Direct oral anticoagulant-eluting medical device

Abstract

To provide medical devices, more specifically, anticoagulant coatings on medical devices for preventing device-related thrombosis, and methods for using such medical devices.SOLUTION: A device for permanent placement across an atrial appendage ostium in a patient includes a support structure having a contracted delivery configuration and an expanded deployed configuration defining a radially enlarged portion to permanently engage an interior wall of the atrial appendage, a membrane attached to the support structure and configured to extend across the atrial appendage ostium when the support structure is in the expanded deployed configuration, and a polymer coating disposed on at least one of the support structure and the membrane, the polymer coating including a direct oral anticoagulant (DOAC) dispersed in a polymer.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to medical devices, and more particularly to anticoagulant coatings for medical devices to prevent device-associated thrombosis, and methods of using such medical devices. [Background technology]

[0002] A wide variety of medical devices have been developed for medical applications. Among these are, for example, medical devices utilized in the treatment of non-valvular atrial fibrillation. These medical devices can be used to isolate the left atrial appendage (LAA). An implantable medical device can be inserted into the LAA to prevent blood clots from leaving the heart and entering the systemic circulation. Over time, the exposed surface structure of the implanted medical device that spans the ostium of the LAA becomes covered with tissue. Known medical devices and methods each have certain advantages and disadvantages. There is a continuing need to provide alternative medical devices and alternative methods for manufacturing and using medical devices. Summary of the Invention

[0003] The present disclosure provides alternatives for medical device designs, materials, manufacturing methods, and uses. An exemplary medical device includes a support structure having a contracted delivery configuration and an expanded deployed configuration defining a radially expanded portion for permanently engaging the inner wall of the atrial appendage, a membrane attached to the support structure and configured to extend across the atrial appendage ostium when the support structure is in the expanded deployed configuration, and a polymer coating disposed on at least one of the support structure and the membrane. The polymer coating includes a direct oral anticoagulant (DOAC) dispersed in the polymer.

[0004] Alternatively or additionally to the above embodiments, the DOAC is apixaban, rivaroxaban, or edoxaban. Alternatively or additionally to any of the above embodiments, the polymer coating is disposed on the membrane.

[0005] Alternatively or additionally to any of the above embodiments, the DOAC is present in the polymer coating in a ratio of polymer to DOAC of 60 / 40 to 90 / 10 wt / wt.

[0006] Alternatively or additionally to any of the above embodiments, the DOAC is present in the polymer coating in an amount of 10 to 10,000 μg. Alternatively or additionally to any of the above embodiments, the polymer coating may have a membrane surface area of ​​1 mm 2 The DOAC is contained at a coating density of 100 to 50,000 ng of DOAC per capsule.

[0007] Alternatively or additionally to any of the above embodiments, the polymer is poly(vinylidene fluoride)-co-hexafluoropropylene and the polymer coating has a thickness of about 10-20 μm.

[0008] Alternatively or additionally to any of the above embodiments, the polymer coating is disposed directly on the support structure. Alternatively or additionally to any of the above embodiments, the polymer coating has a thickness of 20 μm.

[0009] Alternatively or additionally to any of the above embodiments, the DOAC is present in an amount of 100-300 μg. Alternatively or additionally to any of the above embodiments, the polymer coating is disposed on a proximal end of the support structure.

[0010] Alternatively or additionally to any of the above embodiments, the polymer coating is a film having a thickness of 1 to 10 μm laminated to the membrane. Alternatively or additionally to any of the above embodiments, the film contains 100 to 450 μg of the DOAC.

[0011] Alternatively or additionally to any of the above embodiments, the film comprises a plurality of pores. Alternatively or additionally to any of the above embodiments, the plurality of pores are 20 to 150 μm.

[0012] Alternatively or additionally to any of the above embodiments, the film is disposed on the atrial surface of the membrane. Alternatively or additionally to any of the above embodiments, the film comprises a base layer comprising the DOAC and a top layer comprising a modulating compound.

[0013] Another example of a device for permanent placement across a patient's left atrial appendage ostium includes a self-expanding support structure having a first contracted configuration for delivery and a second expanded configuration configured to engage an inner wall of the left atrial appendage, the support structure including a plurality of struts defining an atrial surface that extends across the left atrial appendage ostium when in the second expanded configuration; a membrane disposed on the atrial surface and extending along at least a portion of a side of the support structure and configured to extend across the atrial appendage ostium in the second expanded configuration; and a polymeric drug coating disposed on one or both of the support structure and the membrane, the polymeric drug coating including a direct oral anticoagulant (DOAC) dispersed in a polymer.

