JP2016503689A - Medical device having a lubricating coating containing a hydrophilic compound in an intertwined network structure - Google Patents

Abstract

Medical device and medical device having at least a part of a lubricious coating that is a network structure of short-chain and long-chain hydrophilic compounds that are cross-linked with each other and intertwined with the network structure of the cross-linked and polymerized polyfunctional monomer or polymer Coating method. The coating can include one or more agents that enhance adhesion of the coating to the device and increase hydration and / or lubricity of the coating. Further, the lubricious coating can be provided with one or more therapeutic or diagnostic agents, and in one embodiment, the agent concentrates from the lubricious coating as soon as the coating is hydrated. Elutes relatively quickly in a targeted release form. [Selection] Figure 1

Description

(Cross-reference of related applications)
This application is US Patent Serial No. 11 / 834,164, filed Aug. 6, 2007, the entire disclosure of which is incorporated herein by reference.

  The present invention relates to the field of lubricious / hydrophilic coatings for in-vivo medical devices such as catheters or guidewires.

  The use of medical devices within a patient's body can be facilitated by the presence of a lubricious surface on the device. For example, intravascular devices such as catheters and guidewires are easier to manipulate within the patient's vasculature when the friction between the vessel wall and the intravascular device is reduced. The device may be coated with a hydrophilic compound that becomes slippery after absorbing a significant amount of water to reduce such friction. Thus, the hydrophilic coating exposes the coated device to an aqueous solution, such as when the coated device is exposed to water prior to insertion into the patient's body or to the patient's blood during use. Provides lubricity when done.

  In addition to reducing the coefficient of friction of the coated device, an effective lubricious coating must adhere strongly to the device surface. Such a lubricious coating must remain adhered to the device surface during storage that can be prolonged and when subjected to abrasive forces encountered during use. Poor adhesive strength is undesirable because the peeled coating can be left in the patient's body during use, thereby reducing the lubricity of the device. Typically, there is a trade-off between the lubricity of the coating and the adhesion and cohesive strength of the coating, so attempts to increase the durability of the lubricious coating unintentionally Lubricity may be reduced. Durability is particularly a problem with catheter and guidewire surfaces that are subject to high friction and polishing forces as the device is slidably advanced through the patient's tortuous vasculature. Accordingly, one challenge is to provide a very smooth coating with long lasting lubricity on the surface of the catheter or guidewire. A further challenge faced is to provide a hydrophilic coating that is very durable yet can provide lubricity very quickly when exposed to an aqueous solution.

  Providing a highly durable hydrophilic coating on the surface of a medical device that makes it very fast and very smooth when exposed to an aqueous solution is a breakthrough. The present invention fulfills these and other needs.

  The present invention relates to a medical device having at least a part of the medical device having a lubricating coating containing a network structure of hydrophilic compounds that are cross-linked with each other and intertwined with the network structure of a polyfunctional polymerizable compound. One aspect of the present invention is a method of coating a medical device with the lubricious coating. A further aspect of the invention relates to the inclusion of one or more agents in the coating that enhance the adhesion of the coating to the device or that further accelerates the hydration of the coating and / or enhances lubricity. . Further, the lubricious coating can be provided with one or more therapeutic or diagnostic agents, and in one embodiment, the agents are hydrated during use of the device. And elution relatively fast in a concentrated release form from the coating.

  The lubricious coating comprises a curing reaction product of a solution mixture that is applied to the surface of a medical device and then cured on the device. The solution mixture comprises at least the following components: a multifunctional monomer or polymer network-forming compound, at least two hydrophilic compounds, one or more first crosslinking agents for crosslinking the multifunctional monomer or polymer, and One or more second crosslinking agents different from the first crosslinking agent for crosslinking the hydrophilic compound are mixed together to form. The first cross-linking agent preferentially cross-links the multifunctional monomer or polymer to the hydrophilic compound, and the second cross-linking agent preferentially cross-links the hydrophilic compound to the polyfunctional monomer or polymer. To do. The hydrophilic compound includes a combination of a long chain hydrophilic polymer and a short chain polymer. In a currently preferred embodiment, the network-forming compound is an oligomer during the preparation of the solution mixture. However, in order to increase or decrease the degree of polymerization that occurs on the device depending on whether it is added as a monomer, oligomer or longer chain polymer, the monomer (before polymerization) or longer chain is used instead of the oligomer. It may be added to the solution mixture as a polymer. Of course, regardless of whether the network-forming compound is added to the solution mixture in the form of a monomer or a relatively low or high molecular weight polymer, the multifunctional monomer or polymer of the solution mixture is Present in the finished state in a polymerized state.

  The cross-linking agent is preferably a photo-crosslinking agent that initiates a cross-linking reaction in response to irradiation with light (for example, ultraviolet light or light having a visible wavelength). However, in other embodiments, thermal initiators such as peroxides that respond to temperature increases can be used. Thus, although described below primarily with respect to preferred photocrosslinkers for photocuring the coating, it should be appreciated that other embodiments may include one or more other initiators that react by other mechanisms. May be included. The term photocrosslinker refers to compounds that act by various mechanisms that cause network-forming crosslinks, such as crosslinkers incorporated into the network structure or alternatively photoinitiators that form radicals that cause a crosslinking reaction. Shall.

