CN114845746A

CN114845746A - UV-cured coatings for medical devices

Info

Publication number: CN114845746A
Application number: CN202080088287.1A
Authority: CN
Inventors: T·R·龙; C·S·伊兰德
Original assignee: Biocoatings Srl
Current assignee: Biocoatings Srl
Priority date: 2019-10-21
Filing date: 2020-10-21
Publication date: 2022-08-02
Anticipated expiration: 2040-10-21
Also published as: EP4048332A1; CN114845746B; EP4048332A4; JP2022553294A; WO2021081036A1

Abstract

The present invention relates to hydrophobic and hydrophilic coating compositions for medical devices or medical implants. The hydrophilic coating composition comprises a water or water-alcohol solution soluble polymer made from monomers comprising: (a) at least one monomer that is a photo radical generator, and (b) at least one monomer comprising one or both of: (i) olefinic monomers comprising at least one acidic group and (ii) one or more acrylates or acrylamides: one or both of the following: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides in a molar ratio to photoradical generator groups of from 20:1 to 500: 1. Such hydrophilic coating compositions may provide the entire coating or, along with the hydrophobic base coat, may be the top coat of a 2-coat system.

Description

UV-cured coatings for medical devices

Technical Field

The present invention relates to uv curable coatings for medical devices and medical implants.

Background

The present invention relates to the field of non-thrombogenic and lubricious coatings for medical devices, particularly devices for temporary or permanent implantation in vivo and blood contact applications.

One of the many advances in medical practice in recent years has been the development of medical devices that complement the skill of the surgeon. Examples of these devices are various vascular catheters and guidewires that can be used to treat distal regions in the circulatory system that would otherwise be accessible only through major surgery. Another is a stent, a device that strengthens the arterial wall and prevents occlusion after angioplasty. The other is an intraocular lens, which allows the elderly with cataracts to restore youthful vision. The list of other such devices, such as heart valves, artificial cardiac pacemakers and orthopedic implants, is growing.

Almost all of the above devices are constructed of plastic and metal which are never intended to invade the body and sometimes remain in the body for long periods of time. They present surfaces that bear little or no resemblance to the surface of human organs, which are generally hydrophilic, slippery and biocompatible.

Of equal importance for devices that must be inserted and moved in body tissue is their lubricity. Most metals and plastics have poor lubricity to body tissue, resulting in mechanical wear and discomfort as the device is passed through the tissue.

The surfaces of devices designed and fabricated from such materials can be rendered biocompatible, hydrophilic and slippery by appropriately designed coatings. Accordingly, methods have been developed to construct medical devices from conventional plastics and metals having the particular physical properties desired, and then apply suitable coatings to impart the desired properties to the surface thereof.

It has been shown that polymers having a low coefficient of friction when wet are water soluble polymers that crosslink or otherwise set and swell when exposed to water, but do not dissolve. Polysaccharides have proven useful for making hydrophilic, lubricious coatings on substrates. Such coatings are described in U.S. patent nos. 4,801,475, 5,023,114, 5,037,677, and 6,673,453, the disclosures of which are incorporated herein by reference. Polysaccharide-based lubricious coatings exhibit excellent biocompatibility and lubricity, but relatively poor resistance to ionizing radiation.

For some applications, lubricious coatings made from synthetic polymers are needed to achieve longer shelf life and stability to radiation sterilization processes. Hydrophilic synthetic polymers, such as poly (acrylic acid) and its copolymers, are often proposed for the production of lubricious, hydrophilic coatings because they are capable of producing a hydrated layer on the surface.

Many attempts have been made to immobilize poly (acrylic acid) on surfaces so that they can be used as coatings on medical devices. The processes in U.S. patent nos. 4,642,267 and 4,990,357 include physical blends of poly (acrylic acid) copolymers with polyurethane dispersions. A disadvantage of this approach is that the interpolymer network that physically connects the hydrophilic polymer to the substrate surface often breaks down in prolonged turbulence or soaking, and the hydrophilic species may be washed away, rendering the article insufficiently lubricious.

Other inventive methods of utilizing poly (acrylic acid) as a hydrophilic coating on a surface include radiation grafting of carboxylic acid monomers and their polymers as described in U.S. Pat. Nos. 2,999,056, 5,531,715, 5,789,018 and 6,221,061 and EP 0669837, plasma grafting of acrylic acid monomers as described in EP 0220919, and anchoring polyacrylic acid using primers containing isocyanate, aziridine, amine and hydroxyl functional groups as described in U.S. Pat. Nos. 5,091,205, 5,509,899, 5,702,754, 6,048,620, 6,558,798, 6,709,706, 6,087,416, 6,534,559 and EP 0379156, EP 0480809, EP 0728487 and EP 0963761. The disclosures of all of the above patents are incorporated herein by reference.

Such poly (acrylic) coatings exhibit relatively poor lubricity and/or durability due to insufficient coating thickness and/or poor adhesion to the surface of the hydrophilic polymer. High density surface coverage is difficult to achieve via photoinitiated polymeric grafting or chemical attachment of the polymer surface. Multiple coating iterations may increase the thickness of the photo-initiated polymeric coating, but may significantly reduce productivity and increase manufacturing costs.

The use of a cross-linking agent can significantly increase the thickness of the hydrophilic coating. The prior art includes methods of crosslinking polyacrylic acid coatings by light irradiation and by reaction of polyfunctional reactive compounds such as melamine and aziridine, as described in U.S. patent nos. 5,531,715, 6,558,798 and EP 533821. However, crosslinked hydrophilic coatings in the art often face a trade-off between lubricity and wear resistance, both of which are indispensable properties of hydrophilic coatings. Highly crosslinked coatings have poor lubricity due to low hydration capability and reduced mobility of the polymer segments in aqueous media. Coatings with low crosslink density have high swelling ratios, generally resulting in poor abrasion resistance and low mechanical strength.

U.S. patent application publication No. 2011/0200828 teaches a duplex coating that includes a basecoat layer that is strongly adhered to a substrate and a topcoat layer that is chemically grafted to the basecoat layer. The topcoat comprises a mixture of a water-soluble polymer containing carboxylic acid groups and a water-soluble chromium (III) compound. The coating forms a very durable lubricating layer when wet. However, the carboxylate anions that make up the coating exhibit poor performance in thrombosis tests, such as the Partial Thromboplastin Time (PTT) test. The disclosures of the above references are incorporated herein by reference.

Contacting blood with foreign matter having a plastic or metal surface induces a complex series of clot forming reactions at the blood surface interface. Thromboembolism is a major complication associated with clinical use of prosthetic devices, such as catheters, guide wires, mechanical heart valves, ventricular assist devices, implantable prosthetic hearts, vascular grafts, and the like. In particular, thromboembolism is an important complication of angiographic procedures, particularly in catheter and guidewire procedures in the proximal portion of the brachiocephalic vessels.

Surface modification is generally used to make the material more compatible with blood, while minimizing any loss of mechanical properties. Two methods are generally employed for modification. The use of polyethylene oxide (PEO), a neutral, hydrophilic and highly flexible polymer, or other hydrophilic polymer coatings to inhibit nonspecific protein adsorption for surface passivation has been investigated. Uncontrolled, non-specific protein adsorption, which typically occurs within seconds after exposure of the foreign surface to blood, can initiate blood coagulation and complement pathways.

