CN114845746B

CN114845746B - UV curable coatings for medical devices

Info

Publication number: CN114845746B
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: 2024-04-16
Anticipated expiration: 2040-10-21
Also published as: EP4048332A4; EP4048332A1; JP2022553294A; WO2021081036A1; CN114845746A

Abstract

The present invention relates to hydrophobic and hydrophilic coating compositions for medical devices or medical implants. The hydrophilic coating composition comprises a water-soluble or water-alcohol solution 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) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides: wherein one or both of: (i) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylate or acrylamide, in a molar ratio to the photoradical generator groups of from 20:1 to 500:1. Such hydrophilic coating compositions may provide an overall coating, or together with a hydrophobic base coat, may be a top coat of a 2-coat system.

Description

UV curable coatings for medical devices

Technical Field

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

Background

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

One of the many advances in medical practice in recent years has been the development of medical devices that supplement the skill of the surgeon. Examples of such devices are various vascular catheters and guidewires, which can be used to treat distal regions in the circulatory system that would otherwise be accessible only by major surgery. The other is a stent, a device that reinforces the arterial wall and prevents occlusion after angioplasty. The other is an intraocular lens, which allows the elderly person suffering from cataract to recover younger vision. The list of heart valves, artificial cardiac pacemakers, and orthopedic implants among other such devices is growing.

Almost all of the above devices are constructed of plastics and metals that are never used to invade the body and sometimes remain in the body for a long period of time. They exhibit little or no resemblance to the surface of human organs, which are generally hydrophilic, slippery and biocompatible.

The lubricity of devices that must be inserted and moved in body tissue is also important. Most metals and plastics have poor lubricity to body tissue, resulting in mechanical wear and discomfort as the device passes through the tissue.

By properly designed coatings, the surface of devices designed and fabricated from such materials can be rendered biocompatible, hydrophilic and slippery. Thus, methods have been developed for constructing medical devices from conventional plastics and metals having the particular physical properties desired, and then applying an appropriate coating to impart the desired properties to the surface thereof.

Polymers having a low coefficient of friction when wet have been shown to be water soluble polymers that crosslink or otherwise fix and swell, but do not dissolve when exposed to water. Polysaccharides have proven useful in the manufacture of 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 are relatively poor in resistance to ionizing radiation.

For some applications, it is desirable to have a lubricious coating made of a synthetic polymer to achieve longer shelf life and stability to the radiation sterilization process. Hydrophilic synthetic polymers, such as poly (acrylic acid) and copolymers thereof, are often proposed for making lubricious, hydrophilic coatings because they are capable of producing a hydrated layer on a 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 methods 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 hydrophilic species may be washed away, thereby 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 polymers thereof as described in U.S. patent 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 of polyacrylic acid using primers containing isocyanate, aziridine, amine and hydroxyl functionality as described in U.S. patent 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 acid) coatings exhibit relatively poor lubricity and/or durability due to insufficient thickness of the hydrophilic polymer coating and/or poor adhesion to the surface. High density surface coverage is difficult to achieve via photoinitiated polymeric grafting or surface chemical attachment of polymers. Multiple iterations of the coating process may increase the thickness of the photoinitiated polymeric coating, but may greatly 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 irradiation with light and by reaction of polyfunctional reactive compounds such as melamine and aziridines, as described in U.S. patent nos. 5,531,715, 6,558,798 and EP 533821. However, crosslinked hydrophilic coatings in the art are often faced with a tradeoff between lubricity and abrasion resistance, both of which are essential properties of hydrophilic coatings. Highly crosslinked coatings have poor lubricity because of their low hydration capacity and reduced flowability of the polymer segments in aqueous media. Coatings with low crosslink density have a high swelling ratio, generally resulting in poor abrasion resistance and low mechanical strength.

U.S. patent application publication No. 2011/0200828 teaches a two-layer coating that includes a base coat layer that adheres strongly to a substrate and a top coat layer that is chemically grafted to the base coat 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 thrombotic tests, such as Partial Thromboplastin Time (PTT) tests. 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 formation reactions at the blood surface interface. Thromboembolism is a major complication associated with the clinical use of prosthetic devices such as catheters, guidewires, 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 catheter and guidewire procedures performed at the proximal end of the brachiocephalic vessel.

