4'-tetracarboxylic dianhydride, 4-benzoylbiphenyl, 4,4'-bis (diethylamino) Benzophenone, 4,4′-bis [2- (1-propenyl) phenoxy] benzophenone, 4- (diethylamino) benzophenone, 4,4′-dihydroxybenzophenone, 4- (dimethylamino) benzophenone, 3,4-dimethylbenzophenone, Examples include, but are not limited to, 3-hydroxybenzophenone, 4-hydroxybenzophenone, 2-methylbenzophenone, 3-methylbenzophenone, 4-methylbenzophenone, methylbenzoylformate and Michler's ketone. Other suitable benzophenones are available from IGM resin under the brand name Omnipol. Such substrates are sometimes referred to as benzophenone derivatives in this disclosure.

  Xanthone-based preferred type II photoinitiators include 9-xanthenone, 1-hydroxy-3,7-dimethoxyxanthone, 1-hydroxy-3,5-dimethoxyxanthone, 1-hydroxy-3,5,6, Examples include, but are not limited to, 7-tetramethoxyxanthone, 1-hydroxy-3,5,6,7,8-pentamethoxyxanthone, 1-hydroxy-3,7,8-trimethoxyxanthone and 2-benzoylxanthone. There is nothing.

  Suitable type II photoinitiators based on thioxanthone include 1-chloro-4-propoxy-9H-thioxanthen-9-one, 2-chlorothioxanthen-9-one, 2,4-diethyl-9H-thio Examples include, but are not limited to, xanthen-9-one, isopropyl-9H-thioxanthen-9-one, 10-methylphenothiazine and thioxanthen-9-one. Other suitable thioxanthones are available from IGM resin under the Omnipol brand name. Such substrates are sometimes referred to as thioxanthone derivatives in this disclosure.

  Various other photoinitiators that may be suitable include anthraquinone-2-sulfonic acid sodium salt monohydrate, 2-tert-butylanthraquinone, camphorquinone, diphenyl (2,4,6-trimethylbenzoyl) Examples include, but are not limited to, phosphine oxide, 9,10-phenanthrenequinone and phenylbis (2,4,6-trimethylbenzoyl) phosphine oxide.

  Cationic photoinitiators that may be suitable include bis (4-tert-butylphenyl) iodonium perfluoro-1-butanesulfonate, bis (4-tert-butylphenyl) iodonium p-toluenesulfonate, bis (4 -Tert-butylphenyl) iodonium triflate, BOC-methoxyphenyldiphenylsulfonium triflate, (4-bromophenyl) diphenylsulfonium triflate, (tert-butoxycarbonylmethoxynaphthyl) -diphenylsulfonium triflate, (4-tert-butyl Phenyl) diphenylsulfonium triflate, diphenyliodonium 9,10-dimethoxyanthracene-2-sulfonate, diphenyliodonium hexafluorophosphate, Phenyliodonium nitrate, diphenyliodonium perfluoro-1-butanesulfonate, diphenyliodonium p-toluenesulfonate, diphenyliodonium triflate, (4-fluorophenyl) diphenylsulfonium triflate, (4-methoxyphenyl) diphenylsulfonium triflate, 2 -(4-methoxystyryl) -4,6-bis (trichloromethyl) -1,3,5-triazine, (4-methylphenyl) diphenylsulfonium triflate, (4-methylthiophenyl) methylphenylsulfonium triflate, 1 -Naphtyldiphenylsulfonium triflate, (4-phenoxyphenyl) diphenylsulfonium triflate, (4-phenylthiophenyl) diphenylsulfoniu Triflate, triarylsulfonium hexafluoroantimonate salt mixed in 50% by weight in propylene carbonate, triarylsulfonium hexafluorophosphate salt mixed in 50% in propylene carbonate, triphenylsulfonium perfluoro-1-butanesulfonate (butanesulfonate), Examples include, but are not limited to, triphenylsulfonium triflate, tris (4-tert-butylphenyl) sulfonium perfluoro-1-butanesulfonate and tris (4-tert-butylphenyl) sulfonium triflate.

  In one embodiment, the radical initiator is selected from the group consisting of benzophenone and derivatives thereof and xanthone and derivatives thereof.

Benzophenone In one embodiment, the initiator is benzophenone. Benzophenone is a type II photoinitiator and is widely used especially with amines due to the high quantum efficiency of hydrogen abstraction / proton transfer. A typical reaction scheme for photoinitiated polymerization using benzophenone is shown in Scheme 1 below.

As shown in Scheme 1, when exposed to ultraviolet light, a triplet excited state of benzophenone is formed, drawing hydrogen from another molecule (co-initiator) and the ketyl radical ([Ph ₂ C ^· -OH]) and it is possible to form a co-initiator radical (R ^·). Due to steric hindrance and delocalization of unpaired electrons, ketyl radicals usually do not react at all with vinyl (ie unsaturated) monomers. Thus, usually a co-initiator radical will initiate the polymerization. In the context of the present invention, RH represents a substrate having a surface containing abstractable hydrogen atoms. Accordingly, triplet excited benzophenone extracts hydrogen atoms from the surface to form surface-bonded radicals on the surface of the substrate. These surface-bound radicals then react with at least one of components A, B and optionally C and / or D (“monomer” in Scheme 1) to form the substrate (“polymer” in Scheme 1). Form components A, B and optionally a copolymer of C and / or D covalently bound to the surface. The description of benzophenone as a radical initiator shown in Scheme 1 is equally applicable to other radical initiators. Preferably, the radical initiator is a type II initiator.

  In the method of the present invention, surface-bonded radicals are generated by extracting hydrogen atoms from the surface of the substrate to be coated. This radical then reacts with at least one of components A, B, C (if present) and D (if present) to form a covalent point between the surface and the coating. From this, the amount of radical initiator present in the polymerization solution can affect the amount of covalent bonds between the surface and the entire coating, and as a result of the final hydrophilic coating. Durability and lubricity may be affected.

  As described in Example 2, experiments were performed to measure the absorbance of various concentrations of benzophenone in ethanol. As discussed in detail in Example 2, the inventors have found that the concentration of benzophenone is preferably at least 1 mmol / L in order for benzophenone to exert its hydrogen abstraction properties effectively. The concentration was evaluated in solution. The actual concentration of benzophenone on the surface after evaporation of the solvent before curing appears to be higher than 1 mmol / L.

  However, an interactive increase in the amount of benzophenone in the polymerization solution may not continuously improve the properties of the final hydrophilic coating. Benzophenone is extremely hydrophilic due to its two aromatic rings and exhibits poor solubility in water. If the concentration of benzophenone is too high, this will result in side reactions such as radical-radical termination, including the reaction of intermediate benzophenone radicals with surface-bound radicals resulting in benzidolol covalently bound to the surface of the substrate. . This causes a hydrophobic region on the surface of the final coating, reducing its hydrophilicity (through its reduced ability to absorb water) and its lubricity. A further disadvantage of the use of high concentrations of benzophenone is an increase in the amount of low molecular weight eluting material. Therefore, the upper limit of benzophenone in the polymerization mixture is preferably about 0.5-5% by weight. In one embodiment, the concentration of benzophenone is 0.1-100 mM.

Side Radical Initiator Combinations of This Embodiment of the Invention Schematically Shown in FIG. 4 Radical polymerization may be increased by initiating polymerization through the use of one or more radical initiators. In one embodiment, the radical initiator of step (a) is a mixture of two or more radical initiators, in particular two or more ultraviolet photoinitiators. In one embodiment, the radical initiator of step (a) is from benzophenone, xanthone, thioxanthone, benzoin ether, benzyl ketal, α-dialkoxyacetophenone, α-hydroxyalkylphenone, α-aminoalkylphenone and acylphosphine oxide. A mixture of two or more ultraviolet photoinitiators selected from the group consisting of: In one embodiment, the radical initiator of step (a) is benzophenone and / or a derivative thereof and a mixture of thioxanthone and / or a derivative thereof. Preferably, the radical initiator of step (a) is a mixture of benzophenone and thioxanthone.

  Each ultraviolet photoinitiator will absorb a certain wavelength of ultraviolet radiation and consequently some wavelengths of ultraviolet radiation will not be absorbed. The efficiency of the radical initiator can be improved by the addition of a second ultraviolet photoinitiator that will absorb ultraviolet radiation at a wavelength that the first ultraviolet initiator will not absorb. This is shown in FIG. 12 for benzophenone and thioxanthone and shows how these two photoinitiators are complementary in this respect.

  Benzophenone may be used in combination with a derivative of benzophenone, for example, providing a combination with a flatter range of radiation spectrum.

  A substrate coated with the coating of the present invention according to this embodiment (i) was prepared according to the method described in the examples.

Embodiment (ii)
In a second embodiment, in the process initiated by free radicals formed in contact with the surface in the liquid phase, the reactive groups on the surface of the substrate are at least components A and B and optional components C and D. React with one to covalently bond the copolymer to the surface.

  As shown in FIG. 2, in this embodiment, the polymerization is performed with polymerizable functional groups on the surface of the substrate and alkene and / or alkyne groups on components A, B, and C (if present), As well as the functional groups of component D (if present), leading to components A, B and optional copolymers of C and / or D covalently bound to the surface of the substrate (in FIG. 2 Only the alkene groups on the surface of the substrate and components A and B are shown). In practice, the polymerizable functional groups on the surface of the substrate act as anchor groups for the covalent bonding of the copolymer. Suitable functional groups on the surface of the substrate include alkene, alkyne and thiol groups.

Thus, in another embodiment, the present invention is a method of forming a hydrophilic coating that is covalently bonded to the surface of a substrate, wherein the substrate has a surface containing polymerizable functional groups, said method comprising:
(A) contacting the surface with a liquid phase mixture comprising components A and B, optional component C, optional component D and radical initiator, wherein the radical initiator is in the liquid phase Can generate radicals,
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers, each containing an alkyne group, also now happens Preferably,
Component B comprises, and preferably consists of, one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups
Component C, if present, includes and preferably consists of one or more beneficial chemicals each containing one or more (eg, one) alkene or alkyne groups, and Component D is present The process comprising, and preferably consisting of, one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from thiol, alkene, and alkyne groups;
And (b) an alkene and / or alkyne group of components A, B and C (if present), a substrate, to form a cross-linked copolymer of component A, component B, and optional components C and D Initiating radical polymerization involving the polymerizable functional groups on the surface of the polymer and the functional groups of component D (if present), wherein the copolymer is covalently bonded to the surface; and (c) optional Optionally, incorporating component E comprising and preferably consisting of one or more beneficial chemicals into the hydrophilic coating, wherein component E comprises components A, B, C (if present) ) And D (if present) do not form a copolymer.

  As discussed above, the need for abstractable hydrogen atoms at the surface is avoided if the surface contains groups that can act as anchor groups for the covalent bonding of the copolymer. For example, the surface can include alkene and / or alkyne or thiol groups that can participate in the polymerization reaction. In an embodiment, the surface is a polydopamine surface, which is functionalized with alkene and / or alkyne groups or thiol groups. Such polydopamine surfaces can be made by polymerization of dopamine and dopamine analogs containing at least some proportion of alkene and / or alkyne or thiol group functionalized dopamine (or analog). Preferably, synthetic dopamine analogs are formed by primary amine functionalization of dopamine.

Examples of this type of dopamine analog are shown below.

  Such dopamine analogs can be polymerized using the method of preparing a polydopamine coating described above with respect to embodiment (ii).

Radical initiator capable of generating radicals in the liquid phase Radical initiators capable of generating radicals in the liquid phase include photoinitiators (type I and type II radical initiators) and thermal initiators. Is mentioned.

  Examples of type I radical initiators include benzyl, benzoin and acetophenone based photoinitiators.

  Benzyl and benzoin based photoinitiators include, but are not limited to, benzoin, benzoin ethyl ether, benzoin methyl ether, 4,4'-dimethoxybenzoin, and 4,4'-dimethylbenzyl.

  Acetophenone-based photoinitiators include 2-benzyl-2- (dimethylamino) -4′-morpholinobutyrophenone, 3,6-bis (2-methyl-2-morpholinopropionyl) -9-octylcarbazole, 4'-tert-butyl-2 ', 6'-dimethylacetophenone, 2,2-diethoxyacetophenone, 2,2-dimethoxy-2-phenylacetophenone, diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide / 2 -Hydroxy-2-methylpropiophenone, 4'-ethoxyacetophenone, 3'-hydroxyacetophenone, 4'-hydroxyacetophenone, 1-hydroxycyclohexyl phenyl ketone, 2-hydroxy-4 '-(2-hydroxyethoxy) -2 -Methylpropiophenone, 2-H Proxy-2-methyl propiophenone, 2-methyl-4 '- (methylthio) -2-morpholino propiophenone and 4'-phenoxy acetophenone but non the like is not limited.

  Thermal initiators may be used to initiate radical polymerization of components A and B and optional C and D. Thermal initiators generate free radicals that, when heated, split evenly and initiate the polymerization process. Ideally, the thermal initiator should be relatively stable at room temperature, but should decompose quickly enough at the polymerization temperature to ensure that the reaction rate is maintained. The use of thermal initiators may be preferred over photoinitiators depending on the substrate to be coated. Substrates such as tubes have an inner surface that may be difficult or practically impossible to be exposed to visible or ultraviolet light. Using heat initiators would be more practical in this situation because heat can be distributed evenly over all parts of the substrate.

  Examples of thermal initiators include tert-amyl peroxybenzoate, 4,4-azobis (4-cyanovaleric acid), 1,1′-azobis (cyclohexanecarbonitrile), 2,2′-azobisisobutyro Nitrile (AIBN), benzoyl peroxide 2,2,2-bis (tert-butylperoxy) butane, 1,1-bis (tert-butylperoxy) cyclohexane, 2,5-bis (tert-butylperoxy) -2,5 -Dimethylhexane, 2,5-bis (tert-butylperoxy) -2,5-dimethyl-3-hexyne, bis (1- (tert-butylperoxy) -1-methylethyl) benzene, 1,1-bis ( tert-butylperoxy) -3,3,5-trimethylcyclohexane, tert-butylhydroperoxy Side, tert-butyl peroxide, tert-butyl peroxide, tert-butyl peroxybenzoate; tert-butyl peroxyisopropyl carbonate, cumene hydroperoxide, cyclohexanone peroxide, dicumyl peroxide, lauroyl peroxide, 2,4-pentanedione peroxide, Examples include peracetic acid and potassium persulfate.

Other Embodiments In a further embodiment, the covalent bond between the surface of the substrate and the hydrophilic coating is a polymerization that includes both embodiments (i) and (ii) (eg, the surface of the substrate can be withdrawn). Formed through a hydrogen atom and an active functional group).

  In both embodiments (i) and (ii), the copolymer formed by the polymerization of components A, B and optionally C and D is a random copolymer, given a component at a specific point in the polymer chain. The possibility of finding the type is equal to the mole fraction of that component in the polymerization solution.

  In one embodiment, the surface of the substrate contains both abstractable hydrogen atoms and reactive groups that can react with the reactive groups of the components in the polymerization solution. In this embodiment, the choice of radical initiator will dictate the initiation pathway that leads to the covalent attachment of the hydrophilic coating to the surface of the substrate. Thus, when selecting a type II initiator, a covalent bond will be formed as described in embodiment (i). If a type I or thermal initiator is selected, a covalent bond will be formed as described in embodiment (ii). If both a type II initiator and a type I or thermal initiator are selected, a covalent bond will be formed through mixing of the processes described in embodiments (i) and (ii).