The second approach is to use a coating that actively assists surface anticoagulation activity. Certain plasma proteins, such as Antithrombin (AT) which inhibits thrombin and factor Xa (FXa), or heparin, a glycosaminoglycan which catalyzes the plasma AT reaction, have been used for this purpose. Frech et al, in "Simple non-invasive Technique for testing non-thrombogenic Surfaces (A Simple non-invasive Technique to Test non-thrombogenic Surfaces)", "Journal of American radiology (The American Journal of Roentgenology"), Vol.113 (1971), p.765-768 disclose a guidewire coated with benzalkonium chloride-heparin complex. Ovitt et al, reported Teflon (Teflon) -coated guidewires treated with benzalkonium chloride heparin in "Guidewire thrombosis and Its Reduction" (Radiology), Vol.111 (1974), pp.43-46. U.S. patent No. 4,349,467 (William) shows heparin being applied to a solid polymer resin substrate by soaking the substrate in an ammonium salt solution and contacting the substrate with a heparin salt solution.

Many attempts have also been made to invent hydrophilic polymers which have a range of applications including electrophoresis, hair treatment and paper treatment. Just as in Albraghouthi et al in "poly-N-hydroxyethyl acrylamide (polyDuramide): a novel hydrophilic self-coating polymer matrix (Poly-N-hydroxyethyleneacrylamide) (A novel, hydrophic, self-coating polymer matrix for DNA sequencing) for DNA sequencing by capillary Electrophoresis, disclosed in Electrophoresis (Electrophoresis), Vol.23 (2002), pp.1429-1440, non-ionic monomers, such as N-hydroxyethylacrylamide, are highly hydrophilic.

The following references, i.e., WO10041527A, W010041530A, W011125713A, JP2011046619A, JP2011046652A, JP2010126482A and JP2010090049A, teach copolymers composed of 5 to 30 mole% of a carboxylic acid monomer and 70 to 95 mole% of an alcohol-containing acrylic acid monomer for use in hair treatment formulations. These patent applications do not disclose the use of the copolymers as lubricating, biocompatible coatings, nor their resistance to ionizing radiation. JP2006176934A teaches that copolymers made from methacrylamide, hydroxyethyl acrylamide and ionic vinyl monomers are used as additives to increase the strength of the paper. The latter reference does not disclose the use of the copolymers as lubricating, biocompatible coatings, nor their resistance to ionizing radiation.

There is a need for improved lubricious, biocompatible coatings that are resistant to ionizing radiation.

Typically, the primer coating is located between the substrate of the medical device or medical implant and the lubricious coating. The primer layer may improve the stability of the lubricious coating. There is a need in the art for improved basecoats, such as basecoats that provide faster adhesion of lubricious topcoats. This need can be met by a primer that is bonded to a hydrophilic top coat by Ultraviolet (UV) curing.

Disclosure of Invention

The present invention relates to a coating composition for a medical device or medical implant. These novel compositions comprise a hydrophobic basecoat polymer and a hydrophilic topcoat polymer.

In some embodiments, the present invention relates to a coating composition comprising a hydrophobic polymer for use as a photoreactive primer coating for a medical device or medical implant, comprising a polymer made from monomers comprising:

(a)1 to 12 mol% of at least one photoactive monomer as a hydrogen atom extractant, and

(b)99 to 88 mole% of one or more of acrylamide, methacrylamide, acrylate, methacrylate, and N-vinyl pyrrolidone; wherein the polymer has a glass transition temperature (Tg) of less than 40 ℃.

In certain embodiments, the primer layer additionally comprises a polyfunctional aziridine. (a)95 wt% to 99.8 wt% of a hydrophobic polymer as described herein; and (b)0.2 wt% to 5 wt% of polyfunctional aziridine, based on the total weight of the primer layer.

The present invention also relates to a medical device or medical implant comprising a photoreactive primer coating comprising the coating composition described herein. In preferred compositions, the primer layer is hydrophobic. In some embodiments, the device or implant contains a hydrophilic top coat, wherein the primer layer is on the substrate and the top coat is on the primer layer. The hydrophilic topcoat composition may, but need not, contain photoactive groups.

In other embodiments, the present invention relates to a coating solution comprising a coating composition of a hydrophobic base coat layer as described herein and a solvent.

In other embodiments, the coating solution comprises a polymer soluble in a water or water-alcohol solution, the polymer being made from monomers comprising: (a) at least one monomer that is a photo radical generator, and (b) at least one monomer comprising one or both of: (i) olefinic monomers comprising at least one acidic group and (ii) one or more acrylates or acrylamides: one or both of the following: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides in a molar ratio to photoradical generator groups of from 20:1 to 500: 1.

The present invention also relates to a coated substrate comprising a substrate and a lubricious coating made using the coating composition described herein.

Additional embodiments relate to coating the compositions described herein in an aqueous solution.

In yet another embodiment, the present invention is directed to a method of coating a substrate. In some embodiments, both the base coat and the top coat are applied to the substrate. When both the basecoat and topcoat are cured by UV light, (a) the basecoat is applied and cured before the topcoat is applied or (b) the basecoat is applied and dried, the topcoat is added, and then the basecoat and topcoat are cured by UV light.

Other embodiments include a medical device or medical implant wherein the lubricious coating contains a pharmaceutical agent or antimicrobial agent blended with the coating composition.

Detailed Description

The requirements of any coating intended for a medical device will first be set forth and explained. The specification will then show how the invention meets these requirements.

The coatings of the present invention are suitable for use in medical devices. The coating of the invention has the following properties:

(1) the coating must be capable of forming a continuous, adherent film with good integrity on the surface of the material being coated when dried. This means that the minimum film-forming temperature of the coating solution must be lower than the expected drying temperature used in the device manufacturing process;

(2) the polymer film formed must have sufficient flexibility and adhesion to conform to the bending and twisting of the coated device without cracking under the intended use conditions;

(3) when the coated device is immersed in an aqueous medium such as human blood for a long time, the film cannot be weakened or lose the integrity;

(4) the coating must present a surface that is non-cytotoxic and hemocompatible. The coating must not initiate blood clotting and complement pathways when in contact with human blood;

(5) the coating must adhere firmly and securely to the substrate so that no particles or debris or leachable components can contaminate aqueous media such as human blood; and

(6) the coating must withstand some form of acceptable sterilization without loss of integrity, durability, or biocompatibility.

Coatings meeting the above requirements are made as follows.

The disclosure may be understood more readily by reference to the following description taken in connection with the accompanying drawings and the examples, all of which form a part of this disclosure. It is to be understood that this disclosure is not limited to the particular products, methods, conditions or parameters described and/or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed disclosure. Similarly, any description of possible mechanisms or modes of action or reasons for improvement is meant to be illustrative only and the invention is not to be limited herein to the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement, unless specifically stated otherwise. Throughout this text, it is recognized that these descriptions relate to both methods of operating devices and systems, and to devices and systems that provide the methods. That is, where the present disclosure describes and/or claims a coating composition, medical device, coating solution, or method, it is to be understood that such description and/or claims also describe and/or claim a device, apparatus, or system for accomplishing such methods.

In some embodiments, the present invention relates to coating compositions comprising hydrophobic polymers for use as a photoreactive primer coating for a medical device or medical implant, comprising a polymer made from monomers comprising:

(a)1 to 12 mol% of at least one photoactive monomer as hydrogen atom extractant, and

(b)99 to 88 mole% of one or more of acrylamide, methacrylamide, acrylate, methacrylate, and N-vinyl pyrrolidone; wherein the hydrophobic polymer has a glass transition temperature (Tg) of less than 40 ℃.

Preferred hydrophobic polymers have a glass transition temperature of less than 40 ℃,20 ℃, 15 ℃ or 10 ℃.