[0014] Alternatively or additionally to the above embodiment, the polymeric drug coating is a 1-10 μm thick film laminated directly onto the membrane. An exemplary method of manufacturing an expandable device for permanent placement across a patient's left atrial appendage ostium includes forming an expandable support structure having a contracted delivery configuration and an expanded deployed configuration defining a radially expanded portion sized to permanently engage the inner wall of the left atrial appendage, attaching a membrane onto at least a proximal end of the support structure, and applying a polymeric coating to at least one of the support structure and the membrane, the polymeric coating including a direct oral anticoagulant dispersed in the polymer.

[0015] The above summary of some embodiments, aspects, and / or examples is not intended to describe each embodiment or every implementation of the present disclosure. The following figures and detailed description more particularly exemplify these embodiments. [Brief explanation of the drawings]

[0016] The present disclosure may be more fully understood from the following detailed description of various embodiments, taken in conjunction with the accompanying drawings. [Figure 1] 1 illustrates a portion of an exemplary medical device according to the present disclosure. [Figure 2] 2 shows the medical device shown in FIG. 1 with a membrane. [Figure 3] 3 is an example of the medical device shown in FIG. 2 deployed within a partial cross-sectional view of a patient's left atrial appendage. [Figure 4A] 1 is a partial cross-sectional view of an exemplary medical device having a polymer thin film disposed on a membrane. [Figure 4B] 10A is a partial cross-sectional view of another exemplary medical device having a thin polymer film disposed between the membrane and the support structure. FIG. [Figure 5] 1 shows thrombi formed on membranes coated with polymer and various direct anticoagulants at various time points. [Figure 6] 6 is a graph showing thrombus weight from FIG. 5. [Figure 7] FIG. 1 is a top view of a laser cut 25 μm thick polyethylene terephthalate (PET) film. [Figure 8] 1 is a graph showing drug release over time from spray-coated PET films. [Figure 9] 9A-9D show the control and spray-coated devices after exposure to blood. [Figure 10] 10A and 10B show the partially masked spray coated device before and after blood exposure. DETAILED DESCRIPTION OF THE INVENTION

[0017] While aspects of the present disclosure are susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and will be described in detail. It is to be understood, however, that it is not intended to limit aspects of the present disclosure to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure.

[0018] Detailed Description For the following defined terms, these definitions shall be applied, unless a different definition is given in the claims or elsewhere in this specification.

[0019] As used herein, all numerical values ​​are deemed to be modified by the term "about," whether explicitly stated or not. The term "about" in the context of numerical values ​​generally refers to a range of numerical values ​​that one of ordinary skill in the art would consider equivalent to the stated value (e.g., having the same function or result). In many cases, the term "about" may include numerical values ​​that are rounded to the nearest significant figure. Other uses of the term "about" (e.g., in contexts other than numerical values) may be deemed to have the ordinary and customary definition understood from and consistent with the context of this specification, unless otherwise specified.

[0020] The recitation of numerical ranges by upper and lower limits includes all numbers within that range, inclusive of the limits (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5). Although several suitable dimensions, ranges, and / or values ​​for various components, features, and / or specifications are disclosed, one of ordinary skill in the art, inspired by this disclosure, will recognize that desired dimensions, ranges, and / or values ​​may deviate from those expressly disclosed.

[0021] As used in this specification and the appended claims, the singular forms "a," "an," "the," and "said" include plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term "or" is used in its general sense including "and / or" unless the content clearly dictates otherwise. For ease of understanding, it should be noted that certain features of the present disclosure may be described in the singular even if they are multiple or repeated within a disclosed embodiment. Each instance of a feature may comprise and / or be encompassed by a single disclosure unless expressly stated to the contrary. For purposes of simplicity and clarity, not every element of the present disclosure is necessarily shown in every figure or described in detail below. However, it will be understood that the following description may apply equally to any and / or all of a plurality of components unless expressly stated to the contrary. Moreover, for clarity, not every instance of some element or feature may be shown in every figure.

[0022] Relative terms such as "proximal," "distal," "advance," "retract," and variations thereof are typically considered with respect to the positioning, orientation, and / or operation of various elements relative to a user / operator / manipulator of a device, where "proximal" and "retract" indicate or refer to being closer to or toward the user, and "distal" and "advance" indicate or refer to being further from or away from the user. In some cases, the terms "proximal" and "distal" may be assigned arbitrarily to facilitate understanding of the present disclosure, and such examples will be readily apparent to those skilled in the art. Other relative terms, such as "upstream," "downstream," "inflow," and "outflow," refer to the direction of fluid flow within a body lumen, a lumen such as a blood vessel, or within a device.