According to a preferred aspect of the present invention, a substrate having a surface having a first primer coating layer of polydopamine and a second hydrophilic coating layer comprising a cross-linked copolymer of components A and B,
Component A, one or more alkenes and / or alkyne group (e.g., component A acrylic acid, methacrylic acid and mixtures thereof) one or more C ₂ -C ₁₆ hydrophilic monomers, each containing Including
One or more hydrophilic polymers wherein component B each comprises two or more alkene and / or alkyne groups (eg, component B is selected from compounds of structural formulas (I) and (II) as defined above) Including
The crosslinked copolymer is formed by radical polymerization involving alkene and / or alkyne groups of components A and B;
Also provided is a substrate in which a second hydrophilic coating layer is covalently bonded to the polydopamine first primer coating layer. Said covalent bond is preferably achieved via reaction of surface-bonded radicals on the dopamine with components of the hydrophilic coating (surface-bonded radicals are generated through abstraction of hydrogen atoms from dopamine). .

According to a preferred aspect of the present invention, there is provided a method for forming a hydrophilic coating that is covalently bonded to the surface of a substrate, the method comprising
(A) creating a first primed coating layer of polydopamine on a substrate by contacting the coating with dopamine under conditions such that polymerization of dopamine can occur (eg, in the presence of an oxidizing agent); ,
(B) contacting a substrate primed with dopamine with a mixture comprising components A and B and a radical initiator,
Component A, one or more alkenes and / or alkyne group (e.g., component A acrylic acid, methacrylic acid and mixtures thereof) one or more C ₂ -C ₁₆ hydrophilic monomers, each containing And component B contains one or more alkene and / or alkyne groups (eg, component B is selected from compounds of structural formulas (I) and (II) as defined above) Containing a hydrophilic polymer,
And (c) initiating radical polymerization involving the alkene and / or alkyne groups of components A and B to form a crosslinked copolymer of component A and component B, wherein the copolymer is a polydopamine first There is provided a method comprising the step of covalently bonding to an undercoat coating layer.

Further aspects of the method of the present invention Prior to coating, the surface of the substrate may be improved to improve adhesion to polymers containing abstractable hydrogen atoms, or to coatings optionally containing beneficial chemicals. Can be washed or pretreated. Pre-cleaning or pre-treatment of the surface may also improve the uniformity of any coating.

  Suitable cleaning or pretreatment agents include solvents such as ethanol or isopropanol (IPA), high pH solutions such as solutions containing a mixture of alcohol and an aqueous solution of a hydroxide compound (eg sodium hydroxide), hydroxylation Solutions containing tetramethylammonium hydroxide (TMAH), such as sodium solution, basic piranha (ammonia and hydrogen peroxide), acidic piranha (mixture of sulfuric acid and hydrogen peroxide), and sulfuric acid and potassium permanganate or various Other oxidizing agents including peroxosulfuric acid or peroxodisulfuric acid solutions (also ammonium, sodium, and potassium salts such as ammonium persulfate) or combinations thereof may be mentioned.

  Two specific pretreatment methods—Method A and Method B—are described in the basic procedure. Method A involves IPA treatment of the substrate to be coated, while in Method B, the substrate is treated with IPA and then with a solution of APS. As discussed in Example 1a, Pretreatment Method B produced a more uniform coating of polydopamine than when Method A was used. Thus, in one embodiment, the surface of the substrate is pretreated with an oxidizing agent prior to the formation of the polydopamine surface coating. In another embodiment, the surface of the substrate is treated with IPA and an oxidizing agent prior to formation of the polydopamine surface coating. In a further embodiment, the surface to be coated is pretreated with IPA and ammonium persulfate prior to formation of the polydopamine surface coating.

  When coating a substrate with a surface primer coating of a polymer containing abstractable hydrogen atoms, the alignment of the substrate during the primer step can affect the amount of granulation observed on the surface of the substrate. is there. When the surface subbing coating of the polymer containing abstractable hydrogen atoms is polydopamine, we have found that the horizontal alignment of the substrate during the subbing can be achieved in deposition (via deposition) and in bulk solution. It was observed that it would result in adhesion of the formed polydopamine particles / aggregates. Large scale rinsing is necessary to remove particles / aggregates known to have adverse effects. Vertical alignment of the substrate is preferred in the primer step to minimize polydopamine particle / aggregate adhesion formed in the bulk solution. Since fewer numbers of agglomerates / particles will be present on the primed substrate, the vertical alignment method does not require a similar large-scale rinse.

Properties of the hydrophilic coating The lubricity of the coating can be measured using the basic procedure and the lubricity test described in Example 3b.

  In an embodiment, the hydrophilic coating is lubricious and using the lubricity test, for example, the lubricity of the coating is <100 g, for example <50 g, for example <15 g.

  More generally, using a lubricity test, the lubricity of the coating may be <200 g. If the coating includes beneficial chemicals that impart properties other than lubricity (eg, where the beneficial chemical is a pharmacological chemical), acceptable lubricity can be higher.

  The durability of the coating can be measured using the basic procedure and the durability test described in Example 3b. In one embodiment, using a durability test, the durability of the coating is <50 g, such as <25 g, such as <15 g.

  As illustrated by the examples, the coatings of the present invention were applied to PEBAX and stainless steel shafts, and all were found to have good durability and lubricity.

  Without wishing to be bound by theory, the inventors have shown that the good durability of the coating of the present invention is that monomer components A and B and optionally copolymers of C and D, the surface of the substrate, We believe that this is the result of a covalent bond between. In an embodiment, the covalent bond is formed by the reaction of surface-bonded radicals (on the surface of the substrate) with monomer components A and B and optionally C and D.

In one embodiment, the coating comprises heparin and the density of heparin is> 0.1 μg / cm ² , for example> 0.5 μg / cm ² in the heparin density evaluation test. In one embodiment, the coating is an antithrombotic drug and the residual platelets maintain a value of> 70% in the blood contact assessment test.

  In another embodiment, the coating comprises an antimicrobial agent and exhibits an antimicrobial effect for up to 15 days when measuring the inhibition zone.

  In a further embodiment, the coating is biocompatible, as measured according to ISO 10993-5.

The hydrophilic coating according to the present invention is expected to have, in at least some embodiments, one or more of the following advantages.
Less sensitive to granulation. For example, measure according to the granulation test,
High durability. For example, measuring using a durability test,
Have good coating uniformity. For example, using a staining method and visual inspection,
High lubricity. For example, using a lubricity test or a wet glove test,
Good antithrombogenicity when component C and / or E is present and is an anticoagulant such as heparin. For example, using a blood contact evaluation test,
Good antimicrobial activity when components C and / or E are present and are antimicrobial agents. For example, measured using a stopband test
Stable against sterilization,
Good biocompatibility and low cytotoxicity. For example, the measurement is performed according to ISO 10993-5.

The method according to the invention is expected to have, in at least some embodiments, one or more of the following advantages.
Necessity for organic solvents other than those listed as Class 3 and Class 2 solvents in the residual solvents described in the USP chapter (especially excluding the need for organic solvents other than those listed as Class 3) and such residual organic solvents Eliminating the extra reaction steps required for the removal of
Wide applicability such that the coating can be applied to the surface of many different substrates.

Definitions and abbreviations “C ₁ -C ₈ alkyl” refer to straight or branched aliphatic carbon chains having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- Butyl, pentyl, isopentyl, hexyl, heptyl and octyl and the corresponding alkylene groups such as methylene, ethylene.

'C ₂ -C ₈ alkene' refers to a straight or branched aliphatic carbon chain having 2 to 8 carbon atoms and containing at least one carbon-carbon double bond.

'C ₂ -C ₈ alkyne' refers to a straight or branched aliphatic carbon chain having 2 to 8 carbon atoms and containing at least one carbon-carbon triple bond.
AA Acrylic acid APS Ammonium persulfate BP Benzophenone DMF Dimethylformamide DMSO Dimethyl sulfoxide d. i. Deionized dura. Durable EDC 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride EO ethylene oxide EtOAc ethyl acetate FTIR Fourier transform infrared spectroscopy HEMA 2-hydroxyethyl methacrylate IPA isopropanol lubr. Lubricant MES 2- (N-morpholino) ethanesulfonic acid NHS N-hydroxysuccinimide PBS Phosphate buffered saline PEG Polyethylene glycol RH Relative humidity TEA Triethylamine TASSF Average steady state force of the test THF Tetrahydrofuran tris tris (hydroxy Methyl) aminomethane QCM quartz crystal microbalance

Examples Basic procedure Chemical dopamine hydrochloride (dopamine), benzophenone, ethanol 96%, isopropanol, chlorhexidine, triethylamine, acryloyl chloride, sodium cyanoborohydride, hydrochloric acid 37%, pyridine, methacrylic anhydride, heparin sodium salt, N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 2-aminoethyl methacrylate hydrochloride, tetrahydrofuran, 2- (N-morpholino) ethanesulfonic acid sodium salt, phosphate buffered saline, silver carbonate, acrylic Acid and dihydroxyl functionalized PEG variants (4 kDa, 8 kDa and 20 kDa) were purchased from Sigma-Aldrich and used as permitted. Polyethylene glycol (diacrylated PEG) with a molecular weight of 10 kDa was purchased from Creative PEG Works and used as permitted. A diacrylated PEG with a molecular weight of 8 kDa was synthesized according to Example 7. Tris (hydroxymethyl) aminomethane and ammonium persulfate were purchased from VWR and used as permitted. Polyethyleneimine was purchased from BASF.

Material PVC tubing (id 3 mm) was purchased from Action Technology.
PEBAX shafts (BaSO ₄ filled, unfilled, colored, uncolored) were purchased from Arkema.
Glass slides were purchased from VWR.
QCM gold crystals were purchased from Q-Sense.

Evaluation method Parameters evaluated by each method are given in parentheses.

Lubricity test (lubricity)
The lubricity test is performed with a Harland FTS5000 friction tester. Unless otherwise stated, all shafts were set to 37 ° C. prior to testing d. i. Immerse in a water bath for 1 minute to absorb water. Lubricity is given as the average steady state force (TASSF) of the test. This is calculated by taking the average of the cycle forces between cycles 1-15. The parameters of the pull friction test are: cycle = 15, stroke length = 1-5 cm (changed in the examples), speed = 0.8 cm / s, acceleration = 0.2 seconds, force = 300 g and pause = 0 seconds. See Example 3b and Table 2.

Wet glove test (lubricity)
The wet glove test is an alternative method for testing lubricity. The lubricious coating (<100 g in the lubricity test) feels slippery when wet gloves are used after immersion in water.

Durability test (durability)
Durability is the average force of cycles 13, 14 and 15 when the lubricity test is carried out, and the difference between this value and the value obtained by averaging the forces of cycles 3, 4 and 5 is taken. Is calculated by A silicone rubber pad with a durometer of 60 is used for the example. See Example 3b and Table 2.

Sample appearance inspection (polydopamine undercoat uniformity and coating)
A visual inspection of the samples was performed to evaluate the uniformity of the polydopamine subbing layer, ie the surface coverage. See Example 3a.

Visual inspection of the solution (polydopamine undercoat kinetics and particle precipitation)
A visual inspection of the polymerization solution was performed to evaluate the color change of the primer solution, ie the primer kinetics. The appearance of particles in the polymerization solution was also evaluated using visual inspection. See Example 3a.

Granulation test (granulation in solution)
A model method for assessing the granulation that a patient may be exposed to during the deployment of a medical device is to perform a simulated use test on a simulated deployment system. In such a system, a device designed to move through the bloodstream is serpentine consisting of either a glass or plastic vein that mimics how the device will move through the patient's vasculature. Applied to the route. The inventors have included various angles that are representative of clinical use over typical catheter lengths.

  After the experiment, particles are collected from the sample by flowing filtered deionized water through a serpentine path. Particles in the collection medium are in accordance with the test method described in the volume of the test described in United States Pharmacopeia (USP) monograph 788 by Accusizer Particle Sizer (780 / SIS PSS NICOMP, Santa Barbara, Calif.). Can be analyzed. If the average number of particles present in the unit tested does not exceed 6000 per 10 μm or more container and does not exceed 600 per 25 μm or more container, the preparation meets the test ("OK"), eg See 3b and Table 2.

  The particles in the collection medium may be analyzed by visual inspection. In this case, the fraction of the solution from the serpentine path containing the particles is filtered onto a filter membrane and then inspected for appearance of the particles using microscopy. The filter paper is divided into sections. A careful count of visible particles is performed in one or more representative sections, and the total amount of particles is evaluated by multiplying the total number of sections by the particles from that section.

  Preparations that do not meet USP standards (ie not indicated as “Yes” in Table 2) are not sensitive to the amount of granulation on the surface of the substrate to be coated (eg, level of granulation with respect to coating) Note that it may still have utility in certain non-medical substrates or devices or medical devices) that are not subject to regulatory review.

UATR-FTIR spectroscopy (coating composition)
FTIR analysis of the coating was performed on a Perkin Elmer UATR 100S. Each sample was scanned 3 ^* 16 times and processed to produce an average spectrum for each coating. Samples in order to obtain comparable data was normalized by 1775cm ^-1 ~1700cm ^-1. See Example 3a and FIG.

Scanning electron microscopy (SEM-EDS) with energy dispersive X-ray spectroscopy (surface granulation and elemental composition)
SEM images of appropriate polydopamine primer samples were captured using a Hitachi TM 3000 table top SEM. Surface element quantification was performed using a Bruker EDS Quantax70. See Example 1a.

Contact angle evaluation (coating coating)
Static water contact angle measurements were performed on an FTA200 apparatus manufactured by First Ten Angstrom. D. i. Water (droplet size approximately 10 μl) is dropped onto the sample using a syringe. A high resolution camera is then used to capture the image of the droplet. Static contact angles (angles between the liquid / solid and liquid / air interfaces) are evaluated using an image analysis program. See Example 1a.

Dyeing method (coating uniformity)
The coated substrate can be dipped in the solution for 2 minutes and then applied with a toluidine blue staining solution (200 mg / L in water) by extensive water washing. A blue or purple color is observed on the surface of the coating that contains a net negative charge (eg, polyacrylic acid or heparin functional groups). See Example 3a.

  The coated substrate can be immersed in the solution for 2 minutes and then applied with an acidic Ponceau S dyeing solution (200 mg / L in water) by extensive water washing. A red color is observed on the surface of the coating with a net positive charge (eg quaternary nitrogen functionality). See Example 5a.

Tape test (dry adhesion)
An adhesive tape type (Selotape Diamond Ultra Clear) was pressed firmly on the piece for 10 seconds and then peeled off. By comparing the degree of coating material adhered to the tape and the coating material remaining on the substrate, the relative adhesion between the various coatings of the present invention can be assessed. See Example 1a.

Dissipation monitoring quartz crystal microbalance (QCM-D) (primer thickness)
Dissipation monitoring Quartz crystal microbalance method (QCM-D) is used to evaluate the thickness of the polydopamine subbing layer. Primer thickness is monitored on gold coated crystals (QSX301, Q-Sense). See Example 1a.

X-ray photoelectron spectroscopy (XPS) with depth direction analysis (primer and coating composition)
X-ray photoelectron spectroscopy (XPS or ESCA) is the most widely used surface characterization method that provides non-destructive chemical analysis of solid-pair materials. The sample is irradiated with monoenergetic X-rays that generate photoelectrons to be emitted from the top 1-10 nm of the sample surface. Electron energy analysis evaluates the binding energy of photoelectrons. Qualitative and quantitative analysis of all elements except hydrogen and helium is possible, with a detection limit of about 0.1 to 0.2 atomic percent. The spot size for analysis is in the range of 10 μm to 1.4 mm. It is also possible to create a surface image of the properties using elemental and chemical state mapping. Depth direction analysis can be obtained for the full coating depth using non-destructive analysis within the top 10 nm of the surface using angle dependent measurements, or destructive analysis such as ion etching.

Stop zone (ZOI) (elution of antibacterial function)
The coated samples were evaluated in a zone of inhibition (ZOI) test that tests whether the coated samples affect the growth of specific bacteria using agar plates inoculated with bacteria. If bacteria are susceptible to a particular sample, the clear area surrounds the sample, where the bacteria cannot grow (referred to as a zone of inhibition). See Example 5.6 and Example 5a.