  The lubricious coating applied to the surface of the catheter, gating catheter (guide) or guide wire maintains its lubricity despite the high friction and polishing forces encountered during use. The long-chain hydrophilic polymer of the formulation provides a high degree of durability to the lubricious coating, and the short-chain hydrophilic polymer provides the coating almost instantly when exposed to an aqueous solution. Things can be hydrated very quickly. The resulting coating has a significant amount of short chain hydrophilic compounds that are not cross-linked and mechanically contained only relatively weakly in the polymer network.

  While not wishing to be bound by theory, for improved durability and good lubricity, the coating formulation of the present invention causes the hydrophilic compounds to crosslink with each other (via a second photocrosslinker) and chemically entangle it. Together, it is believed that a true interpenetrating network with the crosslinked polymer can be formed without chemically (covalently) bonding the crosslinked polymer to the hydrophilic compound. Thus, the hydrophilic compound network and the polymer network that are chemically formed simultaneously in the same mixture are considered to be essentially permanently mechanically intertwined with each other. Thus, the coating is different from semi-IPN where non-crosslinked hydrophilic compounds are non-permanently mechanically entangled / included in the crosslinked polymer and chemically bonded to the hydrophilic compounds. Unlike coatings where a matrix or underlying polymer is used to bond.

  In one embodiment, the coating includes an adhesion promoter that enhances adhesion of the coating to a polymer or metal surface of a medical device. Adhesion promoters provide sufficiently strong adhesion to the surface of the medical device, thereby avoiding the need for a reactive primer layer under the present coating on the surface of the medical device.

Methods for providing lubricious coatings for medical devices generally include one or more polyfunctional monomers or polymers, long and short chain hydrophilic compounds, one or more that preferentially crosslinks the monomer or polymer to the hydrophilic compound. Preparing a solution mixture comprising a first initiator and one or more second initiators different from the first initiator that preferentially crosslinks the hydrophilic compound to the monomer or polymer; and the solution mixture Applying to the surface of at least a portion of the medical device. The coated coating solution is then irradiated with radiation so that the resulting lubricious coating is a network of hydrophilic compounds that are crosslinked with each other and intertwined with the polyfunctional polymerizable monomer or polymer network. (For example, UV light having a UVC intensity of 3 to 15 mW / cm ² in 5 to 20 seconds).

  In a presently preferred embodiment, the hydrophilic compound is polyvinylpyrrolidone, the second photocrosslinker is a diazide compound, the polyfunctional monomer or polymer is an acrylate oligomer, and the adhesion promoter is an acid functionalized acrylate. The resulting coating has a polyfunctional polymerizable acrylate acrylate network crosslinked to itself and a crosslinked acid functionalized acrylate adhesion promoter such that the hydrophilic compound network is intertwined with the acrylate network. And a hydrophilic compound network structure of polyvinylpyrrolidone crosslinked with each other by a diazide photocrosslinking agent. The coated device can be sterilized with E-beam or ethylene oxide (EtO) without significantly reducing the lubricity or durability of the coating.

  The lubricious coatings of the present invention provide significant and sustained lubricity immediately upon exposure to aqueous solutions such as blood or water. As a result, when applied to catheters, guides and / or guidewires, the hydrated, lubricious coatings can be advanced or retracted within the lumen of the patient's body over an extended period of time with the guidewire and catheter and guide shaft. The frictional force with the surface is significantly reduced. These and other advantages of the present invention will become more apparent from the following detailed description of the invention and the accompanying exemplary drawings.

1 is a partial cross-sectional front view of a balloon catheter having a lubricious coating of the present invention on a catheter shaft. FIG. 2 is a cross-sectional view of the catheter of FIG. 1 taken along line 2-2. FIG. 3 is a cross-sectional view of the catheter of FIG. 1 taken along line 3-3. FIG. 4 is a cross-sectional view of the catheter of FIG. 1 taken along line 4-4. FIG. 10 is a cross-sectional view of another embodiment in which the distal tip of the catheter has a lubricious coating on the inner and outer surfaces of the distal tip, and less lubricious coating on the outer lubricious coating. 2 shows a guidewire having a lubricious coating of the present invention. FIG. 6 is a cross-sectional view of the guidewire of FIG. 5 taken along line 6-6.

  FIG. 1 shows an embodiment of the present invention in which the medical device having the lubricious coating of the present invention is a balloon catheter 10. Balloon catheter 10 is generally inflatable on a distal shaft portion having an elongated catheter shaft 11 having an inflation lumen 12 and a guidewire lumen 13 (see FIG. 2) and an interior in fluid communication with the inflation lumen. Sexual balloon 14. An adapter 16 attached to the proximal end of the catheter shaft provides access to the guidewire lumen and is connected to a source of inflation fluid (not shown) for inflating the balloon 14. As best shown in FIGS. 2 and 3 showing a cross-sectional view of the catheter of FIG. 1 along lines 2-2 and 3-3, in the embodiment of FIG. An outer tubular member 21 having an inflation lumen 12 therein, and a guidewire lumen 13 disposed therein that is disposed in the lumen of the outer tubular member and configured to slidably receive a guidewire 23. An inner tubular member 22. The balloon 14 includes a proximal skirt portion that is sealed and fixed to the distal end of the outer tubular member 21, a distal skirt portion that is sealed and fixed to the distal end of the inner tubular member 22, and an inflatable therebetween. Having a sex part. The catheter 10 is advanced with the guidewire 23 in the lumen of the patient's body to a desired position in the lumen of the patient's body, or slidably advanced over the previously introduced guidewire 23, The balloon 14 can then be inflated to perform medical procedures such as stenosis expansion or stent expansion. When used as a stent delivery catheter, a stent 30 (see FIG. 5) is mounted on the balloon 14 for delivery and expansion within the lumen of the patient's body.

