Polyacrylic acid-containing lubricious coatings for medical devices with improved properties

Abstract

Embodiments herein relate to polyacrylic acid-containing lubricious coatings for medical devices. One embodiment includes a lubricious-coated medical device having a substrate and a first layer disposed on the substrate. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. A second layer can be disposed on the first layer, the second layer including poly(acrylic acid) and non-photoreactive polyvinylpyrrolidone. The non-photoreactive polyvinylpyrrolidone of the second layer forms a complex with the poly(acrylic acid) of the second layer. The non-photoreactive polyvinylpyrrolidone of the second layer has a concentration that exists as a gradient across the thickness of the second layer, with the concentration at the outer surface of the second layer being lower than the concentration at the inner surface of the second layer. Other embodiments are also included herein.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 424,321, filed November 10, 2022, filed as a PCT international patent application on November 10, 2023, in the name of Surmodics, Inc., a U.S. domestic corporation, assignee designating all countries, and U.S. citizen Michael Militello, U.S. citizen Syed Hossainy, and U.S. citizen David E. Babcock, inventors and assignee designating all countries, the contents of which are incorporated herein by reference in their entirety.

[0002] Field FIELD OF THE INVENTION Embodiments herein relate to lubricious coatings. More particularly, embodiments herein relate to polyacrylic acid-containing lubricious coatings for medical devices. [Background technology]

[0003] background Medical devices include chronically implanted devices, temporarily implanted devices, and devices that are not implanted at all. Many types of medical devices are improved by reducing friction between the medical device and the environment surrounding the medical device, especially during insertion of the device. As an example, a catheter is inserted into a subject's body at least temporarily. Reducing friction can lead to improved patient comfort, easier procedures for caregivers, reduced chance of infection, and reduced tissue destruction, among other benefits. One approach to reducing friction between a medical device and the environment surrounding the medical device is to apply a lubricious coating on the medical device. Summary of the Invention [Means for solving the problem]

[0004] overview Embodiments herein relate to polyacrylic acid-containing lubricious coatings for medical devices. One embodiment includes a lubricious-coated coronary or peripheral vascular medical device having a substrate and a first layer, the first layer disposed on the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone, a second non-photoreactive polyvinylpyrrolidone different from the first non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The coated device can also include a second layer, the second layer disposed on the first layer, the second layer including poly(acrylic acid) and a third non-photoreactive polyvinylpyrrolidone. Other embodiments are also included herein.

[0005] In one embodiment, a lubricious-coated neural microcatheter device is provided having a substrate and a first layer disposed on the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone, a second non-photoreactive polyvinylpyrrolidone different from the first non-photoreactive polyvinylpyrrolidone, a third non-photoreactive polyvinylpyrrolidone different from the first and second non-photoreactive polyvinylpyrrolidones, and a cross-linking compound. The lubricious-coated neural microcatheter device can also include a second layer disposed on the first layer, the second layer including poly(acrylic acid), a photoreactive polyvinylpyrrolidone, a fourth non-photoreactive polyvinylpyrrolidone, a fifth non-photoreactive polyvinylpyrrolidone, and a cross-linking compound.

[0006] One embodiment includes a lubricious-coated medical device having a substrate and a first layer disposed on the substrate. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. A second layer can be disposed on the first layer, the second layer including poly(acrylic acid) and non-photoreactive polyvinylpyrrolidone. The non-photoreactive polyvinylpyrrolidone of the second layer forms a complex with the poly(acrylic acid) of the second layer. The non-photoreactive polyvinylpyrrolidone of the second layer has a concentration that exists as a gradient across the thickness of the second layer, with the concentration at the outer surface of the second layer being lower than the concentration at the inner surface of the second layer.

[0007] One embodiment includes a method for preparing a polyacrylic acid-containing coating for a medical device. The method can include applying a first coating composition to a substrate to form a first layer. The first coating composition can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The method can further include applying a second coating composition over the first layer to form a second layer. The second coating composition can include poly(acrylic acid). The method can further include diffusing the non-photoreactive polyvinylpyrrolidone from the first layer to the second layer.

[0008] One embodiment includes a lubricious-coated medical device having a substrate and a first layer disposed on the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The coating can also include a second layer disposed on the first layer. The second layer can include poly(acrylic acid) and a second non-photoreactive polyvinylpyrrolidone. The second non-photoreactive polyvinylpyrrolidone can form a complex with the poly(acrylic acid).

[0009] One embodiment includes a method for making a polyacrylic acid-containing coating for a medical device. The method can include applying a first coating composition to a substrate to form a first layer. The first coating composition can include a photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The method can include applying a second coating composition over the first layer to form a second layer. The second coating composition can include poly(acrylic acid) and a second non-photoreactive polyvinylpyrrolidone. In some embodiments, the second coating composition can have a pH of 4 to 5.

[0010] One embodiment includes a lubricious-coated medical device having a substrate and a first layer. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The coating can also include a second layer, which includes poly(acrylic acid). The coating can also include a third layer, which includes a second non-photoreactive polyvinylpyrrolidone.

[0011] One embodiment includes a method for making a polyacrylic acid-containing coating for a medical device. The method can include applying a first coating composition to a substrate to form a first layer. The first coating composition can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The method can include applying a second coating composition over the first layer to form a second layer. The second coating composition can include poly(acrylic acid). The method can include applying a third coating composition over the second layer to form a third layer. The third coating composition can include a second non-photoreactive polyvinylpyrrolidone. In some embodiments, the third coating composition has a pH of 7 or less.

[0012] One embodiment includes a lubricious coated medical device having a substrate and a first layer disposed on the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. The coating can include a second layer disposed on the first layer. The second layer can include a poly(acrylic acid) and a polyvinylpyrrolidone composition. The polyvinylpyrrolidone composition can include a PVP copolymer. The PVP copolymer forms a complex with the poly(acrylic acid).

[0013] In one embodiment, a lubricious coated medical device is included, having a substrate and a first layer. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. The coating can also include a second layer. The second layer can include poly(acrylic acid). In some embodiments, the second layer can have a pH greater than 5.

[0014] In one embodiment, a lubricious coated medical device is provided having a substrate and a first layer. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. The coating can include a second layer. The second layer can include a poly(acrylic acid) homopolymer and a poly(acrylic acid) copolymer.

[0015] This summary is an overview of some of the teachings of the present application and is not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details are found in the detailed description and the appended claims. Other aspects will become apparent to those skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof, each of which should not be construed in a limiting sense. The scope of the present specification is defined by the appended claims and their legal equivalents.

[0016] The embodiments may be more fully understood in connection with the following drawings (figures). [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a schematic illustration of a coated medical device, according to various embodiments herein.

[0018] [Figure 2] FIG. 2 is a cross-sectional view of a coating according to various embodiments herein.

[0019] [Figure 3] FIG. 3 is a cross-sectional view of a coating according to various embodiments herein.

[0020] [Figure 4] FIG. 4 is a cross-sectional view of a coating according to various embodiments herein.

[0021] [Figure 5] FIG. 5 is a diagram of PVP complexed with PAA, according to an embodiment of the present disclosure.

[0022] [Figure 6] FIG. 6 is a schematic diagram of some of the layers of a coating, according to various embodiments herein.

[0023] [Figure 7] FIG. 7 is a schematic diagram of some of the layers of a coating, according to various embodiments herein.

[0024] [Figure 8] FIG. 8 is a graph showing coating hardness versus coating contact depth.

[0025] [Figure 9] FIG. 9 is a graph showing the effect of basecoat thickness on lubricity for two different coatings.

[0026] [Figure 10] FIG. 10 is a graph showing the effect of crosslink density on lubricity for different coatings. DETAILED DESCRIPTION OF THE INVENTION

[0027] While the embodiments are susceptible to various modifications and alternative forms, details thereof are shown by way of example and drawings and will be described in detail. It should be understood, however, that the scope of the specification is not limited to the particular embodiments described. On the contrary, it is intended to cover modifications, equivalents, and alternatives that are within the spirit and scope of the specification.

[0028] Detailed Description As mentioned above, one approach to reducing friction between a medical device and the environment surrounding the medical device is to apply a lubricious coating to the medical device. However, many lubricious coatings do not reduce friction between the device and the environment surrounding the device as desired. Furthermore, many lubricious coatings lack sufficient durability, leading to the possibility of increased friction during use.

[0029] Polyacrylic acid (PAA) is a biocompatible hydrophilic polymer. However, it contains exposed COOH groups, and when PAA and lubricious coatings containing exposed COOH groups are sterilized using ethylene oxide (EO)-based techniques, the EO can react with the COOH groups to form polyethylene glycol (PEG), which acts to reduce the overall lubricity of the coating.

[0030] Embodiments herein include coatings, particularly poly(acrylic acid)-containing coatings, that are highly lubricious and exhibit good durability, can be sterilized using EO-based techniques, and exhibit substantially reduced or substantially no polyethylene glycol (PEG) formation.

[0031] In some embodiments, non-photoreactive polyvinylpyrrolidone can be added to a layer (such as a top layer) of a coating containing polyacrylic acid. Without being bound by theory, polyvinylpyrrolidone can hydrogen bond with the COOH groups of the polyacrylic acid chains, thereby preventing reaction with ethylene oxide and subsequent formation of polyethylene glycol. By way of example, various embodiments include a lubricious-coated medical device having a substrate and a first layer disposed on the substrate. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. A second layer can be disposed on the first layer. The second layer can include poly(acrylic acid) and a second non-photoreactive polyvinylpyrrolidone, where the second non-photoreactive polyvinylpyrrolidone forms a complex with the poly(acrylic acid) and protects the COOH groups of the polyacrylic acid.

[0032] As another example, various embodiments include a lubricious-coated medical device having a substrate and a first layer disposed on the substrate. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. A second layer can be disposed on the first layer, and the second layer can include poly(acrylic acid) and a polyvinylpyrrolidone composition. The polyvinylpyrrolidone composition can include a polyvinylpyrrolidone copolymer. The polyvinylpyrrolidone copolymer can form a complex with the poly(acrylic acid) and protect the COOH groups of the polyacrylic acid.

[0033] In some embodiments, a layer containing non-photoreactive polyvinylpyrrolidone can be disposed on a layer containing polyacrylic acid, thereby protecting the polyacrylic acid. For example, various embodiments include a lubricious-coated medical device having a substrate and a first layer, the first layer comprising photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. A second layer can be disposed on the first layer, the second layer can comprise poly(acrylic acid). A third layer can be disposed on the second layer, the third layer can comprise a second non-photoreactive polyvinylpyrrolidone.

[0034] In some embodiments, the pH of the environment surrounding the PAA polymer chains can be controlled (e.g., by adding a salt, which can be a PAA salt monomer). The pH controls the degree of protonation of groups such as COOH groups. Without being bound by theory, the elevated pH environment acts to protect exposed COOH groups on the PAA polymer chains, preventing their reaction with ethylene oxide (CHO), thereby preventing the formation of polyethylene glycol (PEG), which would otherwise function to reduce the lubricity of the coating. However, partial protonation prevents components of the coating solution used to create the coating from precipitating out of solution. As an example of controlling the pH of the environment surrounding the PAA polymer chains, various embodiments include a lubricious-coated medical device having a substrate and a first layer, where the first layer can comprise photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. A second layer can be disposed on the first layer, where the second layer can comprise poly(acrylic acid). In some embodiments, the second layer can have a pH greater than 5.

[0035] In some embodiments, the COOH groups of the polyacrylic acid can be protected using a poly(acrylic acid) copolymer. As an example of this approach, various embodiments include a lubricious coated medical device having a substrate and a first layer, where the first layer can comprise a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. A second layer can be disposed on the first layer, where the second layer can comprise a poly(acrylic acid) homopolymer and a poly(acrylic acid) copolymer. Subunits (such as non-acrylic acid subunits) of the poly(acrylic acid) copolymer can interact with the COOH groups of the polyacrylic acid, protecting them and thereby preventing the formation of polyethylene glycol (PEG), which would otherwise function to reduce the lubricity of the coating.

[0036] Many different medical devices can be coated with the lubricious coatings herein, including, but not limited to, chronically implantable medical devices, temporarily implantable medical devices, and the like. Further examples of implantable medical devices are provided below. However, in various embodiments, various types of catheters and / or devices with long shafts can be coated.