[0023] The term "range" may be understood to mean the maximum measurement of a stated or specified dimension; however, if the range or dimension is preceded by or identified as "minimum," it may be understood to mean the minimum measurement of the stated or specified dimension. For example, an "outer range" may be understood to mean the maximum outer dimension, a "radial range" may be understood to mean the maximum radial dimension, and a "longitudinal range" may be understood to mean the maximum longitudinal dimension. Examples of "range" may vary (e.g., axially, longitudinally, laterally, radially, circumferentially, etc.) and will be apparent to those skilled in the art from the context of the particular usage. Typically, a "range" is considered the maximum possible dimension measured according to the intended use, while a "minimum range" is considered the smallest possible dimension measured according to the intended use. In some cases, a "range" may typically be measured orthogonally in a plane and / or cross-section, but may also be measured differently, such as (but not limited to) angularly, radially, circumferentially (e.g., along an arc), etc., as apparent from the particular context.

[0024] The terms "monolithic" and "single" shall generally refer to an element made of or consisting of a single structure or basic unit / element. Monolithic and / or single element shall not include structures and / or features made by assembling or joining multiple individual elements.

[0025] References herein to "one embodiment," "some embodiments," "other embodiments," etc., indicate that the described embodiment may include a particular feature, structure, or characteristic, but it should be noted that not all embodiments necessarily include that particular feature, structure, or characteristic. Moreover, such phrases do not necessarily refer to the same embodiment. Furthermore, if a particular feature, structure, or characteristic is described in connection with one embodiment, unless expressly stated to the contrary, it is within the knowledge of one of ordinary skill in the art to enable that particular feature, structure, or characteristic in connection with other embodiments, whether explicitly stated or not. That is, it is contemplated that various individual elements described below, even if not explicitly shown in specific combinations, can be combined or arranged with one another to form other or additional embodiments, or to supplement and / or enrich the described embodiments, as would be understood by one of ordinary skill in the art.

[0026] For purposes of clarity, certain distinguishing numerical nomenclature (e.g., first, second, third, fourth, etc.) may be used throughout this specification and / or claims to name and / or distinguish various features described and / or claimed. It should be understood that the numerical nomenclature is not intended to be limiting, but is merely exemplary. In some embodiments, variations and departures from previously used numerical nomenclature may be made for brevity and clarity. That is, a feature identified as a "first" element may later be referred to as a "second," "third," etc., or may be omitted entirely, and / or a different feature may be referred to as the "first" element. The meaning and / or name in each instance will be apparent to one of ordinary skill in the art.

[0027] The following description should be read with reference to the drawings, which are not necessarily to scale and in which similar elements in different drawings are numbered the same. The detailed description and drawings are for illustrative purposes only and are not intended to limit the present disclosure. Those skilled in the art will recognize that the various elements described and / or illustrated can be arranged in various combinations and configurations without departing from the scope of the present disclosure. The detailed description and drawings illustrate exemplary embodiments of the present disclosure. However, for clarity and ease of understanding, not all features and / or elements may be shown in each drawing, although it can be understood that such features and / or elements are present unless otherwise specified.

[0028] Non-valvular atrial fibrillation (a-fib) is a condition that increases a patient's risk of stroke because reduced blood flow through the left atrial appendage (LAA) creates a low-flow condition favorable for clot formation. As a result of this condition, patients with a-fib may require lifelong oral anticoagulation therapy. Oral anticoagulants are a systemic treatment that can pose unique risks to patients, particularly those at high risk for bleeding. To reduce the incidence of clot formation within the LAA and prevent clots from entering the bloodstream from within the LAA, medical devices have been developed that isolate the LAA from the heart and / or circulatory system, thereby reducing the risk of stroke or other embolic ischemic events due to thrombolytic agents entering the bloodstream from the left atrial appendage.