  Catheter 10 has at least a portion coated with a lubricious coating 18 of the present invention, and more specifically, has a lubricious coating 18 on at least a portion of shaft 11. In the embodiment of FIG. 1, the lubricity coating 18 is on the outer surface of the outer tubular member 21 (outer lubricity coating), on the inner surface of the inner tubular member 22 (see FIGS. 2 and 3), and Located at the distal tip 26 of the shaft 11. An outer lubricious coating 18 extends from the proximal adapter 16 to the distal-most end of the distal tip 26 (ie, along the outer surface of the outer tubular member 21, the balloon 14 and the distal tip 26). Various outer lengths, or shorter lengths such that the outer lubricious coating 18 typically extends proximally from at least about 25 to about 40 cm from the most distal end of the catheter. It can be provided on the length of the catheter 10 surface. For example, in one embodiment, the lubricious coating 18 extends along the 25-40 cm portion of the catheter along only the outer surface of the distal tip 26, the balloon 14, and the distal portion of the outer tubular member 21. doing. When the catheter 10 is used for delivery of a stent, a portion of the balloon is shielded during coating so that the stent can be attached to an uncoated portion of the balloon for good stent retention. Also good. The lubricious coating 18 on the inner surface of the inner tubular member may extend along the entire length of the inner tubular member 22 from its proximal end to the distal end, or along a shorter length. In embodiments where the lubricious coating 18 is on the inner surface of the inner tubular member and the coating 18 is photocured, the inner tubular member is a radiation permeable polymer used to crosslink the coating 18. Preferably it is formed. In the embodiment of FIG. 1, the outer surface of the balloon 14 has a coating 28 (typically a lubricious coating) that is different from the lubricious coating 18 on the shaft 11, as will be described in more detail below. However, as described above, the balloon 14 may additionally or alternatively be coated with a lubricious coating 18.

  The distal tip 26 of the shaft 11 formed by the distal end of the inner tubular member 22 and / or the flexible distal tip member secured to the distal end of the inner tubular member 22 and / or the proximal skirt of the balloon is , Having a lubricious coating 18 on its outer and inner surfaces, as best shown in FIG. 4 which shows a cross-section of the distal tip 26 of the catheter 10 of FIG. However, in other embodiments, the lubricity coating 18 is located only on the outer surface or only the inner surface of the distal tip 26. FIG. 4A shows that the lubricity coating 18 on the outer surface of the distal tip 26 is further coated with a second different lubricity coating (the same lubricity coating 28 on the balloon in the embodiment of FIG. 4A). FIG. 4 shows another embodiment. Because the lubricious coating 18 is durable enough to remain on the distal tip 26 during assembly of the catheter 10, in one embodiment, for example, a dip coating or wiping on the distal tip member is provided. Thus, prior to assembly and processing of the catheter 10, a lubricious coating 18 is applied to the distal tip 26 of the catheter and then attached to the inner member and / or balloon. After assembly of the catheter, a second lubricious coating 28 is applied to the balloon 14 and tip 26. The lubricious coating 18 of the present invention is primed on the distal tip 26 to minimize deformation and increase the lubricity durability of the fully assembled catheter distal tip 26, thereby Improves the ability of the catheter to cross tight stenosis within the patient's body lumen. In the presently preferred embodiment, the hydrophilic coating applied to its distal tip prior to attachment to the catheter is an intertwined network lubricious coating 18 described in more detail below, although other embodiments Now, various suitable hydrophilic / lubricant coatings, such as PEO or PVP-based coatings, can be applied to the distal tip prior to attachment to the catheter according to the method of the present invention.

  In the embodiment of FIG. 1, the outer tubular member 21, the inner tubular member 22 and the distal tip 26 of the catheter 10 are shown, but it will be appreciated that the covering 18 may instead be replaced by the outer tubular member 21 alone, etc. Can be applied to smaller areas of the catheter 10 or to different areas of the catheter 10. Accordingly, the lubricious coating 18 of the present invention can be applied to various suitable locations on the catheter 10. Furthermore, the lubricious coating 18 can be applied to a variety of other suitable medical devices. For example, FIG. 5 shows the lubricious coating 18 on the guidewire 23. The guidewire 23 includes a metal core and a coiled wire distal tip, and the covering 18 is preferably along at least the distal portion of the guidewire, such as a flexible distal tip. The guidewire 23 having the lubricious coating 18 of the present invention on its surface is preferably advanced and retracted with very low frictional force within the guidewire lumen of the catheter.

  As best shown in FIG. 6, which shows a cross-section of the guide wire of FIG. 5, in the embodiment of FIG. 5, the guide wire is such that the lubricity coating 18 is on the outer surface of the polymer layer 24 of the guide wire. And a polymer layer 24 on the outer surface of the metal core. In one embodiment, the polymer layer 24 is a polyurethane coating or layer on the surface of a guidewire stainless steel or NiTi core, although the polymer layer 24 may be a variety of polyolefins, copolyamides, copolyesters or filled polyurethanes, etc. It can be made of any polymer. In general, fillers such as tungsten, barium and bismuth and their compounds can be added to increase radiopacity.

  The lubricious coating 18 on the catheter 10 and / or guidewire 23 may be a multifunctional monomer or polymer network-forming compound, a combination of long and short chain hydrophilic compounds, a multifunctional monomer or a hydrophilic compound. One or more first cross-linking agents for cross-linking polymers, preferentially cross-linking polymers, and hydrophilic compounds pre-cross-linking hydrophilic compounds to multi-functional monomers or polymers And a curing reaction product of a solution mixture containing one or more second crosslinking agents different from the first crosslinking agent for crosslinking. The resulting cured coating on the medical device is a network of hydrophilic compounds that are cross-linked to one another and intertwined with the cross-linked polyfunctional polymerizable monomer or polymer network.