[0037] Referring to FIG. 1 , a schematic diagram of a coated medical device 100 is shown in accordance with various embodiments herein. It is recognized that the coated medical device 100 of FIG. 1 is merely one example of a medical device that can be coated with the coatings described herein. In this example, the coated medical device 100 can include a catheter shaft 102, a balloon 104, and a connection manifold 106 (or proximal connector). The balloon 104 can be inflated and, in some embodiments, can also carry a drug-eluting coating. In various embodiments, the catheter shaft 102 can be coated with a lubricious coating herein. In some embodiments, the balloon 104 can be coated with a lubricious coating herein. In some embodiments, the catheter shaft 102 and the balloon 104 can be coated with a lubricious coating herein.

[0038] Referring to FIG. 2, a cross-sectional view of a coating is shown in accordance with various embodiments herein. FIG. 2 illustrates a lubricious-coated medical device 100. The lubricious-coated medical device 100 includes a substrate 202. Examples of substrates can include polymers, metals, ceramics, composites, and the like. In various embodiments, the substrate 202 can be at least one selected from the group consisting of a polymer and a metal. Further examples of substrates are provided below. In this example, the lubricious-coated medical device 100 includes a first layer 204. The first layer 204 can be disposed on the substrate 202. In some embodiments, the first layer 204 can be disposed directly on the substrate 202. In some embodiments, an intermediate layer can be disposed between the first layer 204 and the substrate 202.

[0039] Lubricious coated medical device 100 also includes second layer 206. Second layer 206 can be disposed on first layer 204. In some embodiments, second layer 206 can be disposed directly on first layer 204. In some embodiments, an intermediate layer can be disposed between first layer 204 and second layer 206. First layer 204 and second layer 206 can be composed of the same material and / or different materials.

[0040] In some embodiments, second layer 206 may be the outermost portion of the coating, such that the outer surface of second layer 206 is configured to be in direct contact with the in vivo environment into which lubricious-coated medical device 100 is inserted. However, in some embodiments, a third layer (not shown in this figure) may be disposed over second layer 206.

[0041] The second layer 206 can be held onto the first layer 204 in a variety of ways. For example, in some embodiments, the second layer 206 can be held onto the first layer 204 by hydrogen bonding and photocrosslinking between the poly(acrylic acid) in the second layer 206 and unreacted active groups in the polymer chains of the first layer 204.

[0042] The combined thickness of the first layer 204 and the second layer 206 can be about 200 nm to about 6500 nm when dry. In some embodiments, the combined thickness of the two layers can be about 1500 nm to about 4000 nm. In some embodiments, the combined thickness of the two layers can be about 3000 nm to about 4000 nm. The thickness of the first layer 204 can comprise a majority of the combined thickness of the first layer 204 and the second layer 206. In some embodiments, the first layer 204 can comprise at least about 60, 70, 75, 80, 85, 90, or 95 percent or more of the total thickness, or an amount within any of the ranges above. In some embodiments, the thickness of the first layer 204 can range from about 100 nm to about 4000 nm, from about 500 nm to about 4000 nm, or from about 1000 nm to about 3500 nm when dry. In some embodiments, the thickness of the second layer 206 when dry can be less than about 200, 150, 100, 75, or 50 nm, or any amount within a range between any of the above.

[0043] In some embodiments herein, the thickness of one or more underlayer coats (e.g., first layer 204 with respect to FIG. 2, or first layer 304 and second layer 306 with respect to FIG. 3) can affect the lubricity of the overall coating on a device, such as that shown with respect to Example 4 herein. In some embodiments, the thickness range (dry) of the one or more underlayer coating layers is from 2.0 μm dry to 6.5 μm dry. In some embodiments, the thickness range (dry) of the one or more underlayer coating layers is from 2.4 μm dry to 6.5 μm dry. In some embodiments, the thickness (when dry) of the one or more underlying coating layers is about 2.25 μm, 2.5 μm, 2.75 μm, 3.0 μm, 3.25 μm, 3.5 μm, 3.75 μm, 4.0 μm, 4.25 μm, 4.5 μm, 4.75 μm, 5.0 μm, 5.25 μm, 5.5 μm, 5.75 μm, 6.0 μm, 6.25 μm, 6.5 μm, or an amount within a range between any of the above.

[0044] In some embodiments herein, the crosslink density of one or more underlayer coats (e.g., first layer 204 with respect to FIG. 2, or first layer 304 and second layer 306 with respect to FIG. 3) can affect the lubricity of the overall coating on a device, such as that shown with respect to Example 5 herein. Crosslink density can be characterized as μmol of benzoylbenzamide (BBA) groups (photoreactive groups used to form crosslinks) per μmol of total polymer used (theoretical basis—assuming 100% crosslinking efficiency). In some embodiments, the crosslink density of one or more underlayer coats can be less than 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 2, or 1 μmol of BBA per μmol of total polymer used, or values ​​within ranges between any of the above.

[0045] The components within first layer 204 and second layer 206 can vary and can include various specific compounds herein. In various embodiments, lubricious-coated medical device 100 can include substrate 202 and first layer 204, where first layer 204 can be disposed on substrate 202. First layer 204 can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a cross-linking compound. Lubricious-coated medical device 100 can also include second layer 206, where second layer 206 can be disposed on first layer 204. Second layer 206 can include poly(acrylic acid) and a second non-photoreactive polyvinylpyrrolidone, where the second non-photoreactive polyvinylpyrrolidone forms a complex with the poly(acrylic acid).

[0046] In various embodiments, lubricious-coated medical device 100 can include a substrate 202 and a first layer 204, where first layer 204 is disposed on substrate 202. First layer 204 can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. Lubricious-coated medical device 100 can also include a second layer 206. Second layer 206 is disposed on first layer 204. Second layer 206 can include a poly(acrylic acid) and polyvinylpyrrolidone composition. The polyvinylpyrrolidone composition includes a PVP copolymer. The PVP copolymer can form a complex with poly(acrylic acid).

[0047] In various embodiments, lubricious-coated medical device 100 can include substrate 202 and first layer 204. First layer 204 can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a cross-linking compound. Lubricious-coated medical device 100 can also include second layer 206, which includes poly(acrylic acid). Second layer 206 can have a pH greater than 3. Second layer 206 can have a pH greater than 4. Second layer 206 can have a pH greater than 5. In various embodiments, second layer 206 has a pH greater than 7. In various embodiments, second layer 206 has a pH greater than 9. In various embodiments, second layer 206 has a pH between 5 and 12.

[0048] In various embodiments, lubricious-coated medical device 100 can include a substrate 202 and a first layer 204. First layer 204 can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a cross-linking compound. Lubricious-coated medical device 100 can also include a second layer 206. Second layer 206 can include a poly(acrylic acid) homopolymer and a poly(acrylic acid) copolymer. In various embodiments, second layer 206 includes a poly(acrylic acid) copolymer and a poly(acrylic acid) homopolymer in a weight ratio of 100:1 to 20:80.

[0049] It will be appreciated that in various embodiments, the lubricious coating can include more than two layers. For example, the lubricious coating can include one or more additional layers disposed above the layer described with reference to FIG. 2, one or more additional layers disposed below the layer described with reference to FIG. 2, and / or one or more additional layers disposed between the layers described with reference to FIG. 2. Referring now to FIG. 3, a cross-sectional view of a coating according to various embodiments herein is shown. FIG. 3 illustrates a lubricious-coated medical device 100. Lubricious-coated medical device 100 includes substrate 202. Lubricious-coated medical device 100 also includes first layer 304. Lubricious-coated medical device 100 also includes second layer 306. Lubricious-coated medical device 100 also includes third layer 302.

[0050] In various embodiments, lubricious-coated medical device 100 can include substrate 202 and first layer 304, where first layer 304 can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a cross-linking compound. Lubricious-coated medical device 100 can also include second layer 306, where second layer 306 can include poly(acrylic acid). Lubricious-coated medical device 100 can also include third layer 302. Third layer 302 can include a second non-photoreactive polyvinylpyrrolidone.

[0051] In various embodiments, the second non-photoreactive polyvinylpyrrolidone of the third layer 302 can form a complex with the poly(acrylic acid) of the second layer 306 through hydrogen bonding at the interface between the second layer 306 and the third layer 302. In various embodiments, the second layer 306 can be disposed directly on the first layer 304, and the third layer 302 can be disposed directly on the second layer 306.

[0052] In various embodiments, the third layer 302 has a thickness when dry of less than about 200, 150, 100, 75, or 50 nm, or an amount falling within any range between the above.

[0053] In some embodiments, the coating layers herein can be formed by applying a coating composition. For example, a first layer can be formed by applying a first coating composition, and a second layer can be formed by applying a second coating composition. In some cases, the layers can be dried or otherwise cured before applying an upper layer. However, in some cases, layers can be applied so that one or more components of the lower layer can diffuse into the newly applied layer. In this approach, a concentration gradient is formed with respect to the diffusing components through a diffusion process. For example, in various embodiments herein, a coating can be formed by applying a first coating composition to a substrate to form a first layer. The first coating composition can include non-photoreactive polyvinylpyrrolidone and other components described herein (such as photoreactive polyvinylpyrrolidone and a crosslinking compound). A second coating composition can then be applied over the first layer to form a second layer. The second coating composition can include, for example, poly(acrylic acid). The non-photoreactive polyvinylpyrrolidone can then diffuse from the first layer to the second layer. In various embodiments, the coating composition can have a compatible solvent to facilitate spreading. For example, in various embodiments, a solvent of isopropyl alcohol (IPA) and water can be used.

[0054] Referring now to Figure 4, a cross-sectional view of a coating is shown, according to various embodiments herein. Figure 4 illustrates a lubricious-coated medical device 100. Similar to Figure 2, lubricious-coated medical device 100 includes substrate 202, first layer 204, and second layer 206. Non-photoreactive polyvinylpyrrolidone from first layer 204 can diffuse into second layer 206 in the direction of arrow 400, forming a concentration gradient of non-photoreactive polyvinylpyrrolidone in second layer 206.

[0055] Referring now to FIG. 5, a diagram of a vinylpyrrolidone polymer (PVP) complexed with a polyacrylic acid polymer (PAA) is shown, according to embodiments herein. For example, the PAA in the second layer can hydrogen bond with the PVP in the first coating layer. More specifically, as shown in FIG. 5, hydrogen bonding between the polymers can occur with the carbonyl oxygens of both the pyrrolidone ring and the carboxylic acid. In this manner, the PVP can complex with the PAA. In some embodiments, the PVP can complex with the PAA within a given layer of the coating. In some embodiments, the PVP can complex with the PAA at the interface between two layers of the coating.

[0056] 6, there is shown a schematic diagram of a portion of a layer 506 of a coating, according to various embodiments herein. In this embodiment, the PAA polymer chains 502 can be seen to form complexes with the PVP polymer chains 504. Without being bound by theory, the PVP polymer chains 504 may act as counterions for the COOH groups on the PAA polymer chains 502, preventing the reaction of ethylene oxide (CHO) with the COOH, thereby preventing the formation of polyethylene glycol (PEG), which would otherwise function to reduce the lubricity of the coating.

[0057] 7, there is shown a schematic diagram of a portion of a layer 606 of a coating, according to various embodiments herein. In this embodiment, the pH of the environment surrounding the PAA polymer chains 502 has been increased, such as by the addition of a salt, which may be a PAA salt monomer. The increased pH environment protects the exposed COOH groups on the PAA polymer chains 502, preventing reaction of the COOH with ethylene oxide (CHO), thereby preventing the formation of polyethylene glycol (PEG), which would otherwise function to reduce the lubricity of the coating.

[0058] method Many different methods are contemplated herein, including, but not limited to, methods of making, methods of using, and the like. Specifically, in some embodiments, a method of making a lubricious-coated medical device is included herein. The method can include obtaining a substrate. The method can further include applying a first layer onto the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The method can further include applying a second layer onto the first layer. The second layer can include poly(acrylic acid) and a second non-photoreactive polyvinylpyrrolidone, where the second non-photoreactive polyvinylpyrrolidone forms a complex with the poly(acrylic acid).

[0059] Some embodiments include a method of making a lubricious-coated medical device. The method can include obtaining a substrate. The method can further include applying a first layer over the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The method can further include applying a second layer over the first layer. The second layer can include poly(acrylic acid). The method can further include applying a third layer over the second layer. The third layer can include a second non-photoreactive polyvinylpyrrolidone.

[0060] Some embodiments include a method for making a lubricious-coated medical device. The method can include obtaining a substrate. The method can further include applying a first layer over the substrate. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. The method can further include applying a second layer over the first layer. The second layer can include a poly(acrylic acid) and polyvinylpyrrolidone composition, where the polyvinylpyrrolidone composition includes a PVP copolymer.