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

The second approach is to use a coating that actively assists in the anticoagulant activity of the surface. 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 Noninvasive Technique to Test Nonthrombogenic Surfaces)", "journal of radiology (The American Journal of Roentgenology), volume 113 (1971), pages 765-768, disclose guidewires coated with benzalkonium chloride-heparin complexes. Ovitt et al, in "guidewire thrombosis and its reduction (Guidewire Thrombogenicity and Its Reduction)", "Radiology (1974), volume 111, pages 43-46 report Teflon (Teflon) coated guidewires treated with benzalkonium chloride heparin. U.S. patent No. 4,349,467 (William) shows heparin applied to a solid polymer resin substrate by immersing 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 for a range of applications including electrophoresis, hair treatment and paper treatment. Just as in Albarg hose et al, "Poly-N-hydroxyethyl acrylamide (Poly Duramide): a novel hydrophilic self-coating polymer matrix for DNA sequencing by capillary Electrophoresis (Poly-N-hydroxyethylacrylamide (polyDuramide): A novel, hydrohead-coating polymer matrix for DNA sequencing by capillary Electrophoresis), "Electrophoresis (Electrophoresis)", volume 23 (2002), pages 1429-1440, discloses that nonionic monomers, such as N-hydroxyethyl acrylamide, have a very high hydrophilicity.

The following references, WO10041527A, W010041530A, W011125713A, JP2011046619A, JP2011046652A, JP2010126482a and JP2010090049a, teach copolymers comprised of 5 to 30 mole% carboxylic acid monomer and 70 to 95 mole% alcohol containing acrylic acid monomer for use in hair treatment formulations. These patent applications do not disclose the use of copolymers as lubricating, biocompatible coatings, nor their resistance to ionizing radiation. JP2006176934a teaches that copolymers made of 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 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 layer 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 primer coatings, such as primer coatings that provide a more rapid adhesion of lubricating topcoats. This need is met by an Ultraviolet (UV) cured primer that adheres to the hydrophilic topcoat.

Disclosure of Invention

The present invention relates to a coating composition for a medical device or medical implant. These novel compositions include a hydrophobic primer 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 glass transition temperature (Tg) of the polymer is less than 40 ℃.

In certain embodiments, the primer layer further comprises a polyfunctional aziridine. (a) 95 wt% to 99.8 wt% of a hydrophobic polymer described herein; and (b) from 0.2% to 5% by weight of a 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 layer comprising a coating composition as described herein. In preferred compositions, the primer layer is hydrophobic. In some embodiments, the device or implant contains a hydrophilic topcoat, wherein the basecoat is located on the substrate and the topcoat is located on the basecoat. 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 basecoat as described herein and a solvent.

In other embodiments, the coating solution comprises a water-soluble or water-alcohol solution 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) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides: wherein one or both of: (i) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylate or acrylamide, in a molar ratio to the photoradical generator groups of from 20:1 to 500:1.

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

Further 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 primer and topcoat are applied to the substrate. When both the primer and topcoat are cured by UV light, (a) the primer is applied and cured prior to application of the topcoat or (b) the primer is applied and dried, the topcoat is added, and then the primer and topcoat are cured by UV light.

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

Detailed Description

The requirements of any coating intended for a medical device will first be elucidated 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 present 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 coated material when dried. This means that the minimum film forming temperature of the coating solution must be lower than the intended drying temperature used in the device manufacturing process;

(2) The polymer film formed must be flexible and adhesive enough to conform to the bending and twisting of the coated device without breaking under the intended conditions of use;

(3) When the coating device is immersed in aqueous media such as human blood for a long time, the film cannot be weakened or the integrity of the film cannot be lost;

(4) The coating must present a non-cytotoxic and hemocompatible surface. The coating must not trigger 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 fragments or leachable components can contaminate aqueous media such as human blood; and

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

Coatings meeting the above requirements are made as follows.

The present disclosure may be understood more readily by reference to the following description taken in conjunction with the accompanying drawings and 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 shown 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, unless otherwise specifically indicated, and the invention is not limited herein by the correctness or incorrectness of any such suggested mechanisms or modes of action or reasons for improvement. Throughout this text, it is recognized that these descriptions relate to both the method of operating the apparatus and system, and the apparatus and system providing the method. 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 devices, apparatuses, or systems for implementing such methods.