  The polyfunctional network structure-forming compound is preferably a triacrylate oligomer such as high molecular weight ethoxylated trimethylolpropane triacrylate (ETMPTA) (for example, PHOTOMER® 4158 available from Cognis). The ETMPTA oligomer polymerizes and crosslinks during curing to form a crosslinked ETMPTA network. Other crosslinkable polymers (formed with other polyfunctional monomers or polymers) to form a network intertwined with hydrophilic compounds include urethanes, epoxies, polyester acrylates and unsaturated polyesters. However, due to compatibility with common solvents for improved hydrophilicity and good manufacturability, triacrylates, particularly ETMPTA, are preferred. Methacrylate is less preferred due to the slow reaction and sensitivity to oxygen.

  A preferred crosslinking agent is a photosensitive molecule (photocrosslinking agent). Specifically, in embodiments where the polyfunctional oligomer is a triacrylate, the solution mixture can be benzophenone and 2,2-dimethoxy-2-phenylacetophenone (PHOTOMER® 51 available from Cognis), etc. And a first photoinitiator mixture for photocuring the triacrylate. As is generally known, various first photoinitiator mixtures are typically provided that act by different mechanisms to initiate the polymerization and crosslinking of triacrylates (and generally acrylates). For example, upon irradiation, PHOTOMER® 51 causes single molecule bond cleavage to produce free radicals, while benzophenone produces hydroxyl (or ketal) radicals in the presence of alcohol by hydrogen abstraction. Causes a bimolecular reaction. However, various suitable first photocrosslinking agents that preferentially crosslink multifunctional polymerizable monomers or polymers (eg, triacrylate oligomers) can be used. For example, other photoinitiators for cross-linking triacrylates include 1-hydroxy-cyclohexyl-phenyl-ketone and 2-hydroxy-2-methyl-1-phenyl-1-propanone, but preferred photoinitiation The agent provides excellent manufacturability due to at least one good solubility. In contrast to visible light, a photoinitiated reaction with ultraviolet light is preferred to speed up the curing time.

Currently preferred hydrophilic compounds are polyvinylpyrrolidone (PVP, which, when combined with a second photocrosslinker such as diazidostilbene (DAS) or a derivative thereof, crosslinks during curing to form a crosslinked PVP network. (Poly (N-vinyl-2-pyrrolidone)). According to the present invention, a combination of PVP K90 and PVP K30 (where K number relates to the molecular weight of PVP) may be used. Has a molecular weight greater than 1,000,000 g / mol, while PVP K30 has a molecular weight of about 44,000 g / mol, PVP K30 and PVP K90 are available from ISP Chemicals, Inc. or POLYOX WSR N-10 a _(M w = 100,000g / mol) or _{POLYOX WSR N-80 (M w} = 200,000g / mol) can be used instead of PVP K30. such polymers are all The addition of short chain polymers has the added benefit of reducing the overall viscosity of the formulation, thereby minimizing the generation of bubble defects, especially in balloon catheter applications. The brushing process is advantageous to the extent that it can be suppressed.The presently preferred diazidostilbene for preferentially crosslinking PVP is 4,4'-diazido-2,2'-stilbene disulfonic acid disodium salt Other possible diazide-based second photocrosslinkers that can be used include US Pat. No. 5,041,570 (“Summary of Invention” and “Mode for Carrying Out the Invention”). Diazide stilbene derivatives, including those described in US Pat. No. 6,077,096, the contents of which are incorporated herein by reference. ) Form very reactive intermediate nitrene groups at both ends, and then the nitrene groups on DAS react with PVP to form a cross-linked network of PVP. , DAS preferentially crosslinks PVP to polyfunctional monomers or polymer network-forming compounds (eg triacrylates), ie DAS is a polymer of substantially multifunctional polymerizable monomers or polymers. The PVP polymer chains are crosslinked to each other without crosslinking the chains Similarly, the first photocrosslinker is not expected to crosslink the hydrophilic compound (PVP) of the coating of the present invention. Curing of the coating involves cross-linking, grafting, or chemically bonding the hydrophilic compound to the polymerizable monomer or polymer or their substrate. There. Accordingly, various hydrophilic compounds used for lubricious coatings for medical devices are well known, but in the coatings of the present invention, hydrophilic compounds can be combined with each other to the desired extent. Has specific initiators that can be added to the solution mixture to preferentially crosslink. As a combination of another hydrophilic compound that can be used in the coating of the present invention and the second photocrosslinking agent, polyethylene glycol diacrylate (PEGDA) and a photoinitiator 2,2-dimethoxy-2- A combination with phenylacetophenone is mentioned.