[0029] Patients receiving an LAA closure device are often recommended to take oral anticoagulants (OACs) for approximately 45 days after implantation, followed by at least 6 months of dual antiplatelet therapy (DAPT). OAC therapy after LAA closure device implantation aims to ensure a low risk of device-related thrombosis (DRT) during the first 6 weeks after implantation, when tissue grows over the device. While OAC therapy is highly effective in reducing the risk of DRT, it is a systemic treatment and, as such, can cause serious systemic adverse effects in some patients, such as cerebral hemorrhage, gastrointestinal bleeding, and internal bleeding from blunt trauma such as falls. For patients at high risk of bleeding, it is recommended that they avoid taking OACs after LAA closure device implantation. Patient non-adherence to OACs after LAA closure device implantation is also a potential issue. Approximately 3–4% of patients develop device-related thrombosis between 45 days and 1 year after implantation after discontinuing OACs. Patients who develop DRT must return to OACs until the DRT resolves.

[0030] Applicants have developed a closure device that (a) eliminates the need for systemic OAC therapy after device implantation and (b) continues to reduce the risk of DRT over the long term. This closure device employs traditional systemic OAC therapy and instead uses direct oral anticoagulants (DOACs) and provides them only on the surface of the device where needed, thereby mitigating potential side effects of systemic OAC therapy. This can be achieved by incorporating the DOAC into a polymer coating disposed on one or more portions of the LAA closure device. The closure device can include a support structure and a membrane, and the polymer coating can be disposed on one or both of the support structure and the membrane.

[0031] Unlike traditional anticoagulants such as heparin and warfarin, which inhibit various cofactors in the clotting cascade and can contribute to serious systemic adverse effects, a category of anticoagulants known as direct oral anticoagulants (DOACs) binds directly to specific clotting factors. Examples of DOACs include apixaban, rivaroxaban, edoxaban, dabigatran, betrixaban, and argatroban, which bind directly to factor Xa, and dabigatran, which binds directly to factor IIa. LAA closure devices provide a method for localized release of these DOACs at the surface of the device.

[0032] FIG. 1 shows a perspective view of an exemplary LAA closure device portion or implant 100. The implant 100 can include a self-expanding support structure 110 extending from a proximal collar 112 to a distal collar 114. In some embodiments, the support structure 110 can include multiple struts 111 forming a lattice. The support structure 110, including the proximal collar 112 and struts 111, can be monolithic or formed from multiple pieces. The proximal end 116 of the support structure 110 faces the left atrium when implanted within the LAA and may be referred to as the atrial face of the support structure. In some embodiments, the proximal and distal ends of the struts can be directly attached to the proximal and / or distal collars, respectively. In some embodiments, the support structure 110 can include multiple anchors 150 provided to secure the implant 100 to the lateral wall of the left atrial appendage after deployment, thereby preventing proximal migration of the implant 100 relative to the LAA. In the illustrated embodiment, each of the plurality of anchors 150 extends distally from a strut-node junction 156. However, it will be understood that other alternative positions and arrangements of the plurality of anchors 150 are possible. The support structure 110 has a contracted delivery shape or configuration and an expanded deployed shape or configuration, as shown in FIG. 1 . In this illustration, the support structure 110 defines a radially enlarged portion that permanently engages the inner wall of the atrial appendage. When the support structure 110 is in the expanded configuration, the atrial face is configured to extend completely across the ostium of the LAA.

[0033] FIG. 2 illustrates the exemplary implant 100 shown in FIG. 1 with a membrane 130 disposed over at least a portion of the support structure 110. In some embodiments, at least some of the multiple anchors 150 protrude through the membrane 130. In some embodiments, the membrane 130 can be attached to the support structure 110 at each anchor 150, for example, by threading each anchor 150 through a pore or opening in the membrane 130. In other embodiments, the membrane 130 can be attached to the support structure 110 by other suitable attachment means, such as, but not limited to, adhesives, sutures or threads, welding or soldering, or combinations thereof. In some embodiments, the membrane 130 can be permeable or impermeable to other fluids, such as blood and / or water. In some embodiments, the membrane 130 can include a polymeric membrane, a metal or polymeric mesh, a porous filter-like material, or other suitable structure. The membrane 130 can extend to completely cover the proximal end 116 or the atrial surface of the support structure 110. In some examples, membrane 130 can also extend along at least a portion of side 118 of support structure 110, as shown in FIG. 2. In this manner, membrane 130 is configured to extend across the ostium of the LAA when support structure 110 is in the expanded, deployed configuration. In some embodiments, membrane 130 prevents thrombus (i.e., blood clots, etc.) formed in the LAA from passing through membrane 130 and entering the bloodstream from the LAA. In some embodiments, membrane 130 promotes endothelialization after implantation, thereby effectively removing the LAA from the patient's circulatory system.