(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 glass transition temperatures below 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 as a hydrogen atom extractant comprises one or more of the following: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxybenzophenone and 2-hydroxy-4-methacryloxy-ethoxybenzophenone.

4-methacryloxy-2-hydroxybenzophenone (MHB) is copolymerizable with the (meth) acrylate monomers to produce hydrophobic photoactive polymers. After UV curing, this polymer acts as a tie layer, bonding the substrate to the hydrophilic topcoat. The topcoat cured in the presence of such a photoactive basecoat adheres well even though the topcoat does not contain a photoactive component.

4-methacryloyloxy-2-hydroxybenzophenone (MHB)

The monomer 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 following 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 aid in forming a low glass transition temperature copolymer. The copolymer also contains monomers with some hydrophilic characteristics to provide good interaction with the top coating solution and the polymer. Examples include hydroxyethyl methacrylate and N-vinylpyrrolidone monomers.

In certain embodiments, the monomer that contributes a low glass transition temperature to the hydrophobic polymer is a polymer having C ₄ -C ₂₀ Alkyl acrylates, such as butyl acrylate.

In still other aspects, the invention relates to coating solutions comprising 2 wt% to 15 wt% of the hydrophobic polymer 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-propanediol 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, methylene chloride, dimethyl sulfoxide, methyl butyl ketone, and xylene.

In certain embodiments, the primer layer further comprises a polyfunctional aziridine. In some embodiments, the coating composition comprises (a) 95 wt.% to 99.8 wt.% of a 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 water-soluble or water-alcohol solution polymer made from monomers comprising:

(a) At least one monomer as a photoradical generator, and

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

wherein one or both of: (i) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylate or acrylamide, in a molar ratio to the 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 typically 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 generator comprises one or more of the following: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxybenzophenone, 2, 4-dihydroxy-4' -vinylbenzophenone and 2-hydroxy-4-methacryloxy-ethoxybenzophenone. A preferred photo radical generator group comprises 4-methacryloxy-2-hydroxybenzophenone.

4-methacryloxy-2-hydroxybenzophenone (MHB) may 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 lubricating topcoat. It can also be used as an additive to other hydrophilic (non-photoactive) polymers to form a lubricious coating after UV curing.

Random copolymers 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 half esters, half amides, and half thioesters of maleic acid, fumaric acid, and itaconic acid, and mixtures thereof. In some embodiments, the olefinic monomer comprises 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-methylenebutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl-methacrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, or any mixture 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, and a molar ratio of 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) of between 20,000 and 800,000 or 20,000 to 400,000 or 50,000 and 400,000.

Some hydrophilic polymer coating compositions additionally comprise a second polymer that is soluble in water or a water-alcohol solution. 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, 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-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl-methacrylamide, N-tris (hydroxymethyl) -methyl-acrylamide, 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 invention also relates to coated substrates, including substrates and lubricious coatings made using the coating compositions described herein. The preferred embodiment also includes a primer layer in contact with both the substrate and the lubricious coating composition. The preferred primer layer is hydrophobic.

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

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

The preferred coated substrate has a lubricity of less than 25gf friction and a durability of less than 50gf friction as measured by the pinch 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 a pharmaceutical agent or antimicrobial agent blended with the coating composition.

Preferred medical devices include catheters or guidewires.

In some aspects, the invention relates to methods of coating an article. Some methods include 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 topcoat.

In still other embodiments, the coating methods include coating the substrate with an basecoat comprising the coating compositions described herein, coating the basecoat with a hydrophilic topcoat, and curing the basecoat and topcoat with UV light. The hydrophilic topcoat 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 topcoat is not necessary.

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 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 glass transition temperature (Tg) of the polymer is less than 40 ℃.

Aspect 1B. A coating composition comprising a hydrophobic polymer for use as a photoreactive primer 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 as 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 glass transition temperature (Tg) of the polymer is less than 40 ℃.

Aspect 2. The coating composition according to aspects 1A to 1B, further comprising a polyfunctional aziridine.

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

Aspect 4.The coating composition of any one of aspects 1A to 3, comprising a structureWherein 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 Acrylic esters of alkyl groups.

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

Aspect 9 the coating composition of aspect 8, wherein the photoactive monomer as a hydrogen atom extractant comprises one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxybenzophenone and 2-hydroxy-4-methacryloxy-ethoxybenzophenone.