In a preferred embodiment of the hydrophobic polymer, the photoactive monomer as a hydrogen atom extractant is a benzophenone compound. In certain embodiments, the photoactive monomer that is a hydrogen atom extractant comprises one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy benzophenone, 4-methacryloxy benzophenone, acrylamido benzophenone, methacrylamido benzophenone, 2-hydroxy-4-acryloxy ethoxy benzophenone, and 2-hydroxy-4-methacryloxy ethoxy benzophenone.

4-methacryloxy-2-hydroxybenzophenone (MHB) can be copolymerized with a (meth) acrylate monomer to produce a hydrophobic photoactive polymer. After UV curing, this polymer acts as a tie layer, adhering the substrate to the hydrophilic top coat. Topcoats cured in the presence of such photoactive basecoat layers adhere well even if the topcoat layer does not contain a photoactive component.

4-methacryloxy-2-hydroxybenzophenone (MHB)

The monomer that is copolymerized with the photoactive monomer may be one or more acrylates, methacrylates, or other monomers known to copolymerize well with them. In certain embodiments, the polymer comprises a methacrylate of the structure

Wherein R is optionally substituted C ₁ -C ₂₀ An alkyl group. In some embodiments, R may be methyl, ethyl, or butyl. Preferably, the copolymer will contain monomers such as ethylhexyl, isodecyl, dodecyl or other monomers that contribute to the formation of a low glass transition temperature copolymer. The copolymer also contains monomers with some hydrophilic character to provide good interaction with the top coating solution and the polymer. Examples include hydroxyethyl methacrylate and N-vinyl pyrrolidone monomers.

In certain embodiments, the monomer contributing a low glass transition temperature to the hydrophobic polymer is a monomer having C ₄ -C ₂₀ Alkyl acrylates, for example butyl acrylate.

In yet other aspects, the present invention relates to a coating solution comprising 2 wt.% to 15 wt.% of the hydrophobic polymeric coating composition described herein. In other embodiments, the solution comprises 3 to 13 wt%, or 4 to 12 wt%, or 5 to 10 wt% of the coating composition described herein. In a preferred embodiment, the solution comprises an organic solvent. Preferred solvents include one or more of the following: toluene, ethanol, acetone, isopropanol, ethyl acetate, dimethylformamide, tetrahydrofuran, butanol, N-methyl-2-pyrrolidone, N-butyl acetate, 1, 2-propylene glycol monomethyl ether acetate, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 1-pentanol, 2-propanol, propyl acetate, dichloromethane, dimethyl sulfoxide, methyl butyl ketone, and xylene.

In certain embodiments, the primer layer additionally comprises a polyfunctional aziridine. In some embodiments, the coating composition comprises (a)95 wt% to 99.8 wt% hydrophobic polymer; and (b)0.2 wt% to 5 wt% polyfunctional aziridine. In other embodiments, the coating composition comprises (a)98 wt% to 99.5 wt% of a hydrophobic polymer; and (b)0.5 wt% to 2 wt% polyfunctional aziridine.

In some embodiments, the present invention relates to a hydrophilic polymer coating composition for a medical device or medical implant, the composition comprising a polymer soluble in a water or water-alcohol solution, the polymer being made from monomers comprising:

(a) at least one monomer as a photo radical generator, and

(b) at least one monomer comprising one or both of: (i) olefinic monomers comprising at least one acidic group and (ii) one or more acrylates or acrylamides;

one or both of the following: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides in a molar ratio to photoradical generator groups of from 20:1 to 500: 1.

The polymer may be packaged in water or a water-alcohol mixture. The alcohol is usually C ₁ -C ₆ An alcohol. Preferred alcohols include methanol, ethanol and isopropanol. The ratio of water to alcohol may be 100:0 to 50: 50.

Some preferred photo radical generators for hydrophobic polymers are benzophenone compounds. In some embodiments, the photo-radical generating agent comprises one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy benzophenone, 4-methacryloxy benzophenone, acrylamido benzophenone, methacrylamido benzophenone, 2-hydroxy-4-acryloxy ethoxy benzophenone, 2, 4-dihydroxy-4' -vinylbenzophenone, and 2-hydroxy-4-methacryloxy ethoxy benzophenone. One preferred photoradical generator group comprises 4-methacryloxy-2-hydroxybenzophenone.

4-methacryloxy-2-hydroxybenzophenone (MHB) can be copolymerized with polar acrylates such as acrylic acid and N- (2-hydroxyethyl) acrylamide to produce hydrophilic photoactive polymers. After UV curing, this polymer acts as a lubricious topcoat. It can also be used as an additive to other hydrophilic (non-photoactive) polymers to form a lubricious coating after UV curing.

Random copolymer of MHB, acrylic acid and N- (2-hydroxyethyl) acrylamide

A variety of olefinic monomers can be used to form the hydrophilic polymer. In some embodiments, the monomer comprises at least one acidic group comprising acrylic acid, methacrylic acid, 2-ethacrylic acid, 2-propylacrylic acid, acryloxypropionic acid, isocrotonic acid, maleic anhydride, maleic acid, and the half esters, half amides, and half thioesters of maleic, fumaric, and itaconic acids, and mixtures thereof. In some embodiments, the olefinic monomers comprise N- (2-hydroxyethyl) acrylamide and acrylic acid. In certain embodiments, the molar ratio of N- (2-hydroxyethyl) acrylamide to acrylic acid is 2:1 to 5: 1.

Preferred acrylates and acrylamides include acrylamide, N- (2-hydroxyethyl) acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, N- (2-hydroxyethyl) methacrylamide, N-acrylamido-ethoxyethanol, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, 2-hydroxyethyl methacrylate, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, 3-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol, and propylene glycol, and propylene, and, N, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-methylolmethacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, or a mixture of any of the foregoing.

In some embodiments, one or both of (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides, in a molar ratio to the photo radical generator comprising at least one photopolymerizable group is from 40:1 to 200: 1.

In certain embodiments, the hydrophilic polymer has a weight average molecular weight (Mw) between 20,000 and 800,000 or 20,000 to 400,000 or 50,000 and 400,000.

Some hydrophilic polymeric coating compositions additionally comprise a second polymer that is soluble in water or water-alcohol solutions. In some embodiments, the second polymer comprises one or both of: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides. In a second polymer, the olefinic monomer of the second polymer comprises at least one acidic group, the olefinic monomer of the second polymer comprising the at least one acidic group comprising one or more of: acrylic acid, methacrylic acid, 2-ethacrylic acid, 2-propylacrylic acid, acryloxypropionic acid, isocrotonic acid, maleic anhydride, maleic acid, and the half esters, half amides, and half thioesters of maleic acid, fumaric acid, itaconic acid, and any combination thereof. Further, in the second polymer, the acrylate or acrylamide comprises acrylamide, N- (2-hydroxyethyl) acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, N- (2-hydroxyethyl) methacrylamide, N-acrylamido-ethoxyethanol, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylenebutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, N- (2-hydroxyethyl) acrylamide, N-hydroxy-methyl methacrylate, N- (2-hydroxy-methyl acrylate, N- (2-hydroxy-methyl) acrylamide, N-2-allyloxyethanol-methyl acrylate, N- (2-hydroxy-methyl) acrylamide, N-methyl acrylate, N-hydroxy-methyl acrylate, N-2-hydroxy-2-methyl acrylate, N-2-hydroxy-methyl acrylate, N-propyl acrylate, N-allyl-2-methyl acrylate, N-2-allyl-2-allyl-vinyl ether, N-2-vinyl ether, N-2-vinyl-2-vinyl-acrylamide, N-vinyl-acrylate, N-vinyl-acrylamide, N-acrylate, N-acrylamide, N-vinyl-acrylate, N-vinyl-2-acrylate, N-2-acrylate, N-vinyl-2-acrylamide, N-vinyl-acrylate, N-2-, Ethylene glycol vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-methylolmethacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, and mixtures of any of the foregoing.