[0034] Figure 3 shows a partial cross-sectional view of the implant 100 in a deployed position disposed within an exemplary left atrial appendage 50. As can be seen in Figure 3, the support structure 110 can conform to and substantially conform and / or sealingly engage the contour and / or surface shape of the side wall 54 of the left atrial appendage 50 in the deployed position. The implant 100 can expand to its maximum size, extent, or shape to a fully unconstrained position in the deployed position.

[0035] The LAA closure implant 100 described above is just one of many different LAA implants that can incorporate a DOAC-containing polymer coating. The following example refers to LAA closure devices such as those described in U.S. Patent Nos. 6,652,556, 6,689,150, 6,949,113, 7,727,189, 9,913,652, and 11,241,237, the disclosures of which are incorporated herein by reference.

[0036] The polymer coating may include a hemocompatible polymer, such as poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP), and an anticoagulant, such as a direct oral anticoagulant (DOAC). The resulting drug coating can be applied to the membrane 130 and / or support structure 110 to act as a drug reservoir for sustained local release. The relatively large size of the implant allows for the incorporation of a drug reservoir, allowing for the long-term (1-year) release of DOACs and other drugs to locally treat DRT and other cardiac conditions.

[0037] In one embodiment, a polymer coating, such as PVDF-HFP, and one or more DOACs are dissolved in a solvent suitable for dissolving the polymer. This solution can be applied directly to the membrane 130 by dip coating or a spray process. Spray coating can place the polymer coating on only one side of the membrane 130, with the uncoated side attached to the support structure 110. Spray coating can be performed on the membrane before or after the membrane is attached to the support structure. The polymer coating can be applied to a concentration of 100-50,000 ng drug / mm on the membrane. 2 In some instances, the polymer coating can be applied to achieve a coating density of 10,000 ng drug / mm on the membrane. 2The polymer to drug ratio can be, for example, 50 / 50 to 90 / 10 (wt / wt). Some examples include polymer to drug ratios of 60 / 40, 70 / 30, or 80 / 20 (wt / wt). The average coating thickness on the membrane can be about 10 to 30 μm. In one example, the amount of drug contained in the coated membrane of a 24 mm device can be about 10 to 20,000 μg.

[0038] In another example, the drug-containing polymer coating can be disposed directly on the support structure 110. The support structure 110 can be Nitinol. In some examples, only the proximal end 116 of the support structure 110 can be conformally coated with a blend of PVDF-HFP and DOAC. In other examples, the polymer coating can be disposed on the proximal end 116 and at least a portion of the side surface 118 of the support structure 110. Alternatively, the entire support structure 110 can be covered with the polymer coating. When the polymer coating is disposed directly on the support structure 110, significantly thicker coatings can be achieved compared to coating the membrane 130. The thickness of the membrane coating is limited by the impact of membrane folding and unfolding during device loading and deployment. A thicker membrane coating can crack, peel, or interfere with the folding and unfolding process. By directly coating the support structure 110, polymer coatings up to 30 μm thick and containing 100-300 μg of anticoagulant can be achieved. A significantly thicker coating on the support structure 110 may result in a longer drug release time compared to coating the membrane 130. In some instances, slower drug release can be achieved by applying a drug-containing base coat, allowing the device to dry, and then applying a drug-free top coat. In other instances, by masking the device during the coating process, the drug coating can be applied to selected, unmasked areas or regions of the device. This allows the drug to be applied only to specific, desired areas.

[0039] In some instances, both the membrane 130 and the support structure 110 may be coated with the polymer and DOAC coating, which may increase the amount of drug delivered compared to coating only the support structure or only the membrane.

[0040] In a further example, a thin layer of PVDF-HFP containing DOAC is formed into a thin film 160 and laminated directly onto membrane 130. This film may be very thin compared to the membrane 130, which may be polyethylene terephthalate (PET). For example, the thin film 160 of polymer and DOAC may have a thickness of 1-10 μm compared to the 120 μm thick membrane 130. The polymer film is very flexible and conformable to the membrane 130 and does not adversely affect device loading or deployment. The thin film 160 may be significantly thicker, such as 10-100 times thicker, than a direct dip or spray coating of the polymer and DOAC onto the membrane 130. In some instances, the film may be formed with multiple layers. Thicker or multilayered films can retain more drug and therefore provide a longer duration of drug release. For example, the thin film may contain approximately 100-450 μg of anticoagulant. In some instances, the thin film 160 may be positioned on the atrial surface of the membrane 130, as shown in FIG. 4A. In other instances, the thin film 160 may be sandwiched between the membrane 130 and the support structure 110, as shown in FIG. 4B.