[0061] Some embodiments include a method of making a lubricious-coated medical device. The method can include obtaining a substrate. The method can further include applying a first layer over the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The method can further include applying a second layer over the first layer. The second layer can include a second layer comprising poly(acrylic acid). In various embodiments, the coating solution used to apply the second layer has a pH greater than 5. In some embodiments, the second layer can include a salt to increase the pH of the second layer. In some embodiments, the salt can be a PAA salt monomer or polymer.

[0062] Some embodiments include a method for making a lubricious-coated medical device. The method can include obtaining a substrate. The method can further include applying a first layer over the substrate. The first layer can include photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and a crosslinkable compound. The method can further include applying a second layer over the first layer. The second layer can include a poly(acrylic acid) homopolymer and a poly(acrylic acid) copolymer.

[0063] Polyvinylpyrrolidone Compounds Various embodiments herein include polyvinylpyrrolidone homopolymers and / or copolymers. Further details regarding exemplary polyvinylpyrrolidone polymers (homopolymers and copolymers) are provided below. However, it is recognized that this is provided by way of example only, and that further variations are contemplated herein.

[0064] The polyvinylpyrrolidone polymers herein can include polyvinylpyrrolidone homopolymers and copolymers containing polyvinylpyrrolidone subunits. By way of example, polyvinylpyrrolidone copolymers can include polyvinylpyrrolidone subunits as follows: [ka]

[0065] In various embodiments, the PVP copolymer may include at least one of PVP-co-PEO (polyvinylpyrrolidone-co-polyethylene oxide) and PVP-co-PSB (polyvinylpyrrolidone-co-polysulfobetaine), including at least one of PVP-co-PAA, and photo-PVP-co-PAA (photoderivatized PVP, such as PVP modified to include benzophenone functional groups or another photoactivatable functional group).

[0066] The polyvinylpyrrolidone polymers herein can be linear or branched. The polyvinylpyrrolidone polymers herein can have various molecular weights, such as an average molecular weight of 1 kDa to 3,000 kDa. In various embodiments, the polyvinylpyrrolidone polymer has an average molecular weight of 10 kDa to 50 kDa. Without being bound by theory, a lower molecular weight PVP polymer may be more effective in forming a complex with PAA. In various embodiments, the polyvinylpyrrolidone polymer has an average molecular weight of less than 15, 12, 10, 8, 6, or 4 kDa, or a molecular weight within any of the above ranges. In various embodiments, the polyvinylpyrrolidone polymer has an average molecular weight of between 4 kDa and 12 kDa.

[0067] In various embodiments, the polyvinylpyrrolidone component is a blend of PVP compounds of different molecular weights.

[0068] Exemplary polyvinylpyrrolidone polymers that are not photoderivatized can include, for example, PVP K12, PVP K17, PVP K30, PVP K90, and the like.

[0069] The polyvinylpyrrolidone polymers herein can be used to form PVP hydrogels.

[0070] In various embodiments, the polyvinylpyrrolidone can include non-photoreactive polyvinylpyrrolidone. However, instead of or in addition to non-photoreactive polyvinylpyrrolidone, in various embodiments, the polyvinylpyrrolidone can also include photoreactive polyvinylpyrrolidone ("photo-PVP"). The photoreactive polyvinylpyrrolidone can include homopolymers and / or copolymers that have been derivatized to include photoreactive groups. In various embodiments, the photoreactive polyvinylpyrrolidone can specifically include benzophenone groups.

[0071] An exemplary photoreactive polyvinylpyrrolidone copolymer can include poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide] (or PVP-co-APMA, which contains 80 to 99.9 mole percent PVP and 20 to 0.1 mole percent APMA). By way of example, an exemplary photoreactive polyvinylpyrrolidone is as follows: [ka]

[0072] Another exemplary photoreactive polyvinylpyrrolidone copolymer (acetylated PVP-APMA-BBA, or acetylated photo-PVP) is as follows: [ka]

[0073] This compound can be prepared by copolymerization of 1-vinyl-2-pyrrolidone and N-(3-aminopropyl) methacrylamide (APMA), followed by photoderivatization of the polymer using 4-benzoylbenzoyl chloride under Schotten-Baumann conditions. Unreacted amines in the photopolymer can be further acetylated using acetic anhydride.

[0074] The polyvinylpyrrolidone used herein can have a variety of molecular weights. In some embodiments, the non-photoreactive polyvinylpyrrolidone herein can have an average molecular weight of 1 kDa to 3000 kDa. In various embodiments, the non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 10 kDa to 50 kDa. In various embodiments, the non-photoreactive polyvinylpyrrolidone can be a blend of PVP compounds of different molecular weights. For example, in various embodiments, the second non-photoreactive polyvinylpyrrolidone of the second layer can be a blend of PVP compositions of at least two different average molecular weights.

[0075] In various embodiments, the weight ratio of branched PVP to poly(acrylic acid) in the same or different layers is from 70:100 to 10:90.

[0076] In various embodiments, the non-photoreactive polyvinylpyrrolidone of the outer layer or PAA-containing layer can comprise a blend of branched and unbranched PVP.

[0077] Poly(acrylic acid) homopolymers and copolymers Various embodiments herein include poly(acrylic acid) (PAA) homopolymers or PAA-containing copolymers. Further details regarding exemplary PAA homopolymers and copolymers are provided below. However, it is recognized that this is provided by way of example only, and that further variations are contemplated herein.

[0078] As used herein, "acrylic acid polymer" refers to a polymer containing acrylic acid monomer units. The acrylic acid polymer can be an acrylic acid homopolymer or an acrylic acid copolymer containing acrylic acid and one or more (e.g., two, three, four, five, etc.) other monomer units different from acrylic acid. In some embodiments, in a poly(acrylic acid) copolymer, acrylic acid can be the predominant monomer (molar fraction) present in an amount greater than 50% (mol), 55% (mol) or more, 60% (mol) or more, 65% (mol) or more, 70% (mol) or more, 75% (mol) or more, 80% (mol) or more, 85% (mol) or more, 90% (mol) or more, 92.5% (mol) or more, 95% (mol) or more, 97.5% (mol), or 99% (mol) or more, etc. In exemplary embodiments, acrylic acid is present in the copolymer in a range from about 75% (mol) to about 100% (mol), from about 85% (mol) to about 100% (mol), from about 95% (mol) to about 100% (mol), or from about 98% (mol) to about 100% (mol).

[0079] In some embodiments, the acrylic acid polymer in the top coating can have an average molecular weight of 150 kDa or greater, hi still other embodiments, the acrylic acid polymer in the top coating can have an average molecular weight of 250 kDa or greater, 350 kDa, 450 kDa, 550 kDa, 650 kDa or greater, or even in some cases, 750 kDa or greater.

[0080] In some preparation methods, acrylic acid polymers are prepared by free radical polymerization of acrylic acid (e.g., about 0.8 M concentration) in deionized water. In methods where some of the acid groups are neutralized, a concentrated base (e.g., NaOH) is added to the acrylic acid solution. An initiator, such as ammonium persulfate, is then added with stirring. The polymerization solution can be degassed with nitrogen and stirred at elevated temperatures (e.g., above 50°C) for several hours (e.g., 12-24 hours). The polymer can then be polymerized against a continuous flow of deionized water using dialysis tubing at 12-14 K and then isolated by lyophilization.

[0081] In some embodiments, an acrylic acid polymer in one layer can hydrogen bond with a vinylpyrrolidone polymer in a different layer. More specifically, as shown in Figure 4, hydrogen bonding between the polymers can occur with the carbonyl oxygens of both the pyrrolidone ring and the carboxylic acid. In some embodiments, an acrylic acid polymer in one layer can hydrogen bond with a vinylpyrrolidone polymer in the same layer.

[0082] In various embodiments, the poly(acrylic acid) is 50 to 90 percent protonated. In various embodiments, the poly(acrylic acid) is 60 to 80 percent protonated.

[0083] Various embodiments herein can also include PAA-containing copolymers. In various embodiments, the poly(acrylic acid) copolymer can include a random copolymer. In various embodiments, the poly(acrylic acid) copolymer can include a block copolymer.

[0084] The PAA-containing copolymers herein can include PAA subunits along with various other polymer subunits. By way of example, in various embodiments, the poly(acrylic acid) copolymer can include at least one of PAA-co-PVP (photoreactive or non-photoreactive), PAA-co-PAAm, and PAA-co-PVA. Such copolymers can be prepared by copolymerization of acrylic acid and / or PAA with PVP, PAAm, and / or PVA.

[0085] In various embodiments, a poly(acrylic acid) copolymer is used in conjunction with a poly(acrylic acid) homopolymer. Various ratios of the two polymers can be used. In some embodiments, the second layer can include a poly(acrylic acid) copolymer and a poly(acrylic acid) homopolymer in a weight ratio of 100:1 to 20:80. In various embodiments, the poly(acrylic acid) copolymer can have a poly(acrylic acid) to comonomer backbone molar ratio of 85:15 to 30:70.

[0086] crosslinking compound Various embodiments herein include crosslinkable compounds. Further details regarding crosslinkable compounds are provided below. However, it is recognized that this is provided by way of example only, and that further variations are contemplated herein.

[0087] In some embodiments, the crosslinker(s) can have a molecular weight of less than about 1500 kDa, but can be greater in other embodiments, hi some embodiments, the crosslinker can have a molecular weight of about 1200, 1100, 1000, 900, 800, 700, 600, 500, or 400 or less, or a molecular weight falling within a range between any of the foregoing.

[0088] In various embodiments, the crosslinker comprises one or more photoreactive groups attached to a linking group. 1 -LG-Photo 2where Photo 1 and Photo 2 independently represent at least one photoreactive group, and LG represents a linking group. The term "linking group," as used herein, refers to a molecular segment or group configured to bond two or more molecules together. In some embodiments, the linking group can include a heteroatom. In some embodiments, the linking group lacks a heteroatom. In one embodiment, the linking group includes at least one silicon atom. In another embodiment, the linking group includes at least one phosphorus atom.

[0089] In some embodiments, the linking group may be a degradable linking group, while in other embodiments, the linking group may be a non-degradable linking group. The term "degradable linking group," as used herein, refers to a moiety configured to attach one molecule to another, where the linking group is cleavable under one or more conditions. The term "biodegradable," as used herein, refers to degradation in a biological system, including, for example, enzymatic degradation or hydrolysis. It should be noted that the term "degradable," as used herein, includes both enzymatic and non-enzymatic (or chemical) degradation. It is also understood that hydrolysis can occur in the presence or absence of acid or base. In one embodiment, the linking agent is water-soluble. In another embodiment, the linking agent is not water-soluble.

[0090] In various embodiments, the linking group can function as a spacer, for example, to increase the distance between the photoreactive groups of the linking agent. For example, in some cases, it may be desirable to provide a spacer to reduce steric hindrance that may occur between the photoreactive groups, which may interfere with the ability of the photoreactive groups to form covalent bonds with the support surface or to act as a photoinitiator for polymerization. As described herein, the distance between the photoreactive groups can be changed, for example, by increasing or decreasing the spacing between one or more photoreactive groups.

[0091] As described herein, one or more photoreactive groups can be attached to a linking group by a degradable or non-degradable linkage. In various embodiments, the degradable linkage between the photoreactive group and the linking group includes at least one heteroatom, including, but not limited to, oxygen, nitrogen, selenium, sulfur, or a combination thereof. In one embodiment, the photoreactive group, the linking group, and the heteroatom are bonded together via an ether (R 1 -OR 2 ), where R 1 is a photoreactive group, and R 2 is a linking group. In another embodiment, the photoreactive group, the linking group, and the heteroatom are an amine [ka] where R 1 is a photoreactive group, and R 2 is a linking group, and R 3 is hydrogen, aryl or alkyl, a photoreactive group, or hydroxyl or a salt thereof. 3 is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. The stability of the ether and / or amine linkage can be affected depending on the size of the substituent (e.g., chain length, branching, bulkiness, etc.). For example, the bulkier the substituent, the more stable the linkage will generally be (i.e., the slower the linker will decompose in the presence of water and / or acid).

