Medical devices comprising therapeutic coatings for topical delivery of direct anticoagulants

Abstract

A medical device may be coated with a therapeutic composition comprising a direct oral anticoagulant. An exemplary drug coating composition may include an excipient including polylactic acid (PLA), poly (lactic acid-co-glycolic acid) (PLGA), or poly (vinylidene fluoride-co-hexafluoropropylene (PVDF-HFP), and a direct oral anticoagulant (DOAC). An exemplary pharmaceutical coating may be applied to an exterior surface of a medical device.

Description

Cross-references to related applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 579,191, filed August 28, 2023, and U.S. Provisional Patent Application Serial No. 63 / 458,731, filed April 12, 2023, the entire disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to medical devices, and more specifically to medical devices comprising a therapeutic coating for local delivery of a direct-acting anticoagulant. Background Technology

[0003] A wide variety of medical devices have been developed for medical applications, such as intravascular / cardiac uses. Some of these devices include guidewires, catheters, balloons, stents, etc. These devices are manufactured using any of a variety of different manufacturing methods and can be used according to any of these methods. Some of these medical devices may include therapeutic agents. Each of the known medical devices and methods has certain advantages and disadvantages. There has always been a need for alternative medical devices and alternative methods for manufacturing and using these devices. This may include the formation of therapeutic agents for the local delivery of direct anticoagulants. Summary of the Invention

[0004] This disclosure relates to medical devices, and more specifically to medical devices comprising a therapeutic coating having local activity and bioabsorbability in a reversible thermogelling excipient (reversible thermosensitive excipient).

[0005] In the first example, the drug coating composition may include an excipient and a direct oral anticoagulant (DOAC), said excipient comprising polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), or poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP).

[0006] As an alternative to or supplement to any of the above examples, in another example, DOAC could be apixaban, rivaroxaban, or edoxaban.

[0007] As an alternative to or supplement to any of the above examples, in another example, DOAC may be present in the pharmaceutical coating composition in the range of about 5% by weight to about 40% by weight.

[0008] As an alternative to or supplement to any of the above examples, in another example, DOAC may be present in the pharmaceutical coating composition in an amount of 100-4000 nanograms per square millimeter.

[0009] As an alternative to or supplement to any of the above examples, in another example, the pharmaceutical coating composition may further comprise an antiproliferative agent.

[0010] As an alternative to or supplement to any of the above examples, in another example, the antiproliferative agent may include one or more of paclitaxel, everolimus, sirolimus, and rapamycin.

[0011] As an alternative to or supplement to any of the above examples, in another example, the pharmaceutical coating composition may further include an antioxidant.

[0012] In another example, the balloon catheter may include an elongated shaft, an inflatable balloon coupled to a distal portion of the elongated shaft, and a drug-coated composition disposed on the outer surface of the inflatable balloon. The drug-coated composition may contain excipients and a direct oral anticoagulant (DOAC).

[0013] As an alternative to or supplement to any of the above examples, in another example, the excipient may comprise polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA).

[0014] As an alternative to or supplement to any of the above examples, in another example, DOAC could be rivaroxaban.

[0015] As an alternative to or supplement to any of the above examples, in another example, the excipient may comprise about 60 to 95% by weight of the pharmaceutical coating composition, and DOAC may comprise about 5 to 40% by weight of the pharmaceutical coating composition.

[0016] As an alternative to or supplement to any of the above examples, in another example, the pharmaceutical coating composition may further comprise an antiproliferative agent.

[0017] As an alternative to or supplement to any of the above examples, in another example, the antiproliferative agent may include one or more of paclitaxel, everolimus, sirolimus, and rapamycin.

[0018] As an alternative to or supplement to any of the above examples, in another example, an antiproliferative agent may be provided as a second layer.

[0019] As an alternative to or supplement to any of the above examples, in another example, the excipient may further comprise ethyl cellulose or acetylated tributyl citrate (ATBC).

[0020] In another example, the stent may include an elongated tubular body having a strut frame and a drug coating composition disposed on the outer surface of the strut frame. The drug coating composition may contain excipients and a direct oral anticoagulant (DOAC).

[0021] As an alternative to or supplement to any of the above examples, in another example, the excipient may comprise poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP).

[0022] As an alternative to or supplement to any of the above examples, in another example, DOAC could be rivaroxaban.

[0023] As an alternative to or supplement to any of the above examples, in another example, the excipient may comprise about 55-95% by weight of the pharmaceutical coating composition, and DOAC may comprise about 5-45% by weight of the pharmaceutical coating composition.