[0041] The thin film 160 can also be porous to allow blood to rapidly pass through the device. The pores can be formed during the film manufacturing process or after the film is formed, such as by laser cutting or other processes such as high temperature annealing. The pores can be approximately 20 μm to 150 μm in diameter to match the pores in the membrane 130.

[0042] In some examples, thin film 160 can include multiple different layers. For example, thin film 160 can include a base layer of a polymer and an anticoagulant and a top layer that includes a modulating compound.

[0043] In some examples, a method of manufacturing implant 100 may include the steps of: (1) forming an expandable support structure 110 having a contracted delivery configuration and an expanded deployed configuration defining a radially expanded portion sized to permanently engage the inner wall of the left atrial appendage; (2) attaching membrane 130 over at least the proximal end 116 of support structure 110; and (3) applying a polymer coating comprising a DOAC dispersed in the polymer to at least one of support structure 110 and membrane 130. The polymer coating can be applied directly to membrane 130, directly to support structure 110, directly to both membrane 130 and support structure 110, or the polymer coating can be formed into a thin film 160 and then laminated to membrane 130.

[0044] In some examples, a method of forming an expandable support structure may include the steps of: (a) obtaining an elongate tubular member having a lumen and an annular ring member extending therethrough; (b) laser cutting the tubular member to form a proximal collar 112, a plurality of struts 111 having free distal ends, and a plurality of anchors 150 interspersed among the plurality of struts as a single monolithic structure; (c) forming the plurality of struts 111 into a lattice of generally diamond-shaped wire segments; and (d) fixedly attaching a plurality of free distal ends of the struts 111 to the distal collar 114. Attaching the membrane 130 over at least the proximal end 116 of the support structure 110 may include attaching the membrane 130 over the proximal end 116 and along at least a portion of the side 118 such that the plurality of anchors 150 extend through the membrane 130.

[0045] Example 1: Coating placed directly on membrane Solutions of PVDF-HFP and DOAC were prepared in 80 / 20 acetone / DMSO (w / w). The PVDF-HFP to drug ratio was 90 / 10 (w / w), with a solution solids content of 0.7%. The DOAC drugs evaluated were apixaban (Eliquis®), rivaroxaban (Xarelto®), and edoxaban (Savaysa®). Polyethylene terephthalate (PET) fiber discs with a diameter of 15 mm were dip-coated into the polymer / drug solution at a dip rate of 5 mm / sec. The coated discs were dried in a convection oven at 125°C for 30 minutes. The drug-coated discs and a control disc containing only PVDF-HFP were placed in cups containing heparinized bovine blood whose activated clotting time (ACT) had been adjusted to approximately 190 seconds using protamine. The cup was placed in a 37°C orbital shaker incubator, and the discs were removed and imaged at various time points. Images are shown in Figure 5. The discs were then dried and weighed to determine clot weight. The clot weights are shown in Figure 6. As can be seen in Figure 5, all three drugs demonstrated significantly fewer thrombi (clots) compared to the PVDF-HFP-coated control, indicating that these drugs are highly effective in preventing the formation of acute clots on the fabric. The clot weights provided in Figure 6 confirm that the amount of clots formed on the DOAC-treated fabric was minimal.

[0046] Example 2: Coatings Disposed on Laser Cut PET Film A 25 μm thick PET film was laser cut to create 150 μm holes spaced 100 μm apart, as shown in Figure 7. A solution of PVDF / rivaroxaban (70 / 30 (wt / wt), 4% total solids in 48 / 52 (wt / wt) acetone / DMF) was spray coated onto the PET film, resulting in a coating drug dose density of 6.3 μg drug / mm. 2One sample of the coated film was overlaminated with a 1.5 μm thick PVDF film to act as a drug release barrier layer to slow drug release. Drug release was measured after incubation in PBS / Tween® 20 at 37° C. for various time points. See Figure 8. Without the laminated barrier layer, all of the drug is released in about two weeks. Adding the laminated barrier layer extends the drug release period to well over one month.