  The amount of second crosslinker provided to the solution mixture relative to the amount of hydrophilic compound, and the duration of cure, are sufficient to form a three-dimensionally crosslinked network of hydrophilic compound. The hydrophilic compound increases or decreases the degree of crosslinking depending on the desired performance characteristics of the lubricious coating 18. The control provided by the present invention for cross-linking of hydrophilic compounds readily provides the desired lubricity and durability that can be tailored to different applications. Therefore, the degree of crosslinking of PVP, which is a part of the network structure in the lubricating coating 18, is high or low. Further, in order to increase lubricity at the expense of potential durability, in some embodiments, some of the non-crosslinked hydrophilic compound (ie, non-crosslinked PVP and thus the mesh) A non-crosslinked second hydrophilic compound such as PEO or not part of the structure is present in the lubricious coating. Specifically, a lubricious coating with a network structure in which durability is a problem and lubricity is not a problem is the durability of this coating at the expense of lubricity by crosslinking a hydrophilic compound to a higher degree. Which can be tolerated in some applications. Furthermore, since the crosslinking of hydrophilic compounds is more easily controllable with the lubricious coatings of the present invention, the amount of crosslinking that occurs by first photocuring the coating on the device can be, for example, E-beam Or, when the device coated with EtO is sterilized, it can be adjusted to compensate for any further crosslinking that may occur later, such that sterilization results in further crosslinking of the coating. In one embodiment, the coated device is sterilized with E-beam, and the method of coating the device comprises subjecting the coating on the device to a relatively short duration that is insufficient to crosslink the compound to the desired extent ( Curing (UV), for example, as determined by a performance test of the coated medical device, and then sterilizing the coated device with E-beam so that the compound is further crosslinked to the desired extent; including. Similarly, the amount of photocrosslinker in the coating can be limited to control the amount of crosslinking that occurs upon photocuring.

  A solution mixture consists of a multifunctional monomer or polymer, a short and long chain hydrophilic compound, one or more first crosslinkers, and one or more second crosslinkers together in a single solution. (The compounds are typically first dissolved in a suitable solvent and then grouped together to form a single solution). The solution mixture is then applied to the surface of the catheter shaft 11 and / or guide wire 23 and the solution is dipped, sprayed, wiped on the surface of the catheter or guide wire, or the solution is guided through the guide wire lumen 13 of the catheter. Various suitable methods such as stretching through can be used to apply to the device. The coating is then typically dried on the device and then cured, and the resulting cured coating has a substantially uniform composition obtained by the entangled network within the monolayer. . In one embodiment, the adhesion promoting primer is first coated on the device and allowed to cure, and then a solution mixture of the lubricious coating is applied onto the cured primer. The cured coating 18 must be hydrated and lubricious for use in medical procedures. The water induction time, i.e., the time required to hydrate the coating, will depend on the coating formulation, and more specifically the amount of short chain hydrophilic polymer in the composition. Accordingly, as used herein, the term “lubricating coating” refers to a device either before or after hydrating the hydrophilic compound to render the coating lubricious for use. It shall refer to the top finish coating.

  In one embodiment, the solution mixture includes an adhesion promoter that includes an acid functionalized acrylate that adheres to the surface of the medical device to enhance adhesion of the lubricious coating 18 to the medical device. Preferred adhesion promoters bind to the surface of the substrate (eg, the polymer surface of the catheter shaft or guidewire) and crosslink to the multifunctional polymerizable monomer or polymer. Thus, the first initiator crosslinks the adhesion promoter such that the adhesion promoter is crosslinked to itself and to the crosslinked polyfunctional polymerizable monomer or polymer in the cured lubricious coating. It is preferable. A presently preferred adhesion promoter is PHOTOMER® 4173 (acid functionalized monoacrylate) from Cognis that binds to a polymer (especially polyurethane) substrate layer. Other adhesion promoters that can be used include PHOTOMER® 4703 and 4846, acid functionalized acrylates from Cognis. The adhesion promoter is generally from about 0.2% to about 20%, more specifically from about 1% to about 2% by weight of the solution mixture. Reactive primer layers on devices such as these acid functionalized adhesion promoters (+ photoinitiators) or other primer compounds such as urethane acrylates can be used in addition or as an alternative to enhance adhesion. Whether or not an adhesion promoter is used, the coating 18 of the present invention requires that the hydrophilic compound be functionalized or otherwise chemically bonded to the matrix or substrate polymer by reaction. Adhere to the surface of the device.

  In one embodiment, the solution mixture includes a second hydrophilic compound such as polyethylene oxide (PEO) that is different from the network-forming hydrophilic compound (eg, PVP). The second hydrophilic compound is not substantially crosslinked in the lubricious coating. Therefore, the initiator that preferentially crosslinks the second hydrophilic compound is not included in the solution mixture, and does the curing of the coating result in relatively little crosslinking of the second hydrophilic compound? It does not occur at all. By being substantially uncrosslinked, the second hydrophilic compound is at least initially more lubricious and / or has a shorter water induction time (ie, faster response to the hydration procedure). It is preferred to provide a coating. For example, substantially uncrosslinked hydrophilic compounds such as polyethylene oxide (PEO) in the coating hydrate relatively quickly. Specifically, by combining a first hydrophilic compound such as PVP and a second hydrophilic compound such as PEO or polyacrylamide, the water induction time is improved and shortened after sterilization by E-beam or EtO treatment. It is preferable to obtain a coated product. The non-crosslinked PEO or polyacrylamide preferably compensates for the increased water induction time of the lubricious coating due to both E-beam and EtO sterilization. A variety of suitable hydrophilic compounds can be used as the second hydrophilic compound, such as PEO, acrylamide-acrylic acid copolymers, and polyacrylamide. In one embodiment, a relatively small amount of the second hydrophilic compound is present in the coating. For example, in one embodiment, the second hydrophilic compound is PVP in an amount of only about 5% by weight in the lubricious coating.