Surface inhibition (antibacterial function that does not elute)
Gently rinse the coated sample from the ZOI test with buffer. The sample is then placed on a fresh agar plate (no bacterial inoculation) and the growth of attached bacteria is evaluated. If bacteria are susceptible to components in the surface coating, no colonies or small amounts of colonies are observed.

Heparin density evaluation test (quantitative heparin adhesion)
Quantification of surface-immobilized heparin is basically performed by Smith R.C. L. and Gilkerson E (1979), Anal Biochem 98, pages 478-480. See Examples 5.2-5.4 and Example 5a.

Doxorubicin staining (drug uptake / elution)
A drug containing coating can be prepared by immersing the coating in a solution of the drug. When soaked in doxorubicin, the red coloration of the coating indicates that doxorubicin is successfully incorporated into the coating. The drug can be released by exposing the coating to a 2M NaCl solution. A reduced level of red indicates that doxorubicin eluted from the coating. Fluorescence may also be used to detect doxorubicin uptake and subsequent release. See Example 5.5 and Example 5a.

Blood contact evaluation test (platelet loss)
Blood contact assessment was performed on samples modified with heparin to assess antithrombogenicity. First, the catheter was washed with 0.15 M saline solution for 15 minutes to wash away all loosely bound heparin and ensure a stable coating residue. The washed coating was placed in a heparinized falcon tube containing whole blood and placed on a rocking tube roller set at 20 rpm and rotated (Experimental Medicine and Biology, 2013, 735, 257- (See Ekdahl KN, Advances on page 270). Platelets from intact blood and blood collected from tubes were counted in a cell counter to determine platelet loss. The large loss of platelets indicates a lack of coating performance. See Examples 5.2-5.4 and Example 5a.

Biocompatibility evaluation (cytotoxicity)
BaSO ₄ filled PEBAX made using the method of the present invention is cut to an appropriate length so that the total surface area is 30 cm ² . A similar process is performed with a native BaSO ₄ filled PEBAX shaft as a reference. The coating is evaluated using the Minimal Essential Medium (MEM) dissolution test described in ISO10993. See Example 3b.

Pretreatment Method Method A: Rinse with IPA The substrate was rinsed with IPA for 5 minutes. D. i. Rinse with H ₂ O and dry at room temperature.

Method B: Rinse with IPA and APS The substrate was rinsed with IPA for 5 minutes, then rinsed with an APS (50 g / L) (in diH ₂ O) solution for 10 minutes. The substrate was rinsed in H ₂ O and dried at room temperature.

Example 1: Formation of a surface subbing coating of a polymer containing abstractable hydrogen atoms on a substrate In the following example, a polydopamine surface subbing coating was formed on various substrates. When the QCM crystal and the PVC tube base material were immersed in the polymerization solution, they were aligned horizontally. All other substrates were aligned vertically. The uniformity, adhesion and other properties of the polydopamine coating were then analyzed. The results are summarized in Example 1a.

Example 1.1 Preparation of polydopamine surface subbing coating on PEBAX shaft at pH 8 using Pretreatment Method A A PEBAX shaft was pretreated according to Method A. The pre-treated shaft was prepared with d. Of Tris buffer (1.21 g / L) and APS (0.6 g / L). i. It was immersed in an aqueous solution and the pH was adjusted to 8.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 15, 30, 60 or 120 minutes, respectively. The polydopamine primed shaft was rinsed with EtOH and analyzed after drying at room temperature.

Example 1.2 Preparation of surface coating of polydopamine on PEBAX shaft at pH 8 using pretreatment method B A PEBAX shaft was pretreated according to Method B. The pre-treated shaft was prepared with d. Of Tris buffer (1.21 g / L) and APS (0.6 g / L). i. It was immersed in an aqueous solution and the pH was adjusted to 8.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 15, 30, 60 or 120 minutes, respectively. Polydopamine primed coated shafts were rinsed with EtOH and analyzed after drying at room temperature.

Example 1.3 Preparation of a surface subbing coating of polydopamine on a slide glass at pH 8 using pretreatment method A A slide glass was pretreated according to Method A. The pre-treated glass slides were prepared using a Tris buffer (1.21 g / L) and APS (0.6 g / L) d. i. It was immersed in an aqueous solution and the pH was adjusted to 8.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 15, 30, 60 or 120 minutes, respectively. Polydopamine primed glass slides were rinsed with EtOH and analyzed after drying at room temperature.

Example 1.4 Preparation of a surface subbing coating of polydopamine on a glass slide at pH 8 using pretreatment method B A glass slide was pretreated according to Method B. The pre-treated glass slides were prepared using a Tris buffer (1.21 g / L) and APS (0.6 g / L) d. i. It was immersed in an aqueous solution and the pH was adjusted to 8.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 15, 30, 60 or 120 minutes, respectively. Polydopamine primed glass slides were rinsed with EtOH and analyzed after drying at room temperature.

Example 1.5 Preparation of a surface subbing coating of polydopamine on a PVC tube at pH 8 using Pretreatment Method A A PVC tube was pretreated according to Method A. Pre-treated PVC tubes were prepared using a Tris buffer (1.21 g / L) and APS (0.6 g / L) d. i. It was immersed in an aqueous solution and the pH was adjusted to 8.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 15, 30, 60 or 120 minutes, respectively. Polydopamine-primed PVC tubes were analyzed after EtOH was circulated through the tube at a rate of 100 mL / min and dried at room temperature.

Example 1.6 Preparation of a surface subbing coating of polydopamine on a PVC tube at pH 8 using Pretreatment Method B A PVC tube was pretreated according to Method B. Pre-treated PVC tubes were prepared using a Tris buffer (1.21 g / L) and APS (0.6 g / L) d. i. It was immersed in an aqueous solution and the pH was adjusted to 8.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 15, 30, 60 or 120 minutes, respectively. Polydopamine-primed PVC tubes were analyzed after EtOH was circulated through the tube at a rate of 100 mL / min and dried at room temperature.

Example 1.7 Preparation of a surface subbing coating of polydopamine on (QCM) gold crystals at pH 8 without pre-treatment QCM gold crystals were prepared in pH 8.0 tris buffer (1.21 g) containing APS (0.6 g / L). / L) d. i. Soaked in an aqueous solution, then dopamine (1 g / L) was added and the polymerization was allowed to proceed for 120 minutes.

Example 1.8 were pretreated BaSO ₄ filler PEBAX shaft in compliance with the manufacturing method B of the surface primer coating of poly dopamine on BaSO ₄ filler PEBAX shaft in pH7,6,5 and 4 using the pretreatment method B. Tris (1.21 g / L) d. i. Added to water followed by APS (0.6 g / L). The solution was poured into 4 separate beakers. The pH of each beaker was adjusted to 7, 6, 5 or 4 using HCL (1M), then the pretreated BaSO ₄ filled PEBAX shaft was immersed in the solution, then dopamine (1 g / L) was added. The color change of the four solutions was monitored over time.

Example 1.9 were pretreated BaSO ₄ filler PEBAX shaft in compliance with the manufacturing method B of the surface primer coating of poly dopamine on BaSO ₄ filler PEBAX shaft in pH6 using pretreatment method B. 4 d. Containing Tris (1.21 g / L) and various amounts of dopamine and APS. i. An aqueous solution was prepared as follows.

The solution was adjusted to pH 6, then a pretreated BaSO4 filled PEBAX shaft was immersed in the solution and then the appropriate amount of dopamine was added. Each solution was visually analyzed for color change and granulation.

Example 1.10 were pretreated BaSO ₄ filler PEBAX shaft in compliance with the manufacturing method B of the surface primer coating of poly dopamine on BaSO ₄ filler PEBAX shaft in pH6.9 using pretreatment method B. The pre-treated shaft was prepared with d. Of Tris buffer (1.21 g / L) and APS (0.6 g / L). i. It was immersed in an aqueous solution and the pH was adjusted to 6.9 using HCl (1M). Dopamine (1 g / L) was added to the solution and the polymerization was allowed to proceed for 4 hours. During the polymerization, the pH of the solution was observed to decrease gradually, so NaOH was added continuously in an amount sufficient to maintain a neutral or slightly acidic pH. Polydopamine primed coated shafts were rinsed with EtOH and analyzed after drying at room temperature.

Example 1.11 were pretreated BaSO ₄ filler PEBAX shaft in compliance with the manufacturing method B of the surface primer coating of poly dopamine on BaSO ₄ filler PEBAX shaft at pH6 in during MES buffer using a pretreatment method B. The pretreated shafts were prepared using MES buffer (9.76 g / L) and NaCl (8.76 g / L) d. i. It was immersed in an aqueous solution and the pH was adjusted to 6.0 using HCl (1M). Dopamine (1 g / L) was added to the solution and after 5 hours the shaft was withdrawn from the solution. Polydopamine coated shafts were rinsed with EtOH and analyzed after drying at room temperature. Polymerization in bulk was allowed to proceed for 24 hours.

Example 1.12. Preparation of surface coating of polydopamine on stainless steel strip at pH 6.0 in a mixture of IPA and water using Pretreatment Method B MES (4.88 g / L) and NaCl (4.38 g / L) d. i. Dissolved in water to pH 6.0 and then doubled in volume by addition of IPA. The mixture was stirred for 2 minutes before dopamine (0.5 g / L) was added. A piece of stainless steel pretreated according to Method B was immersed in a water / IPA buffer solution to allow the reaction to proceed for 4 hours. The stainless steel pieces were then rinsed with EtOH and analyzed after drying at room temperature.

EXAMPLE 1.13 Preparation of a surface subbing coating of polydopamine on titanium pieces at pH 6 in a mixture of IPA and water using Pretreatment Method B MES (4.88 g / L) and NaCl (4.38 g / L). d. i. Dissolved in water to pH 6.0 and then doubled in volume by addition of IPA. The mixture was stirred for 2 minutes before dopamine (0.5 g / L) was added. A piece of titanium pretreated according to Method B was immersed in a water / IPA buffer solution to allow the reaction to proceed for 4 hours. The titanium pieces were then rinsed with EtOH and analyzed after drying at room temperature.

Example 1.14 Preparation of polydopamine primer for hydrogen abstraction on PTFE strips in a mixture of IPA and water PTFE may be primed with polydopamine using essentially the procedure described in Example 1.12.

Example 1a: Evaluation of the polydopamine primer coating of Examples 1.1 to 1.13 The coating uniformity of the polydopamine coating was evaluated by visual inspection and / or contact angle measurement. Adhesion was also evaluated using the tape test using the procedure described in the Basic Procedure section. The amount of precipitation observed in the polymerization solution was assessed visually or by SEM-EDS method. In all cases, the polymerization reaction was stopped by removing the substrate from the solution.

Visual inspection of solutions and substrates All solutions were initially colorless before the addition of dopamine. A color change was observed when dopamine was added. This indicates that dopamine polymerization occurred and polydopamine was formed. In general, a color change of colorless → yellow → orange → brown was observed as the polymerization progressed.

  For all of Examples 1.1 to 1.13, a color change was observed indicating that polymerization occurred to form polydopamine. A visual observation of the rate of color change of the colorless → yellow → orange → brown polymerization solution was used to compare the polymerization rates under various reaction conditions (ie, evaluate the undercoat kinetics). Further, the brown tone obtained on the surface of the substrate after the polymerization reaction showed the amount and / or uniformity of the polydopamine primer coating. The smaller brown tone of the substrate indicates a thinner polydopamine coating and the stronger brown tone indicates a thicker polydopamine coating. In our experience, darker colors are associated with larger precipitates.

Effect of pH on Polymerization In Example 1.8, the effect of pH of the solution on the polymerization rate was evaluated by visual inspection of four solutions at pH 7, 6, 5, and 4. The largest color change (ie the fastest conversion of dopamine in its oxidized state) was observed in a beaker containing a pH 7 solution. The beaker with the pH 4 solution changed its color the least and showed the slowest reaction kinetics. The solution in the pH 7 beaker shifted from colorless to orange after 1 hour, while the solution in the pH 4 beaker was slightly yellowish after 1 hour. The color of the pH 5 and pH 6 solutions was more orange than the pH 4 solution, but to a lesser degree than the pH 7 solution. When the solution was allowed to stand for 6 hours, all pH solutions shifted to orange, with the pH 7 solution being the strongest.

Effect of buffering on polymerization In Example 1.10, it was observed that the pH of the solution decreased during the polymerization of dopamine. To offset the reduced pH, NaOH was added to keep the pH constant during the polymerization process. The absence of polydopamine particle / aggregate formation was observed at the end of the polymerization. The primed shaft according to Example 1.10 was uniform as shown by visual inspection.

  As described in Example 1.11, when MES buffer was added to the dopamine solution, the pH of the solution during polymerization was maintained without the addition of NaOH. This shows the buffering effect of the MES buffer. Visual inspection of the dopamine solution showed that continuous polymerization occurred. No polydopamine particle / aggregate formation was seen at the end of the polymerization. Based on visual inspection, the shaft was uniformly primed with polydopamine.

Evaluation of Solvent Mixture in Polymerization In Examples 1.12 and 1.13, stainless steel pieces and titanium pieces were primed with polydopamine using a mixed solvent of water and IPA. Polymerization kinetics were not significantly affected by the addition of IPA, as measured using a solution visual inspection test. Based on visual inspection, the polydopamine primer showed a uniform coating.

Evaluation of Adhesion of Polydopamine Coating Tape tests were performed as described in General Procedures on PEBAX shafts and glass slides primed according to Examples 1.1-1.4. The adhesive tape was applied to the primed substrate, which was then removed using a 90 ° peel. It was found that removal of the adhesive tape worked well for all samples and showed no visual negative effect in terms of delamination or poor adhesion to the substrate.

Evaluation of Polydopamine Coating Thickness A quartz crystal microbalance coated with gold was mounted in QSense QCM-D, and then the gold surface was primed according to Example 1.7. As described in the basic procedure, the undercoat solution was allowed to pass over the crystals while monitoring the undercoat thickness in a dry state for a long time. After 40 minutes, it was found that the thickness of the polydopamine layer did not increase, and the final dry state thickness of the polydopamine was about 20 nm. The polydopamine-coated gold crystals were dried overnight in a desiccator and again measured for thickness (dry thickness). It was found that the dry thickness coincided with the calculated thickness of about 20 nm in the dry state.

Evaluation of the chemical composition and thickness of the polydopamine coating The chemical composition and thickness of the polydopamine coating may be evaluated using XPS depth analysis.

Evaluation of granulation While making a polydopamine coated PEBAX shaft (made at pH 6) according to Example 1.11, filter paper that collects particles from the polydopamine solution was collected after 5 and 24 hours. It was. SEM-EDS and visual inspection showed that the amount and size of polydopamine particles formed after 24 hours were slightly larger than those after 5 hours. In the case of the 5 hour sample, no visible particles could be seen on the filter paper and only a slight color change of the filter paper fibers due to the absorption of the colored dopamine solution in the filter paper fibers could be seen.

  From experience in assessing the extent of granulation in various samples, we conclude that the degree of granulation increases as the degree of polymerization increases (as evidenced by the greater color change).

Effect of Oxidizing Agent (APS) and Dopamine on Polymerization In Example 1.9 (see Table 1), the effect of the amount of dopamine and APS in the primer solution (pH 6) was evaluated. The solution labeled number 1 contains 1 g / L dopamine and 0.6 g / L APS, the solution labeled number 2 contains 1 g / L dopamine and 3 g / L APS, and the solution labeled number 3 contains 5 g dopamine. / L and APS 0.6 g / L, the solution labeled number 4 contains dopamine 5 g / L and APS 3 g / L. The solution of No. 4 changed its color fastest due to the highest dopamine and APS concentrations and became dark brown after 6 hours. Furthermore, it was found that faster color changes were observed in solutions with higher amounts of APS (No. 1 → No. 2 and No. 3 → No. 4) when the dopamine concentration was kept constant. This indicates that the reaction kinetics can be increased by the addition of an oxidizing agent (APS). It was also found that faster color changes were observed in solutions with higher amounts of dopamine (No. 1 → No. 3 and No. 2 → No. 4) when the APS concentration was kept constant. However, fast polymerization kinetics may result in greater precipitation of polydopamine in the bulk solution. Thus, control of polymerization kinetics is important to ensure that a final product with the desired properties is obtained. One skilled in the art can optimize this parameter. The substrates immersed in the solutions of Nos. 1 to 4 showed a uniform coating of the polydopamine primer, but since the thickness of the undercoat layer was different depending on the four types of solutions, the color of the undercoat substrate was strong. It was different. For a given polymerization time, a controlled system with less particle / aggregate formation may be obtained when the reaction kinetics are lowered (ie, the amount of dopamine and / or APS in solution is reduced). . The solution of number 1 is believed to give the most acceptable reaction rate with an apparently low rate of granulation (based on the degree of color change).