[0024] As an alternative to or supplement to any of the above examples, in another example, the pharmaceutical coating composition may further comprise an antiproliferative agent.

[0025] As an alternative to or supplement to any of the above examples, in another example, the stent may also include a surface coating disposed above the drug-coated composition, the surface coating being free of therapeutic agents.

[0026] As an alternative to or supplement to any of the above examples, in another example, the surface coating may contain PVDF-HFP.

[0027] In another example, a method for manufacturing a pharmaceutical coating composition may include: dissolving polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) and rivaroxaban in a mixture of dichloromethane and dimethylformamide to form a first solution; adding the first solution to an aqueous solution of poly(vinyl acid) (PVA) while mixing to form a bead solution; filtering the bead solution to collect a plurality of microspheres; and drying the plurality of microspheres.

[0028] As an alternative to or supplement to any of the above examples, in another example, PLA or PLGA and rivaroxaban can be dissolved at a ratio of about 85 to 95% by weight of PLA or PLGA to about 5 to about 15% by weight of rivaroxaban.

[0029] As an alternative to or supplement to any of the above examples, in another example, the mixture of dichloromethane and dimethylformamide may be about 75% by weight of dichloromethane and about 25% by weight of dimethylformamide.

[0030] As an alternative or supplement to any of the above examples, in another example, the PVA aqueous solution may be approximately 2% PVA.

[0031] As an alternative to or supplement to any of the above examples, in another example, the method may further include adding the bead solution to a 0.1% PVA aqueous solution and mixing for a first time period.

[0032] As an alternative or supplement to any of the above examples, in another example, the first time period can be in the range of about 1 hour to about 3 hours.

[0033] As an alternative to or supplement to any of the above examples, in another example, drying the plurality of microspheres may include drying the microspheres under vacuum at room temperature for a second time period.

[0034] As an alternative or supplement to any of the above examples, in another example, the second time period can be in the range of about 2 days to about 4 days.

[0035] The foregoing description of some implementations is not intended to describe every disclosed implementation or every embodiment of this disclosure. The following figures and detailed descriptions illustrate these implementations in more detail. Brief description of the attached figures

[0036] This disclosure can be more fully understood in conjunction with the following detailed description of the embodiments, in conjunction with the accompanying drawings, in which:

[0037] Figure 1 This is a schematic side view of an exemplary drug delivery balloon catheter.

[0038] Figure 2 It is along Figure 1 A cross-sectional view of the catheter-based balloon taken from line 2-2.

[0039] Figure 3 An exemplary drug-coated scaffold in a contraction or delivery configuration is depicted.

[0040] Figure 4 An exemplary drug-coated scaffold in an expanded or deployed configuration is depicted.

[0041] Figure 5 A drug coating is schematically depicted along the outer surface or the distal lumen side surface of an exemplary drug-coated stent.

[0042] Figure 6 The drug coating is schematically depicted along the inner surface or near-nuclear side surface of an exemplary drug-coated stent.

[0043] Figure 7 The illustration schematically depicts a drug coating disposed along the outer surface or distal lumen side surface of an exemplary drug-coated stent and along the inner surface or proximal lumen side surface of an exemplary drug-coated stent.

[0044] Figure 8 It is a graphical representation of experimental data.

[0045] Figure 9It is a graphical representation of experimental data.

[0046] Figure 10 It is a graphical representation of experimental data.

[0047] While the embodiments are readily adaptable to various modifications and alternatives, their details have been illustrated by way of example in the accompanying drawings and will be described in detail. Nevertheless, it should be understood that the invention is not limited to the specific embodiments described. Rather, it is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of this disclosure. Detailed Implementation

[0048] The following definitions shall apply to terms unless otherwise defined in the claims or elsewhere in this specification.

[0049] Whether explicitly stated or not, all numerical values ​​herein are considered to be modified by the term "approximately". The term "approximately" generally refers to a range of numbers that a person skilled in the art would consider equivalent to the value stated (e.g., having the same function or result). In many cases, the term "approximately" may include numbers rounded to the nearest significant figure.

[0050] The range of values ​​listed by endpoints includes all values ​​within that range (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0051] As used in this specification and the appended claims, the singular forms “a” and “the”, and where no quantifier is used, include plural indicators, unless otherwise expressly stated. As used in this specification and the appended claims, the term “or” is generally used in the sense that it includes “and / or”, unless otherwise expressly stated.