Aspect 10. The coating composition according to any one of aspects 1A to 9, having a Tg below 20 ℃.

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

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

Aspect 13 the medical device of aspect 12, wherein the topcoat comprises one or more of: polyacrylate, polyvinylpyrrolidone, hyaluronic acid and polyacrylamide.

Aspect 14. The medical device of aspect 12, wherein the topcoat comprises an 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 a guidewire.

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

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

Aspect 18 the coating solution according to 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-propanediol 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, methylene chloride, dimethyl sulfoxide, methyl butyl ketone, and xylene.

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

Aspect 23. 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.

Aspect 24 a coating composition for a medical device or medical implant comprising a water-soluble or water-alcohol solution polymer made from monomers comprising: (a) At least one monomer as a photo radical generator comprising one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxybenzophenone, 2, 4-dihydroxy-4' -vinylbenzophenone, and 2-hydroxy-4-methacryloxy-ethoxybenzophenone, and (b) at least one monomer comprising one or both of the following: (i) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylates or acrylamides; wherein the olefinic 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 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-methylenebutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl-acrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, or any mixture of the foregoing; wherein one or both of: (i) An olefinic monomer comprising at least one acidic group and (ii) one or more acrylate or acrylamide, in a molar ratio to the 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 monomer comprises 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 from 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) between 20,000 and 800,000.

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

Aspect 31 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.

Aspect 32 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, 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-methylenebutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl acrylamide, N-trimethyl) -acrylamide, 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) 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 of any one 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 to 40, wherein the coated substrate has a lubricity with a friction force of less than 25gf and a durability with a friction force of less than 50gf, as measured by a pinch test.

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

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

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

Examples

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 the copolymer with photoactivity. It was purchased from Polysciences and Bimax. Purity was confirmed by nuclear magnetic resonance NMR using Bruker 400MHz NMR at usciices.

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

The coating is applied to various substrates in rod or tube form. The rod was 0.125 inch diameter stainless steel or PMMA. Pebax ^TM The outer diameter of the 35D and 55D plastic tubes was 0.079 inches and the wall thickness was 0.005 inches. The tube was placed on a stainless steel rod for stability prior to coating. The coating process consists of the following steps: the rod was wiped with isopropanol, dip coated in primer solution at 0.2 inch/sec, dried at 60℃Drying for 10 minutes, dip coating in the topcoat solution at 0.2 inches/second, and drying at 60 ℃ for 10 minutes. Only after all the coatings have been applied, the rod is subjected to UV radiation.

UV curing was performed in a model Uvitron IntelliRay UV0832 UV curing unit equipped with UVA 600 watt metal halogen lamp. The irradiance was measured using a EIT Uvicure Plus II radiometer available from INPRO Technologies. Such single channel UVA radiometers measure 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 to rotate the coated rod as it is cured. The sample may then be subjected to 6 rotations to expose all sides. The rotation modes are 0 °, 120 °, 240 °, 60 °, 180 °, and 300 °. In the second method, the rod is continuously rotated by a motor at 20rpm during UV curing.

Typical irradiation times in the examples are 2-30 minutes and typical irradiance is 100-200mW/cm2 (from UVA metal halogen lamps at 320-390 nm). Notably, all 320-390nm radiation cannot be used for photocrosslinking, and only the wavelength actually absorbed by the photoactive group will cause the reaction. It should also be appreciated that irradiance lower than that used in these examples may be accommodated by increasing the irradiation time.

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

The photoactive primer coating is made by copolymerizing 4-methacryloxy-2-hydroxybenzophenone and a low glass temperature (meth) acrylate monomer. The resulting photoactive primer polymers are summarized in table 1.

Table 1: photoactive primer polymers

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

Poly (methyl methacrylate) (PMMA) rods were coated with an undercoat polymer BP-5 and a polyvinylpyrrolidone (PVP) topcoat (Aldrich 1,300,000 molecular weight, based on light scattering). At 186 milliwatts per square centimeter (mW/cm) ² ) The coated rod was cured after each of six rotations under irradiance. After the pinch test, the rod was rinsed under flowing cold tap water for 10 seconds, immersed in 0.5% congo Red (Gongo Red) aqueous solution, and then rinsed again for 10 seconds. The strong red color indicates the presence of bound PVP, which indicates grafting between the photoactive primer and the PVP topcoat.