  In one embodiment, the solution mixture includes a soluble ionic compound (ie, salt), such as sodium chloride, and the resulting cured lubricious coating hydrates the coating for at least use. Before the hydration procedure used to have the salt contained therein (dissolvably). It is believed that the water induction time is reduced for a salt-free coating due to the presence of salt in the cured coating.

  In one embodiment, the cured lubricious coating has a therapeutic or diagnostic agent. For example, the drug added to the solution mixture is releasably included in the cured coating so that the cured coating swells (hydrates) during use and the drug elutes therefrom. Yes. The cured lubricious coating can be provided with a variety of agents. Anti-platelet drugs, antithrombotic drugs, anticoagulant drugs, anti-inflammatory drugs, vasodilator drugs, etc., can be used for the main lubricity of the balloon 14, the outer member 21, the guide wire 23 and / or the guide wire lumen 13 of the catheter shaft 11. Particularly preferred for addition to the coating. Relatively small molecule drugs such as aspirin (acetylsalicylic acid, acetolsal) are particularly desirable for the lubricious coating, because of its relatively fast dissolution time from the lubricious coating, and Alternatively, intensive rapid administration of aspirin is obtained while the guidewire is initially introduced and advanced into the patient's body lumen. Long-term controlled dissolution of drugs from medical device coatings is the goal of many prior art coatings, but aspirin is eluted relatively uncontrolled from the lubricating coatings of the present invention. It is desirable. Concentrated release of aspirin from the coating immediately after hydration of the lubricious coating provides an antiplatelet effect during placement of the catheter within the body lumen, thereby providing a catheter guidewire. The immobility of the guide wire within the lumen is further reduced. Aspirin has a small molecular weight (eg, 180 g / mol), but other molecular weights greater than aspirin such as Hirudin (about 7,000 g / mol) or heparin (about 12,000 to about 15,000 g / mol) These agents can also be used in the coating of the present invention.

  The lubricious coatings of the present invention can be provided with a variety of suitable agents (small or large molecule agents) such as anti-restenosis agents, anti-inflammatory agents, anticoagulants or healing-promoting agents. The drug is typically provided by adding it into the solution mixture prior to application to the device, which method provides good manufacturability, control over the amount and location of the drug on the device, and the coating. This is the preferred method due to minimal breakdown of the lubricity of the object. A less preferred method is to swell the cured coating on the device with a solution of the drug prior to use.

  In the embodiment shown in FIG. 1, the coating 28 on the balloon 14 is different from the lubricious coating 18 on the shaft. For example, the coating 28 on the balloon may be a less lubricious coating and may contain a different therapeutic agent than the coating on the shaft. In other embodiments described above, the same lubricious coating 18 on the shaft 11 may be provided on the balloon 14.

  In one embodiment, the lubricious coating 28 on the balloon 14 has a relatively short water induction time (fast hydrates), treats arterial disease and / or prevents restenosis or Contains anti-restenosis drugs such as zotarolimus. Since the drug is well stored in the drug delivery lubricous coating 28 prior to balloon inflation and the absorption of water by the drug delivery lubricious coating 28 occurs quickly, the drug has a sufficient dose of drug. Is released as soon as the balloon 14 is inflated to provide the desired site. Typically, the pre-inflation balloon is folded, thus protecting a portion of the coating while it is folded as the catheter is first hydrated and advanced through the vessel. To do. In one embodiment, the drug delivery lubricity coating 28 on the balloon is an intertwined network lubricity coating to which is added a non-crosslinked second hydrophilic compound that provides rapid water guidance. Product embodiments (e.g., PEO not cross-linked within an intertwined network of cross-linked PVP and cross-linked triacrylate). As described above, it is preferred to add the agent to the solution mixture of the lubricious coating prior to coating the balloon. The balloon with the drug delivery lubricity coating on its surface is then folded into a small shape in other ways to fold or advance within the lumen of the patient's body.

  In one embodiment, the coating 28 on the balloon prevents or inhibits the inflated balloon from slipping out of the desired treatment location within the patient's body lumen (commonly referred to as “watermelon seeding”). Therefore, the coating is less lubricous than the lubricious coating 18 on the shaft. There are several other approaches to making the coating 28 on the balloon a less lubricious coating than the lubricious coating 18 on the shaft. For example, after applying the same or more concentrated solution to the shaft and balloon, a more dilute concentration solution of the same component can be applied to the balloon. In another example, a coating consisting of a solution incorporating one hydrophilic polymer (eg PEO) can be applied to the balloon and a coating consisting of a solution incorporating a different hydrophilic polymer (eg PVP). Things can be applied to the shaft. In another example, the lubricious coating 28 is a binding multifunctional oligomer (or monomer or higher molecular weight polymer), a photocrosslinker for crosslinking the binding oligomer, and a hydrophilic property of the less lubricious coating. The reaction product of a solution mixture containing a hydrophilic compound that does not contain a photocrosslinking agent for preferentially crosslinking the functional compound can be included. Therefore, the coating 28 on the balloon can be formed of a compound having the same component as the coating 18 on the shaft except that the second photocrosslinking agent is not included, so that a coating with low lubricity can be obtained. Although the covering 28 is shown extending along the entire length of the balloon from the proximal end to the distal end of the balloon, it will be appreciated that in other embodiments, the covering 28 may be It may extend along a shorter length or beyond the end of the balloon.

The following example shows a solution mixture for the lubricious coating 18 of the present invention. In addition to the specific formulations used in the following examples (including the amount of each component expressed in weight percent of the solution mixture), the following table is used in preparing the coatings of the present invention. An exemplary solution weight percent range for ingredients that can be provided is also provided.