[0052] Note that references to "one embodiment," "some embodiments," "other embodiments," etc., in the specification indicate that the described embodiment may include one or more specific features, structures, and / or characteristics. However, such descriptions do not necessarily mean that all embodiments include that specific feature, structure, and / or characteristic. Furthermore, when a specific feature, structure, and / or characteristic is described in conjunction with an embodiment, it should be understood that these features, structures, and / or characteristics may also be used in conjunction with other embodiments, whether explicitly described or not, unless explicitly stated otherwise.

[0053] The following detailed description should be read with reference to the accompanying drawings, in which similar elements in different drawings are numbered the same. The drawings (which are not necessarily to scale) depict illustrative embodiments and are not intended to limit the scope of the invention.

[0054] In the United States, deep vein thrombosis (DVT) of the lower extremities may affect up to 900,000 people annually. DVT can be divided into three distinct phases: the acute phase, the subacute phase (the onset of post-thrombotic syndrome (PTS), and the chronic phase (PTS). During the acute phase, damaged endothelial cells may express tissue factor, release von Willebrand factor and P-selectin, and produce E-selectin, all of which promote and enhance coagulation. Enhanced coagulation can lead to an increased inflammatory response. The subacute phase sees a maximum influx of monocytes, leading to thrombolysis and an inflammatory response driven by reduced flow and oxygenation. When thrombolysis is inhibited, circulating progenitor cells can damage the venous wall. The chronic phase is described as the point in time when the thrombus is predominantly composed of collagen and has a high monocyte count. At this point, venous outflow is obstructed or restricted due to defective fibrinolysis and incomplete, inappropriate revascularization.

[0055] Approximately 25-50% of patients with proximal deep vein thrombosis (DVT) continue to develop peripheral venous thrombosis (PTS). PTS is likely caused by fibrotic tissue obstructing the normal path of blood flow through the vessels. Due to this obstruction, blood pools in the veins, leading to impaired venous function and unhealthy pressure levels within the vein walls. Symptoms and complications of PTS include, but are not limited to, leg swelling (edema), throbbing pain in the legs, dry skin, skin discoloration, heaviness and fatigue in the legs, ulcers, recurrent thrombosis, and a generalized decrease in quality of life. In some cases, PTS can be debilitating. PTS may result from venous hypertension, which can be a consequence of valvular dysfunction leading to valvular regurgitation and persistent partial venous occlusion.

[0056] Coagulation factor Xa (FXa) is a serine protease involved in the coagulation cascade and the expression of various inflammatory cytokines, such as IL-6. FXa is known to activate prothrombin to thrombin, ultimately leading to the formation of cross-linked blood clots. Furthermore, FXa is also associated with inflammation through protease-activated receptors. Drugs that directly bind to and inhibit factor Xa (e.g., but not limited to direct oral anticoagulants (DOACs), such as rivaroxaban and apixaban) are highly effective in preventing thrombosis in patients with atrial fibrillation (A-fib) and deep vein thrombosis (DVT) by reducing the risk of recurrent DVT. Moreover, clinical studies have shown that oral rivaroxaban significantly reduces the risk of prothromboembolic syndrome (PTS). This may be partly attributed to the anti-inflammatory properties of rivaroxaban. Clinical data suggest that anticoagulation therapy can reduce the risk of PTS by up to 78%. The risk of PTS can be reduced by up to 54% in patients treated with DOACs compared to those treated with conventional anticoagulants such as warfarin.

[0057] Mechanistically, in human aortic endothelial cells, FXa stimulation increases the expression of inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesion molecules (all of which can be reversed by combination therapy with DOACs (e.g., rivaroxaban)). Furthermore, FXa can promote the proliferation and migration of vascular smooth muscle cells, which can be blocked in the presence of DOACs. Elevated levels of inflammatory cytokines such as interleukin-6 (IL-6) are associated with the development of PTS. Inflammation may play a role in promoting PTS by delaying thrombolysis and by inducing venous wall fibrosis (promoting valvular regurgitation). Studies using a mouse DVT model have shown that mice treated with anti-IL-6 exhibited less thrombus weight, a 44% reduction in intimal wall thickness, and a 30% reduction in venous wall collagen formation compared to controls.