In some embodiments, the second polymer has a weight average molecular weight (Mw) between 50,000 and 800,000.

The present invention also relates to a coated substrate comprising a substrate and a lubricious coating made using the coating composition described herein. Preferred embodiments also include a primer layer in contact with both the substrate and the lubricious coating composition. Preferably the primer layer is hydrophobic.

The present invention also relates to a medical device or medical implant comprising a photoreactive primer coating comprising the coating composition described herein. In some embodiments, the primer layer is located between the substrate and the hydrophilic top coat. Some preferred topcoat layers include one or more of polyacrylates, polyvinylpyrrolidone, hyaluronic acid, and polyacrylamide. In other embodiments, the topcoat comprises N- (2-hydroxyethyl) acrylamide and an acrylic acid copolymer. Some embodiments include a plurality of covalent crosslinks between the basecoat layer and the hydrophilic topcoat layer.

The coating may be used with any medical device or medical implant suitable for coating applications. In some embodiments, the substrate is plastic or metal.

Preferred coated substrates have lubricity of less than 25gf friction and durability of less than 50gf friction as measured by the nip test.

The invention also relates to medical devices and medical implants comprising the coated substrates described herein. In some embodiments, the medical device or medical implant is sterilized by at least one of gamma radiation, electron beam, and ethylene oxide.

In further embodiments, the coatings described herein contain an agent or antimicrobial agent blended with the coating composition.

Preferred medical devices include catheters or guidewires.

In some aspects, the present invention relates to methods of coating articles. Some methods comprise coating a substrate with a primer layer comprising a coating composition described herein. The primer layer may be cured by exposing the primer layer to UV light. In some embodiments, the primer layer may be coated with a hydrophilic top coat.

In still other embodiments, the coating method comprises coating the substrate with a primer comprising the coating composition described herein, coating the primer with a hydrophilic top coat, and curing the primer and top coat with UV light. The hydrophilic top coat may be photoactive (i.e., contain groups that absorb UV radiation and react upon exposure to UV radiation), but the presence of photoactive groups in the top coat is not required.

The present invention relates to at least the following aspects.

Aspect 1a. a coating composition comprising a hydrophobic polymer for use as a photoreactive primer coating for a medical device or medical implant, comprising a polymer made from monomers comprising: (a)1 to 12 mole% of at least one photoactive monomer that is a hydrogen atom extractant, and (b)99 to 88 mole% of one or more of acrylamide, methacrylamide, acrylate, methacrylate, and N-vinyl pyrrolidone; wherein the polymer has a glass transition temperature (Tg) of less than 40 ℃.

Aspect 1b. a coating composition comprising a hydrophobic polymer for use as a photoreactive primer coating for a medical device or medical implant, the coating composition comprising a polymer made from monomers comprising: (a)1 to 5 mole% of at least one photoactive monomer that is a hydrogen atom extractant, and (b)99 to 95 mole% of one or more of acrylamide, methacrylamide, acrylate, methacrylate, and N-vinyl pyrrolidone; wherein the polymer has a glass transition temperature (Tg) of less than 40 ℃.

Aspect 2. the coating composition of aspects 1A-1B, further comprising a polyfunctional aziridine.

Aspect 3. the coating composition of aspect 2 comprising (a) 95-99.8 wt% of the hydrophobic polymer; and (b)0.2 wt% to 5 wt% polyfunctional aziridine.

Aspect 4. the coating composition of any of aspects 1A to 3, comprising the structure

Wherein R is optionally substituted C ₁ -C ₂₀ An alkyl group.

Aspect 5. the coating composition of aspect 4, wherein R is one or more of methyl, ethylhexyl, isodecyl, or dodecyl.

Aspect 6. the coating composition of aspect 4, wherein the hydrophobic polymer comprises hydroxyethyl methacrylate and N-vinyl pyrrolidone.

Aspect 7. the coating composition of any one of aspects 1A to 6, wherein the hydrophobic polymer comprises a polymer having C ₄ -C ₂₀ Alkyl acrylates.

Aspect 8. the coating composition of any one of aspects 1A to 7, wherein the photoactive monomer that is a hydrogen atom extractor comprises a benzophenone moiety.

Aspect 9. the coating composition of aspect 8, wherein the photoactive monomer that is a hydrogen atom extractor comprises one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy benzophenone, 4-methacryloxy benzophenone, acrylamido benzophenone, methacrylamido benzophenone, 2-hydroxy-4-acryloxy ethoxy benzophenone, and 2-hydroxy-4-methacryloxy ethoxy benzophenone.

Aspect 10. the coating composition of any one of aspects 1A to 9, having a Tg of less than 20 ℃.

Aspect 11A medical device or medical implant comprising a photoreactive primer coating comprising the coating composition according to any one of aspects 1A to 10.

Aspect 12 the medical device of aspect 11, wherein the primer coating is located between the substrate and the hydrophilic top coating.

The medical device of aspect 12, wherein the topcoat includes one or more of: polyacrylate, polyvinylpyrrolidone, hyaluronic acid and polyacrylamide.

The medical device of aspect 12, wherein the topcoat comprises N- (2-hydroxyethyl) acrylamide and an acrylic acid copolymer.

Aspect 15 the medical device of aspect 11, wherein the medical device is a catheter or guidewire.

The medical device of aspect 12, comprising a plurality of covalent crosslinks between the primer layer and the hydrophilic top coat.

Aspect 17. a coating solution comprising from 2 to 15 wt.% of the coating composition of any one of aspects 1 to 10 in a solvent.

Aspect 18. the coating solution of aspect 17, wherein the solvent is an organic solvent.

Aspect 19 the coating solution of aspect 18, wherein the solvent comprises one or more of: toluene, ethanol, acetone, isopropanol, ethyl acetate, dimethylformamide, tetrahydrofuran, butanol, N-methyl-2-pyrrolidone, N-butyl acetate, 1, 2-propylene glycol monomethyl ether acetate, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 1-pentanol, 2-propanol, propyl acetate, dichloromethane, dimethyl sulfoxide, methyl butyl ketone, and xylene.

Aspect 20 a method of forming a coated article comprising coating a substrate with a primer coating comprising the coating composition of any of aspects 1A to 10.

Aspect 21 the method of aspect 20, further comprising curing the primer layer by exposing the primer layer to UV light.

Aspect 22. the method of aspect 21, further comprising coating the basecoat with a hydrophilic topcoat.

The method of aspect 20, further comprising (a) coating the basecoat with a hydrophilic topcoat and (b) curing the basecoat and the topcoat with UV light.