[0092] In various embodiments, the linking group comprises one or more silicon atoms. In certain embodiments, the linking group comprises one silicon atom covalently bonded to at least two photoreactive groups (which may be referred to as a monosilane). In other embodiments, the linking group comprises at least two silicon atoms (which may be referred to as a disilane). In one embodiment, the linking group may be represented by the formula Si-Y-Si, where Y is null (e.g., the linking group comprises a direct Si-Si bond), an amine, an ether, a linear or branched C1-C 10In one embodiment, Y represents a linker that can be O, CH, OCHCHO, and O(CHCHO). n where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. One embodiment of a disilane linking agent is shown below: [ka] where R 1 , R 2 , R 8 , and R 9 may be any substituent, including but not limited to H, alkyl, halide, hydroxyl, amine, or combinations thereof, and R 3 , R 4 , R 6 , and R 7 may be alkyl, aryl, or a combination thereof; R 5 may be any substituent, including but not limited to O, alkyl, or combinations thereof, and each X may independently be O, N, Se, S, or alkyl, or combinations thereof. One particular embodiment is shown below. [ka]

[0093] In various embodiments, the linking agent has the formula [ka] where Photo 1 and Photo 2independently represent one or more photoreactive groups, n is an integer between 1 and 10, and the linking agent comprises a covalent linkage between at least one photoreactive group and the linking group, the covalent linkage between at least one photoreactive group and the linking group being interrupted by at least one heteroatom. Generally, a longer hydrocarbon chain between the two silicon atoms tends to increase the flexibility of the linking agent and can facilitate crosslinking between a larger number of polymers than a linking agent having a shorter carbon chain, because the photoreactive groups can react with polymers that are located farther apart from each other. In the formula shown above, R 1 , R 2 , R 3 , R 4 is independently alkyl or aryl, including but not limited to cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or combinations thereof. 1 ~R 4 is independently phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. 1 ~R 4 may also independently be a photoreactive group. 1 ~R 4 may also independently be hydroxyl or a salt thereof. In one embodiment, the hydroxyl salt includes a counterion that is lithium, sodium, potassium, or a combination thereof.

[0094] In another embodiment, the linking agent has the formula [ka] where Photo 1 and Photo 2 independently represent one or more photoreactive groups; the linking agent comprises a covalent linkage between at least one photoreactive group and a linking group, the covalent linkage between at least one photoreactive group and a linking group being interrupted by at least one heteroatom; and R 1and R 2 is independently alkyl or aryl, including but not limited to cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or combinations thereof. 1 and R 2 R is independently phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. 1 and R 2 may also independently be a photoreactive group (the linking agent comprises a covalent linkage between at least one photoreactive group and the linking group, wherein the covalent linkage between the at least one photoreactive group and the linking group is interrupted by at least one heteroatom), or hydroxyl or a salt thereof. In one embodiment, the hydroxyl salt comprises a counterion that is lithium, sodium, potassium, or a combination thereof. One embodiment of a monosilane linking agent is shown below: [ka] where R 1 and R 5 may be any substituent, including but not limited to H, halogen, amine, hydroxyl, alkyl, or combinations thereof, and R 2 and R 4 may be any substituent except OH, including but not limited to H, alkyl, or combinations thereof, and R 3 may be alkyl, aryl, or combinations thereof, including, for example, methyl, ethyl, propyl, isopropyl, and butyl, and X may independently be O, N, Se, S, alkyl, or combinations thereof.

[0095] In another embodiment, the linking group comprises one or more phosphorus atoms. In one embodiment, the linking group comprises one phosphorus atom (which may be referred to as a monophosphorus linking group). In another embodiment, the linking group comprises two phosphorus atoms (which may be referred to as a bisphosphorus linking group). In one embodiment, the linking group comprises at least one phosphorus atom having a phosphorus-oxygen double bond (P=O), and at least one or two photoreactive groups are bonded to the phosphorus atom. In another embodiment, the linking group comprises one phosphorus atom having a phosphorus-oxygen double bond (P=O), and two or three photoreactive groups are covalently bonded to the phosphorus atom. In another embodiment, the linking group comprises at least two phosphorus atoms, and at least one phosphorus atom comprises a phosphorus-oxygen double bond (P=O), and at least one or two photoreactive groups are covalently bonded to each phosphorus atom.

[0096] In further particular embodiments, the linking agent has the formula [ka] where Photo 1 and Photo 2 independently represent one or more photoreactive groups, the linking agent comprises a covalent bond between at least one photoreactive group and the linking group, the covalent bond between at least one photoreactive group and the linking group being interrupted by at least one heteroatom, and R is an alkyl or aryl, a photoreactive group, hydroxyl or a salt thereof, or a combination thereof. In one embodiment, the hydroxyl salt comprises a counterion that is lithium, sodium, potassium, or a combination thereof. In further specific embodiments, R is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In further specific embodiments, R is phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof.

[0097] In another embodiment, the linking agent has the formula [ka] where Photo 1 and Photo 2 independently represent one or more photoreactive groups, the linking agent comprises a covalent linkage between at least one photoreactive group and the linking group, the covalent linkage between at least one photoreactive group and the linking group being interrupted by at least one heteroatom, and R is an alkyl or aryl, a photoreactive group (the covalent linkage between the photoreactive group and the linking group may be interrupted by at least one heteroatom), hydroxyl or a salt thereof, or a combination thereof. In one embodiment, the hydroxyl salt comprises a counterion that is lithium, sodium, potassium, or a combination thereof. In a more specific embodiment, R is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In one embodiment, R is phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof.

[0098] In another embodiment, the linking agent has the formula [ka] where Photo 1 and Photo 2 independently represent one or more photoreactive groups, the linking agent comprises a covalent linkage between at least one photoreactive group and the linking group, wherein the covalent linkage between at least one photoreactive group and the linking group is interrupted by at least one heteroatom, and Y is either absent (i.e., not present, such that the linking group comprises a P—P direct bond), N or O, a linear or branched C-C heteroatom, 10 R represents a linker which may be alkyl, aryl, arylsulfonyl ... 1 and R 2is independently alkyl, aryl, a photoreactive group (the covalent bond between the photoreactive group and the linking group can be interrupted by at least one heteroatom), hydroxyl or a salt thereof, or a combination thereof. In one embodiment, Y is selected from the group consisting of O, CH, OCHO, OCHCHO, and O(CHCHO). n where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. In one embodiment, the counterion of the hydroxyl salt is lithium, sodium, potassium, or a combination thereof. In further particular embodiments, R 1 and R 2 is independently cyclic, linear or branched hydrocarbon, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. 1 and R 2 is independently phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. In general, a longer hydrocarbon chain between the two phosphorus atoms tends to increase the flexibility of the linking agent and can facilitate crosslinking between more polymers than a linking agent having a shorter carbon chain, because the photoreactive groups can react with polymers that are located farther apart from each other. In one embodiment, Y is selected from the group consisting of O, CH, OCHCHO, and O(CHCHO). n where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. One embodiment is shown below: [ka] where R 1 , R 2 , R 4 and R 5 may be any substituent, including but not limited to H, alkyl, halogen, amine, hydroxyl, or combinations thereof, and R 3may be any substituent, including but not limited to O, alkyl, or combinations thereof, and each X may independently be O, N, Se, S, alkyl, or combinations thereof. In one embodiment, the linking agent comprises one or more phosphoester linkages and one or more phosphoramido linkages and has the formula [ka] where X and X 2 are independently O, N, Se, S, or alkyl, and R 1 and R 2 are independently one or more photoreactive groups, and X 3 is O, N, Se, S, alkyl, or aryl, and R 3 is alkyl or aryl, including but not limited to cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or combinations thereof. 3 R is phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. 3 can also be a photoreactive group, or hydroxyl or a salt thereof. In one embodiment, the counterion of the hydroxyl salt is lithium, sodium, potassium, or a combination thereof.

[0099] In one embodiment, the linking agent has the formula [ka] wherein R 1 and R 2 are independently one or more photoreactive groups, and R 3 is alkyl or aryl, including but not limited to cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or combinations thereof. 3R is phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. 3 may also be a photoreactive group or hydrogen, or a hydroxyl salt. In one embodiment, the counterion of the hydroxyl salt is lithium, sodium, potassium, or a combination thereof.

[0100] Some particular embodiments include the following linking agents: (a) bis(4-benzoylphenyl) hydrogen phosphate [ka] (b) Sodium bis(4-benzoylphenyl phosphate) [ka] (c) Tris(4-benzoylphenyl)phosphate [ka] (d) Tetrakis(4-benzoylphenyl)methylenebis(phosphonate) [ka]

[0101] In another embodiment, the linking agent has the formula [ka] wherein R 1 ~R 6 are independently a photoreactive group, hydroxyl or a salt thereof, alkyl or aryl, or a combination thereof; R 1 ~R 6At least two of R are independently photoreactive groups. In one embodiment, the counterion of the hydroxyl salt is lithium, sodium, potassium, or a combination thereof. In a further particular embodiment, R 1 ~R 6 is independently cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. 1 ~R 6 is independently phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof.

[0102] In some embodiments, the photoactivatable crosslinking agent may be ionic and have good solubility in aqueous compositions, such as the first and / or second coating compositions. Thus, in some embodiments, at least one ionic photoactivatable crosslinking agent is used to form the coating. In some cases, the ionic photoactivatable crosslinking agent can crosslink the polymer in the second coating layer, thereby improving the durability of the coating.

[0103] Any suitable ionic photoactivatable crosslinker can be used. In some embodiments, the ionic photoactivatable crosslinker is a compound of formula I: X1--Y--X2, where Y is a radical containing at least one acidic group, basic group, or salt of an acidic or basic group. X1 and X2 are each independently a radical containing a latent photoreactive group. The photoreactive group may be the same as those described herein. Along with the latent photoreactive group, a spacer may also be part of X1 or X2. In some embodiments, the latent photoreactive group includes an aryl ketone or a quinone.

[0104] The radical Y in Formula I provides the ionic photoactivatable crosslinker with the desired water solubility (at room temperature and optimal pH) of at least about 0.05 mg / ml. In some embodiments, the water solubility is from about 0.1 to about 10 mg / ml or from about 1 to about 5 mg / ml.

[0105] In some embodiments of Formula I, Y is a radical containing at least one acidic group or its salt. Such photoactivatable crosslinkers can be anionic depending on the pH of the coating composition. Suitable acidic groups include, for example, sulfonic acid, carboxylic acid, phosphonic acid, and the like. Suitable salts of such groups include, for example, sulfonate, carboxylate, and phosphate salts. In some embodiments, ionic crosslinkers include sulfonic acid or sulfonate groups. Suitable counterions include alkali, alkaline earth metals, ammonium, protonated amines, and the like.

[0106] For example, compounds of formula I can have a radical Y that contains a sulfonic acid or sulfonate group, and X 1 and X 2 can contain a photoreactive group such as an aryl ketone. Such compounds include 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid or salt, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid or salt, 2,5-bis(4-benzoylmethyleneoxy)benzene-1-sulfonic acid or salt, N,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid or salt, and the like. See U.S. Patent No. 6,278,018. The counterion of the salt can be, for example, ammonium or an alkali metal such as sodium, potassium, or lithium.

[0107] In other embodiments of Formula I, Y can be a radical containing a basic group or a salt thereof. Such Y radicals can include, for example, ammonium, phosphonium, or sulfonium groups. This group can be neutral or positively charged, depending on the pH of the coating composition. In some embodiments, the radical Y includes an ammonium group. Suitable counterions include, for example, carboxylate, halide, sulfate, and phosphate. For example, a compound of Formula I can have a Y radical containing an ammonium group, and X1 and X2 can contain photoreactive groups including aryl ketones. Such photoactivatable crosslinkers include ethylene bis(4-benzoylbenzyldimethylammonium) salts, hexamethylene bis(4-benzoylbenzyldimethylammonium) salts, 1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinediium) salts, bis(4-benzoylbenzyl)hexamethylenetetraminediium salts, bis[2-(4-benzoylbenzyldimethylammonio)ethyl]-4-benzoylbenzylmethylammonium salts, 4,4-bis(4-benzoylbenzyl)morpholinium salts, ethylene bis[(2-(4-benzoylbenzyldimethylammonio)ethyl)-4-benzoylbenzylmethylammonium] salts, and 1,1,4,4-tetrakis(4-benzoylbenzyl)piperazinediium salts. See U.S. Patent No. 5,714,360. The counterion is typically a carboxylate ion or a halide. In one embodiment, the halide is bromide.