[0058] Patients with persistent venous occlusion (PTS) may frequently be treated with bare-metal stents. While patency after stent placement can be quite good, in-stent restenosis is a common problem. Analysis of in-stent restenosis in PTS patients suggests that stenosis can occur through a thrombotic process, with the thrombus eventually transforming into intimal hyperplasia and progressing. Therefore, it may be desirable to provide stents with a therapeutic coating that can reduce the risk of PTS.

[0059] Further anticipation may include providing inflatable balloons with therapeutic coatings that can reduce thrombus formation and / or growth. For example, there may be a need to deliver medications or therapeutic agents to pathways within the body, such as, but not limited to, natural blood vessels, stent vessels, and body lumens. These pathways sometimes become occluded (e.g., by tumors, thrombi, atherosclerotic plaques, etc.). To widen occluded blood vessels, balloon catheters can be used, for example, in angioplasty. In some embodiments, the balloon catheter may comprise an inflatable and retractable balloon carried by a long, narrow catheter body. The balloon may initially be folded around the catheter body to reduce the radial profile of the balloon catheter for easy insertion into the body. During use, the folded balloon is delivered to a target location in the blood vessel, such as a plaque-occluded portion, by passing the balloon catheter through a guidewire previously located in the vessel. The balloon is then inflated, for example, by introducing fluid (such as gas or liquid) into the interior of the balloon. Inflating the balloon causes radial expansion of the vessel, allowing for increased blood flow rates. After use, the balloon is typically deflated and removed from the body. In some cases, it may be desirable to coat, layer, or otherwise apply a drug or therapeutic agent to the outer surface of the balloon to deliver and / or administer the drug or therapeutic agent to the inner wall of the lumen during balloon inflation. During deployment (e.g., balloon inflation), the coating containing the drug or therapeutic agent may break down into particles. Some of these particles may partially deposit on the inner surface of the blood vessel.

[0060] Although the therapeutic coatings described herein are discussed in relation to balloons, balloon catheters, and stents, it is contemplated that therapeutic coatings can be applied to and / or used in combination with other medical devices, such as, but not limited to, embolization filters, implantable devices, therapeutic devices, etc.

[0061] The medical device disclosed herein can deliver a direct oral anticoagulant (DOAC) onto its surface. The device can then be delivered to the site where local treatment is required. This can offer the advantage of reducing the potential side effects of systemic oral anticoagulant (OAC) therapy. This can be achieved by incorporating the DOAC into a polymer coating disposed on one or more portions of the medical device (e.g., but not limited to balloons or stents).

[0062] Unlike conventional anticoagulants (such as heparin and warfarin) that inhibit various cofactors in the internal and external coagulation cascades and can lead to serious systemic adverse effects, the class of anticoagulants known as direct oral anticoagulants (DOACs) binds directly to specific coagulation factors. Examples of DOACs include apixaban, rivaroxaban, edoxaban, dabigatran, betroxaban, and argatroban, which directly bind to factor Xa, and dabigatran, which directly binds to factor IIa (thrombin). The medical devices disclosed herein provide a means of achieving local release of these DOACs at the device surface.

[0063] Figure 1 This is a schematic side view of the drug delivery balloon catheter 10. A cross-sectional view of the drug delivery balloon catheter 10 is shown in... Figure 2 In the depicted embodiment, catheter 10 may include an elongated shaft 12, an inflatable balloon 14 coupled to or coupled to a distal portion 16 of shaft 12, and other components. The elongated shaft 12 may include a tubular member having a proximal portion 18 and one or more lumens extending between the proximal portion 18 and the distal portion 16. The elongated shaft 12 may be configured to have a substantially circular cross-section; however, it may be configured to have other suitable cross-sectional shapes, such as elliptical, oval, polygonal, irregular, etc. Additionally, the elongated shaft 12 may be flexible along its entire length or adapted to bend only along a portion of its length. The desired degree of flexibility of the elongated shaft 12 may be predetermined based on its intended navigation to a target vascular channel and the amount of inertial force required to advance the elongated shaft 12 through the vascular channel. The catheter 10 may be configured as an over-the-wire (OTW) catheter, a single-operator exchange (SOE) catheter, a fixed-wire catheter, and / or similar types.

[0064] The cross-sectional dimensions of the elongated shaft 12 can be varied depending on the desired application. Typically, the cross-sectional dimensions of the elongated shaft 12 can be designed to be smaller than the size of a typical blood vessel in which the catheter 10 will be used. The length of the elongated shaft 12 can vary depending on the location of the vascular access required for drug delivery. In some cases, a 6F or 5F catheter can be used as the elongated shaft 12, where "F" is also known as the French catheter scale and is a unit for measuring catheter diameter (1F = 1 / 3 millimeter (mm)). Additionally, the elongated shaft 12, or a portion thereof, can be selectively manipulated. If desired, mechanisms such as drawstrings and / or other actuators can be used to selectively manipulate the elongated shaft 12.