Comparison of Pretreatment Methods A and B A slide glass having a polydopamine coating produced according to Examples 1.3 and 1.4 was analyzed using the outline of the contact angle measurement procedure in the basic procedure. The results of Example 1.3 (Pretreatment Method A) and Example 1.4 (Pretreatment Method B) are shown in FIG. A surface with a complete polydopamine coating will have a contact angle of about 50 ° (Lee et al., Science, 2007, 318, 426). Comparing the contact angles between methods A and B, it is clear that a slightly lower static contact angle was observed after pretreatment method A when compared to slide glass pretreated using method B. This indicates that after pretreatment method B, a more complete coating of polydopamine on the surface of the glass slide was obtained. Furthermore, the glass slide pre-treated with Method B is 15 minutes after dopamine polymerization compared to the glass slide pre-treated with Method A that reached a similar static contact angle after 120 minutes of dopamine polymerization. A stable static contact angle has been reached. This indicates a better overall coverage of polydopamine and also indicates that the glass slide pretreated with Method B reached the coating faster. The contact angle of an unprimed slide glass is shown as a reference data point in FIG. It is clear that the polydopamine primer glass slide (using either pretreatment method A or method B) has a surface with a higher contact angle demonstrating the primer coating compared to the case where the surface is not primed. .

Example 2-Evaluation of the amount of benzophenone used in the formation of the hydrophilic coating of the invention Benzophenone was dissolved in EtOH at various concentrations (1.0E- ¹¹ mol / L to 1 mol / L). The UV absorbance of benzophenone was monitored as a function of concentration. The results are shown in FIG. It is clear from FIG. 6 that the absorption appears only at a concentration of benzophenone exceeding 1.0E ⁻³ mol / L (1 mmol / L). Accordingly, within the present invention, the benzophenone reacts to show its ability to abstract hydrogen so that it reacts to copolymer of components A, B and C (if present) and D (if present). It is believed that the concentration of benzophenone should be at least 1 mmol / L and preferably 1-100 mM to form surface-bound radicals that covalently bond to the surface.

Example 3: Formation of a hydrophilic coating on a polydopamine subbing substrate In the following example, a substrate coated with a polydopamine subbing coating prepared according to Example 1 was prepared by applying the method of the present invention. A hydrophilic coating was formed. In each case, component A was acrylic acid, component B was a diacrylated PEG polymer, and the radical initiator was benzophenone (the radical initiator can abstract hydrogen atoms from the surface of polydopamine. ). The solvent used was ethanol and in each case the radical polymerization was initiated by UV light. The resulting hydrophilic coating was analyzed. The results are also summarized in Examples 3a and 3b.

Example 3.1 Formation of hydrophilic coating on polydopamine-primed PEBAX shaft using benzophenone (1 wt%) and low intensity lamp 8 kDa diacrylated PEG polymer of structural formula (I) (30 mg to 1050 mg, for preparation See Example 7), various solutions of benzophenone (1 wt%) in acrylic acid (300 mg) (mass ratio 0.1: 1 to 3.5: 1), ethanol (2 mL to 6 mL). did. A PEBAX shaft made according to Example 1.2 was then manually dipped into the solution, then removed and cured for 10 minutes using a 365 nm B-100AP UV lamp (provided by UVP). The intensity was recorded as about 15 mW / cm ² using a sensor and radiometer.

Example 3.2 Formation of a hydrophilic coating on a polydopamine-primed PEBAX shaft using benzophenone (1 wt%) and a medium intensity lamp Structural formula (I) 10 kDa diacrylated PEG (450 mg and 1350 mg respectively), acrylic acid (300 mg and 1800 mg respectively) (mass ratios are 1.5: 1 and 0.75: 1 respectively), and two solutions containing benzophenone (1 wt%) in ethanol (10.5 mL and 29 mL respectively) did. The PEBAX shaft made according to Example 1.2 was then immersed in any solution (residence time 5 seconds) and then removed (drawing speeds 5 cm / sec and 2.5 cm / sec, respectively) and RDX UV Cured for 75 seconds using a curing system (240-400 nm) (provided by Harland Medical). The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer. The coated shaft was allowed to swell for 10 minutes in a 37 ° C PBS solution prior to evaluation.

Example 3.3 Formation of Hydrophilic Coating on Polydopamine Primed PEBAX Shaft Using Benzophenone (3 wt%) and Medium Intensity Lamp Structural Formula (I) 10 kDa diacrylated PEG (360 mg-9.0 g), acrylic A reagent consisting of acid (3.6 g) (mass ratio 0.1: 1 to 2.5: 1) and benzophenone (3 wt%) in ethanol (24 mL, 36 mL, 42 mL or 48 mL) was prepared. The PEBAX shaft made according to Example 1.10 was then immersed in the solution (residence time 5 seconds) and then removed (drawing speed 5-15 cm / sec) and RDX UV curing system (240-400 nm) ( Cured for 90 seconds using Harland Medical). The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 3.4 Formation of hydrophilic coating on polydopamine-primed BaSO ₄ filled PEBAX shaft using benzophenone (1 wt%) and high intensity lamp 8 kDa diacrylated PEG of structural formula (I) (75 mg to 1.2 g) , See Example 7 for preparation), a reagent consisting of acrylic acid (300 mg) (mass ratio is 0.25: 1 to 4: 1), and benzophenone (1 wt%) in ethanol (2 mL to 16 mL) Adjusted. A BaSO ₄ filled PEBAX shaft made according to Example 1.2 was removed after manual immersion in the solution and cured for 6 seconds using a Fusion lamp. The intensity was recorded as approximately 200 mW / cm ² using a sensor and radiometer. The coated shaft was allowed to swell for 10 minutes in a water bath set at 37 ° C. prior to evaluation.

Example 3.5 Formation of a hydrophilic coating on a polydopamine primed BaSO ₄ filled PEBAX shaft using benzophenone (1 wt%) and a high intensity lamp 8 kDa diacrylated PEG of structural formula (I) (450 mg, for preparation) See Example 7), a reagent consisting of acrylic acid (300 mg) (mass ratio 1: 5.1), and benzophenone (1 wt%) in ethanol (6 mL), and 8 kDa diacrylated PEG (900 mg ), Acrylic acid (300 mg) (mass ratio is 3: 1), and a reagent consisting of benzophenone (1 mass%) in ethanol (10 mL) was prepared. A BaSO ₄ filled PEBAX shaft made according to Example 1.2 was removed after manual immersion in the solution and cured for 6 seconds using a Fusion lamp. The intensity was recorded as approximately 200 mW / cm ² using a sensor and radiometer. The coated shaft was allowed to swell for 10 minutes in a water bath set at 37 ° C. prior to evaluation.

Example 3.6 Sterilization and Aging Treatment of the Hydrophilic Coating of the Invention A BaSO ₄ filled PEBAX shaft with a hydrophilic coating made in accordance with Example 3.5 is EO sterilized (standard sterilization used for medical devices). Process) and then aged for 46 days in a climatic chamber (RH = 75%, 55 ° C.). The coated shaft was allowed to swell for 10 minutes in a water bath set at 37 ° C. prior to evaluation.

Example 3.7 Formation of hydrophilic coating on polydopamine-primed stainless steel shaft using benzophenone (1 wt%) and low-intensity lamp Stainless steel shaft was prepared according to Example 1.2 polymerizing dopamine for 30 minutes . 8 kDa diacrylated PEG polymer of structural formula (I) (300 mg, see Example 7 for preparation), acrylic acid (100 mg) (mass ratio 3: 1), benzophenone (1 mL in ethanol (2 mL)) % By weight) solution and then manually dipped into the solution a stainless steel shaft and then cured for 30 minutes using a 365 nm B-100AP UV lamp (provided by UVP). The intensity was recorded as about 15 mW / cm ² using a sensor and radiometer.

Example 3a: Surface Coating and Composition Evaluation of the Hydrophilic Coating of the Invention Surface Coating A hydrophilic coating prepared according to the optional procedure of Example 3 was dyed with toluidine blue according to a dyeing test. For all of the examples, it was observed that the hydrophilic coating was uniformly dyed, confirming that negatively charged groups were present on the surface of the PEBAX shaft (ie, good surface coverage of the hydrophilic coating).

Coating Composition The hydrophilic coating prepared according to Example 3.3 was analyzed using the FTIR method. The spectrum is shown in FIG. Clear visualization of notable peaks attributed to ether (C—O, about 1100 cm ⁻¹ ), carbonyl (C═O, about 1730 cm ⁻¹ ), and methylene (C—H, 3000-2800 cm ⁻¹ ). I understood. In addition, signals from NH (3400-3200 cm ⁻¹ ) and amide (NC═O, about 1640 cm ⁻¹ ) associated with the substrate could also be visualized, but these peaks were coated as the PEG component increased. Tended to disappear because it became thicker. The mass ratio of PEG: AA in solution is related to the FTIR peak of its corresponding coating. More specifically, FTIR analysis of coatings within the present invention can be used to assess the PEG: AA mass ratio of unknown solutions used for the preparation of coatings within the present invention.

Example 3b: Evaluation of physical properties of the hydrophilic coating of the invention The hydrophilic coating of the invention prepared according to Examples 3.1 to 3.7 was evaluated using the method described in the general procedure.

The results are summarized in Table 2 below.

Lubricity and Durability The lubricity and durability of the coating were evaluated using the lubricity test and durability test described in the basic procedure. Table 2 of Example 3a generally shows that, as reasonably expected, increasing the ratio of acrylic acid to acrylate-functionalized PEG increases the durability of the coating but decreases its lubricity. Conversely, as the ratio of acrylate functionalized PEG to acrylic acid increases, the coating produced is lubricious but not durable. For example, Examples 3.3.19 (PEG: AA 1.5: 1) and 3.3.15 (PEG: AA 0.25: 1) reduce the ratio of PEG (relative to acrylic acid) by a factor of 6. In this case, the lubricity of the coating decreases (indicated by higher lubricity values) and the durability of the coating increases (indicated by lower durability values). However, the durability value seems to be good <15 g. For Examples 3.3.15 and 3.3.19, lubricity and durability over 15 cycles are shown in FIGS. 8 and 9, respectively.

  The optimal ratio of acrylate functionalized PEG to acrylic acid was found to be in the range of 2.5: 1 to 0.5: 1 (mass ratio). When prepared from an appropriate dilution solution, the lubricity and durability for ratios of coatings outside this range may produce coatings with the desired properties.

  We have surprisingly found that the coating increases in lubricity after successive cycles of lubricity testing. This is shown in Example 3.3.15 (see FIG. 8) in Table 2 where the lubricity value in the first cycle is 19.7 and in the 15th cycle 14.9 g (the lower lubricity (g) value is more lubricated) From this it is clear that the lubricity of the coating has increased.

Intensity of the UV Lamp We have shown that the coatings within this invention will be prepared regardless of the UV lamp intensity test. The strength was changed from 15 mW (low strength) to 200 mW (high strength).

Amount of solvent The concentrations of components A and B, and optionally C and D may be varied in the polymerization solution by the addition of various amounts of solvent. In general, the optimum conditions for the amount of solvent will produce a lubricious coating with good durability. Beyond optimal dilution, the copolymer may wear out due to delamination (high concentration) or due to insufficient coating thickness (low concentration).

Granulation The surface granulation of the coating was evaluated using the granulation test described in the basic procedure. All of the examples tested (apart from Example 3.3.5) passed the USP788 test, indicating that the coating had a proven acceptable level of granulation. For Example 3.3.5, the higher granulation value is not surprising given the high proportion of PEG in a relatively low volume of solution.

Sterilization and Aging FIG. 10 shows lubricity and durability in excess of 15 cycles for Example 3.5, and FIG. 11 shows lubricity in excess of 15 cycles for Example 3.6 (the sample in Example 3.5 is Sterilized and aged). Comparing the lubricity and durability values between FIGS. 10 and 11 (and the values in Table 2), the sterilization and aging process has little, if any, effect on the lubricity and durability of the hydrophilic coating. Is clear.

Biocompatibility A PEBAX shaft with a hydrophilic coating made according to Example 3.2 was evaluated in a cytotoxicity test. The shaft was cut into pieces so that the total surface area would be 30 cm ² / sample. The cut shaft was subjected to a minimal essential medium (MEM) elution test according to ISO 10993 part 5. All tested samples were found to be non-toxic in the MEM dissolution test.

Example 4-Formation of a hydrophilic coating of the present invention based on diacrylated PEG of structural formula (II), benzophenone and thioxanthone 4.1 Hydrophilicity on primed PEBAX shaft using benzophenone (3 wt%) and medium intensity lamp Of a 10 kDa diacrylated PEG of structural formula (II) (3.6 g), acrylic acid (1.8 g) (mass ratio 2: 1), and benzophenone (3 wt%) in ethanol (24 mL) ) Was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.2 Formation of a hydrophilic coating on a primed PEBAX shaft using benzophenone (3 wt%) and thioxanthone (1.5 wt%) and a medium intensity lamp Structural formula (II) 10 kDa diacrylated PEG (3 0.6 g), acrylic acid (1.8 g) (mass ratio is 2: 1), a reagent consisting of benzophenone (3 mass%) and thioxanthone (1.5 mass%) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.3 Formation of hydrophilic coating on primed PEBAX shaft using benzophenone (3 wt%) and medium intensity lamp Structural formula (II) 10 kDa diacrylated PEG (4.5 g), acrylic acid (1. 8 g) (mass ratio is 2.5: 1) and a reagent consisting of benzophenone (3% by mass) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.4 Formation of hydrophilic coating on subbed PEBAX shaft using benzophenone (3 wt%) and thioxanthone (1.5 wt%) and medium intensity lamp 10 kDa diacrylated PEG of formula (II) (4 0.5 g), acrylic acid (1.8 g) (mass ratio is 2.5: 1), a reagent consisting of benzophenone (3 mass%) and thioxanthone (1.5 mass%) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.5 Formation of a hydrophilic coating on an uncoated PEBAX shaft using benzophenone (3 wt%) and a medium intensity lamp 10 kDa diacrylated PEG (3.6 g), acrylic acid (1.8 g) (mass) The ratio was 2: 1) and a reagent consisting of benzophenone (3% by weight) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.6 Formation of a hydrophilic coating on an unprimed PEBAX shaft using benzophenone (3 wt%) and a medium intensity lamp Structural formula (II) 10 kDa diacrylated PEG (3.6 g), acrylic acid ( 1.8 g) (mass ratio is 2: 1) and a reagent consisting of benzophenone (3 wt%) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.7 Formation of a hydrophilic coating on an unprimed PEBAX shaft using benzophenone (3 wt%) and thioxanthone (1.5 wt%) and a medium intensity lamp Structurally (II) 10 kDa diacrylated PEG A reagent consisting of (3.6 g), acrylic acid (1.8 g) (mass ratio is 2: 1), benzophenone (3 mass%) and thioxanthone (1.5 mass%) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.8 Formation of hydrophilic coating on unprimed PEBAX shaft using benzophenone (3 wt%) and medium intensity lamp 10 kDa diacrylated PEG (4.5 g), acrylic acid (1.8 g) (mass) The ratio was 2.5: 1) and a reagent consisting of benzophenone (3% by weight) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.9 Formation of Hydrophilic Coating on Unprimed PEBAX Shaft Using Benzophenone (3 wt%) and Medium Intensity Lamp Structural Formula (II) 10 kDa diacrylated PEG (4.5 g), acrylic acid ( 1.8 g) (mass ratio is 2.5: 1) and a reagent consisting of benzophenone (3% by mass) in ethanol (24 mL) was prepared. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.10 Formation of a hydrophilic coating on an unprimed PEBAX shaft using benzophenone (3 wt%) and thioxanthone (1.5 wt%) and a medium intensity lamp Structurally (II) 10 kDa diacrylated PEG (4.5 g), acrylic acid (1.8 g) (mass ratio is 2.5: 1), a reagent consisting of benzophenone (3 mass%) and thioxanthone (1.5 mass%) in ethanol (24 mL) was prepared. did. The PEBAX shaft made in accordance with Example 1.11. Was then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 seconds) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.11 Formation of hydrophilic coating on primed colored PEBAX shaft using benzophenone (3 wt%) and medium intensity lamp Structural formula (II) 10 kDa diacrylated PEG (3.6 g), acrylic acid ( 1.8 g) (mass ratio is 2: 1) and a reagent consisting of benzophenone (3 wt%) in ethanol (24 mL) was prepared. The yellow colored PEBAX shaft made according to Example 1.11. Is then removed (drawing speed 15 cm / sec) after soaking in the solution (residence time 5 sec) and RDX UV curing system (240-400 nm) (Harland) (Provided by Medical) for 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4.12. Formation of hydrophilic coating on primed colored PEBAX shaft using benzophenone (3 wt%) and thioxanthone (1.5 wt%) and medium intensity lamp Structurally (II) 10 kDa diacrylated PEG A reagent consisting of (3.6 g), acrylic acid (1.8 g) (mass ratio is 2: 1), benzophenone (3 mass%) and thioxanthone (1.5 mass%) in ethanol (24 mL) was prepared. The yellow colored PEBAX shaft made according to Example 1.11. Is then removed (drawing speed 15 cm / sec) after soaking in the solution (residence time 5 sec) and RDX UV curing system (240-400 nm) (Harland) (Provided by Medical) for 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 4a: Surface coating and evaluation of composition of hydrophilic coating of the invention based on diacrylated PRG of structure (II), benzophenone and thioxanthone Surface coating Hydrophilic prepared according to any of the procedures of Example 4 The coating was dyed with toluidine blue according to the dyeing test. For all of the examples, it was observed that the hydrophilic coating was uniformly dyed, confirming that negatively charged groups were present on the surface of the PEBAX shaft (ie, good surface coverage of the hydrophilic coating).
Example 4b: Evaluation of physical properties of a hydrophilic coating of the invention based on diacrylated PRG of structure (II), benzophenone and thioxanthone Hydrophilicity of the invention prepared according to Examples 4.1 to 4.12. The coating was evaluated using the method described in the general procedure.