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

Table 2: UV curing with PVP topcoat and different primer polymers

Primer coating polymers	Primer monomer	First cyclic friction force	Last cyclic friction force
				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 top coats (surfactant added). The Hydrophilic Acrylic Polymer (HAP) is a copolymer of acrylic acid and 2-hydroxyethyl acrylamide. At 180mW/cm ² Is rotated six times under irradiance to perform UV curing. The results are shown in Table 3. All three bars of each sample exhibited good lubricity and durability over 30 cycles.

Table 3: effect of cure time on coating Properties of HAP/PVP topcoat blends

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

Measurement of the HAP part of the bonded topcoat

The results summarized in the examples above do show that good lubricity and durability can be obtained from the 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. This approach is not only more convenient, but also provides even better lubricity and durability in even shorter curing times, as shown below.

Table 4 shows a comparison of several compositions using different monomer compositions and different amounts of photoactive monomers. The results indicate 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: influence of the amount of photoactive monomer and comonomer composition

Footnotes of table 4:

the primer coating is coated on Pebax ^TM 55D tube.

After drying the base coat, a surfactant-containing poly (HEAA-co-AA) topcoat was added and dried prior to UV curing.

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

Table 5: influence of trifunctional aziridines

Footnotes of table 5:

the primer coating is coated on Pebax ^TM 55D tube.

After drying the base coat, 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.

The samples were subjected to the pinching test after soaking in a 50 ℃ aqueous PBS solution for 18 hours.

The above examples demonstrate that the combination of the photoactive basecoat of the present invention and the hydrophilic topcoat that does not have inherent photoactivity provides good lubricity and durability. The examples below illustrate that even better performance can be achieved 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 water. The polymerization initiator is ammonium persulfate and sodium hydroxymethanesulfinate hydrate. 0.015mL of 1% FeSO was added ₄ The solution catalyzes the reaction. Polymerization reaction at N ₂ And at 40 ℃. Purification of the polymer by dialysis or precipitation with acetone (similar to US2013/0Example 1 of 323291 A1).

Poly (HEAA-co-AA-co-MHB) 1-4 in Table 6. The photoactive polymer was prepared by reacting 15.29g HEAA, 3.19g AA, and 1.00g, 0.50g, or 0.25g MHB in 40mL LIPA and 30mL 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 completed, the polymer was precipitated with 150mL of ethyl acetate. The solvent was decanted off and 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. The photoactive polymer was prepared by reacting 15.29g HEAA, 3.19g AA, and 1.00g, 0.50g, or 0.25g MHB in 40mL ethanol and 30mL 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 completed, the polymer was precipitated with 150mL of ethyl acetate. The solvent was decanted off and 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, waters 2489 UV/visible detector set at 276nm and 290nm, waters 2414 refractive index detector and 3 chromatographic columns (2 numbers Waters Ultrahydrogel 2000 and 1 number Waters Ultrahydrogel 250). Molecular weights were calculated by comparison with poly (acrylic acid) standards using Empower 3 software.

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

Poly (HEAA-co-AA-co-MHB)	Mole% 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

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

UV curing was performed in a model Uvitron IntelliRay UV0832 UV curing unit equipped with UVA 600 watt metal halogen lamp. Irradiance was measured using a EIT Uvicure PlusII radiometer from INPRO Technologies. Such single channel UVA radiometers measure radiation between 320 and 390 nm.

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

Primer solutions were prepared using the two photoactive primer polymers described above. The primer polymer may be diluted with a variety of different solvents, including isopropyl alcohol (IPA) and ethanol. Primer coating a: 10% by weight of a copolymer of 2-ethylhexyl methacrylate (EHMA), N-vinylpyrrolidone (NVP), (hydroxyethyl) methacrylate (HEMA) and MHB in propylene glycol methyl ether acetate PMA and polyethylenimine crosslinker. Primer coating B: 10% by weight of a copolymer of Butyl Acrylate (BA), methyl Methacrylate (MMA), NVP, HEMA and MHB in a solution of PMA and polyethylenimine crosslinker.

Pebax ^TM 55D was coated with primer A and after 5 minutes UV curing, with a topcoat containing the photoactive polymer described in Table 6, as well as 2% poly (HEAA-co-AA) and surfactant in water. Table 7 shows the friction test results for different topcoats cured at different UV light intensities.