[0108] In other embodiments, the ionic photoactivatable crosslinker has the formula [ka] wherein X 1 comprises a first photoreactive group, and X 2 comprises a second photoreactive group, Y comprises a core molecule, Z comprises at least one charged group, and D 1 comprises a first degradable linker, and D 2comprises a second degradable linker. Further exemplary degradable ionic photoactivatable crosslinkers are described in U.S. Patent Application Publication No. 2011 / 0144373 (Swan et al., "Water Soluble Degradable Crosslinker"), the disclosure of which is incorporated herein by reference.

[0109] In some embodiments, non-ionic photoactivatable crosslinkers can be used. In one embodiment, the non-ionic photoactivatable crosslinker has the formula XR1R2R3R4, where X is a chemical backbone and R1, R2, R3, and R4 are radicals containing latent photoreactive groups. Exemplary non-ionic crosslinkers are described, for example, in U.S. Pat. Nos. 5,414,075 and 5,637,460 (Swan et al., "Restrained Multifunctional Reagent for Surface Modification"). Chemically, the first and second photoreactive groups and their respective spacers can be the same or different.

[0110] In other embodiments, the non-ionic photoactivatable crosslinker has the formula PG 2 -LE 2 -X-LE 1 -PG 1 where PG 1 and P.G. 2 independently comprise one or more photoreactive groups, e.g., an aryl ketone photoreactive group, including, but not limited to, an aryl ketone, e.g., an acetophenone, a benzophenone, an anthraquinone, an anthrone, an anthrone-like heterocycle, a substituted derivative thereof, or a combination thereof; 1 and L.E. 2are independently linking elements including segments containing, for example, urea, carbamate, or combinations thereof, and X represents a core molecule, which can be either polymeric or non-polymeric, including, but not limited to, hydrocarbons, including hydrocarbons that are linear, branched, cyclic, or combinations thereof; aromatic, non-aromatic, or combinations thereof; monocyclic, polycyclic, carbocyclic, heterocyclic, or combinations thereof; benzene or a derivative thereof; or combinations thereof. Other nonionic crosslinkers are described, for example, in U.S. Application Serial No. 13 / 316,030, filed December 9, 2011 (U.S. Publication No. 2012 / 0149934) (Kurdyumov, "Photocrosslinker"), the disclosure of which is incorporated herein by reference.

[0111] Further embodiments of non-ionic photoactivatable crosslinkers can include, for example, those described in U.S. Provisional Application No. 61 / 494,724, filed June 8, 2011 (now U.S. Application No. 13 / 490,994) (Swan et al., "Photo-Vinyl Primers / Crosslinkers"), the disclosure of which is incorporated herein by reference. Exemplary crosslinkers include those of the general formula R 1 -XR 2 and non-ionic photoactivatable crosslinkers having the formula: 1 is a radical containing a vinyl group, X is a radical containing from about 1 to about 20 carbon atoms, and R 2 is a radical containing a photoreactive group.

[0112] Some suitable crosslinkers are formed by mixing a chemical backbone molecule (such as pentaerythritol) and an excess of a derivative of a photoreactive group (such as 4-bromomethylbenzophenone). An exemplary product is tetrakis(4-benzoylbenzyl ether) of pentaerythritol (tetrakis(4-benzoylphenylmethoxymethyl)methane). See U.S. Patent Nos. 5,414,075 and 5,637,460.

[0113] A single photoactivatable crosslinker or any combination of photoactivatable crosslinkers can be used to form the coating. In some embodiments, at least one nonionic crosslinker, such as tetrakis(4-benzoylbenzyl ether) of pentaerythritol, can be used in combination with at least one ionic crosslinker. For example, at least one nonionic photoactivatable crosslinker can be used in combination with at least one cationic photoactivatable crosslinker, such as ethylenebis(4-benzoylbenzyldimethylammonium) salt, or at least one anionic photoactivatable crosslinker, such as 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid or salt. In another example, at least one nonionic crosslinker can be used in combination with at least one cationic crosslinker and at least one anionic crosslinker. In yet another example, at least one cationic crosslinker can be used in combination with at least one anionic crosslinker, but no nonionic crosslinker is used.

[0114] An exemplary cross-linking agent is disodium 4,5-bis[(4-benzoylbenzyl)oxy]-1,3-benzenedisulfonate (DBDS), which can be prepared by combining 4,5-dihydroxybenzyl-1,3-disulfonate (CHBDS) with 4-bromomethylbenzophenone (BMBP) in THF and sodium hydroxide, then refluxing and cooling the mixture, followed by purification and recrystallization (also described in U.S. Pat. No. 5,714,360, incorporated herein by reference).

[0115] A further exemplary cross-linking agent is ethylene bis(4-benzoylbenzyldimethylammonium) dibromide, which can be prepared as described in U.S. Pat. No. 5,714,360, the contents of which are incorporated herein by reference.

[0116] Additional cross-linking agents may include those described in U.S. Patent Application Publication No. 2010 / 0274012 and U.S. Patent No. 7,772,393, the entire contents of which are incorporated herein by reference.

[0117] In some embodiments, the crosslinking agent may include a boron-containing linking agent, including but not limited to those disclosed in U.S. Ser. No. 61 / 666,516, entitled "Boron-Containing Linking Agents," by Kurdyumov et al., the contents of which are incorporated herein by reference. By way of example, the linking agent may include a borate, borazine, or boronate group, as well as coatings and devices incorporating such linking agents, along with related methods. In one embodiment, the linking agent has the structure (I): [ka] and compounds having the formula: 1 is a radical containing a photoreactive group, and R 2 is selected from OH and radicals including photoreactive groups, alkyl groups and aryl groups; R 3 is selected from OH and radicals containing photoreactive groups. 1 , B.R. 2 and B.R. 3 may be independently selected to be interrupted by heteroatoms such as O, N, S, or mixtures thereof.

[0118] Additional agents for use in conjunction with embodiments herein may include stilbene-based reactive compounds, including, but not limited to, those disclosed in U.S. Ser. No. 61 / 736,436, entitled "Stilbene-Based Reactive Compounds, Polymeric Matrices Formed Therefrom, and Articles Visualizable by Fluorescence" by Kurdyumov et al., the contents of which are incorporated herein by reference.

[0119] Additional photoreactive agents, crosslinkers, hydrophilic coatings, and related reagents are disclosed in U.S. Patent Nos. 2011 / 0059874, 2011 / 0046255, and 2010 / 0198168, the contents of which are all incorporated herein by reference. Further exemplary crosslinkers are described in U.S. Patent Application Publication No. 2011 / 0245367, the contents of which are incorporated herein by reference in their entirety.

[0120] Base material The substrate can be formed from any desired material or combination of materials suitable for use in the body. In some embodiments, the substrate is formed from a soft and flexible material, such as an elastomer (a polymer with elastic properties). Exemplary elastomers can be formed from a variety of polymers, including polyurethane and polyurethane copolymers, polyethylene, styrene-butadiene copolymers, polyisoprene, isobutylene-isoprene copolymers (butyl rubber), including halogenated butyl rubber, butadiene-styrene-acrylonitrile copolymers, silicone polymers, fluorosilicone polymers, polycarbonates, polyamides, polyesters, polyvinyl chloride, polyether-polyester copolymers, polyether-polyamide copolymers, and the like. The substrate can be made from a single elastomeric material or a combination of materials.

[0121] Other materials for the substrate may include those formed from polymers, including oligomers, homopolymers, and copolymers obtained by addition or condensation polymerization. Examples of suitable addition polymers include, but are not limited to, acrylics, such as those polymerized from methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and acrylamide; vinyls, such as ethylene, propylene, vinyl chloride, vinyl acetate, vinylpyrrolidone, vinylidene difluoride, and styrene. Examples of condensation polymers include, but are not limited to, nylons, such as polycaprolactam, polylauryllactam, polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, as well as polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), polydimethylsiloxanes, and polyether ketones.

[0122] Besides polymers, the substrate can also be formed from other inorganic materials such as metals (including metal foils and metal alloys), glasses and ceramics, depending on the type of device.

[0123] The processes for modifying the above-mentioned substrates can include chemical modifications to improve the performance characteristics of the substrate. Specific chemical processes that can be used include ozone treatment, chemical oxidation, acid chemical etching, base chemical etching, plasma and corona treatment, surface grafting, thermally activated coating processes (both covalent and non-covalent), and surface modifications including coatings containing dopamine, tannic acid, plant polyphenols, and other catechol or catechol-containing derivatives of hydrophilic moieties.

[0124] Additionally, the process for forming the above-described substrates may include physical modifications such as, but not limited to, sandblasting and surface texturing (e.g., either during or after the polymer molding process).

[0125] In some embodiments, the substrate modifications described herein allow for the omission of a base coating layer (such as a hydrophilic layer), as the modified substrate surface provides improved adhesion of hydrophobic therapeutic agents and cationic agents compared to a hydrophilic layer.

[0126] medical devices It will be appreciated that embodiments herein include and can be used in combination with various types of medical devices, including, but not limited to, various types of catheters, drug delivery devices, e.g., drug-eluting balloon catheters, drug-containing balloon catheters, stents, grafts, and the like.

[0127] Some embodiments described herein can be used in combination with balloon-expandable flow diverters and self-expanding flow diverters. Other embodiments can include use in conjunction with angioplasty balloons (e.g., but not limited to, percutaneous transluminal coronary angioplasty and percutaneous transluminal angioplasty). Still other embodiments can include use in conjunction with sinoplasty balloons for ENT procedures, urethral balloons and stents for urological procedures, and gastrointestinal procedures (e.g., devices used in colonoscopy). Hydrophobic active agents can migrate from balloon-like inflatable devices or patch-like devices to tissue. Other embodiments of the present disclosure can also be used in combination with micro-infusion catheter devices. In some embodiments, micro-infusion catheter devices can be used to target active agents to renal sympathetic nerves, for example, to treat hypertension.

[0128] Other exemplary medical applications in which embodiments of the present disclosure may be used further include treatment for bladder neck stenosis (e.g., after transurethral resection of the prostate), treatment for laryngotrachial stenosis (e.g., combined with serial endoscopic dilation to treat subglottic stenosis), oral cancer and herpes labialis, and treatment for bile duct strictures (e.g., after pancreatic cancer, hepatocellular carcinoma, or bile duct cancer). As a further example, embodiments herein may be used in combination with drug applicators. Drug applicators may include those for use in various procedures, including surgical procedures, that require the application of active agents to specific tissue locations. Examples include, but are not limited to, drug applicators that can be used in orthopedic surgery to apply active agents to specific surfaces of bone, cartilage, ligaments, or other tissues by physically contacting the drug applicator with the tissue. Drug applicators may include, but are not limited to, handheld drug applicators, drug patches, drug stamps, drug application disks, and the like.

[0129] It has been found that the optimal formulation / construction herein may vary depending on the particular structure and / or end use of the medical device bearing the coating, due to differences in factors such as tortuosity, vessel diameter, and the like.

[0130] In some embodiments herein, the medical device can be a coronary or peripheral vascular device, such as a coronary or peripheral vascular catheter. In some embodiments, the medical device is a coronary or peripheral vascular device.

[0131] One embodiment includes a lubricious-coated coronary or peripheral vascular medical device having a substrate and a first layer disposed on the substrate. The first layer can include a photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone, a second non-photoreactive polyvinylpyrrolidone different from the first non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The first non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 1000 kDa to 4000 kDa. In some embodiments, the first non-photoreactive polyvinylpyrrolidone can be PVP K90. The second non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 30 kDa to 70 kDa. In some embodiments, the second non-photoreactive polyvinylpyrrolidone can be PVP K30.

[0132] The lubricious-coated coronary or peripheral vascular medical device can also include a second layer, the second layer disposed on the first layer, the second layer can include poly(acrylic acid) and a third non-photoreactive polyvinylpyrrolidone. The third non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 3 kDa to 8 kDa. In some embodiments, the third non-photoreactive polyvinylpyrrolidone can be PVP K12 and / or PVP K17.

[0133] In some embodiments herein, the medical device may be a neural device such as a neural microcatheter. One embodiment includes a lubricious-coated neural microcatheter device having a substrate and a first layer, the first layer disposed on the substrate. The first layer may include a photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone, a second non-photoreactive polyvinylpyrrolidone different from the first non-photoreactive polyvinylpyrrolidone, a third non-photoreactive polyvinylpyrrolidone different from the first and second non-photoreactive polyvinylpyrrolidones, and a crosslinking compound. The first non-photoreactive polyvinylpyrrolidone may have an average molecular weight of 1000 kDa to 4000 kDa. In some embodiments, the first non-photoreactive polyvinylpyrrolidone may be PVP K90. The second non-photoreactive polyvinylpyrrolidone may have an average molecular weight of 30 kDa to 70 kDa. In some embodiments, the second non-photoreactive polyvinylpyrrolidone may be PVP K30. The third non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 3 kDa to 8 kDa. In some embodiments, the third non-photoreactive polyvinylpyrrolidone can be PVP K12 or PVP K17.