  The results are summarized in Table 3 below.

Lubricity and Durability The lubricity and durability of the coating were evaluated using the lubricity test and durability test described in the basic procedure. Table 3 of Example 4b shows that the diacrylated PEG according to structural formula (II) gives comparable or lower lubricity and durability values than the diacrylated PEG according to structural formula (I). In general, durability values were close to zero or less than zero for samples tested. Durability and lubricity values <15 g appear to be good.

Effect of thioxanthone Furthermore, the introduction of a second initiator (thioxanthone) that may aid benzophenone in curing the coating clearly shows a decrease in the lubricity value (better lubricity) (eg Example 4.2). Example 4.1 and Example 4.9 compared to Example 4.9). This phenomenon was observed both on the base coat substrate and on the substrate with a unique surface containing abstractable hydrogen atoms. The beneficial effect of thioxanthone could also be seen during the curing of the colored substrate. Examples 4.11 and 4.12 show how the incorporation of thioxanthone reduces the lubricity and durability values. Lubricity is improved from 29.2 g to 4.3 g, and durability is improved from 5.6 g to 0.4 g.

Example 5-Formation of Hydrophilic Coating with Beneficial Chemical In the following example, a hydrophilic coating with a beneficial chemical was formed on an already coated substrate with a polydopamine surface primer coating.

Example 5.1 Formation of a thrombotic coating Hydrophilic coating prepared according to Example 3.3.18 (PEG: AA ratio 1: 1, 3 wt% BP, 42 mL EtOH; 55 mW / cm ² 90 seconds) was soaked in a solution of polyethyleneimine in water (0.010 wt% / L, pH 6) for about 1 minute and then rinsed extensively in water.

Example 5.2 Formation of an antithrombogenic coating using natural heparin A hydrophilic coating prepared according to Example 3.3.14 was added to 50 mL of a solution containing polyethyleneimine (0.01 wt% / L, pH 6). After soaking for 10 minutes, it was rinsed with running water (di water). Adhesion of natural heparin was performed essentially as in Example 2.11 of US 2012/231043, which is hereby incorporated by reference in its entirety. The coating is then d. i. Rinse with water and then rinse with borate-phosphate buffer wash (pH 8).

Example 5.3 Formation of an antithrombotic coating using conjugated heparin-polyethyleneimine An antithrombogenic coating is described in Example 3 of US 2012/231043, which is hereby incorporated by reference in its entirety. May be prepared basically by using conjugated heparin-polyethyleneimine from .3 and by using the procedure described in Example 5.2 above. Such coatings are expected to exhibit antithrombogenic properties.

Example 5.4 Formation of an antithrombogenic coating using heparin end attachment 50 mL of a hydrophilic coating prepared according to Example 3.3.14 in a solution containing polyethyleneimine (0.01 wt% / L, pH 7) And then rinsed with running water (d.i. water). The positively charged coating is then essentially aldehyde functionalized heparin (325 mg) and NaCl (as prepared in Example 2 of US Pat. No. 4,613,665, which is hereby incorporated by reference in its entirety). 29.2 g) in an aqueous solution (1 L) and allowed to react for about 5 minutes, after which NaCNBH ₃ (2, 5% by weight solution (di water in 5 mL)) was added, then about 1 hour Additional reaction was performed. The ionically bound heparin was removed by extensive rinsing with a borate-phosphate buffer solution (pH 8).

Example 5.5 Formation of a doxorubicin-eluting coating A coating prepared according to Example 3.3.18 was placed in an aqueous solution of doxorubicin (1 mg / 25 mL, in water) for 2 minutes and then the drug was loaded with water. The coating was carefully rinsed to remove excess prior to visual inspection of the coating. As described in the basic procedure doxorubicin staining (drug incorporation / elution), a red coloration of the coating indicates that the doxorubicin has been successfully incorporated into the coating.

Example 5.6 Formation of antimicrobial coating A coating prepared according to Example 3.3.18 was soaked in a solution of silver carbonate and chlorhexidine in EtOH (96%) for 30 seconds. Chlorhexidine and silver carbonate incorporation was confirmed by evaluating the coating components using the SEM-EDS method.

Example 5.7 Formation of an antithrombotic coating using methacrylated heparin An antithrombotic coating may be prepared by using the procedure according to Example 3.3 with the addition of methacrylated heparin from Example 6. Such coatings are expected to exhibit antithrombogenic properties.

Example 5.8 Formation of an antithrombotic coating using methacrylated heparin An antithrombotic coating was prepared by using the procedure according to Example 5.1 and then adding and mixing the methacrylated heparin and benzophenone from Example 6. May be prepared. Methacrylated heparin will covalently bind to the coating when irradiated with ultraviolet light. Such coatings are expected to exhibit antithrombogenic properties.

Example 5a-Evaluation of hydrophilic coatings containing beneficial chemicals Coatings containing thrombogenic agents Polyethyleneimine coatings prepared according to Example 5.1 were evaluated primarily in terms of surface coating. The coating was well stained using Ponceau S, indicating the presence of a net positive charge on the surface. Coated shafts are also evaluated for their ability to form clots by placing them in a test tube containing whole blood provided by healthy volunteers, compared to a control of whole blood without a thrombogenic coating. , Resulting in a significant decrease in clotting time. Clotting time was reduced by approximately 40% (7 minutes to complete thrombus compared to moderate thrombus formed after 11 minutes for control). This experiment was repeated once to confirm the thrombus formation of the coating.

Coating containing natural heparin as antithrombotic agent A coating prepared according to Example 5.2 was evaluated for its antithrombogenicity. The heparinized shaft was analyzed for its surface density of heparin. The heparin density was measured to be 1.4 μg / cm ² . Heparin containing the coating was applied to whole blood provided by a healthy donor and then the possibility of thrombus formation was monitored. The coated shaft was placed in a Falcon tube containing whole blood and placed on a rocker tube roller for 20 minutes, then the remaining amount of platelets in the blood was counted. After 20 minutes, it was found that no thrombus was formed, but it was found that a decrease in the amount of residual platelets was detected (platelet loss = about 25%).

Coating containing heparin end-attached as an antithrombotic agent A coating prepared according to Example 5.4 was evaluated for its antithrombogenicity. The heparinized shaft was analyzed for its surface density of heparin. This heparin density was measured to be 2.6 μg / cm ² . Heparin containing the coating was applied to whole blood provided by a healthy donor and then the possibility of thrombus formation was monitored. The coated shaft was placed in a Falcon tube containing whole blood and placed on a rocker tube roller for 20 minutes, then the remaining amount of platelets in the blood was counted. After 20 minutes, it was found that no thrombus was formed, but it was found that a decrease in the amount of residual platelets was detected (platelet loss = about 25%).

Coatings containing doxorubicin as beneficial chemical The coatings prepared according to Example 5.5 were evaluated for their drug elution properties. The doxorubicin supported on the coating was exposed to a 2M NaCl solution to facilitate drug release and then dried in vacuo prior to further visual inspection. A reduction in the red level indicated that doxorubicin eluted from the coating.

Coatings containing antimicrobial agents as beneficial chemicals Coatings prepared according to Example 5.6 were evaluated for their antimicrobial activity against S. aureus bacteria. Two replicates of the coating were applied to S. aureus bacteria, and then the inhibition zone was monitored over time. The two replicates showed antibacterial effects over 7 and 15 days, respectively. Uncoated PEBAX shaft, polydopamine primed PEBAX shaft and according to Example 3.3.18 (PEG: AA ratio 1: 1, 3 wt% BP, 42 mL EtOH) as a control Using. None of the controls showed antimicrobial properties longer than 1 day.

  The coating prepared according to Example 5.6 was also evaluated for its antibacterial activity against Pseudomonas aeruginosa bacteria. Two replicates of the coating were applied to Pseudomonas aeruginosa bacteria and then the zone of inhibition was monitored over time. The two replicates showed antibacterial effects over 3 and 4 days, respectively. Uncoated PEBAX shaft, polydopamine primed PEBAX shaft and according to Example 3.3.18 (PEG: AA ratio 1: 1, 3 wt% BP, 42 mL EtOH) as a control Using. None of the controls showed antimicrobial properties longer than 1 day.

Example 6-Synthesis of terminally methacrylated heparin Aldehyde functionalized heparin (5.00 g) prepared essentially as described in Example 2 of US Pat. No. 4,613,665, which is hereby incorporated by reference in its entirety. Was dissolved in 15 mL of acetate buffer (pH 5) by vigorous stirring. 2-Aminoethyl methacrylate hydrochloride (250 mg) was added to the heparin solution followed by 10 mL of 2.5% sodium cyanoborohydride solution (in di water). The reaction scheme is shown in Scheme 2. The solution was stirred overnight at room temperature, then transferred to a dialysis bag (MWCO 1000 Da) and dialyzed against 3 L of 1 M NaCl aqueous solution for 1 hour. After 1 hour, the 1M NaCl solution was replaced with fresh solution and dialysis continued for another hour. At the end of the purification sequence step, NaCl solution is added d. i. Substitution with water and dialysis continued overnight. The specific activity of heparin after correction was estimated to be> 100 IU / mg.

Example 7 Synthesis of 8 kDa Diacrylated PEG Polymer of Structural Formula (I) Dihydroxyl functionalized PEG (8 kDa, 20 g) was dissolved in THF (50 mL), TEA (3.5 mL) and pyridine (15 mL). Acryloyl chloride (1.1 g) was added dropwise to the solution. The reaction scheme is shown in Scheme 3. The reaction was allowed to proceed for 4 hours, after which the precipitated salt was filtered and the solution was dropped into 1 L of diethyl ether. The precipitate (beige / white powder) was dried overnight in a vacuum. The introduction of acrylic end groups was confirmed using the FTIR method. FTIR showed absorption near 1720 cm ⁻¹ indicating incorporation of a carbonyl group (ester) into the PEG chain.

Example 8-Formation of a hydrophilic coating on a metal substrate with and without a surface primer coating containing abstractable hydrogen atoms Example 8.1 On a polydopamine primed nitinol rod using benzophenone (3 wt%) and a medium intensity lamp A 10 kDa diacrylated PEG of structural formula (I) (3.6 g), acrylic acid (1.8 g) (mass ratio 2: 1), and benzophenone (3) in ethanol (24 mL) (Mass%) was prepared. Nitinol rods made according to Example 1.11 were then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 sec) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 8.2 Formation of a hydrophilic coating on an unprimed nitinol rod using benzophenone (3 wt%) and a medium intensity lamp Structural formula (I) 10 kDa diacrylated PEG (3.6 g), acrylic acid ( 1.8 g) (mass ratio is 2: 1) and a reagent consisting of benzophenone (3 wt%) in ethanol (24 mL) was prepared. Nitinol rods made according to pretreatment method B were then immersed in the solution (residence time 5 seconds) and then removed (drawing speed 15 cm / sec) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 8.3 Formation of Hydrophilic Coating on Polydopamine Primed Nitinol Rod Using Benzophenone (3 wt%) and Medium Intensity Lamp Structural Formula (I) 10 kDa diacrylated PEG (4.5 g), acrylic acid ( 1.8 g) (mass ratio is 2.5: 1) and a reagent consisting of benzophenone (3% by mass) in ethanol (24 mL) was prepared. Nitinol rods made according to Example 1.11 were then removed (drawing speed 15 cm / sec) after soaking in solution (residence time 5 sec) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.

Example 8.4 Formation of a hydrophilic coating on an unprimed nitinol rod using benzophenone (3 wt%) and a medium intensity lamp Structural formula (I) 10 kDa diacrylated PEG (4.5 g), acrylic acid ( 1.8 g) (mass ratio is 2.5: 1) and a reagent consisting of benzophenone (3% by mass) in ethanol (24 mL) was prepared. Nitinol rods made according to pretreatment method B were then immersed in the solution (residence time 5 seconds) and then removed (drawing speed 15 cm / sec) and RDX UV curing system (240-400 nm) (from Harland Medical) For 90 seconds. The intensity was recorded at about 55 mW / cm ² using a sensor and radiometer.
Example 8a: Surface Coating and Composition Evaluation of the Hydrophilic Coating of the Invention Surface Coating A hydrophilic coating prepared according to any of the procedures of Example 3 was dyed with toluidine blue according to a staining test. For all of the examples, it was observed that the hydrophilic coating was uniformly dyed, confirming that negatively charged groups were present on the surface of the PEBAX shaft (ie, good surface coverage of the hydrophilic coating).
Example 8b: Evaluation of the durability of a hydrophilic coating on a metal substrate with and without a surface subbing coating containing abstractable hydrogen atoms The hydrophilic coating of the present invention prepared according to Examples 8.1-8.4 Was evaluated using the method described in the basic procedure.

  The results are summarized in Table 4 below.

Durability The durability of the coating was evaluated using the durability test described in the basic procedure. Nitinol is a metal substrate that does not have an inherent surface that contains abstractable hydrogen atoms. Table 4 of Example 8b shows that a Nitinol substrate with no primer generally exhibits higher durability values (ie, poorer durability properties) compared to a primer analog of the same substrate (eg, Example 8.3 example) Compare with 8.4). Example 8.3 shows that the coating becomes more lubricious when performing the test. This is not the case with Example 8.4. In this case, the coating is less lubricious when performing the test.