Table 7: testing of different photoactive surface coatings on basecoat A

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

Table 8: testing of different photoactive surface coatings on basecoat B

The examples of table 9 illustrate that the photoactive basecoat performed well when applied directly to a substrate. That is, the hydrophobic primer is not necessary for good lubricity and durability of the photoactive hydrophilic topcoat. The photoactive topcoat was applied twice, each for 5 minutes of curing. As described above, the topcoat solution contained one of the photoactive topcoat layers of table 6, poly (HEAA-co-AA), and a surfactant in water.

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

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

In the present disclosure, the singular forms "a," "an," and "the" include plural referents, and reference to a particular value includes at least the 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 antecedent "about," it will be understood that the particular value forms another embodiment. In general, use of the term "about" refers to an approximation that may vary from the desired properties sought to be obtained by the disclosed subject matter, and will be explained in the specific context in which it is used based on its function. Those skilled in the art will be able to interpret this as a conventional problem. In some cases, the number of significant digits used for a particular value can be one non-limiting method of determining the range of the word "about". In other cases, a progression used in a series of values may be used to determine the expected range in which the term "about" for each value is available.

Where present, all ranges are inclusive and combinable. That is, references to values in a range include each value within the range, including the endpoint value.

When presenting a list, it is to be understood that each individual element of the list and each combination of the list is to be construed as a separate embodiment unless otherwise indicated. For example, a list 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 expressly incompatible or clearly excluded, each individual embodiment is considered to be combinable with any other possible embodiment, and such combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Furthermore, although an embodiment may be described as part of a series of steps or as part of a more general structure, each step or portion itself may be considered a separate embodiment.

As used herein, the terms "article" and "substrate" are not limited to any shape or size, as it may be a layer of material, a plurality of layers, or a block having at least one surface modified by the coating compositions described herein.

The glass transition temperature (Tg) was determined using 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 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 having low T _g Is a copolymer of (a) and (b). Examples include butyl acrylate (tg= -54 ℃), 2-ethylhexyl methacrylate (tg= -10 ℃), isodecyl methacrylate (tg= -30 ℃) and dodecyl methacrylate (tg= -65 ℃). The homopolymer Tg of some of the other monomers used was 100℃for MMA, 20℃for BMA, 120℃for NVP, 105℃for HEMA, 143℃for MHB and 105℃for acrylic acid.

For both 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 polymers that are insoluble in aqueous solutions. The crosslinked hydrophobic polymer does not swell significantly in water (less than 50%, < 50%).

The term "hydrophilic" refers to polymers that are 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 in aqueous alcohol solutions having more than 50% water.

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

Claims

1. 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:

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

wherein the glass transition temperature (Tg) of the polymer is 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 wt% to 99.8 wt% of the hydrophobic polymer; and

(b) 0.2% to 5% by weight of a polyfunctional aziridine.

4. A coating composition according to any one of claims 1 to 3 comprising a methacrylate of the following 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 Acrylic esters of alkyl groups.

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

9. The coating composition of claim 8, wherein the photoactive monomer as a hydrogen atom extractant comprises one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxybenzophenone and 2-hydroxy-4-methacryloxy-ethoxybenzophenone.

10. The coating composition according to any one of claims 1 to 9, having a Tg below 20 ℃.

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

12. The medical device of claim 11, wherein the medical device is a medical implant.

13. The medical device of claim 11, wherein the primer layer is located between the substrate and the hydrophilic topcoat.

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

15. The medical device of claim 13, wherein the topcoat comprises N- (2-hydroxyethyl) acrylamide and an acrylic acid copolymer.

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

17. The medical device of claim 13, comprising a plurality of covalent crosslinks between the primer layer and the hydrophilic topcoat layer.

18. A coating solution comprising 2 to 15 wt.% of the coating composition according to any one of claims 1 to 10 in a solvent.

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

20. The coating solution of claim 19, 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-propanediol 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, methylene chloride, dimethyl sulfoxide, methyl butyl ketone, and xylene.

21. A method of forming a coated article comprising coating a substrate with an undercoating layer comprising the coating composition of any of claims 1-10.

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

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

24. The method of claim 21, further comprising (a) coating the base coat with a hydrophilic top coat and (b) curing the base coat and the top coat with UV light.