An aspect 24. a coating composition for a medical device or medical implant comprising a polymer soluble in a water or water-alcohol solution, the polymer being made from monomers comprising: (a) at least one monomer that is a photo radical generator comprising one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy benzophenone, 4-methacryloxy benzophenone, acrylamido benzophenone, methacrylamido benzophenone, 2-hydroxy-4-acryloxyethoxy benzophenone, 2, 4-dihydroxy-4' -vinyl benzophenone, and 2-hydroxy-4-methacryloxyethoxy benzophenone, and (b) at least one monomer comprising one or both of: (i) olefinic monomers comprising at least one acidic group and (ii) one or more acrylates or acrylamides; wherein the ethylenic monomer comprises at least one acidic group comprising acrylic acid, methacrylic acid, 2-ethacrylic acid, 2-propylacrylic acid, acryloxypropionic acid, isocrotonic acid, maleic anhydride, maleic acid, and the half esters, half amides, and half thioesters of maleic acid, fumaric acid, and itaconic acid, and mixtures thereof; wherein the acrylate or acrylamide comprises acrylamide, N- (2-hydroxyethyl) acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate and N- (2-hydroxyethyl) methacrylamide, N-acrylamido-ethoxyethanol, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, N- (hydroxyethyl) acrylamide, N- (2-hydroxyethyl) methacrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, N- [ 4- (hydroxymethyl) methyl ] acrylamide, N- (2-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, N- (2-hydroxyethyl) ethyl methacrylate, N- (hydroxymethyl) acrylamide, N- (2-hydroxy-methyl) acrylamide, N- (2-hydroxy-methyl) acrylamide, N-methyl-butyl acrylate, N- (2-hydroxy-2-methyl-2-hydroxy-methyl-2-methyl-2-allyl-vinyl) acrylate, N-vinyl ether, N-vinyl-butyl acrylate, N-vinyl-2-vinyl-acrylate, N-vinyl-acrylate, N-vinyl-acrylate, N-vinyl-2-acrylate, N-vinyl-2-vinyl-acrylate, N-vinyl-acrylate, N-vinyl-acrylate, N-vinyl-acrylate, N-vinyl-acrylate, N-2-acrylate, N-vinyl-2-vinyl-acrylate, N-2-acrylate, N-2-acrylate, N-2-, N, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-methylolmethacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, or a mixture of any of the foregoing; one or both of the following: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides in a molar ratio to photoradical generator groups of from 20:1 to 500: 1.

Aspect 25. the coating composition of aspect 24, wherein the photoradical generator group comprises 4-methacryloxy-2-hydroxybenzophenone.

Aspect 26. the coating composition of aspect 24, wherein the olefinic monomers comprise N- (2-hydroxyethyl) acrylamide and acrylic acid.

Aspect 27. the coating composition of aspect 26, wherein the molar ratio of N- (2-hydroxyethyl) acrylamide to acrylic acid is 2:1 to 5: 1.

Aspect 28. the coating composition of aspect 24, wherein one or both of: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides in a molar ratio to the photo radical generator comprising at least one photopolymerizable group of from 40:1 to 200: 1.

Aspect 29. the coating composition of aspect 24, wherein the polymer has a weight average molecular weight (Mw) of between 20,000 and 800,000.

Aspect 30. the coating composition of aspect 24, further comprising a second polymer soluble in a water or water-alcohol solution.

The coating composition of aspect 30, comprising one or both of: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides.

The coating composition of aspect 31, wherein the olefinic monomer of the second polymer comprises at least one acidic group, the olefinic monomer of the second polymer comprising the at least one acidic group comprising one or more of: acrylic acid, methacrylic acid, 2-ethacrylic acid, 2-propylacrylic acid, acryloxypropionic acid, isocrotonic acid, maleic anhydride, maleic acid, and the half esters, half amides, and half thioesters of maleic acid, fumaric acid, itaconic acid, and any combination thereof.

Aspect 33. the coating composition of aspect 31, wherein the acrylate or acrylamide of the second polymer comprises acrylamide, N- (2-hydroxyethyl) acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, and N- (2-hydroxyethyl) methacrylamide, N-acrylamido-ethoxyethanol, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylobutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, N- (2-hydroxyethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, 3-hydroxy-2-methylenebutanoic acid methyl ester, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, N- (2-hydroxyethyl) acrylamide, N- (2-hydroxy-methyl) methacrylate, N- (2-ethylhydroxy-2-methylbutanoic acid, N-methyl ester, N-hydroxy-2-ethylbutanoic acid, N-methyl ester, N-hydroxy-carboxylic acid, N-carboxylic acid, or a-carboxylic acid or a salt, or a salt thereof, di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-methylolmethacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, and mixtures of any of the foregoing.

Aspect 34. the coating composition of aspect 31, wherein the second polymer has a weight average molecular weight (Mw) of between 50,000 and 800,000.

Aspect 35. the coating composition of aspect 24, further comprising water or a water/alcohol mixture.

Aspect 36. a coated substrate, comprising: a substrate and a lubricious coating made using the coating composition according to any of aspects 24-35.

Aspect 37. the coated substrate of aspect 36, further comprising a primer layer in contact with both the substrate and the lubricious coating composition.

Aspect 38. the coated substrate of aspect 37, wherein the primer layer is hydrophobic.

Aspect 39. the coated substrate of aspect 36, wherein the substrate is plastic.

Aspect 40. the coated substrate of aspect 36, wherein the substrate is metallic.

Aspect 41 the coated substrate of any one of aspects 36-40, wherein the coated substrate has a lubricity of less than 25gf friction and a durability of less than 50gf friction, as measured by the nip test.

Aspect 42. a medical device or medical implant comprising the coated substrate of any one of aspects 36-41.

The medical device or medical implant of aspect 42, wherein the medical device or medical implant is sterilized by at least one of gamma radiation, electron beam, and ethylene oxide.

Aspect 44. the medical device or medical implant of aspect 42 or 43, wherein the lubricious coating contains a pharmaceutical agent or antimicrobial agent blended with the coating composition.

Examples of the invention

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

The following abbreviations are used herein:

MHB-4-methacryloxy-2-hydroxybenzophenone is a monomer that provides photoactivity to the copolymer. It was purchased from Polysciences and Bimax. Purity was confirmed by nuclear magnetic resonance NMR using Bruker 400MHz NMR in USciences.

BA-butyl acrylate

MMA-methyl methacrylate

HEMA-hydroxyethyl methacrylate

NVP-N-vinylpyrrolidone

EHMA-ethylhexyl methacrylate

iDMA-isodecyl methacrylate

DDMA-dodecyl methacrylate

AA-acrylic acid

HEAA-N- (2-hydroxyethyl) acrylamide

PVP-polyvinylpyrrolidone

HAP-hydrophilic acrylic copolymer, copolymer of AA and HEAA

Coatings are applied to a variety of substrates in rod or tube form. The rod is 0.125 inch diameter stainless steel or PMMA. Pebax ^TM The 35D and 55D plastic tubes had an outer diameter of 0.079 inches and a wall thickness of 0.005 inches. Prior to coating, the tube was placed on a stainless steel rod for stabilization. The coating process consists of: the rods were wiped with isopropyl alcohol, dip coated at 0.2 inches/sec in the basecoat solution, dried at 60 ℃ for 10 minutes, dip coated at 0.2 inches/sec in the topcoat solution, and dried at 60 ℃ for 10 minutes. Only after all coatings have been applied, the rods are subjected to UV radiation.

UV curing was carried out in a Uvitron IntelliRay model UV0832 UV curing unit equipped with a UVA 600 watt metal halogen lamp. The irradiance was measured using an EIT Uvicure Plus II radiometer from INPRO Technologies. This single channel UVA radiometer measures radiation between 320 and 390 nanometers (nm).

Two different methods are used to provide uniform radiation around the rod. In the first method, a hex coupler is attached to the rod to provide a fixed geometry for rotating the coated rod as it is cured. The sample may then be subjected to 6 revolutions to expose all faces. The rotation patterns are 0 °, 120 °, 240 °, 60 °, 180 °, and 300 °. In the second method, the rod is continuously rotated by a motor at a speed of 20rpm during UV curing.

Typical irradiation times in the examples are 2-30 minutes and typical irradiance is 100-. It is noteworthy that all 320-390nm radiation cannot be used for photocrosslinking, only the wavelengths actually absorbed by the photoactive groups are responsible for the reaction. It is also understood that irradiance lower than that used in these examples can be accommodated by increasing the irradiation time.