  The solution mixture of Formulation A listed in the table above was applied by dip coating to a guidewire having a metal core covered with a polymer layer of tungsten-filled polyurethane polymer. Test procedure in which a coated guidewire is repeatedly advanced and retracted through the guidewire lumen of a catheter inner tubular member having an HDPE inner surface (the inner tubular member is filled with sterile water and is added by a 1.25 inch loop to 37 Maintained), the resulting friction force caused by movement of the coated guidewire within the guidewire lumen remains low after multiple cycles (up to 1000 cycles) and after 24 hours. It was. Friction forces after multiple cycles include lubricious coatings containing PEO in cross-linked acrylates (ie, 2-propanol, water, PEO, trimethylolpropyl triacrylate (TMPTA), hydroxycyclohexyl phenyl ketone and benzophenone). Solution mixture, where PEO is POLYOX WSR N12K, which is about 1.6% by weight of the solution mixture) and is lower when compared to a guidewire that is the same. It was. For example, after 30 cycles, the frictional force while pushing and pulling a guidewire coated with Formulation A listed in the above table is about 5 grams compared to about 35-55 grams for a comparative guidewire. Met.

  The size of the catheter 10 depends primarily on the size of the balloon and guidewire used, the type of catheter and the size of the artery or other body lumen that the catheter must pass through or the size of the stent being delivered. It is determined. Typically, the outer tubular member 21 has an outer diameter of about 0.025 to about 0.04 inches (0.064 to 0.10 cm), usually about 0.037 inches (0.094 cm); The wall thickness of the outer tubular member 21 is about 0.002 to about 0.008 inches (0.0051 to 0.02 cm), typically about 0.003 to 0.005 inches (0.0076 to 0). .013 cm). Inner tubular member 22 typically has an inner diameter of about 0.01 to about 0.018 inches (0.025 to 0.046 cm), usually about 0.016 inches (0.04 cm), and about 0.004 to With a wall thickness of about 0.008 inch (0.01-0.02 cm). The total length of the catheter 10 may range from about 100 to about 150 cm, typically about 143 cm. Preferably, the balloon 14 has a length of about 0.8 cm to about 6 cm and an inflation working moving diameter of about 2 mm to about 10 mm. Guidewire 23 typically has a length of about 190 to about 300 cm and an outer diameter of about 0.010 to about 0.035 inches.

  Various coupling components may be coupled using conventional coupling methods such as fusion or the use of adhesives. The shaft 11 is shown as having inner and outer tubular members, but using a variety of suitable shaft configurations including a dual lumen extrusion shaft with side-by-side lumens extending therein. Also good. Further, although the embodiment shown in FIG. 1 is an over-the-wire balloon catheter having a guidewire lumen that extends the entire length of the catheter, it will be appreciated that the coating 18 of the present invention may be a catheter or other Various suitable catheters, such as a gating catheter having a device lumen configured to deliver the device or a rapid exchange balloon catheter having a guidewire proximal port spaced distally from the proximal end of the catheter shaft Can be used for

  Although the present invention has been described herein with reference to certain preferred embodiments, those skilled in the art will recognize that various modifications and improvements can be made to the present invention without departing from the scope thereof. I will. For example, although primarily described with respect to coatings on catheter shafts or guidewires, it will be appreciated that the lubricious coating 18 of the present invention can be applied to a variety of medical devices during use or assembly and processing. Particularly suitable for use on surfaces that encounter large frictional or abrasive forces. Further, individual features of one embodiment of the present invention are described herein, and may be shown in one drawing of the embodiment but not in other embodiments. , May be combined with one or more features of another embodiment or features of multiple embodiments.

Claims (42)