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

(a) At least one monomer as a photo radical generator comprising one or more of: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxy-benzophenone, 2, 4-dihydroxy-4' -vinyl-benzophenone and 2-hydroxy-4-methacryloxy-ethoxy-benzophenone, and

wherein the olefinic monomer comprises at least one acidic group, the at least one acidic group comprising acrylic acid;

wherein the acrylate or acrylamide comprises N- (2-hydroxyethyl) acrylamide;

26. The coating composition of claim 25, wherein the photo radical generator group comprises 4-methacryloyloxy-2-hydroxybenzophenone.

27. The coating composition of claim 25, wherein the molar ratio of N- (2-hydroxyethyl) acrylamide to acrylic acid is from 2:1 to 5:1.

28. The coating composition of claim 25, 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 25, wherein the polymer has a weight average molecular weight (Mw) of between 20,000 and 800,000.

30. The coating composition of claim 25, further comprising a second polymer that is soluble in water or a 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, 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-methylenebutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, ethylene glycol vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl acrylamide, N-tris (hydroxymethyl) -methyl-acrylamide, or a mixture of any of the foregoing.

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

35. The coating composition of claim 25, further comprising water or a water/alcohol mixture.

36. A coated substrate, comprising:

-substrate

-a lubricating coating made using a coating composition according to any one of claims 25 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 friction force of less than 25gf and a durability with a friction force of less than 50gf, as measured by a pinch test.

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

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

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

45. The medical device of any one of claims 42-44, wherein the medical device is a medical implant.

46. The coating composition of claim 1, wherein the polymer is made from monomers consisting essentially of:

(a) The photoactive monomer comprises one or more of the following: 4-methacryloxy-2-hydroxybenzophenone, 4-acryloxy-benzophenone, 4-methacryloxy-benzophenone, acrylamido-benzophenone, methacrylamidophenone, 2-hydroxy-4-acryloxy-ethoxybenzophenone and 2-hydroxy-4-methacryloxy-ethoxybenzophenone, and

(b) One or more of the acrylamides, methacrylamides, acrylates, methacrylates, and N-vinyl pyrrolidone comprising (i) at least one monomer comprising an olefinic monomer comprising at least one acidic group and (ii) at least one monomer comprising one or more acrylates or acrylamides;

wherein the olefinic 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 half esters, half amides and half thioesters of maleic acid, fumaric acid and itaconic acid, or 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-methylenebutyrate, hydroxypropyl methacrylate, 2-allyloxyethanol, 3-allyloxy-1, 2-propanediol, 1, 4-butanediol vinyl ether, di (ethylene glycol) vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl acrylamide, N-tris (hydroxymethyl) -methyl-methacrylamide, or any mixture of the foregoing;

wherein 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 of 20:1 to 500:1 to monomer (a) comprising a photoradical generator.

47. The coating composition of claim 46, wherein the polymer is made from monomers consisting of:

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 of 20:1 to 500:1 to monomer (a) comprising a photoradical generator.

48. The coating composition of claim 46, wherein the photo radical generator comprises 4-methacryloxy-2-hydroxybenzophenone.

49. The coating composition of claim 46, wherein the olefinic monomer comprises N- (2-hydroxyethyl) acrylamide and acrylic acid.

50. The coating composition of claim 49, wherein the molar ratio of N- (2-hydroxyethyl) acrylamide to acrylic acid is from 2:1 to 5:1.

51. The coating composition of claim 46, 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.

52. The coating composition of claim 46, wherein the polymer has a weight average molecular weight (Mw) of between 20,000 and 800,000.

53. The coating composition of claim 46, further comprising a second polymer that is soluble in water or a water-alcohol solution.

54. The coating composition of claim 53, 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, half esters, half amides and half thioesters of maleic acid, fumaric acid, itaconic acid, or any combination thereof.

55. The coating composition of claim 53, wherein the acrylate or acrylamide of the second polymer 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, ethylene glycol vinyl ether, N-1, 2-dihydroxyethylene-bis-acrylamide, N-1, 2-dihydroxyethylene-bis-methacrylamide, N-hydroxymethyl acrylamide, N-tris (hydroxymethyl) -methyl acrylamide, or a mixture of any of the foregoing.

56. The coating composition of claim 53, wherein the second polymer has a weight average molecular weight (Mw) between 50,000 and 800,000.

57. The coating composition of claim 46, further comprising water or a water/alcohol mixture.