The coating was tested for friction on a Chatillon CS225 force measuring machine. It is equipped with a hot water bath and a nip pad pressed together with a constant force. The water bath was filled with PBS solution and heated to 37 ℃. The nip pads were immersed in water and pressed together with a force of 470 grams (g). The friction force is measured in grams of force required to push and pull the sample through the pad. Lubricity and durability were determined by averaging the grams of force as the sample was pulled through the pad. Lubricity is the average of cycles 1-3 and durability is the force during cycle 30.

Photoactive basecoats are made by copolymerizing 4-methacryloxy-2-hydroxybenzophenone and a low glass transition temperature (meth) acrylate monomer. The synthesized photoactive undercoat polymers are summarized in table 1.

Table 1: photoactive undercoat polymer

The undercoat polymer also contained 12.7% HEMA and 21.7% NVP

A poly (methyl methacrylate) (PMMA) rod was coated with a primer polymer BP-5 and a polyvinylpyrrolidone (PVP) topcoat (Aldrich 1,300,000 molecular weight, according to light scattering). At 186 milliwatts per square centimeter (mW/cm) ² ) The coated rod was cured with each of six revolutions. After the pinch test, the rods were rinsed under running cold tap water for 10 seconds, immersed in a 0.5% congo Red (Gongo Red) aqueous solution, and then rinsed again for 10 seconds. The strong red color indicates the presence of adherent PVP, indicating that grafting occurred between the photoactive undercoat and the PVP topcoat.

PVP topcoat with four different UV-cured primer polymers were tested on PMMA substrate rods. At 166mW/cm ² Spoke ofUV curing was completed in each of six revolutions over 20 minutes under illumination. Although the samples showed good lubricity, they lasted only 10-20 cycles. The results are summarized in table 2.

Table 2: UV curing Using PVP topcoat and different basecoat polymers

Primer polymers	Primer monomer	First cycle friction	Last cycle friction
				BP-3	EHMA	53	66
BP-5	iDMA	38	62
				BP-7	DDMA/MMA	77	94
BP-11	BA/MMA	72	95

Hydrophilic acrylic polymers and blends of such hydrophilic acrylic polymers with PVP were evaluated as topcoats (with the addition of a surfactant). The Hydrophilic Acrylic Polymer (HAP) is a copolymer of acrylic acid and 2-hydroxyethyl acrylamide. At 180mW/cm ² Six revolutions at irradiance for UV curing. The results are in table 3. All three rods of each sample exhibited good lubricity and durability over 30 cycles.

Table 3: effect of curing time on coating Performance of HAP/PVP topcoat blends

The primer polymer for all samples was BP-3(EHMA) and was coated at 8% solids.

Adherent topcoat measurement of the HAP portion of the adherent topcoat

The results summarized in the above examples do show that good lubricity and durability can be obtained from a photoactive basecoat without any photoactivity in the topcoat. One disadvantage of the UV curing process used in these examples is that it requires stopping the UV curing and manually rotating the sample five times during the curing process. To overcome this problem, a motor was provided to continuously rotate the sample at 20rpm during the curing process. This is expected to provide a more uniform UV cure around the circumference of the rod or tube. Not only is this approach more convenient, but it also provides even better lubricity and durability in even shorter cure times, as shown below.

Table 4 shows a comparison of several compositions using different monomer compositions and different amounts of photoactive monomers. The results show that a variety of low glass transition temperature monomers can be used to provide a lubricious, durable coating. These examples have no photoactive component in the topcoat.

Table 4: effect of amount of photoactive monomer and comonomer composition

Footnotes of table 4:

the base coat is coated on Pebax ^TM 55D tube.

After drying the basecoat, a surfactant-containing poly (HEAA-co-AA) topcoat is added and dried before UV curing.

By including some trifunctional aziridines, such as trimethylolpropane tris (2-methyl-1-aziridinepropionate) (crosslinker CX-100) in the primer layer, coated rods with even better durability can be obtained. Polyfunctional aziridines are known crosslinking agents in thermal curing processes. The results in table 5 demonstrate the improvement in durability.

Table 5: effect of trifunctional aziridines

Footnotes of table 5:

the base coat is coated on Pebax ^TM 55D tube.

After drying the basecoat, a poly (HEAA-co-AA) topcoat is added and dried.

6(+ hot) means that the sample was heated at 60 ℃ for 30 minutes after UV curing.

6 denotes that the samples were subjected to the pinch test after soaking in 50 ℃ PBS aqueous solution for 18 hours.

The above examples show that the combination of the photoactive basecoat of the present invention and the hydrophilic topcoat without intrinsic photoactivity provides good lubricity and durability. The following examples illustrate that even better performance can be obtained if the photoactivity is also designed into the topcoat.

Poly (HEAA-co-AA) in table 6. The polymer was prepared by reacting 29.79g N- (2-hydroxyethyl) acrylamide (HEAA), 6.21g Acrylic Acid (AA) in 263mL of water. The initiators of polymerization were ammonium persulfate and sodium hydroxymethanesulfinate hydrate. 0.015mL of 1% FeSO was added ₄ The solution is used to catalyze the reaction. Polymerization in N ₂ And 40 ℃. The polymer was purified by dialysis or precipitation with acetone (similar to example 1 of US2013/0323291a 1).

Poly (HEAA-co-AA-co-MHB) 1-4 in table 6. Photoactive polymers are prepared by reacting 15.29g of HEAA, 3.19g of AA, and 1.00g, 0.50g, or 0.25g of MHB in 40mL of LIPA and 30mL of water. 0.59mL of a 50mg/mL solution of Azobisisobutyronitrile (AiBN) in THF was added to the monomer solution. The solution was bubbled for 30 minutes to remove oxygen and then heated to 60 ℃ for 24 hours. After the reaction was complete, the polymer was precipitated with 150mL of ethyl acetate. The solvent was decanted off, the polymer was then dried in an oven at 60 ℃, and any remaining solvent was removed under vacuum. The polymer was dissolved in a 50:50 mixture of IPA and water.

Poly (HEAA-co-AA-co-MHB) 5-7 in table 6. Photoactive polymers are prepared by reacting 15.29g of HEAA, 3.19g of AA, and 1.00g, 0.50g, or 0.25g of MHB in 40mL of ethanol and 30mL of water. 0.245mL of a 20mg/mL (AiBN) solution in THF was added to the monomer solution. The solution was bubbled for 30 minutes to remove oxygen and then heated to 60 ℃ for 24 hours. After the reaction was complete, the polymer was precipitated with 150mL of ethyl acetate. The solvent was decanted off, the polymer was then dried in an oven at 60 ℃, and any remaining solvent was removed under vacuum. The polymer was dissolved in a 50:50 mixture of ethanol and water.

The molecular weight of these hydrophilic photoactive polymers was determined by SEC using a Waters 1515 isocratic high performance liquid chromatography HPLC pump, a Waters 2489 UV/visible detector set at 276nm and 290nm, a Waters 2414 refractive index detector, and 3 chromatography columns (2 Waters Ultrahydrogel 2000 and 1 Waters Ultrahydrogel 250). Molecular weights were calculated by comparison with poly (acrylic acid) standards using Empower 3 software.