  Throughout the specification and the following claims, unless the context requires otherwise, variations such as the words 'comprise' and 'comprises' and 'comprising' are defined integers, steps Will be understood to mean the inclusion of a group of integers or groups of steps, but not the exclusion of any other integers, steps, groups of integers or groups of steps.

  The present invention encompasses all combinations of preferred and more preferred groups and preferred and more preferred groups as well as the embodiments listed above.

（式中、ｎは１０〜５００００、例えば１５〜５０００、例えば１００〜４００、例えば１５０〜２６０である。）である、上記態様１０に記載の基材。
［１２］
１種以上のジアクリレート官能化ＰＥＧポリマーが、構造式（ＩＩ）

（式中、ｎは１０〜５００００、例えば１５〜５０００、例えば１００〜４００、好適には１５０〜２６０である。）である、上記態様１０に記載の基材。
［１３］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上の親水性ポリマーを含み、前記アルケン及び／又はアルキン基が、末端アルケン及び／又はアルキン基である、上記態様１〜１０のいずれかに記載の基材。
［１４］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上の親水性ポリマーを含み、並びに各親水性ポリマーの分子量が、独立に６００〜４００００Ｄａ、例えば４０００〜１６０００Ｄａである、上記態様１〜１３のいずれかに記載の基材。
［１５］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む２種の異なる親水性ポリマーを含む、上記態様１〜１４のいずれかに記載の基材。
［１６］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む２種の異なる分子量のＰＥＧポリマーを含む、上記態様１５に記載の基材。
［１７］
成分Ｃが、１つのアルケン又はアルキン基を各々含む１種以上の有益な化学物質を含む、上記態様１〜１６のいずれかに記載の基材。
［１８］
成分Ｃの前記有益な化学物質が、薬理活性を有する化学物質、導電剤又は接着剤である、上記態様１〜１７のいずれかに記載の基材。
［１９］
薬理活性を有する化学物質が、抗血栓薬、血管新生阻害剤、抗増殖剤又は抗菌剤である、上記態様１８に記載の基材。
［２０］
成分Ｃの分子量が、１０００００Ｄａ以下、例えば５００００Ｄａ以下、例えば２５０００Ｄａ以下である、上記態様１〜１９のいずれかに記載の基材。
［２１］
成分Ｃの分子量が、９０００Ｄａ〜２００００Ｄａ、例えば９０００Ｄａ〜１１０００Ｄａである、上記態様２０に記載の基材。
［２２］
成分Ｃが、ヘパリンである、上記態様１〜２１のいずれかに記載の基材。
［２３］
成分Ｄが、２つ以上のチオール基を各々含む１種以上の低分子量の架橋剤を含む、上記態様１〜２２のいずれかに記載の基材。
［２４］
成分Ｅの前記有益な化学物質が、薬理活性を有する化学物質、導電剤又は接着剤である、上記態様１〜２３のいずれかに記載の基材。
［２５］
薬理活性を有する化学物質が、抗血栓薬、血管新生阻害剤、抗増殖剤又は抗菌剤である、上記態様２４に記載の基材。
［２６］
成分Ｃが存在し、かつ、成分Ｄは存在しない、上記態様１〜２５のいずれかに記載の基材。
［２７］
成分Ｄが存在し、かつ、成分Ｃは存在しない、上記態様１〜２５のいずれかに記載の基材。
［２８］
成分Ｃ及びＤが存在しない、上記態様１〜２５のいずれかに記載の基材。
［２９］
成分Ｃ及びＤが存在する、上記態様１〜２５のいずれかに記載の基材。
［３０］
成分Ｅが存在し、かつ、コポリマーに共有結合している、上記態様１〜２９のいずれかに記載の基材。
［３１］
成分Ｅが存在し、かつ、コポリマーに共有結合していない、上記態様２９に記載の基材。
［３２］
成分Ｅが存在しない、上記態様１〜２９のいずれかに記載の基材。
［３３］
親水性コーティングが潤滑性であり、また潤滑性試験を用いた潤滑性が＜１００ｇ、例えば＜５０ｇ、例えば＜１５ｇである、上記態様１〜３２のいずれかに記載の基材。
［３４］
親水性コーティングの耐久性試験を用いた耐久性が、＜５０ｇ、例えば＜２５ｇ、例えば＜１５ｇである、上記態様３３に記載の基材。
［３５］
成分Ｂの成分Ａに対する質量比が、２．５：１〜０．５：１である、上記態様１〜３４のいずれかに記載の基材。
［３６］
基材が、医療用デバイスである、上記態様１〜３５のいずれかに記載の基材。
［３７］
医療用デバイスが、二股ステント、バルーン拡張型ステント及び自己拡張型ステントを包含するステント、二股ステントグラフトを包含するステントグラフト、血管グラフト及び二股グラフトを包含するグラフト、拡張器、血管閉塞器、塞栓フィルター、塞栓除去デバイス、マイクロカテーテル、中心静脈カテーテル、抹消静脈カテーテル及び血液透析カテーテルを包含するカテーテル、人工血管、リトラクタブルシースを包含するシース、血管内在性モニタリングデバイス、人工心臓弁、ペースメーカー電極、ガイドワイヤー、カーディアックリード、心肺バイパスサーキット、カニューレ、プラグ、ドラッグデリバリーデバイス、バルーン、組織パッチデバイス及び血液ポンプからなる群より選択される、上記態様３６に記載の基材。
［３８］
基材の表面に共有結合する親水性コーティングの形成方法であって、前記方法が、
（ａ）表面と、成分Ａ及びＢ、任意選択の成分Ｃ、任意選択の成分Ｄ及びラジカル開始剤を含む混合物とを接触させるステップであって、
成分Ａが、１つ以上のアルケン及び／又はアルキン基を各々含む１種以上のＣ ₂ 〜Ｃ ₁₆ 親水性モノマーを含み、
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上の親水性ポリマーを含み、
成分Ｃが、存在する場合には、１つ以上のアルケン又はアルキン基を各々含む１種以上の有益な化学物質を含み、並びに
成分Ｄが、存在する場合には、チオール、アルケン、及びアルキン基から独立に選択される２つ以上の官能基を各々含む１種以上の低分子量架橋剤を含むステップ；
並びに
（ｂ）成分Ａ、成分Ｂ、並びに任意選択のＣ及びＤの架橋コポリマーを形成するために、成分Ａ、Ｂ及びＣ（存在する場合には）のアルケン及び／又はアルキン基並びに成分Ｄ（存在する場合には）の官能基が関与するラジカル重合を開始するステップであって、前記コポリマーが表面に共有結合するステップ、並びに
（ｃ）任意選択的に、１種以上の有益な化学物質を含む成分Ｅを親水性コーティング中に組み込むステップであって、成分Ｅが成分Ａ、Ｂ、Ｃ（存在する場合には）及びＤ（存在する場合には）とコポリマーを形成しないステップ
を含む方法。
［３９］
基材が、引き抜き可能な水素原子を含む表面を有する基材である、上記態様３８に記載の方法。
［４０］
基材の表面と接触する液相中のラジカル開始剤が、表面から水素原子を引き抜いて表面結合のラジカルを形成し、前記表面結合のラジカルが、成分Ａ及びＢ並びに任意選択のＣ及びＤの少なくとも１つと反応して表面にコポリマーを共有結合させる、上記態様３９に記載の方法。
［４１］
液相中において表面と接触して形成したフリーラジカルにより開始されたプロセスにおいて、基材の表面上の反応基が、成分Ａ及びＢ並びに任意選択のＣ及びＤの少なくとも１つと反応して表面にコポリマーを共有結合させる、上記態様３９に記載の方法。
［４２］
成分Ａが、１つ以上のアルケン及び／又はアルキン基を各々含む１種以上のＣ ₂ 〜Ｃ ₁₆ 親水性モノマーを含み、また１つ以上の基が、エステル、エーテル、カルボキシル、ヒドロキシル、チオール、スルホン酸、サルフェート、アミノ、アミド、ホスフェート、ケト及びアルデヒド基から選択される、上記態様３８〜４０のいずれかに記載の方法。
［４３］
成分Ａが、アクリル酸及び／又はメタクリル酸を含む、上記態様４２に記載の方法。
［４４］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上の親水性ポリマーを含み、親水性ポリマーが、ヒアルロン酸、ヒアルロン酸誘導体、ポリ‐Ｎ‐ビニルピロリドン、ポリ‐Ｎ‐ビニルピロリドン誘導体、ポリエーテル誘導体（例えば、ポリエチレングリコール（ＰＥＧ）、ポリエチレングリコール（ＰＥＧ）誘導体、ポリプロピレングリコール（ＰＰＧ）、またはポリプロピレングリコール（ＰＰＧ）誘導体）、ポリビニルアルコール、及びポリビニルアルコール誘導体からなる群より独立に選択される、上記態様３８〜４３のいずれかに記載の方法。
［４５］
成分Ｂが、２つのアルケン基を各々含む１種以上の親水性ポリマーを含む、上記態様３８〜４４のいずれかに記載の方法。
［４６］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上のポリエーテル親水性ポリマー（例えば、ポリエチレングリコール（ＰＥＧ）、ポリエチレングリコール（ＰＥＧ）誘導体、ポリプロピレングリコール（ＰＰＧ）、又はポリプロピレングリコール（ＰＰＧ）誘導体）を含む、上記態様４５に記載の方法。
［４７］
成分Ｂが、２つのアルケン基を各々含む１種以上のＰＥＧポリマーを含む、上記態様４６に記載の方法。
［４８］
成分Ｂが、１種以上のジアクリレート官能化ＰＥＧポリマーを含む、上記態様４７に記載の方法。
［４９］
１種以上のジアクリレート官能化ＰＥＧポリマーが、構造式（Ｉ）：

（式中、ｎは１０〜５００００、例えば１５〜５０００、例えば１００〜４００、例えば１５０〜２６０である）である、上記態様４８に記載の方法。
［５０］
１種以上のジアクリレート官能化ＰＥＧポリマーが、構造式（ＩＩ）：

（式中、ｎは１０〜５００００、例えば１５〜５０００、例えば１００〜４００、好適には１５０〜２６０である）である、上記態様４８に記載の方法。
［５１］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上の親水性ポリマーを含み、前記アルケン／及び又はアルキン基が、末端アルケン及び／又はアルキン基である、上記態様３８〜５０のいずれかに記載の方法。
［５２］
成分Ｂが、２つ以上のアルケン及び／又はアルキン基を各々含む１種以上の親水性ポリマーを含み、また各親水性ポリマーの分子量が、独立に６００〜４００００Ｄａ、例えば４０００〜１６０００Ｄａである、上記態様３８〜５１のいずれかに記載の方法。
［５３］
成分Ｃの前記有益な化学物質が、薬理活性を有する化学物質、導電剤又は接着剤である、上記態様３８〜５２のいずれかに記載の方法。
［５４］
薬理活性を有する化学物質が、抗血栓薬、血管新生阻害剤、抗増殖剤又は抗菌剤である、上記態様５３に記載の方法。
［５５］
成分Ｃの分子量が、１０００００Ｄａ以下、例えば５００００Ｄａ以下、例えば２５０００Ｄａ以下である、上記態様３８〜５４のいずれかに記載の方法。
［５６］
成分Ｃの分子量が、９０００Ｄａ〜２００００Ｄａ、例えば９０００Ｄａ〜１１０００Ｄａである、上記態様５５に記載の方法。
［５７］
成分Ｃがヘパリンである、上記態様３８〜５６のいずれかに記載の方法。
［５８］
成分Ｄが、２つ以上のチオール基を各々含む１種以上の低分子量架橋剤を含む、上記態様３８〜５７のいずれかに記載の方法。
［５９］
成分Ｅの前記有益な化学物質が、薬理活性を有する化学物質、導電剤又は接着剤である、上記態様３８〜５８のいずれかに記載の方法。
［６０］
薬理活性を有する化学物質が、抗血栓薬、血管新生阻害剤、抗増殖剤又は抗菌剤である、上記態様５９に記載の方法。
［６１］
成分Ｃが存在し、かつ、成分Ｄは存在しない、上記態様３８〜６０のいずれかに記載の方法。
［６２］
成分Ｄが存在し、かつ、成分Ｃは存在しない、上記態様３８〜６１のいずれかに記載の方法。
［６３］
成分Ｃ及びＤが存在しない、上記態様３８〜６１のいずれかに記載の方法。
［６４］
成分Ｃ及びＤが存在する、上記態様３８〜６１のいずれかに記載の方法。
［６５］
成分Ｅがコポリマーに共有結合するステップ（ｃ）を含む上記態様３８〜６４のいずれかに記載の方法。
［６６］
成分Ｅがコポリマーに共有結合しないステップ（ｃ）を含む上記態様３８〜６４のいずれかに記載の方法。
［６７］
ステップ（ｃ）を含まない、上記態様３８〜６４のいずれかに記載の方法。
［６８］
成分Ｂの成分Ａに対する質量比が、２．５：１〜０．５：１である、上記態様３８〜６７のいずれかに記載の方法。
［６９］
親水性コーティングが潤滑性であり、また潤滑性試験を用いた潤滑性が＜１００ｇ、例えば＜５０ｇ、例えば＜１５ｇである、上記態様３８〜６８のいずれかに記載の方法。
［７０］
親水性コーティングの耐久性試験を用いた耐久性が、＜５０ｇ、例えば＜２５ｇ、例えば＜１５ｇである、上記態様３８〜６９のいずれかに記載の方法。
［７１］
引き抜き可能な水素原子を含む基材の表面が、引き抜き可能な水素原子を含むポリマーの表面下塗りコーティングである、上記態様３８〜７０のいずれかに記載の方法。
［７２］
引き抜き可能な水素原子を含むポリマーが、カテコール官能基及び／又はキノン官能基及び／又はセミキノン官能基を含むポリマーである、上記態様７１に記載の方法。
［７３］
引き抜き可能な水素原子を含むポリマーが、ポリドーパミンである、上記態様７１または７２に記載の方法。
［７４］
ポリドーパミンの表面コーティングが、基材の表面と、酸化剤及びドーパミン及び／又はドーパミン類縁体を含む混合物と接触させることにより形成する、上記態様７３に記載の方法。
［７５］
ポリドーパミンの表面コーティングが、ｐＨ４〜７にて形成される、上記態様７３又は７４に記載の方法。
［７６］
ポリドーパミンの表面コーティングが、ｐＨ５．５〜６．５にて形成される、上記態様７５に記載の方法。
［７７］
ポリドーパミンの表面コーティングが、水と有機アルコール（例えば水とＩＰＡの混合物）の混合物である溶媒の存在下において形成される、上記態様７３〜７６のいずれかに記載の方法。
［７８］
ポリドーパミンの表面コーティングの形成に先立って、コートされるべき表面が酸化剤で前処理されている、上記態様７３〜７７のいずれかに記載の方法。
［７９］
ステップ（ａ）のラジカル開始剤が、ベンゾフェノン及びこれらの誘導体並びにキサントン及びこれらの誘導体からなる群より選択される、上記態様３８〜７８のいずれかに記載の方法。
［８０］
前記ラジカル開始剤が、ベンゾフェノンである、上記態様７９に記載の方法。
［８１］
ステップ（ａ）のラジカル開始剤が、ベンゾフェノン及び／又はこれらの誘導体並びにチオキサントン及び／又はこれらの誘導体の混合物である、上記態様３８〜７８のいずれかに記載の方法。
［８２］
ステップ（ａ）のラジカル開始剤が、ベンゾフェノン及びチオキサントンの混合物である、上記態様８１に記載の方法。
［８３］
ステップ（ｂ）のラジカル重合が、紫外光に対する光開始剤を含むステップ（ａ）の混合物の曝露により開始される、上記態様３８〜８２のいずれかに記載の方法。
［８４］
基材が、医療用デバイスである、上記態様３８〜８３のいずれかに記載の方法。
［８５］
医療用デバイスが、二股ステント、バルーン拡張型ステント及び自己拡張型ステントを包含するステント、二股ステントグラフトを包含するステントグラフト、血管グラフト及び二股グラフトを包含するグラフト、拡張器、血管閉塞器、塞栓フィルター、塞栓除去デバイス、マイクロカテーテル、中心静脈カテーテル、抹消静脈カテーテル及び血液透析カテーテルを包含するカテーテル、人工血管、リトラクタブル シースを包含するシース、血管内在性モニタリングデバイス、人工心臓弁、ペースメーカー電極、ガイドワイヤー、カーディアックリード、心肺バイパスサーキット、カニューレ、プラグ、ドラッグデリバリーデバイス、バルーン、組織パッチデバイス及び血液ポンプからなる群より選択される、上記態様８４に記載の方法。
［８６］
上記態様３８〜８４のいずれかに記載の方法に従って得られた親水性コーティングを有する基材。
The present invention encompasses all combinations of preferred and more preferred groups and preferred and more preferred groups as well as the embodiments listed above.
Hereinafter, embodiments of the present invention will be listed.
[1]
A substrate having a surface having a hydrophilic coating comprising components A and B and optional crosslinked copolymers of components C and D, wherein component A comprises one or more alkene and / or alkyne groups, respectively includes C ₂ -C ₁₆ hydrophilic monomers or species,
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups,
Component C, if present, comprises one or more beneficial chemicals each containing one or more alkene or alkyne groups, and
Component D, if present, comprises one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from thiol, alkene and alkyne groups;
The crosslinked copolymer is formed by radical polymerization involving the alkene and / or alkyne groups of components A, B and C (if present) and the functional groups of component D (if present);
The hydrophilic coating optionally includes a component E that contains one or more beneficial chemicals, where component E includes components A, B, C (if present) and D (if present); Does not form a copolymer,
And a substrate having a hydrophilic coating covalently bonded to the surface of the substrate.
[2]
A covalent bond between the surface of the substrate and the hydrophilic coating is formed through the reaction of the components of the hydrophilic coating with surface-bonded radicals on the surface of the substrate, and the surface-bonded radicals are The base material according to the aspect 1, which is generated through extraction of hydrogen atoms from the surface.
[3]
A substrate according to embodiment 1 or 2, wherein the substrate has a first surface subbing coating of polydopamine to which a hydrophilic coating is covalently bonded.
[4]
Component A contains one or more C ₂ -C ₁₆ hydrophilic monomers each containing one or more alkene and / or alkyne groups, and one or more groups are esters, ethers, carboxyls, hydroxyls, thiols, 4. The substrate according to any one of the above aspects 1 to 3, selected from sulfonic acid, sulfate, amino, amide, phosphate, keto and aldehyde groups.
[5]
The base material of the said aspect 4 with which the component A contains acrylic acid and / or methacrylic acid.
[6]
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is hyaluronic acid, a hyaluronic acid derivative, poly-N-vinylpyrrolidone, poly-N- Independently from the group consisting of vinylpyrrolidone derivatives, polyether derivatives (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene glycol (PPG) derivatives), polyvinyl alcohol, and polyvinyl alcohol derivatives The base material in any one of the said aspects 1-5 selected by these.
[7]
The base material in any one of the said aspects 1-6 in which the component B contains the 1 or more types of hydrophilic polymer each containing two alkene groups.
[8]
Component B is one or more polyether hydrophilic polymers each containing two or more alkene and / or alkyne groups (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene) The base material of the said aspect 6 containing a glycol (PPG) derivative).
[9]
9. A substrate according to aspect 8 above, wherein component B comprises one or more PEG polymers each containing two alkene groups.
[10]
The substrate of embodiment 9, wherein component B comprises one or more diacrylate functionalized PEG polymers.
[11]
One or more diacrylate functionalized PEG polymers have the structural formula (I)