[0047] Example 3: Coatings deposited directly onto devices by spray coating A drug / polymer solution of PVDF-HFP and DOAC was prepared in 80 / 20 acetone / DMSO (w / w). The PVDF-HFP to drug ratio was 60 / 40 (w / w), with a solution solids content of 2%. The DOAC drug evaluated was rivaroxaban (Xarelto®). A base coat was applied to a 24 mm diameter Watchman device by spray coating with the polymer / drug solution at a flow rate of 10 ml / hr. The device was dried in a convection oven at 125°C for 30 minutes and then spray coated with a topcoat solution (2% PVDF-HFP in 100% acetone) at a flow rate of 10 ml / hr. The total basecoat weight was 38.8 mg, and the topcoat weight was 18.7 mg. The spray-coated device was then placed in a PBS / Tween® solution at 37°C for 11 days to simulate in vivo drug elution. The device was then rinsed with DI water and dried. The same incubation and rinsing protocol was applied to a control device coated with PVDF-HFP alone. The thrombogenicity of the DOAC-eluting and control devices was evaluated by placing them in the same container of bovine blood (ACT=210) on an orbital shaker incubator at 37°C for 15 minutes. Figure 9A shows the top view of the control device, and Figure 9B is a close-up of the device, demonstrating significant thrombus formation. Figures 9C and 9D show the top and close-up views of the DOAC-eluting device, demonstrating that the coating significantly reduced thrombus formation on the proximal surface of the device compared to the control device.

[0048] Example 4: Coatings placed directly on masked devices by spray coating A solution of PVDF-HFP and DOAC was prepared in 40 / 60 acetone / DMF (wt / wt). The PVDF-HFP to drug ratio was 70 / 30 (wt / wt), with a solution solids content of 4%. The DOAC drug evaluated was apixaban. A 24 mm diameter Watchman device was masked on the back and exterior of the device using Teflon tape prior to spray coating, ensuring that only the proximal surface of the device (unmasked area) was coated with the drug / polymer coating. See Figure 10A. A basecoat was then applied by spray coating the masked device with the polymer / drug solution at a flow rate of 20 ml / h. A close-up of the unmasked area compared to the uncoated masked area shows the coating on the device. The device was dried in a convection oven at 125°C for 30 minutes and then spray-coated with a topcoat solution (2% PVDF-HFP in 100% acetone) at a flow rate of 10 ml / h. The total basecoat weight was 26.6 mg, and the topcoat weight was 10.5 mg. The spray-coated devices were then placed in a PBS / Tween® solution at 37°C for 7 days to simulate in vivo drug elution. The devices were then rinsed with DI water and dried. The DOAC-eluting devices were placed in bovine blood (ACT=210) on an orbital shaker incubator at 37°C for 15 minutes to evaluate the thrombogenicity of the partially coated devices. As seen in Figure 10B, the DOAC-eluting devices inhibited thrombus formation only on the proximal surface of the device where the drug / polymer coating was applied, while thrombus formation was observed in the distal portion of the device.

[0049] Providing a DOAC directly onto the LAA implant provides desirable local thromboprophylaxis after implantation of the closure device without the need for systemic oral anticoagulation therapy. Although the above embodiment is shown and described as being inserted into the left atrial appendage, it will be understood that the device and method can also be used in the right atrial appendage.

[0050] In some embodiments, the plurality of struts 111 and / or the plurality of anchors 150 of the support structure 110 can be formed from or include metallic materials, metallic alloys, ceramic materials, hard or high-performance polymers, metal-polymer composite materials, combinations thereof, and the like. Examples of some suitable materials can include metallic materials and / or alloys, such as stainless steel (e.g., 303, 304v, or 316L stainless steel), nickel-titanium alloys (e.g., Nitinol, such as superelastic or linear elastic Nitinol), nickel-chromium alloys, nickel-chromium-iron alloys, cobalt alloys, nickel, titanium, platinum, or polymeric materials, such as high-performance polymers, or other suitable materials. The term Nitinol was coined by a group of researchers at the U.S. Naval Ordnance Laboratory (NOL), who first identified the shape memory behavior of this material. The term Nitinol is an acronym that includes the chemical symbol for nickel (Ni), the chemical symbol for titanium (Ti), and the acronym for Naval Ordnance Laboratory (NOL).

[0051] In some embodiments, the plurality of struts 111 and / or the plurality of anchors 150 of the support structure 110 may be mixed with, doped with, coated with, or otherwise include a radiopaque material. A radiopaque material is understood to be a material that can produce a relatively bright image on a fluoroscopy screen or other imaging technique, such as an X-ray, during a medical procedure. This relatively bright image aids the user of the device in locating it. Suitable radiopaque materials include, but are not limited to, bismuth subcarbonate, iodine, gold, platinum, palladium, tantalum, tungsten, or tungsten alloys.