Table 6: composition of photoactive hydrophilic polymers and M _w And M _n

Poly (HEAA-co-AA-co-MHB)	Mol% MHB	M _w	M _n	M _w /M _n
					1	2	72,417	19,150	3.78
2	1	58,864	12,757	4.61
					3	1	191,290	55,687	3.44
4	0.5	216,586	74,642	2.94
					5	2	218,178	79,888	2.73
6	1	254,733	69,063	3.69
					7	0.5	231,294	75,766	3.05
Poly (HEAA-co-AA)	0	649,456	301,998	2.15

Applying a coating to Pebax using dip coating ^TM 55D plastic tube. Pebax ^TM The tube had an outer diameter of 0.201cm (0.079 inch) and a wall thickness of 0.0127cm (0.005 inch). For stabilization, the tube was placed on a stainless steel rod. The tube was first dipped into the primer and withdrawn at 0.508cm (0.2 inch) per second and rotated in a UV chamber set to the desired intensity for 5 minutes. The tube was then dipped into the topcoat and drawn off at 0.508cm (0.2 inch) per second and rotated in a UV chamber set to the desired intensity for 5 minutes.

UV curing was carried out in a Uvitron IntelliRay model UV0832 UV curing unit equipped with a UVA 600 watt metal halogen lamp. Irradiance was measured using an EIT Uvicure plus ii radiometer from INPRO Technologies. This single channel UVA radiometer measures radiation between 320 and 390 nm.

The coating was pinch tested for friction on a Tinius Olsen 5ST electromechanical tester with a 10N load cell and data was collected using Horizon software. Tinius Olsen was equipped with a hot water bath and a nip pad pressed together at constant force. The water bath was filled with PBS solution and heated to 37 ℃. The nip pads were immersed in water and pressed together with a force of 450 g. The friction force is measured by the grams of force required to push and pull the sample through the pad. Lubricity and durability were determined by averaging the grams of force as the sample was pulled through the pad. Lubricity is the average of cycles 2-4 and durability is the average of cycles 28-30.

Priming solutions were prepared using the two photoactive priming polymers described above. The primer polymer may be diluted with a variety of different solvents, including isopropyl alcohol (IPA) and ethanol. And (3) an undercoat layer A: 10 weight percent of a solution of a copolymer of 2-ethylhexyl methacrylate (EHMA), N-vinyl pyrrolidone (NVP), hydroxyethyl methacrylate (HEMA) and MHB in propylene glycol methyl ether acetate PMA and polyethylenimine crosslinker. And (3) an undercoat layer B: 10 weight percent copolymer of Butyl Acrylate (BA), Methyl Methacrylate (MMA), NVP, HEMA and MHB in PMA with polyaziridine crosslinker.

Pebax ^TM The 55D tube was coated with primer a and after 5 minutes UV cure, with a topcoat containing the photoactive polymer described in table 6 and 2% poly (HEAA-co-AA) and surfactant in water. Table 7 shows different sides cured at different UV light intensitiesAnd (5) friction force test results of the coating.

Table 7: testing of different photoactive topcoats on basecoat A

Table 8 shows the results of the friction test of different topcoats using basecoat B. The photoactive topcoat contains poly (HEAA-co-AA-co-MHB), poly (HEAA-co-AA), and surfactant in water as described in table 1.

Table 8: testing of different photoactive topcoats on basecoat B

The examples of table 9 illustrate that the photoactive undercoat layer performs well when applied directly to a substrate. That is, the hydrophobic undercoat is not necessary for good lubricity and durability of the photoactive hydrophilic topcoat. The photoactive topcoat was applied twice and cured for 5 minutes after each application. As described above, the topcoat solution comprises one of the photoactive topcoats of table 6, poly (HEAA-co-AA), and a surfactant in water.

Table 9: in Pebax ^TM Direct application of hydrophilic topcoat on 55D substrate

Throughout the specification, unless otherwise indicated, words will be given their normal meaning as will be understood by those skilled in the relevant art. However, to avoid misunderstandings, the meaning of certain terms will be specifically defined or clarified.

In this disclosure, the singular forms "a", "an" and "the" include plural references, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. Thus, for example, reference to "a material" is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

It is to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. As used in the specification and claims, the term "comprising" may include embodiments "consisting of … … and" consisting essentially of … …. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and the claims that follow, reference will be made to a number of terms that shall be defined herein.

When values are expressed as approximations, by use of the descriptor "about," it will be understood that the particular value forms another embodiment. In general, use of the term "about" denotes an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter, and will be interpreted based on its function in the specific context in which it is used. Those skilled in the art will be able to interpret this as a general problem. In some cases, the number of significant digits for a particular value may be a non-limiting method of determining the range of the word "about". In other cases, the gradations used in a series of values may be used to determine the expected range available for the term "about" for each value.

Where present, all ranges are inclusive and combinable. That is, reference to a value in a range includes every value within the range, including the endpoints.

When a list is presented, it is to be understood that each individual element of the list, and each combination of the list, is to be interpreted as a separate embodiment, unless otherwise specified. For example, a listing of embodiments denoted as "A, B or C" will be interpreted to include embodiments "a", "B", "C", "a and B", "a and C", "B and C", or "A, B and C".

It is appreciated that certain features of the invention, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless clearly incompatible or expressly excluded, each individual embodiment is considered combinable with any other possible embodiment, and such combination is considered another embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Further, while embodiments may be described as part of a series of steps or part of a more general structure, each described step or part may itself be considered a separate embodiment.

As used herein, the terms "article" and "substrate" are not limited to any shape or size, as it can be a layer of material, multiple layers, or a bulk having at least one surface thereof modified with a coating composition described herein.

The glass transition temperature (Tg) was determined using the Fox equation and literature values for homopolymers. The Fox equation is as follows:

1/T _g,mix ≈∑ _i ω _i /T _g,i

wherein T is _g,mix And T _g,i Are the glass transition temperatures in degrees Kelvin of the mixture/copolymer and the component, respectively, and ω _i Is the mass fraction of component i. Production of Low T _g Monomers of homopolymers are required to produce polymers with low T _g The copolymer of (1). Examples include butyl acrylate (Tg ═ 54 ℃), 2-ethylhexyl methacrylate (Tg ═ 10 ℃), isodecyl methacrylate (Tg ═ -30 ℃) and dodecyl methacrylate (Tg ═ -65 ℃). Some of the other monomers used had homopolymer Tg of 100 ℃ for MMA, 20 ℃ for BMA, 120 ℃ for NVP, 105 ℃ for HEMA, 143 ℃ for MHB and 105 ℃ for acrylic acid.

For the two components A and B, the Fox equation reduces to

1/T _g,mix ≈ω _A /T _g,A +ω _B /T _g,B

As used herein, the term "hydrophobic" refers to a polymer that is insoluble in aqueous solutions. The crosslinked hydrophobic polymer did not swell significantly in water (less than 50%, < 50%).

The term "hydrophilic" refers to a polymer that is soluble in water or water-alcohol solutions. The crosslinked hydrophilic polymer swells significantly (> 100%) in aqueous solution. A "hydrophilic" substrate surface is a surface made of a polymer in which the uncured or uncrosslinked polymer is soluble in water or a hydroalcoholic solution having more than 50% water.

All molecular weights are weight average molecular weights (Mw) unless otherwise specified.

Claims

1. A coating composition comprising a hydrophobic polymer for use as a photoreactive primer for a medical device or medical implant, comprising a polymer made from monomers comprising:

(b)99 to 88 mole% of one or more of acrylamide, methacrylamide, acrylate, methacrylate, and N-vinyl pyrrolidone;

wherein the polymer has a glass transition temperature (Tg) of less than 40 ℃.

2. The coating composition of claim 1, further comprising a polyfunctional aziridine.

3. The coating composition of claim 2 comprising

(a) 95% to 99.8% by weight of the hydrophobic polymer; and

(b)0.2 wt% to 5 wt% polyfunctional aziridine.

4. The coating composition of any one of claims 1 to 3 comprising a methacrylate of the structure

Wherein R is optionally substituted C ₁ -C ₂₀ An alkyl group.