(Wherein n is 10 to 50000, such as 15 to 5000, such as 100 to 400, such as 150 to 260).
[12]
One or more diacrylate functionalized PEG polymers have the structural formula (II)

(Wherein n is 10 to 50000, for example 15 to 5000, for example 100 to 400, preferably 150 to 260).
[13]
Embodiment 1 to Component B in which Component B includes one or more hydrophilic polymers each including two or more alkene and / or alkyne groups, and the alkene and / or alkyne group is a terminal alkene and / or alkyne group. The base material in any one of 10.
[14]
Component B comprises one or more hydrophilic polymers each containing two or more alkenes and / or alkyne groups, and the molecular weight of each hydrophilic polymer is independently from 600 to 40000 Da, such as from 4000 to 16000 Da The base material in any one of aspects 1-13.
[15]
15. A substrate according to any of the above aspects 1 to 14, wherein component B comprises two different hydrophilic polymers each comprising two or more alkene and / or alkyne groups.
[16]
16. A substrate according to aspect 15 above, wherein component B comprises two different molecular weight PEG polymers each comprising two or more alkene and / or alkyne groups.
[17]
17. A substrate according to any of the above aspects 1 to 16, wherein component C comprises one or more beneficial chemicals each containing one alkene or alkyne group.
[18]
The base material according to any one of the above aspects 1 to 17, wherein the beneficial chemical substance of Component C is a chemical substance having a pharmacological activity, a conductive agent, or an adhesive.
[19]
The base material according to the above aspect 18, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent or an antibacterial agent.
[20]
The base material in any one of the said aspects 1-19 whose molecular weight of the component C is 100,000 Da or less, for example, 50000 Da or less, for example, 25000 Da or less.
[21]
The base material of the said aspect 20 whose molecular weight of the component C is 9000 Da-20000 Da, for example, 9000 Da-11000 Da.
[22]
The base material in any one of the said aspects 1-21 whose component C is heparin.
[23]
The base material in any one of the said aspects 1-22 in which the component D contains the 1 or more types of low molecular weight crosslinking agent each containing two or more thiol groups.
[24]
24. The substrate according to any one of the above aspects 1 to 23, wherein the beneficial chemical substance of component E is a chemical substance having a pharmacological activity, a conductive agent or an adhesive.
[25]
The base material according to Aspect 24, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent, or an antibacterial agent.
[26]
The base material in any one of the said aspects 1-25 which the component C exists and the component D does not exist.
[27]
The base material in any one of the said aspect 1-25 which the component D exists and the component C does not exist.
[28]
The base material according to any one of the above aspects 1 to 25, wherein components C and D are not present.
[29]
The base material according to any one of the above aspects 1 to 25, wherein components C and D are present.
[30]
30. A substrate according to any of embodiments 1 to 29 wherein component E is present and is covalently bonded to the copolymer.
[31]
30. A substrate according to embodiment 29, wherein component E is present and is not covalently bonded to the copolymer.
[32]
The base material in any one of the said aspects 1-29 in which the component E does not exist.
[33]
33. A substrate according to any of the above embodiments 1-32, wherein the hydrophilic coating is lubricious and the lubricity using a lubricity test is <100 g, for example <50 g, for example <15 g.
[34]
34. A substrate according to aspect 33, wherein the durability using a durability test of the hydrophilic coating is <50 g, for example <25 g, for example <15 g.
[35]
The base material in any one of the said aspects 1-34 whose mass ratio with respect to the component A of the component B is 2.5: 1-0.5: 1.
[36]
The base material in any one of the said aspects 1-35 whose base material is a medical device.
[37]
Medical devices include bifurcated stents, stents including balloon expandable stents and self-expanding stents, stent grafts including bifurcated stent grafts, grafts including vascular grafts and bifurcated grafts, dilators, vascular occluders, embolic filters, embolisms Removal devices, microcatheters, central venous catheters, catheters including peripheral venous catheters and hemodialysis catheters, artificial blood vessels, sheaths including retractable sheaths, vascular intrinsic monitoring devices, artificial heart valves, pacemaker electrodes, guide wires, cardiacs The substrate of embodiment 36, selected from the group consisting of a lead, a cardiopulmonary bypass circuit, a cannula, a plug, a drug delivery device, a balloon, a tissue patch device, and a blood pump.
[38]
A method of forming a hydrophilic coating that is covalently bonded to the surface of a substrate, the method comprising:
(A) contacting the surface with a mixture comprising components A and B, optional component C, optional component D and a radical initiator,
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers each containing an alkyne group,
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups,
Component C, if present, comprises one or more beneficial chemicals each containing one or more alkene or alkyne groups, and
Component D, if present, comprises one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from thiol, alkene, and alkyne groups;
And
(B) the alkene and / or alkyne groups of component A, B and C (if present) and component D (present) to form component A, component B, and optional C and D crosslinked copolymers. Initiating radical polymerization involving functional groups (if any), wherein the copolymer is covalently bonded to the surface; and
(C) optionally incorporating component E containing one or more beneficial chemicals into the hydrophilic coating, wherein component E is component A, B, C (if present) and D Not forming a copolymer with (if present)
Including methods.
[39]
39. A method according to aspect 38, wherein the substrate is a substrate having a surface containing abstractable hydrogen atoms.
[40]
The radical initiator in the liquid phase in contact with the surface of the substrate pulls out hydrogen atoms from the surface to form surface-bound radicals, the surface-bound radicals comprising components A and B and optional C and D 40. The method of embodiment 39, wherein the copolymer is covalently bonded to the surface by reacting with at least one.
[41]
In a process initiated by free radicals formed in contact with the surface in the liquid phase, reactive groups on the surface of the substrate react with components A and B and optionally at least one of C and D on the surface. 40. The method of embodiment 39, wherein the copolymer is covalently bonded.
[42]
Component A contains one or more C ₂ -C ₁₆ hydrophilic monomers each containing one or more alkene and / or alkyne groups, and one or more groups are esters, ethers, carboxyls, hydroxyls, thiols, 41. A method according to any of aspects 38 to 40, selected from sulfonic acid, sulfate, amino, amide, phosphate, keto and aldehyde groups.
[43]
43. A method according to embodiment 42, wherein component A comprises acrylic acid and / or methacrylic acid.
[44]
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is hyaluronic acid, a hyaluronic acid derivative, poly-N-vinylpyrrolidone, poly-N- Independently from the group consisting of vinylpyrrolidone derivatives, polyether derivatives (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene glycol (PPG) derivatives), polyvinyl alcohol, and polyvinyl alcohol derivatives 44. The method according to any one of the above aspects 38 to 43, wherein
[45]
45. A method according to any of aspects 38 to 44, wherein component B comprises one or more hydrophilic polymers each containing two alkene groups.
[46]
Component B is one or more polyether hydrophilic polymers each containing two or more alkene and / or alkyne groups (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene) 46. The method of embodiment 45, comprising a glycol (PPG) derivative).
[47]
47. The method of embodiment 46, wherein component B comprises one or more PEG polymers each containing two alkene groups.
[48]
48. The method of embodiment 47, wherein component B comprises one or more diacrylate functionalized PEG polymers.
[49]
One or more diacrylate functionalized PEG polymers have the structural formula (I):

49. The method of embodiment 48, wherein n is 10 to 50000, such as 15 to 5000, such as 100 to 400, such as 150 to 260.
[50]
One or more diacrylate functionalized PEG polymers have the structural formula (II):

49. A method according to aspect 48 above, wherein n is 10 to 50000, such as 15 to 5000, such as 100 to 400, preferably 150 to 260.
[51]
Embodiments 38 to 38 above wherein Component B comprises one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the alkene / and / or alkyne group is a terminal alkene and / or alkyne group. 50. The method according to any one of 50.
[52]
Component B comprises one or more hydrophilic polymers each containing two or more alkenes and / or alkyne groups, and the molecular weight of each hydrophilic polymer is independently 600 to 40000 Da, such as 4000 to 16000 Da 52. A method according to any of aspects 38-51.
[53]
53. The method according to any one of aspects 38 to 52, wherein the beneficial chemical of component C is a chemical having pharmacological activity, a conductive agent or an adhesive.
[54]
54. The method according to aspect 53, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent, or an antibacterial agent.
[55]
55. The method according to any one of aspects 38 to 54, wherein the molecular weight of component C is 100000 Da or less, such as 50000 Da or less, such as 25000 Da or less.
[56]
56. The method according to aspect 55, wherein the molecular weight of component C is 9000 Da to 20000 Da, such as 9000 Da to 11000 Da.
[57]
57. The method according to any one of aspects 38 to 56, wherein component C is heparin.
[58]
58. A method according to any of aspects 38 to 57, wherein component D comprises one or more low molecular weight crosslinkers each comprising two or more thiol groups.
[59]
59. The method according to any one of aspects 38 to 58, wherein the beneficial chemical of component E is a chemical having pharmacological activity, a conductive agent or an adhesive.
[60]
The method according to the above aspect 59, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent or an antibacterial agent.
[61]
61. The method according to any one of aspects 38-60, wherein component C is present and component D is not present.
[62]
62. A method according to any of aspects 38 to 61, wherein component D is present and component C is not present.
[63]
62. The method according to any of aspects 38 to 61, wherein components C and D are not present.
[64]
62. The method according to any of aspects 38-61, wherein components C and D are present.
[65]
65. A method according to any of aspects 38 to 64, comprising step (c) wherein component E is covalently bonded to the copolymer.
[66]
65. A method according to any of aspects 38 to 64, comprising step (c) wherein component E is not covalently bonded to the copolymer.
[67]
The method according to any one of the above aspects 38 to 64, which does not include step (c).
[68]
68. The method according to any one of aspects 38 to 67, wherein the mass ratio of component B to component A is 2.5: 1 to 0.5: 1.
[69]
69. A method according to any of aspects 38-68, wherein the hydrophilic coating is lubricious and the lubricity using the lubricity test is <100 g, for example <50 g, for example <15 g.
[70]
70. A method according to any of aspects 38 to 69, wherein the durability using a durability test of the hydrophilic coating is <50 g, for example <25 g, for example <15 g.
[71]
71. A method according to any of aspects 38 to 70, wherein the surface of the substrate comprising abstractable hydrogen atoms is a surface subbing coating of a polymer comprising abstractable hydrogen atoms.
[72]
72. The method of embodiment 71, wherein the polymer comprising an abstractable hydrogen atom is a polymer comprising a catechol functional group and / or a quinone functional group and / or a semiquinone functional group.
[73]
The method according to embodiment 71 or 72, wherein the polymer containing an abstractable hydrogen atom is polydopamine.
[74]
74. The method of aspect 73, wherein the polydopamine surface coating is formed by contacting the surface of the substrate with a mixture comprising an oxidizing agent and dopamine and / or dopamine analog.
[75]
75. A method according to embodiment 73 or 74, wherein the polydopamine surface coating is formed at a pH of 4-7.
[76]
The method according to embodiment 75, wherein the polydopamine surface coating is formed at a pH of 5.5 to 6.5.
[77]
77. A method according to any of aspects 73-76, wherein the polydopamine surface coating is formed in the presence of a solvent that is a mixture of water and an organic alcohol (eg, a mixture of water and IPA).
[78]
78. A method according to any of embodiments 73-77, wherein the surface to be coated is pretreated with an oxidizing agent prior to formation of the polydopamine surface coating.
[79]
79. The method according to any of aspects 38-78, wherein the radical initiator of step (a) is selected from the group consisting of benzophenone and derivatives thereof and xanthone and derivatives thereof.
[80]
80. The method of aspect 79, wherein the radical initiator is benzophenone.
[81]
79. The method according to any one of aspects 38 to 78, wherein the radical initiator in step (a) is benzophenone and / or a derivative thereof and a mixture of thioxanthone and / or a derivative thereof.
[82]
84. The method of embodiment 81, wherein the radical initiator in step (a) is a mixture of benzophenone and thioxanthone.
[83]
83. A method according to any of aspects 38 to 82, wherein the radical polymerization of step (b) is initiated by exposure of the mixture of step (a) comprising a photoinitiator to ultraviolet light.
[84]
84. The method according to any one of aspects 38 to 83, wherein the substrate is a medical device.
[85]
Medical devices include bifurcated stents, stents including balloon expandable stents and self-expanding stents, stent grafts including bifurcated stent grafts, grafts including vascular grafts and bifurcated grafts, dilators, vascular occluders, embolic filters, embolisms Removal devices, microcatheters, central venous catheters, catheters including peripheral venous catheters and hemodialysis catheters, artificial blood vessels, sheaths including retractable sheaths, vascular intrinsic monitoring devices, artificial heart valves, pacemaker electrodes, guide wires, cardiacs 85. The method of aspect 84, wherein the method is selected from the group consisting of a lead, a cardiopulmonary bypass circuit, a cannula, a plug, a drug delivery device, a balloon, a tissue patch device, and a blood pump.
[86]
85. A substrate having a hydrophilic coating obtained according to the method of any one of aspects 38 to 84.