[0052] In some embodiments, membrane 130 may be formed from or include a polymeric material, a metallic or metal alloy material, a metal-polymer composite material, combinations thereof, etc. In some embodiments, membrane 130 is preferably formed from polyethylene terephthalate (PET), such as Dacron®, or expanded polytetrafluoroethylene (ePTFE). Other examples of suitable polymers include polyurethanes, polyetheresters such as Arnitel® available from DSM Engineering Plastics, polyesters such as Hytrel® available from DuPont, linear low density polyethylenes such as REXELL™, polyamides such as DURETHAN® available from Bayer or CRISTAMID™ available from Elf Atochem, elastomeric polyamides, block polyamide / ethers, polyether block amides such as PEBA available under the trade name Pebax®, silicones, polyethylene, Marlex high density polyethylene, polytetrafluoroethylene (PTFE), polyetheretherketone (PEEK), polyimide (PI), and polyetherimide (PEI), liquid crystal polymers (LCP) alone or blended with other materials.

[0053] While the above discussion has focused on medical devices and methods for use within a patient's vasculature, it should be understood that other embodiments of medical devices or methods according to the present disclosure may be adapted and configured for use in other parts of a patient's anatomy. For example, devices and methods according to the present disclosure may be adapted for use in the digestive or gastrointestinal tract. Similarly, apparatus and / or medical devices described herein with respect to percutaneous deployment may also be used in other types of surgical procedures, as appropriate. For example, in some embodiments, a medical device may be deployed in a non-percutaneous procedure, such as an open-heart surgery.

[0054] It will be understood that this disclosure is in many respects merely illustrative. Changes may be made in details, particularly in matters of shape, size, and arrangement of steps, without exceeding the scope of the disclosure. This may include, to the extent appropriate, using any of the features of one illustrative embodiment in other embodiments. The scope of the disclosure is, of course, defined in the language of the appended claims.

Claims

1. 1. A device for permanent placement across an atrial appendage ostium of a patient, comprising: a support structure having a contracted delivery configuration and an expanded deployed configuration defining a radially expanded portion for permanently engaging an inner wall of the atrial appendage; a membrane attached to the support structure, the membrane configured to extend across an atrial appendage ostium when the support structure is in the expanded, deployed configuration; a polymer coating disposed on at least one of the support structure and the membrane, the polymer coating including a direct oral anticoagulant (DOAC) dispersed in the polymer; Devices that include:

2. 10. The device of claim 1, wherein the DOAC is apixaban, rivaroxaban, or edoxaban.

3. The device of claim 1 , wherein the polymer coating is disposed on the membrane.

4. 4. The device of claim 3, wherein the DOAC is present in the polymer coating in a ratio of polymer to DOAC of 60 / 40 to 90 / 10 weight / weight.

5. The device of claim 3, wherein the DOAC is present in the polymer coating in an amount of 10 to 10,000 μg.

6. The polymer coating has a membrane surface area of ​​1 mm ２ 4. The device of claim 3, comprising the DOAC at a coating density of 100 to 50,000 ng DOAC per capsule.

7. The device of claim 3, wherein the polymer is poly(vinylidene fluoride)-co-hexafluoropropylene and the polymer coating has a thickness of about 10-20 μm.

8. The device of claim 1 , wherein the polymer coating is disposed directly on the support structure.

9. The device of claim 8, wherein the DOAC is present in an amount of 100 to 300 μg.

10. The device of claim 1, wherein the polymer coating is a film having a thickness of 1 to 10 μm laminated onto the membrane.

11. The device of claim 10, wherein the film comprises 100 to 450 μg of DOAC.

12. The device of claim 10 , wherein the film comprises a plurality of pores.

13. The device of claim 12, wherein the plurality of pores are 20 to 150 μm.

14. 11. The device of claim 10, wherein the film comprises a base layer comprising the DOAC and a top layer comprising a modulating compound.

15. 1. A method of manufacturing an expandable device for permanent placement across a patient's left atrial appendage ostium, comprising: forming an expandable support structure having a contracted delivery configuration and an expanded deployed configuration defining a radially expanded portion sized to permanently engage the interior wall of the left atrial appendage; attaching a membrane onto at least a proximal end of the support structure; and applying a polymer coating to at least one of said support structure and said membrane, said polymer coating comprising a direct oral anticoagulant dispersed in the polymer; A method comprising:

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