5. The coating composition of claim 4, wherein R is one or more of methyl, ethylhexyl, isodecyl, or dodecyl.

6. The coating composition of claim 4, wherein the hydrophobic polymer comprises hydroxyethyl methacrylate and N-vinyl pyrrolidone.

7. The coating composition of any one of claims 1 to 6, wherein the hydrophobic polymer comprises a polymer having C ₄ -C ₂₀ Alkyl acrylates.

8. The coating composition of any one of claims 1 to 7, wherein the photoactive monomer that is a hydrogen atom extractant comprises a benzophenone moiety.

9. The coating composition of claim 8, wherein the photoactive monomer that is a hydrogen atom extractor comprises one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy benzophenone, 4-methacryloxy benzophenone, acrylamido benzophenone, methacrylamido benzophenone, 2-hydroxy-4-acryloxy ethoxy benzophenone, and 2-hydroxy-4-methacryloxy ethoxy benzophenone.

10. The coating composition of any one of claims 1 to 9 having a Tg of less than 20 ℃.

11. A medical device or medical implant comprising a photoreactive primer coating comprising the coating composition according to any one of claims 1 to 10.

12. The medical device of claim 11, wherein the primer coating is located between the substrate and the hydrophilic top coating.

13. The medical device of claim 12, wherein the topcoat layer comprises one or more of a polyacrylate, polyvinylpyrrolidone, hyaluronic acid, and polyacrylamide.

14. The medical device of claim 12, wherein the topcoat comprises N- (2-hydroxyethyl) acrylamide and an acrylic acid copolymer.

15. The medical device of claim 11, wherein the medical device is a catheter or a guidewire.

16. The medical device of claim 12, comprising a plurality of covalent crosslinks between the primer layer and the hydrophilic topcoat layer.

17. A coating solution comprising from 2 to 15% by weight of the coating composition according to any one of claims 1 to 10 in a solvent.

18. The coating solution of claim 17, wherein the solvent is an organic solvent.

19. The coating solution of claim 18, wherein the solvent comprises one or more of: toluene, ethanol, acetone, isopropanol, ethyl acetate, dimethylformamide, tetrahydrofuran, butanol, N-methyl-2-pyrrolidone, N-butyl acetate, 1, 2-propylene glycol monomethyl ether acetate, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 1-pentanol, 2-propanol, propyl acetate, dichloromethane, dimethyl sulfoxide, methyl butyl ketone, and xylene.

20. A method of forming a coated article comprising coating a substrate with a primer coating comprising the coating composition of any one of claims 1 to 10.

21. The method of claim 20, further comprising curing the primer layer by exposing the primer layer to UV light.

22. The method of claim 21, further comprising coating the basecoat with a hydrophilic topcoat.

23. The method of claim 20, further comprising (a) coating the basecoat with a hydrophilic topcoat and (b) curing the basecoat and the topcoat with UV light.

24. A coating composition for a medical device or medical implant comprising a water or hydro-alcohol soluble polymer made from monomers comprising:

(a) at least one monomer that is a photo radical generator comprising one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy benzophenone, 4-methacryloxy benzophenone, acrylamido benzophenone, methacrylamido benzophenone, 2-hydroxy-4-acryloxy ethoxy benzophenone, 2, 4-dihydroxy-4' -vinylbenzophenone, and 2-hydroxy-4-methacryloxy ethoxy benzophenone, and

wherein the ethylenic monomer comprises at least one acidic group comprising acrylic acid, methacrylic acid, 2-ethacrylic acid, 2-propylacrylic acid, acryloxypropionic acid, isocrotonic acid, maleic anhydride, maleic acid, and the half esters, half amides, and half thioesters of maleic acid, fumaric acid, and itaconic acid, and mixtures thereof;

wherein the acrylate or acrylamide comprises acrylamide, N- (2-hydroxyethyl) acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, N- (2-hydroxyethyl) methacrylamide, N-acrylamido-ethoxyethanol, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol ethyl ether, propylene glycol ethyl acrylate, propylene glycol ethyl acrylate, and propylene glycol ethyl acrylate, N, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-methylolmethacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, or a mixture of any of the foregoing;

25. The coating composition of claim 24, wherein the photoradical generator group comprises 4-methacryloxy-2-hydroxybenzophenone.

26. The coating composition of claim 24, wherein the olefinic monomers comprise N- (2-hydroxyethyl) acrylamide and acrylic acid.

27. The coating composition of claim 26, wherein the molar ratio of N- (2-hydroxyethyl) acrylamide to acrylic acid is 2:1 to 5: 1.

28. The coating composition of claim 24, wherein one or both of: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides in a molar ratio to the photo radical generator comprising at least one photopolymerizable group of from 40:1 to 200: 1.

29. The coating composition of claim 24, wherein the polymer has a weight average molecular weight (Mw) between 20,000 and 800,000.

30. The coating composition of claim 24, further comprising a second polymer soluble in a water or water-alcohol solution.

31. The coating composition of claim 30, comprising one or both of: (i) an olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides.

32. The coating composition of claim 31, wherein the olefinic monomer of the second polymer comprises at least one acidic group, the olefinic monomer of the second polymer comprising the at least one acidic group comprising one or more of: acrylic acid, methacrylic acid, 2-ethacrylic acid, 2-propylacrylic acid, acryloxypropionic acid, isocrotonic acid, maleic anhydride, maleic acid, and the half esters, half amides, and half thioesters of maleic acid, fumaric acid, itaconic acid, and any combination thereof.

33. The coating composition of claim 31, wherein the acrylate or acrylamide of the second polymer comprises acrylamide, N- (2-hydroxyethyl) acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, and N- (2-hydroxyethyl) methacrylamide, N-acrylamido-ethoxyethanol, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, N- (2-hydroxyethyl) acrylamide, N- (hydroxymethyl) acrylamide, N- [ tris (hydroxymethyl) methyl ] acrylamide, 4-hydroxybutyl acrylate, hydroxypropyl acrylate, methyl 3-hydroxy-2-methylbutanoate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, N-butylglycol, N- (2-hydroxyethyl) acrylamide, N- (2-hydroxy-2-methyl) methacrylate, N- (2-ethylhydroxy-ethoxyethanol, N- (2-ethylhydroxy) acrylamide, N- (2-ethylhydroxy) acrylamide, N-ethylhydroxy-2-ethylhydroxy-butyrate, N-ethylhydroxy-ethyl methacrylate, or a mixture thereof, Di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-methylolmethacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, and mixtures of any of the foregoing.

34. The coating composition of claim 31, wherein the second polymer has a weight average molecular weight (Mw) between 50,000 and 800,000.

35. The coating composition of claim 24, further comprising water or a water/alcohol mixture.

36. A coated substrate, comprising:

-a substrate and

-a lubricious coating made using the coating composition according to any of claims 24 to 35.

37. The coated substrate of claim 36, further comprising a primer layer in contact with both the substrate and the lubricious coating composition.

38. The coated substrate of claim 37, wherein the primer layer is hydrophobic.

39. The coated substrate of claim 36, wherein the substrate is plastic.

40. The coated substrate of claim 36, wherein the substrate is metallic.

41. The coated substrate of any one of claims 36-40, wherein the coated substrate has a lubricity with a frictional force of less than 25gf and a durability with a frictional force of less than 50gf, as measured by the nip test.

42. A medical device or medical implant comprising the coated substrate of any one of claims 36-41.

43. The medical device or medical implant of claim 42, wherein the medical device or medical implant is sterilized by at least one of gamma rays, electron beam, and ethylene oxide.

44. The medical device or medical implant of claim 42 or 43, wherein the lubricious coating contains a pharmaceutical agent or antimicrobial agent blended with the coating composition.