Claims (86)

A substrate having a surface having a hydrophilic coating comprising components A and B and optional crosslinked copolymers of components C and D, wherein component A comprises one or more alkene and / or alkyne groups, respectively includes C ₂ -C ₁₆ hydrophilic monomers or species,
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups,
Component C, if present, contains one or more beneficial chemicals each containing one or more alkene or alkyne groups, and Component D, if present, from thiol, alkene and alkyne groups Comprising one or more low molecular weight crosslinkers each comprising two or more independently selected functional groups;
The crosslinked copolymer is formed by radical polymerization involving the alkene and / or alkyne groups of components A, B and C (if present) and the functional groups of component D (if present);
The hydrophilic coating optionally includes a component E that contains one or more beneficial chemicals, where component E includes components A, B, C (if present) and D (if present); Does not form a copolymer,
And a substrate having a hydrophilic coating covalently bonded to the surface of the substrate.   A covalent bond between the surface of the substrate and the hydrophilic coating is formed through the reaction of surface-bonded radicals on the surface of the substrate having components of the hydrophilic coating, and the surface-bonded radicals are formed on the substrate. The base material according to claim 1, wherein the base material is generated through extraction of hydrogen atoms from the surface of the substrate.   3. A substrate according to claim 1 or 2 having a first surface subbing coating of polydopamine to which the hydrophilic coating is covalently bonded. Component A contains one or more C ₂ -C ₁₆ hydrophilic monomers each containing one or more alkene and / or alkyne groups, and one or more groups are esters, ethers, carboxyls, hydroxyls, thiols, 4. A substrate according to any one of claims 1 to 3, selected from sulfonic acid, sulfate, amino, amide, phosphate, keto and aldehyde groups.   The base material of Claim 4 in which the component A contains acrylic acid and / or methacrylic acid.   Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is hyaluronic acid, a hyaluronic acid derivative, poly-N-vinylpyrrolidone, poly-N- Independently from the group consisting of vinylpyrrolidone derivatives, polyether derivatives (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene glycol (PPG) derivatives), polyvinyl alcohol, and polyvinyl alcohol derivatives The base material according to claim 1, which is selected by the following.   The substrate according to any one of claims 1 to 6, wherein component B comprises one or more hydrophilic polymers each containing two alkene groups.   Component B is one or more polyether hydrophilic polymers each containing two or more alkene and / or alkyne groups (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene) The base material of Claim 6 containing a glycol (PPG) derivative | guide_body).   9. A substrate according to claim 8, wherein component B comprises one or more PEG polymers each containing two alkene groups.   The substrate of claim 9 wherein component B comprises one or more diacrylate functionalized PEG polymers. One or more diacrylate functionalized PEG polymers have the structural formula (I)

11. The substrate according to claim 10, wherein n is 10 to 50000, such as 15 to 5000, such as 100 to 400, such as 150 to 260. One or more diacrylate functionalized PEG polymers have the structural formula (II)

The base material according to claim 10, wherein n is 10 to 50000, for example 15 to 5000, for example 100 to 400, preferably 150 to 260.   Component B comprises one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the alkene and / or alkyne group is a terminal alkene and / or alkyne group. 11. The substrate according to any one of 10 above.   Component B comprises one or more hydrophilic polymers each comprising two or more alkenes and / or alkyne groups, and the molecular weight of each hydrophilic polymer is independently 600-40000 Da, such as 4000-16000 Da. Item 14. The substrate according to any one of Items 1 to 13.   15. A substrate according to any one of the preceding claims, wherein component B comprises two different hydrophilic polymers each containing two or more alkene and / or alkyne groups.   16. A substrate according to claim 15, wherein component B comprises two different molecular weight PEG polymers each comprising two or more alkene and / or alkyne groups.   17. A substrate according to any one of claims 1 to 16, wherein component C comprises one or more beneficial chemicals each containing one alkene or alkyne group.   The substrate according to any one of claims 1 to 17, wherein the beneficial chemical substance of component C is a chemical substance having a pharmacological activity, a conductive agent or an adhesive.   The base material according to claim 18, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent or an antibacterial agent.   The base material of any one of Claims 1-19 whose molecular weight of the component C is 100,000 Da or less, for example, 50000 Da or less, for example, 25000 Da or less.   The substrate according to claim 20, wherein the molecular weight of component C is 9000 Da to 20000 Da, such as 9000 Da to 11000 Da.   The substrate according to any one of claims 1 to 21, wherein component C is heparin.   23. A substrate according to any one of claims 1 to 22, wherein component D comprises one or more low molecular weight crosslinkers each comprising two or more thiol groups.   24. A substrate according to any one of claims 1 to 23, wherein the beneficial chemical of component E is a chemical having pharmacological activity, a conductive agent or an adhesive.   The base material according to claim 24, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent or an antibacterial agent.   26. A substrate according to any one of claims 1 to 25 wherein component C is present and component D is not present.   26. A substrate according to any one of claims 1 to 25 wherein component D is present and component C is not present.   26. A substrate according to any one of claims 1 to 25, wherein components C and D are not present.   26. A substrate according to any one of claims 1 to 25, wherein components C and D are present.   30. A substrate according to any one of claims 1 to 29 wherein component E is present and is covalently bonded to the copolymer.   30. A substrate according to claim 29 wherein component E is present and is not covalently bonded to the copolymer.   30. A substrate according to any one of claims 1 to 29, wherein component E is not present.   35. A substrate according to any one of claims 1 to 32, wherein the hydrophilic coating is lubricious and the lubricity using a lubricity test is <100 g, for example <50 g, for example <15 g.   34. A substrate according to claim 33, wherein the durability using a durability test of the hydrophilic coating is <50 g, for example <25 g, for example <15 g.   The base material of any one of Claims 1-34 whose mass ratio with respect to the component A of the component B is 2.5: 1-0.5: 1.   The base material according to claim 1, wherein the base material is a medical device.   Medical devices include bifurcated stents, stents including balloon expandable stents and self-expanding stents, stent grafts including bifurcated stent grafts, grafts including vascular grafts and bifurcated grafts, dilators, vascular occluders, embolic filters, embolisms Removal devices, microcatheters, central venous catheters, catheters including peripheral venous catheters and hemodialysis catheters, artificial blood vessels, sheaths including retractable sheaths, vascular intrinsic monitoring devices, artificial heart valves, pacemaker electrodes, guide wires, cardiacs 37. The substrate of claim 36, selected from the group consisting of a lead, a cardiopulmonary bypass circuit, a cannula, a plug, a drug delivery device, a balloon, a tissue patch device, and a blood pump. A method of forming a hydrophilic coating that is covalently bonded to the surface of a substrate, the method comprising:
(A) contacting the surface with a mixture comprising components A and B, optional component C, optional component D and a radical initiator,
Component A comprises one or more alkenes and / or one or more C ₂ -C ₁₆ hydrophilic monomers each containing an alkyne group,
Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups,
Component C, if present, includes one or more beneficial chemicals each containing one or more alkene or alkyne groups, and Component D, if present, includes thiol, alkene, and alkyne groups. Including one or more low molecular weight crosslinkers each comprising two or more functional groups independently selected from:
And (b) the alkene and / or alkyne groups of component A, B and C (if present) and component D (to form a crosslinked copolymer of component A, component B, and optional C and D, if present). Initiating radical polymerization involving functional groups (if present), wherein the copolymer is covalently bonded to the surface; and (c) optionally, one or more beneficial chemicals Incorporating component E into the hydrophilic coating, wherein component E does not form a copolymer with components A, B, C (if present) and D (if present).   40. The method of claim 38, wherein the substrate is a substrate having a surface comprising abstractable hydrogen atoms.   A radical initiator in the liquid phase reacts with components A and B and optionally at least one of C and D to covalently bond the copolymer to the surface by contacting the surface of the substrate and withdrawing hydrogen atoms from the surface. 40. The method of claim 39, wherein a surface-bound radical is formed.   Components A and B and optional C and D for covalently bonding the copolymer to the surface in a process initiated by free radicals formed on the surface of the substrate in contact with the surface and formed in the liquid phase 40. The method of claim 39, wherein the method reacts with at least one of the following. Component A contains one or more C ₂ -C ₁₆ hydrophilic monomers each containing one or more alkene and / or alkyne groups, and one or more groups are esters, ethers, carboxyls, hydroxyls, thiols, 41. The method of claims 38-40, wherein the method is selected from sulfonic acid, sulfate, amino, amide, phosphate, keto and aldehyde groups.   43. The method of claim 42, wherein component A comprises acrylic acid and / or methacrylic acid.   Component B comprises one or more hydrophilic polymers each containing two or more alkene and / or alkyne groups, wherein the hydrophilic polymer is hyaluronic acid, a hyaluronic acid derivative, poly-N-vinylpyrrolidone, poly-N- Independently from the group consisting of vinylpyrrolidone derivatives, polyether derivatives (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene glycol (PPG) derivatives), polyvinyl alcohol, and polyvinyl alcohol derivatives 44. The method according to any one of claims 38 to 43, wherein:   45. A method according to any one of claims 38 to 44, wherein component B comprises one or more hydrophilic polymers each containing two alkene groups.   Component B is one or more polyether hydrophilic polymers each containing two or more alkene and / or alkyne groups (eg, polyethylene glycol (PEG), polyethylene glycol (PEG) derivatives, polypropylene glycol (PPG), or polypropylene) 46. The method of claim 45 comprising a glycol (PPG) derivative).   48. The method of claim 46, wherein component B comprises one or more PEG polymers each containing two alkene groups.   48. The method of claim 47, wherein component B comprises one or more diacrylate functionalized PEG polymers. One or more diacrylate functionalized PEG polymers have the structural formula (I):

49. The method of claim 48, wherein n is 10 to 50000, such as 15 to 5000, such as 100 to 400, such as 150 to 260. One or more diacrylate functionalized PEG polymers have the structural formula (II):

49. The method of claim 48, wherein n is 10 to 50000, such as 15 to 5000, such as 100 to 400, preferably 150 to 260.   Component B comprises one or more hydrophilic polymers each comprising two or more alkene and / or alkyne groups, wherein the alkene / and / or alkyne group is a terminal alkene and / or alkyne group. 50. The method according to any one of 50.   Component B comprises one or more hydrophilic polymers each containing two or more alkenes and / or alkyne groups, and the molecular weight of each hydrophilic polymer is independently 600-40000 Da, such as 4000-16000 Da. Item 52. The method according to any one of Items 38 to 51.   53. A method according to any one of claims 38 to 52, wherein the beneficial chemical of component C is a chemical having pharmacological activity, a conductive agent or an adhesive.   54. The method according to claim 53, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent or an antibacterial agent.   55. A method according to any one of claims 38 to 54, wherein the molecular weight of component C is 100000 Da or less, such as 50000 Da or less, such as 25000 Da or less.   56. The method according to claim 55, wherein the molecular weight of component C is 9000 Da to 20000 Da, such as 9000 Da to 11000 Da.   57. A method according to any one of claims 38 to 56, wherein component C is heparin.   58. A method according to any one of claims 38 to 57, wherein component D is one or more low molecular weight crosslinkers each comprising two or more thiol groups.   59. A method according to any one of claims 38 to 58, wherein the beneficial chemical of component E is a pharmacologically active chemical, conductive agent or adhesive.   60. The method according to claim 59, wherein the chemical substance having pharmacological activity is an antithrombotic agent, an angiogenesis inhibitor, an antiproliferative agent or an antibacterial agent.   61. A method according to any one of claims 38 to 60, wherein component C is present and component D is not present.   62. A method according to any one of claims 38 to 61, wherein component D is present and component C is not present.   62. A method according to any one of claims 38 to 61, wherein components C and D are absent.   62. A method according to any one of claims 38 to 61, wherein components C and D are present.   65. A method according to any one of claims 38 to 64 comprising the step (c) wherein component E is covalently bonded to the copolymer.   65. A method according to any one of claims 38 to 64, comprising step (c) wherein component E is not covalently bonded to the copolymer.   65. A method according to any one of claims 38 to 64, which does not include step (c).   68. A method according to any one of claims 38 to 67, wherein the mass ratio of component B to component A is from 2.5: 1 to 0.5: 1.   69. A method according to any one of claims 38 to 68, wherein the hydrophilic coating is lubricious and the lubricity using the lubricity test is <100 g, for example <50 g, for example <15 g.   70. A method according to any one of claims 38 to 69, wherein the durability using a durability test of the hydrophilic coating is <50 g, for example <25 g, for example <15 g.   71. A method according to any one of claims 38 to 70, wherein the surface of the substrate comprising abstractable hydrogen atoms is a surface subbing coating of a polymer comprising abstractable hydrogen atoms.   72. The method of claim 71, wherein the polymer comprising an abstractable hydrogen atom is a polymer comprising a catechol functional group and / or a quinone functional group and / or a semiquinone functional group.   73. A method according to claim 71 or 72, wherein the polymer containing abstractable hydrogen atoms is polydopamine.   75. The method of claim 73, wherein the polydopamine surface coating is formed by contacting the surface of the substrate with a mixture comprising an oxidizing agent and dopamine and / or dopamine analog.   75. The method of claim 73 or 74, wherein the polydopamine surface coating is formed at a pH of 4-7.   76. The method of claim 75, wherein the polydopamine surface coating is formed at a pH of 5.5 to 6.5.   77. A method according to any one of claims 73 to 76, wherein the polydopamine surface coating is formed in the presence of a solvent that is a mixture of water and an organic alcohol (e.g., a mixture of water and IPA).   78. A method according to any one of claims 73 to 77, wherein the surface to be coated is pretreated with an oxidant prior to the formation of the polydopamine surface coating.   79. The method according to any one of claims 38 to 78, wherein the radical initiator of step (a) is selected from the group consisting of benzophenone and derivatives thereof and xanthone and derivatives thereof.   80. The method of claim 79, wherein the radical initiator is benzophenone.   79. The method according to any one of claims 38 to 78, wherein the radical initiator of step (a) is benzophenone and / or a derivative thereof and a mixture of thioxanthone and / or a derivative thereof.   82. The method of claim 81, wherein the radical initiator of step (a) is a mixture of benzophenone and thioxanthone.   83. The method according to any one of claims 38 to 82, wherein the radical polymerization of step (b) is initiated by exposure of the mixture of step (a) comprising a photoinitiator to ultraviolet light.   84. A method according to any one of claims 38 to 83, wherein the substrate is a medical device.   Medical devices include bifurcated stents, stents including balloon expandable stents and self-expanding stents, stent grafts including bifurcated stent grafts, grafts including vascular grafts and bifurcated grafts, dilators, vascular occluders, embolic filters, embolisms Removal devices, microcatheters, central venous catheters, catheters including peripheral venous catheters and hemodialysis catheters, artificial blood vessels, sheaths including retractable sheaths, vascular intrinsic monitoring devices, artificial heart valves, pacemaker electrodes, guide wires, cardiacs 85. The method of claim 84, selected from the group consisting of a lead, a cardiopulmonary bypass circuit, a cannula, a plug, a drug delivery device, a balloon, a tissue patch device, and a blood pump.   85. A substrate having a hydrophilic coating obtained according to the method of any one of claims 38 to 84.

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