[0134] The lubricious-coated neural microcatheter device can also include a second layer, disposed on the first layer, that can include poly(acrylic acid), a photoreactive polyvinylpyrrolidone, a fourth non-photoreactive polyvinylpyrrolidone, a fifth non-photoreactive polyvinylpyrrolidone, and a crosslinking compound. The fourth non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 30 kDa to 70 kDa. In some embodiments, the fourth non-photoreactive polyvinylpyrrolidone can be PVP K30. The fifth non-photoreactive polyvinylpyrrolidone can have an average molecular weight of 3 kDa to 8 kDa. In some embodiments, the fifth non-photoreactive polyvinylpyrrolidone can be PVP K12 and / or PVP K17.

[0135] Aspects may be better understood with reference to the following examples, which are intended to be representative of particular embodiments, but are not intended to limit the overall scope of the embodiments herein. [Example]

[0136] Example 1 Coating formation

[0137] The first coating composition ("basecoat" formulation) was formed by mixing ingredients together in a solvent of isopropyl alcohol and water (60 / 40) to obtain a composition having photoreactive polyvinylpyrrolidone (having benzophenone photoreactive groups prepared according to the method of U.S. Pat. No. 5,637,460 and having an average MW of approximately 1,450 kDa) (12 mg / ml), high molecular weight non-photoreactive polyvinylpyrrolidone (PVP K90 (1500 kDa), 16 mg / ml) and low molecular weight non-photoreactive polyvinylpyrrolidone (PVP K17 - 7000 Da or PVP K12 - 3500 Da) 5 mg / ml, and a crosslinking compound (sodium bis(4-benzoylphenyl)phosphate - prepared according to the method of U.S. Publication No. 2012 / 0046384) (0.8 mg / ml).

[0138] A second coating composition ("top coat" formulation) was formed by mixing the components together in a solvent of isopropyl alcohol and water (15 / 85) to obtain a composition with low molecular weight, non-photoreactive polyvinylpyrrolidone (PVP K12 (3500 Da, 6 mg / ml) and polyacrylic acid (MW 450 kDa, obtained from Sigma-Aldrich, 5 mg / ml).

[0139] A third coating composition ("alternative topcoat" formulation) was formed by mixing the components together in a solvent of isopropyl alcohol and water (15 / 85) to obtain a composition with polyacrylic acid (MW 450 kDa, obtained from Sigma-Aldrich, 5 mg / ml).

[0140] The first coated device was formed by applying a first coating composition onto a polymeric substrate, curing the first coating composition, and then applying a second coating composition onto the layer formed by the first coating composition.

[0141] A second coated device was formed by applying a first coating composition onto a polymeric substrate, curing the first coating composition, and then applying a third coating composition onto the layer formed by the first coating composition.

[0142] The non-photoreactive polyvinylpyrrolidone was allowed to diffuse from the first layer to the second layer.

[0143] Example 2 Effect of PVP molecular weight on complex formation with PAA and prevention of PEG formation

[0144] Variants of the coating composition from Example 1 above were formed to investigate the effect of different molecular weight PVPs on the formation of complexes with PAA. Specifically, PVPs with molecular weights of K12 (3000-5000 Da), K17 (7000 Da), K30 (44,000 Da to 54,000 Da), and K90 (1,000,000 Da to 1,500,000 Da) were used to form variant coating compositions.

[0145] After forming the coated devices, they were subjected to an ethylene oxide sterilization procedure. The amount of PEG formation was then characterized. PVP K17 (7000 Da) and PVP K12 (3500 Da) were found to be the most effective in preventing PEG formation. PVP K30 (44,000 to 54,000 Da) and PVP K90 (1,000,000 to 1,500,000 Da) were ineffective.

[0146] Example 3 Effect of diffusible PVP on coating hardness

[0147] Coated devices were formed as described in Example 1 above using the above-described first coating composition as the basecoat (Test Coating), as well as the third coating composition as the topcoat, and a variant of the first coating composition (lacking the low molecular weight non-photoreactive polyvinylpyrrolidone) (Comparative Coating) as the basecoat, and the third coating composition as the topcoat.

[0148] After forming the coated devices, the coatings were tested in both the dry and hydrated states using a nanoindentation device (instrumented indentation testing—a type of indentation hardness test). The results are shown in Figure 8, which shows the hardness of the coating versus contact depth. This example shows that the hardness of the test coating in the hydrated state was substantially different from the hardness of the comparative coating in a similar hydrated state. This demonstrates the effect of low molecular weight PVP diffusing from the basecoat to the topcoat.

[0149] Example 4 Effect of basecoat thickness on lubricity

[0150] The effect of basecoat thickness on lubricity was investigated. A first coating composition ("basecoat" formulation) was formed by mixing ingredients together in a solvent of isopropyl alcohol and water (60 / 40) to obtain a composition having the following components: 1. Photoreactive polyvinylpyrrolidone (having benzophenone photoreactive groups prepared according to the method of U.S. Pat. No. 5,637,460 and having an average MW of approximately 1,450 kDa) (12 mg / ml); 2. First non-photoreactive polyvinylpyrrolidone (PVP K90 (900,000-1,300,000 Da), 16 mg / ml), 3. Second non-photoreactive polyvinylpyrrolidone (PVP K30 (35,000-51,000 Da), 20 mg / ml), 4. Crosslinking compound (sodium bis(4-benzoylphenyl)phosphate - prepared according to the method of U.S. Publication No. 2012 / 0046384) (0.8 mg / ml).

[0151] A second coating composition ("top coat" formulation) was formed by mixing the ingredients together in a solvent of isopropyl alcohol and water (15 / 85) at a pH sufficient for solution stability to obtain a composition having the following components: 1. Low molecular weight non-photoreactive polyvinylpyrrolidone (PVP K12 (3500 Da, 3 mg / ml) and 2. Polyacrylic acid (MW 450 kDa, obtained from Sigma-Aldrich, 5 mg / ml).

[0152] In the first test set, coated devices were formed as described in Example 1, including a single base coat and a single top coat. In the second test set, coated devices were formed as described in Example 1, but included two layers of base coat and a single top coat to increase the base coat thickness (the only difference between the two test sets was whether one or two base coat layers were present). The thickness range for the first test set (single base coat) was approximately 2.4 μm when dry and 2.4 μm to 10.0 μm when wet. Wet coatings are always thicker than dry due to swelling, although the degree of swelling is dependent on various factors. The thickness range for the second test set (two base coats) was approximately 5.3 μm when dry and approximately 5.3 μm to 16.0 μm when wet.

[0153] The lubricity of the coating was then tested for lubricity using a track test. The track test measures the force of a coated device as it passes through a tortuous anatomical model. The more lubricious the coating, the less force the device exerts on the model. The track test provides a force value in grams (less force means a more lubricious coating). With a single base coat layer, the force was found to be 132 grams, but with two base coat layers, the force was found to be reduced to 111 grams. The results are also shown in Figure 9. The results show that increasing the thickness of the base coat reduces the force and therefore provides greater lubricity.

[0154] Example 5 Effect of crosslinker concentration and ratio

[0155] The two test sets of devices from Example 4 were then evaluated based on the calculated crosslink density of the devices. Crosslink density was evaluated as μmol of benzoylbenzamide (BBA) groups per μmol of total polymer used. The same force-based lubricity measurements were used as described in Example 4. The results are shown in Figure 10, where Reference Number 1 represents the first formulation from Example 4, Reference Number 2 represents the second formulation from Example 4, Reference Number 3 represents two basecoat formulations similar to Reference Number 1 but diluted with PVP to reduce crosslink density, and Reference Number 4 represents two different basecoat formulations with reduced crosslink density. The results show that a reduction in crosslink density (which affects softness, wet modulus, and dry-to-wet thickness swelling ratio) correlated with a reduction in force (e.g., higher lubricity) measured in a track test similar to that used in Example 4.

[0156] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the context clearly dictates otherwise.

[0157] It should also be noted that, as used in this specification and the appended claims, the phrase "configured" describes a system, apparatus, or other structure that is constructed or arranged to perform a particular task or adopt a particular configuration. The phrase "configured" can be used interchangeably with other similar phrases, such as arranged and configured, built and arranged, built, manufactured and arranged, and the like.

[0158] All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated by reference.

[0159] As used herein, the recitation of numerical ranges by endpoints is intended to include all numbers subsumed within that range (e.g., 2 to 8 includes 2.1, 2.8, 5.3, 7, etc.).

[0160] The headings used herein are provided for consistency with suggestions under 37 CFR 1.77 or to otherwise provide organizational guidance. These headings should not be considered to limit or characterize the invention(s) set forth in any claims that may arise from this disclosure. By way of example, although a heading refers to a "field," such claims should not be limited by the terms selected under that heading to describe the so-called technical field. Furthermore, the description of technology in the "Background" is not an admission that that technology prioritises any invention(s) in this disclosure. The "Summary" section also should not be considered a characterization of the invention(s) set forth in the claims submitted.

[0161] The embodiments described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices. Accordingly, aspects have been described with reference to various specific preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the description.

Claims

1. 1. A lubricious coated medical device, comprising: A substrate; a first layer disposed on the substrate, the first layer comprising: Photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone; a second non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer disposed on the first layer, the second layer comprising: poly(acrylic acid), and Third non-photoreactive polyvinylpyrrolidone a second layer comprising:

1. A lubricious coated medical device comprising:

2. 21. The lubricious coated medical device of any of claims 1 and 3-20, wherein the first layer has a thickness of from 100 nm to 4000 nm.

3. The lubricious coated medical device of any of claims 1-2 and 4-20, wherein the second layer has a thickness of less than 100 nm.

4. 1. A lubricious coated medical device, further comprising a third layer, the third layer contains the same components as the first layer; the third layer is disposed between the first layer and the second layer; The lubricious coated medical device of any one of claims 1 to 3 and 5 to 20.

5. 1. A lubricious coated medical device, further comprising a fourth layer, the fourth layer contains the same components as the second layer; the fourth layer is disposed on the second layer; The lubricious coated medical device of any one of claims 1 to 4 and 6 to 20.

6. The lubricious coated medical device of any of claims 1-5 and 7-20, wherein the crosslinkable compound comprises a photoreactive compound.

7. The lubricious coated medical device of any of claims 1-6 and 8-20, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

8. The lubricious coated medical device of any of claims 1-7 and 9-20, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

9. The lubricious coated medical device of any of claims 1-8 and 10-20, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

10. The lubricious coated medical device of any of claims 1-9 and 11-20, wherein the second layer is disposed directly on the first layer.

11. The lubricious coated medical device of any of claims 1 to 10 and 12 to 20, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

12. 21. The lubricious coated medical device of any of claims 1-11 and 13-20, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

13. The lubricious coated medical device of any of claims 1 to 12 and 14 to 20, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

14. The lubricious coated medical device of any of claims 1-13 and 15-20, wherein the lubricious coated medical device is a lubricious coated coronary or peripheral vascular medical device.

15. 21. The lubricious coated medical device of any of claims 1-14 and 16-20, wherein the first non-photoreactive polyvinylpyrrolidone has an average molecular weight of 1000 kDa to 4000 kDa.

16. 21. The lubricious coated medical device of any of claims 1-15 and 17-20, wherein the first non-photoreactive polyvinylpyrrolidone is PVP K90.

17. 21. The lubricious coated medical device of any of claims 1-16 and 18-20, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 30 kDa to 70 kDa.

18. 21. The lubricious coated medical device of any of claims 1-17 and 19-20, wherein the second non-photoreactive polyvinylpyrrolidone is PVP K30.

19. 21. The lubricious coated medical device of any of claims 1-18 and 20, wherein the third non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3 kDa to 8 kDa.

20. 20. The lubricious coated medical device of any of claims 1-19, wherein the third non-photoreactive polyvinylpyrrolidone is PVP K12.