A medical device having at least a portion having a lubricious coating comprising a cured reaction product of a solution mixture applied to the device, the solution mixture comprising:
a) a polyfunctional monomer or polymer network-forming compound,
b) short chain hydrophilic compounds,
c) a long-chain hydrophilic compound,
d) one or more first cross-linking agents for cross-linking the polyfunctional monomer or polymer preferentially cross-linking the polyfunctional monomer or polymer with respect to the hydrophilic compound, and e) the medical The hydrophilic reaction product on the polyfunctional monomer or polymer is such that the curing reaction product on the device is a network of the hydrophilic compound that is cross-linked to each other and intertwined with the polymerization network of the monomer or polymer. A device comprising one or more second cross-linking agents different from the first cross-linking agent for cross-linking the hydrophilic compound, which preferentially cross-links the hydrophilic compound.   The method of claim 1, wherein the lubricious coating is cured using a radiation source.   The method of claim 1, wherein the lubricious coating is cured using a UV source.   The method of claim 1, wherein the lubricious coating is cured using an electron beam source.   The apparatus according to claim 1, wherein the network structure forming compound is triacrylate.   The apparatus according to claim 1, wherein the network structure forming compound is an ethoxylated trimethylolpropane triacrylate oligomer.   The apparatus of claim 1, wherein the hydrophilic compound comprises polyvinylpyrrolidone.   The apparatus of claim 7, wherein the single chain hydrophilic compound comprises PVP K30.   The apparatus of claim 7, wherein the long-chain hydrophilic compound comprises PVP K90.   The apparatus of claim 1, wherein the hydrophilic compound network is not chemically bonded to the polymerizable monomer or polymer network.   The device of claim 1, wherein the solution mixture includes an adhesion promoter comprising an acid functionalized acrylate that adheres to a surface of the medical device.   12. The first crosslinker crosslinks the adhesion promoter such that the adhesion promoter is crosslinked to itself and the polymerizable monomer or polymer in the lubricious coating. apparatus.   The device is a metal guidewire that includes a polymer outer layer, and the coating is directly bonded to the polymer outer layer of the guidewire without using a reactive primer between the polymer layer and the coating. The apparatus of claim 11.   12. The device of claim 11, wherein the device is a metal guidewire and the coating is directly bonded to the metal guidewire without using a reactive primer between the polymer layer and the coating. The device described.   12. The device of claim 11, wherein the device is a metal guidewire including a polymer outer layer having an adhesion promoter primer layer, and the lubricious coating is adhered to the primer layer.   The device is a guide catheter including an outer polymer layer, and the coating is directly adhered to the outer polymer layer of the guide without a reactive primer between the polymer layer and the coating. Item 12. The apparatus according to Item 11.   12. The guide is a guide catheter including an outer polymer layer, and the coating is adhered to the outer polymer layer of the guide using a reactive primer between the polymer layer and the coating. The device described in 1.   The apparatus of claim 1, wherein the apparatus is a guide wire having a metal surface that includes a primer layer of an adhesion promoter, and the lubricious coating is adhered to the primer layer.   The apparatus of claim 1, wherein the device is a balloon catheter having an elongated catheter shaft and a balloon on a distal shaft portion, the lubrication coating on the surface of at least a portion of the shaft and at least a portion of the balloon. The device described.   The device is a guide catheter including an outer polymer layer, and the coating is directly adhered to the outer polymer layer of the guide without a reactive primer between the polymer layer and the coating. Item 2. The apparatus according to Item 1.   The device is a guide catheter including an outer polymer layer, and the coating is adhered to the outer polymer layer of the guide using a reactive primer between the polymer layer and the coating. The device described in 1.   The apparatus of claim 1, wherein the first and / or second crosslinker is a photocrosslinker such that the coating is photocured.   23. The apparatus of claim 22, wherein the second photocrosslinker is a diazide compound.   24. The apparatus of claim 23, wherein the diazide compound is diazidostilbene or a diazidostilbene derivative.   23. The apparatus of claim 22, wherein the first photocrosslinker is benzophenone and benzyl dimethyl ketal.   The apparatus of claim 1, wherein the coating includes a second hydrophilic compound that is different from the crosslinked hydrophilic compound and that is not substantially crosslinked in the lubricious coating.   The apparatus of claim 1, wherein the solution mixture includes a salt, and wherein the salt is dissolvably contained in the cured coating at least prior to hydration of the coating.   The apparatus of claim 1, wherein the solution mixture includes a therapeutic agent such that the network is formed in the presence of a therapeutic agent and the therapeutic agent is releasably contained in the lubricious coating. .   29. The device of claim 28, wherein the therapeutic agent is a relatively small molecule drug that elutes relatively quickly in a concentrated release form from the lubricious coating at the time of hydration of the coating.   28. The device of claim 27, wherein the therapeutic agent is acetylsalicylic acid. a) a polyfunctional monomer or polymer, a relatively short-chain hydrophilic compound, a relatively long-chain hydrophilic compound, and the monomer or polymer that preferentially crosslinks the monomer or polymer with respect to the hydrophilic compound. What is the one or more first crosslinking agents for crosslinking, and the first crosslinking agent for crosslinking the hydrophilic compound that preferentially crosslinks the hydrophilic compound with respect to the monomer or polymer? Preparing a solution mixture comprising one or more different second crosslinking agents;
b) applying a coating of the solution mixture to at least a portion of the surface of the medical device, and the resulting lubricious coating is crosslinked to itself and entangled with the polymer or polymer polymerization network Curing the coating so as to have a network structure of the hydrophilic compound;
A method for providing a lubricious coating for medical devices.   32. The method of claim 31, wherein the hydrophilic coating is cured using a radiation source.   The method of claim 32, wherein the radiation source is ultraviolet light.   23. The amount of the second cross-linking agent is limited to cure the hydrophilic compound less than desired by curing of the coating, and after the E-beam or EtO to sterilize the device after claim 22. 32. The method of claim 31, further comprising further crosslinking the hydrophilic compound to a desired degree.   Curing the coating limits the duration of the curing to crosslink the hydrophilic compound to a lesser extent as desired, and includes E-beam or EtO to sterilize the device after step b), 32. The method of claim 31, wherein the hydrophilic compound is further crosslinked to the desired extent.   32. The method of claim 31, wherein curing of the coating does not chemically bond the hydrophilic compound to the monomer or polymer.   32. The method of claim 31, wherein the solution mixture comprises an adhesion promoter comprising an acid functionalized acrylate that adheres to the surface of the medical device.   32. The method of claim 31, wherein step b) comprises cross-linking the adhesion promoter to itself and to the polyfunctional polymerizable monomer or polymer.   The solution mixture includes a second hydrophilic compound without an initiator that preferentially crosslinks the second hydrophilic compound, and the second hydrophilic compound is not crosslinked in the lubricious coating. 32. The method of claim 31, wherein the second hydrophilic compound is not crosslinked by curing of the coating.   The device is a balloon catheter having an elongate catheter shaft including a distal tip member and a balloon on a distal shaft portion, and prior to coupling the distal tip member to the catheter shaft, the solution mixture is 32. The method of claim 31, wherein the method is applied to the inner surface and / or outer surface of the distal tip member.   32. The method of claim 31, wherein the lubricious coating is cured using a UV source.   32. The method of claim 31, wherein the lubricious coating is cured using an electron beam source.

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