21. 1. A lubricious coated medical device, comprising: A substrate; a first layer disposed on the substrate, the first layer comprising: Photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone; a second non-photoreactive polyvinylpyrrolidone; a third non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer disposed on the first layer, the second layer comprising: poly(acrylic acid), a second photoreactive polyvinylpyrrolidone; a fourth non-photoreactive polyvinylpyrrolidone; a fifth non-photoreactive polyvinylpyrrolidone, and Second Crosslinking Compound and a second layer comprising:

1. A lubricious coated medical device comprising:

22. 45. The lubricious coated medical device of any of claims 21 and 23-44, wherein the first layer has a thickness of from 100 nm to 4000 nm.

23. 45. The lubricious coated medical device of any of claims 21-22 and 24-44, wherein the second layer has a thickness of less than 100 nm.

24. 1. A lubricious coated medical device, further comprising a third layer, the third layer contains the same components as the first layer; the third layer is disposed between the first layer and the second layer; The lubricious coated medical device of any one of claims 21 to 23 and 25 to 44.

25. 1. A lubricious coated medical device, further comprising a fourth layer, the fourth layer contains the same components as the second layer; the fourth layer is disposed on the second layer; The lubricious coated medical device of any one of claims 21 to 24 and 26 to 44.

26. The lubricious coated medical device of any of claims 21-25 and 27-44, wherein the crosslinkable compound comprises a photoreactive compound.

27. The lubricious coated medical device of any of claims 21-26 and 28-44, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

28. The lubricious coated medical device of any of claims 21-27 and 29-44, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

29. The lubricious coated medical device of any of claims 21-28 and 30-44, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

30. The lubricious coated medical device of any of claims 21-29 and 31-44, wherein the second layer is disposed directly on the first layer.

31. The lubricious coated medical device of any of claims 21-30 and 32-44, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

32. 45. The lubricious coated medical device of any of claims 21-31 and 33-44, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

33. The lubricious coated medical device of any of claims 21-32 and 34-44, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

34. 45. The lubricious coated medical device of any of claims 21-33 and 35-44, wherein the lubricious coated medical device is a lubricious coated nerve microcatheter.

35. 45. The lubricious coated medical device of any of claims 21-34 and 36-44, wherein the first non-photoreactive polyvinylpyrrolidone has an average molecular weight of 1000 kDa to 4000 kDa.

36. 45. The lubricious coated medical device of any of claims 21-35 and 37-44, wherein the first non-photoreactive polyvinylpyrrolidone is PVP K90.

37. 45. The lubricious coated medical device of any of claims 21-36 and 38-44, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 30 kDa to 70 kDa.

38. 45. The lubricious coated medical device of any of claims 21-37 and 39-44, wherein the second non-photoreactive polyvinylpyrrolidone is PVP K30.

39. 45. The lubricious coated medical device of any of claims 21-38 and 40-44, wherein the third non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3 kDa to 8 kDa.

40. The lubricious coated medical device of any of claims 21-39 and 41-44, wherein the third non-photoreactive polyvinylpyrrolidone is PVP K12.

41. 45. The lubricious coated medical device of any of claims 21-40 and 42-44, wherein the fourth non-photoreactive polyvinylpyrrolidone has an average molecular weight of 30 kDa to 70 kDa.

42. 45. The lubricious coated medical device of any of claims 21-41 and 43-44, wherein the fourth non-photoreactive polyvinylpyrrolidone is PVP K30.

43. 45. The lubricious coated medical device of any of claims 21-42 and 44, wherein the fifth non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3 kDa to 8 kDa.

44. 44. The lubricious coated medical device of any of claims 21-43, wherein the fifth non-photoreactive polyvinylpyrrolidone is PVP K12.

45. 1. A lubricious coated medical device, comprising: A substrate; a first layer disposed on the substrate, the first layer comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer disposed on the first layer, the second layer comprising: poly(acrylic acid), and The non-photoreactive polyvinylpyrrolidone a second layer comprising: Including, the non-photoreactive polyvinylpyrrolidone of the second layer forms a complex with the poly(acrylic acid); the non-photoreactive polyvinylpyrrolidone of the second layer has a concentration that is present as a gradient across the thickness of the second layer, the concentration at the outer surface of the second layer being lower than the concentration at the inner surface of the second layer; Lubricant coated medical devices.

46. 67. The lubricious coated medical device of any of claims 45 and 47-66, wherein the non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 2,000 Da to 30,000 Da.

47. 67. The lubricious coated medical device of any of claims 45-46 and 48-66, wherein the non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 3,000 Da to 9,000 Da.

48. 67. The lubricious coated medical device of any of claims 45-47 and 49-66, wherein the non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 3,000 Da to 6,000 Da.

49. 67. The lubricious coated medical device of any of claims 45-48 and 50-66, wherein the non-photoreactive polyvinylpyrrolidone of the second layer is a blend of PVP compositions of at least two different average molecular weights.

50. 67. The lubricious coated medical device of any of claims 45-49 and 51-66, wherein the non-photoreactive polyvinylpyrrolidone of the second layer forms a complex with the poly(acrylic acid) through hydrogen bonding.

51. 67. The lubricious coated medical device of any of claims 45-50 and 52-66, wherein the non-photoreactive polyvinylpyrrolidone comprises branched PVP.

52. 67. The lubricious coated medical device of any of claims 45-51 and 53-66, wherein the weight ratio of the branched PVP to the poly(acrylic acid) is from 70:100 to 10:

90.

53. 67. The lubricious coated medical device of any of claims 45-52 and 54-66, wherein the non-photoreactive polyvinylpyrrolidone comprises a blend of branched and unbranched PVP.

54. 67. The lubricious coated medical device of any of claims 45-53 and 55-66, wherein the crosslinkable compound comprises a photoreactive compound.

55. 67. The lubricious coated medical device of any of claims 45-54 and 56-66, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

56. 67. The lubricious coated medical device of any of claims 45-55 and 57-66, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

57. 67. The lubricious coated medical device of any of claims 45-56 and 58-66, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

58. 67. The lubricious coated medical device of any of claims 45-57 and 59-66, wherein the poly(acrylic acid) is 50 to 100 percent protonated.

59. 67. The lubricious coated medical device of any of claims 45-58 and 60-66, wherein the poly(acrylic acid) is 50 to 90 percent protonated.

60. 67. The lubricious coated medical device of any of claims 45-59 and 61-66, wherein the poly(acrylic acid) is 60 to 80 percent protonated.

61. 67. The lubricious coated medical device of any of claims 45-60 and 62-66, wherein the second layer is disposed directly on the first layer.

62. 67. The lubricious coated medical device of any of claims 45-61 and 63-66, wherein the first layer has a thickness of from 100 nm to 4000 nm.

63. 67. The lubricious coated medical device of any of claims 45-62 and 64-66, wherein the second layer has a thickness of less than 100 nm.

64. 67. The lubricious coated medical device of any of claims 45-63 and 65-66, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

65. 67. The lubricious coated medical device of any of claims 45-64 and 66, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

66. 66. The lubricious coated medical device of any of claims 45-65, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

67. 1. A method of making a polyacrylic acid-containing coating for a medical device, comprising: applying a first coating composition to a substrate to form a first layer, said first coating composition comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound and applying a second coating composition over the first layer to form a second layer, the second coating composition comprising poly(acrylic acid); transferring the non-photoreactive polyvinylpyrrolidone from the first layer to the second layer; A method comprising:

68. 72. The method of any one of claims 67 and 69-71, wherein the step of transferring the non-photoreactive polyvinylpyrrolidone from the first layer to the second layer creates a concentration gradient of the non-photoreactive polyvinylpyrrolidone.

69. 72. The method of any one of claims 67-68 and 70-71, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 2,000 Da to 30,000 Da.

70. 72. The method of any one of claims 67 to 69 and 71, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 9,000 Da.

71. 71. The method of any one of claims 67 to 70, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 6,000 Da.

72. 1. A lubricious coated medical device, comprising: A substrate; a first layer disposed on the substrate, the first layer comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer disposed on the first layer, the second layer comprising: poly(acrylic acid), and a second non-photoreactive polyvinylpyrrolidone, wherein the second non-photoreactive polyvinylpyrrolidone forms a complex with the poly(acrylic acid); a second layer comprising:

1. A lubricious coated medical device comprising:

73. 94. The lubricious coated medical device of any of claims 72 and 74-93, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 2,000 Da to 30,000 Da.

74. 94. The lubricious coated medical device of any of claims 72-73 and 75-93, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 3,000 Da to 9,000 Da.

75. 94. The lubricious coated medical device of any of claims 72-74 and 76-93, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 3,000 Da to 6,000 Da.

76. 94. The lubricious coated medical device of any of claims 72-75 and 77-93, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer is a blend of at least two PVP compositions of different average molecular weights.

77. 94. The lubricious coated medical device of any of claims 72-76 and 78-93, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer forms a complex with the poly(acrylic acid) through hydrogen bonding.

78. 94. The lubricious coated medical device of any of claims 72-77 and 79-93, wherein the second non-photoreactive polyvinylpyrrolidone comprises branched PVP.

79. 94. The lubricious coated medical device of any of claims 72-78 and 80-93, wherein the weight ratio of the branched PVP to the poly(acrylic acid) is from 70:100 to 10:

90.

80. 94. The lubricious coated medical device of any of claims 72-79 and 81-93, wherein the second non-photoreactive polyvinylpyrrolidone comprises a blend of branched and unbranched PVP.

81. The lubricious coated medical device of any of claims 72-80 and 82-93, wherein the crosslinkable compound comprises a photoreactive compound.

82. The lubricious coated medical device of any of claims 72-81 and 83-93, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

83. 94. The lubricious coated medical device of any of claims 72-82 and 84-93, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

84. The lubricious coated medical device of any of claims 72-83 and 85-93, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

85. 94. The lubricious coated medical device of any of claims 72-84 and 86-93, wherein the poly(acrylic acid) is 50 to 100 percent protonated.

86. 94. The lubricious coated medical device of any of claims 72-85 and 87-93, wherein the poly(acrylic acid) is 50 to 90 percent protonated.

87. 94. The lubricious coated medical device of any of claims 72-86 and 88-93, wherein the poly(acrylic acid) is 60 to 80 percent protonated.

88. 94. The lubricious coated medical device of any of claims 72-87 and 89-93, wherein the second layer is disposed directly on the first layer.

89. 94. The lubricious coated medical device of any of claims 72-88 and 90-93, wherein the first layer has a thickness of from 100 nm to 4000 nm.

90. 94. The lubricious coated medical device of any of claims 72-89 and 91-93, wherein the second layer has a thickness of less than 100 nm.

91. 94. The lubricious coated medical device of any of claims 72-90 and 92-93, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

92. 94. The lubricious coated medical device of any of claims 72-91 and 93, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

93. 93. The lubricious coated medical device of any of claims 72-92, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

94. 1. A method of making a polyacrylic acid-containing coating for a medical device, said method comprising: applying a first coating composition to a substrate to form a first layer, said first coating composition comprising: Photoreactive polyvinylpyrrolidone, a first non-photoreactive polyvinylpyrrolidone, and crosslinking compound and applying a second coating composition over the first layer to form a second layer, the second coating composition comprising: poly(acrylic acid), and Second non-photoreactive polyvinylpyrrolidone and Including, The method wherein the second coating composition has a pH of 4 to 5.

95. 101. The method of any one of claims 94 and 96-100, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 2,000 Da to 30,000 Da.

96. The method of any one of claims 94-95 and 97-100, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 9,000 Da.

97. The method of any one of claims 94 to 96 and 98 to 100, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 6,000 Da.

98. 101. The method of any one of claims 94-97 and 99-100, wherein the concentration of the second non-photoreactive polyvinylpyrrolidone in the second coating composition is from 2 mg / ml to 10 mg / ml.

99. 101. The method of any of claims 94-98 and 100, wherein the concentration of the second non-photoreactive polyvinylpyrrolidone in the second coating composition is from 3 mg / ml to 9 mg / ml.

100. 100. The method of any of claims 94 to 99, wherein the concentration of the second non-photoreactive polyvinylpyrrolidone in the second coating composition is from 6 mg / ml.

101. 1. A lubricious coated medical device, comprising: A substrate; A first layer, the first layer comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer, said second layer comprising poly(acrylic acid); a third layer, said third layer comprising a second non-photoreactive polyvinylpyrrolidone; and 1. A lubricious coated medical device comprising:

102. 123. The lubricious coated medical device of any of claims 101 and 103-122, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 2,000 Da to 30,000 Da.

103. 123. The lubricious coated medical device of any of claims 101-102 and 104-122, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 3,000 Da to 9,000 Da.

104. 123. The lubricious coated medical device of any of claims 101-103 and 105-122, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer has an average molecular weight of 3,000 Da to 6,000 Da.

105. 123. The lubricious coated medical device of any of claims 101-104 and 106-122, wherein the second non-photoreactive polyvinylpyrrolidone of the second layer is a blend of at least two PVP compositions of different average molecular weights.

106. 123. The lubricious coated medical device of any of claims 101-105 and 107-122, wherein the second non-photoreactive polyvinylpyrrolidone of the third layer forms a complex with the poly(acrylic acid) of the second layer at the interface between the second layer and the third layer through hydrogen bonding.

107. 123. The lubricious coated medical device of any of claims 101-106 and 108-122, wherein the second non-photoreactive polyvinylpyrrolidone comprises branched PVP.

108. 123. The lubricious coated medical device of any of claims 101-107 and 109-122, wherein the second non-photoreactive polyvinylpyrrolidone comprises a blend of branched and unbranched PVP.

109. 123. The lubricious coated medical device of any of claims 101-108 and 110-122, wherein the poly(acrylic acid) is 50 to 100 percent protonated.

110. 123. The lubricious coated medical device of any of claims 101-109 and 111-122, wherein the poly(acrylic acid) is 50 to 90 percent protonated.

111. 123. The lubricious coated medical device of any of claims 101-110 and 112-122, wherein the poly(acrylic acid) is 60 to 80 percent protonated.

112. 123. The lubricious coated medical device of any of claims 101-111 and 113-122, wherein the second layer is disposed directly on the first layer and the third layer is disposed directly on the second layer.

113. 123. The lubricious coated medical device of any of claims 101-112 and 114-122, wherein the first layer has a thickness of from 100 nm to 4000 nm.

114. 123. The lubricious coated medical device of any of claims 101-113 and 115-122, wherein the second layer has a thickness of less than 100 nm.

115. 123. The lubricious coated medical device of any of claims 101-114 and 116-122, wherein the third layer has a thickness of less than 100 nm.

116. 123. The lubricious coated medical device of any of claims 101-115 and 117-122, wherein the crosslinkable compound comprises a photoreactive compound.

117. 123. The lubricious coated medical device of any of claims 101-116 and 118-122, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

118. 123. The lubricious coated medical device of any of claims 101-117 and 119-122, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

119. 123. The lubricious coated medical device of any of claims 101-118 and 120-122, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

120. 123. The lubricious coated medical device of any of claims 101-119 and 121-122, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

121. 123. The lubricious coated medical device of any of claims 101-120 and 122, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

122. 122. The lubricious coated medical device of any of claims 101-121, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

123. 1. A method of making a polyacrylic acid-containing coating for a medical device, said method comprising: applying a first coating composition to a substrate to form a first layer, said first coating composition comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound and applying a second coating composition over the first layer to form a second layer, the second coating composition comprising poly(acrylic acid); applying a third coating composition over the second layer to form a third layer, the third coating composition comprising a second non-photoreactive polyvinylpyrrolidone; Including, The method wherein said third coating composition has a pH of 7 or less.

124. 127. The method of any one of claims 123 and 125-126, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 2,000 Da to 30,000 Da.

125. 127. The method of any one of claims 123-124 and 126, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 9,000 Da.

126. 126. The method of any one of claims 123 to 125, wherein the second non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 6,000 Da.

127. 1. A lubricious coated medical device, comprising: A substrate; a first layer disposed on the substrate, the first layer comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer disposed on the first layer, the second layer comprising: poly(acrylic acid), and A polyvinylpyrrolidone composition, said polyvinylpyrrolidone composition comprising a PVP copolymer a second layer comprising: Including, A lubricious coated medical device, wherein the PVP copolymer forms a complex with the poly(acrylic acid).

128. 150. The lubricious coated medical device of any of claims 127 and 129-149, wherein the PVP copolymer of the second layer forms a complex with the poly(acrylic acid) through hydrogen bonding.

129. 150. The lubricious coated medical device of any of claims 127-128 and 130-149, wherein the PVP copolymer comprises at least one selected from the group consisting of PVP-co-PEO, PVP-co-PSB, PVP-co-PAA, and photo-PVP-co-PAA.

130. 150. The lubricious coated medical device of any of claims 127-129 and 131-149, wherein the PVP copolymer is non-photoreactive.

131. 150. The lubricious coated medical device of any of claims 127-130 and 132-149, wherein the PVP copolymer is photoreactive.

132. 150. The lubricious coated medical device of any of claims 127-131 and 133-149, wherein the polyvinylpyrrolidone composition further comprises a PVP homopolymer.

133. 150. The lubricious coated medical device of any of claims 127-132 and 134-149, wherein the polyvinylpyrrolidone composition further comprises branched PVP.

134. 150. The lubricious coated medical device of any of claims 127-133 and 135-149, wherein the polyvinylpyrrolidone composition of the second layer has an average molecular weight of from 1 kDa to 3000 kDa.

135. 150. The lubricious coated medical device of any of claims 127-134 and 136-149, wherein the polyvinylpyrrolidone composition of the second layer has an average molecular weight of 10 kDa to 50 kDa.

136. 150. The lubricious coated medical device of any of claims 127-135 and 137-149, wherein the polyvinylpyrrolidone composition of the second layer is a blend of at least two PVP compositions of different average molecular weights.

137. 150. The lubricious coated medical device of any of claims 127-136 and 138-149, wherein the crosslinkable compound comprises a photoreactive compound.

138. 150. The lubricious coated medical device of any of claims 127-137 and 139-149, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

139. 150. The lubricious coated medical device of any of claims 127-138 and 140-149, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

140. 150. The lubricious coated medical device of any of claims 127-139 and 141-149, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

141. 150. The lubricious coated medical device of any of claims 127-140 and 142-149, wherein the poly(acrylic acid) is 50 to 100 percent protonated.

142. 150. The lubricious coated medical device of any of claims 127-141 and 143-149, wherein the poly(acrylic acid) is 50 to 90 percent protonated.

143. 150. The lubricious coated medical device of any of claims 127-142 and 144-149, wherein the poly(acrylic acid) is 60 to 80 percent protonated.

144. 150. The lubricious coated medical device of any of claims 127-143 and 145-149, wherein the second layer is disposed directly on the first layer.

145. 150. The lubricious coated medical device of any of claims 127-144 and 146-149, wherein the first layer has a thickness of from 100 nm to 4000 nm.

146. 150. The lubricious coated medical device of any of claims 127-145 and 147-149, wherein the second layer has a thickness of less than 100 nm.

147. 150. The lubricious coated medical device of any of claims 127-146 and 148-149, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

148. 150. The lubricious coated medical device of any of claims 127-147 and 149, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

149. 149. The lubricious coated medical device of any of claims 127-148, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

150. 1. A lubricious coated medical device, comprising: A substrate; A first layer, the first layer comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer, said second layer comprising poly(acrylic acid); Including, A lubricious coated medical device wherein the second layer has a pH greater than 5.

151. 169. The lubricious coated medical device of any of claims 150 and 152-168, wherein the second layer has a pH greater than 7.

152. 169. The lubricious coated medical device of any of claims 150-151 and 153-168, wherein the second layer has a pH greater than 9.

153. 169. The lubricious coated medical device of any of claims 150-152 and 154-168, wherein the second layer has a pH of from 5 to 12.

154. 169. The lubricious coated medical device of any of claims 150-153 and 155-168, wherein the poly(acrylic acid) is 50 to 90 percent protonated.

155. 169. The lubricious coated medical device of any of claims 150-154 and 156-168, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 2,000 Da to 30,000 Da.

156. 169. The lubricious coated medical device of any of claims 150-155 and 157-168, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 9,000 Da.

157. 169. The lubricious coated medical device of any of claims 150-156 and 158-168, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 6,000 Da.

158. 169. The lubricious coated medical device of any of claims 150-157 and 159-168, wherein the non-photoreactive polyvinylpyrrolidone is a blend of PVP compounds of different molecular weights.

159. 169. The lubricious coated medical device of any of claims 150-158 and 160-168, wherein the second layer is disposed directly on the first layer.

160. 169. The lubricious coated medical device of any of claims 150-159 and 161-168, wherein the first layer has a thickness of from 100 nm to 4000 nm.

161. 169. The lubricious coated medical device of any of claims 150-160 and 162-168, wherein the second layer has a thickness of less than 100 nm.

162. 169. The lubricious coated medical device of any of claims 150-161 and 163-168, wherein the crosslinkable compound comprises a photoreactive compound.

163. 169. The lubricious coated medical device of any of claims 150-162 and 164-168, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

164. 169. The lubricious coated medical device of any of claims 150-163 and 165-168, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

165. 169. The lubricious coated medical device of any of claims 150-164 and 166-168, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

166. 169. The lubricious coated medical device of any of claims 150-165 and 167-168, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

167. 169. The lubricious coated medical device of any of claims 150-166 and 168, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

168. 168. The lubricious coated medical device of any of claims 150-167, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

169. 1. A lubricious coated medical device, comprising: A substrate; A first layer, the first layer comprising: Photoreactive polyvinylpyrrolidone, non-photoreactive polyvinylpyrrolidone, and crosslinking compound a first layer comprising: a second layer, said second layer comprising: poly(acrylic acid) homopolymer, and Poly(acrylic acid) copolymer a second layer comprising:

1. A lubricious coated medical device comprising:

170. 190. The lubricious coated medical device of any of claims 169 and 171-189, wherein the second layer comprises the poly(acrylic acid) copolymer and the poly(acrylic acid) homopolymer in a weight ratio of 100:1 to 20:

80.

171. 190. The lubricious coated medical device of any of claims 169-170 and 172-189, wherein the poly(acrylic acid) copolymer comprises a random copolymer.

172. 190. The lubricious coated medical device of any of claims 169-171 and 173-189, wherein the poly(acrylic acid) copolymer comprises a block copolymer.

173. 190. The lubricious coated medical device of any of claims 169-172 and 174-189, wherein the poly(acrylic acid) copolymer comprises at least one selected from the group consisting of PAA-co-PVP, PAA-co-PAAm, and PAA-co-PVA.

174. 190. The lubricious coated medical device of any of claims 169-173 and 175-189, wherein the poly(acrylic acid) copolymer has a backbone molar ratio of polyacrylic acid to comonomer of from 85:15 to 30:

70.

175. 190. The lubricious coated medical device of any of claims 169-174 and 176-189, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 2,000 Da to 30,000 Da.

176. 190. The lubricious coated medical device of any of claims 169-175 and 177-189, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 9,000 Da.

177. 190. The lubricious coated medical device of any of claims 169-176 and 178-189, wherein the non-photoreactive polyvinylpyrrolidone has an average molecular weight of 3,000 Da to 6,000 Da.

178. 190. The lubricious coated medical device of any of claims 169-177 and 179-189, wherein the non-photoreactive polyvinylpyrrolidone is a blend of PVP compounds of different molecular weights.

179. 190. The lubricious coated medical device of any of claims 169-178 and 180-189, wherein the poly(acrylic acid) homopolymer is 50 to 90 percent protonated.

180. 190. The lubricious coated medical device of any of claims 169-179 and 181-189, wherein the second layer is disposed directly on the first layer.

181. 190. The lubricious coated medical device of any of claims 169-180 and 182-189, wherein the first layer has a thickness of from 100 nm to 4000 nm.

182. 190. The lubricious coated medical device of any of claims 169-181 and 183-189, wherein the second layer has a thickness of less than 100 nm.

183. 190. The lubricious coated medical device of any of claims 169-182 and 184-189, wherein the crosslinkable compound comprises a photoreactive compound.

184. 190. The lubricious coated medical device of any of claims 169-183 and 185-189, wherein the crosslinkable compound comprises a photoreactive phosphate compound.

185. 190. The lubricious coated medical device of any of claims 169-184 and 186-189, wherein the crosslinkable compound comprises bis(4-benzoylphenyl)phosphate, salt thereof.

186. 190. The lubricious coated medical device of any of claims 169-185 and 187-189, wherein the crosslinkable compound comprises sodium bis(4-benzoylphenyl)phosphate.

187. 190. The lubricious coated medical device of any of claims 169-186 and 188-189, wherein the photoreactive polyvinylpyrrolidone comprises a benzophenone group.

188. 190. The lubricious coated medical device of any of claims 169-187 and 189, wherein the photoreactive polyvinylpyrrolidone comprises poly[vinylpyrrolidone-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide].

189. 189. The lubricious coated medical device of any of claims 169-188, wherein the substrate comprises at least one selected from the group consisting of a polymer and a metal.

Images