[0065] The proximal portion 18 of the elongated shaft 12 may include a handle 20, which can be used to manually move the distal portion 16 of the elongated shaft 12. The handle 20 may include one or more ports for introducing any suitable medical device, fluid, or other intervention. For example, the handle 20 may include a guidewire port communicating with the guidewire lumen 22 (in the resection portion at the distal end of the catheter 10 and also in…) Figure 2 As shown in the diagram, the guidewire lumen 22 can be used to introduce a guidewire of appropriate thickness into the elongated shaft 12, which can guide the elongated shaft 12 to a target location inside the artery. Furthermore, the handle 20 may include an inflation port configured to connect to an inflation fluid source for delivering inflation fluid through the inflation lumen of the catheter shaft 12 to an inflatable balloon 14. In some embodiments, the elongated shaft 12 may include one or more additional lumens, which may be configured for various purposes, such as delivering medical devices or for providing fluid (e.g., saline) to a target location.

[0066] The inflatable balloon 14 can be operatively coupled to or attached to the distal portion 16 of the elongated shaft 12. Specifically, the proximal portion or waist 24 of the inflatable balloon 14 can be secured to the distal portion 16 of the elongated shaft 12, such as the outer tubular member 26 of the elongated shaft 12. Furthermore, the distal portion or waist 28 of the inflatable balloon 14 can be secured to the distal portion 16 of the elongated shaft 12, such as the inner tubular member 30 extending through the outer tubular member 26 of the elongated shaft 12. Suitable securing methods can be used to join the two structures as needed, including but not limited to adhesive bonding, thermal bonding (e.g., hot clamping, laser welding, etc.) or other bonding techniques. The inflatable balloon 14 can be configured to expand from a constricted state to an inflated state by delivering an inflatable fluid (e.g., saline) through an inflatable lumen passing through the catheter shaft 12. The balloon 14 can contract during the insertion of the catheter into the patient's body, and once the balloon 14 reaches the target site inside the body's blood vessels, the balloon 14 can inflate.

[0067] The inflatable balloon can be manufactured or otherwise formed from any suitable material, including polymeric materials such as polyamide, polyether block amide (PEBA), polyester, nylon, etc. As shown in the exemplary embodiment, the inflatable balloon 14 can have a generally cylindrical construction with a circular cross-section. However, in other embodiments, the inflatable balloon 14 can have another suitable construction or shape if desired.

[0068] The inflatable balloon 14 may include a balloon wall 32 to which a drug coating 34 is disposed. In some cases, the drug coating or coating composition 34 may include a DOAC, such as, but not limited to, rivaroxaban, as will be described in more detail herein. The drug coating 34 may be disposed along substantially the entire length and / or circumference of the balloon 14 or along one or more portions of the balloon 14. For example, the drug coating 34 may be disposed along the central portion or body portion of the balloon 14. The drug coating 34 disposed on the balloon 14 / balloon wall 32 may have an average thickness, for example, ranging from about 1 micrometer (μm) to about 50 μm.

[0069] Figure 3-4 Depicting structures in contraction or delivery ( Figure 3 ) or in an expansion or deployment structure ( Figure 4 An exemplary drug-coated stent 110 is shown. Typically, the stent 110 can be delivered to a suitable target area via a catheter / delivery system while in a contractile configuration. Upon reaching the target area, the stent 110 can expand or be expanded into an expandable configuration. The stent 110 can be self-expanding (e.g., the stent 110 can be formed of a shape memory material such as nitinol) or it can be balloon expandable. When the stent 110 is self-expanding, the stent 110 can be held / constrained in a contractile configuration during delivery and then unconstrained to allow the stent 110 to expand (e.g., self-expand) into an expandable configuration. When the stent 110 is balloon expandable, the stent 110 can be constrained and coiled onto a delivery device / catheter and then expand at or near the target area (e.g., via an expandable member or balloon).

[0070] The support 110 may include an elongated tubular body having a strut frame 136. The strut frame 136 may define one or more peak or vertex regions 138 and / or one or more connecting regions 140. Intermediate regions 142 may interconnect the vertex regions 138 and / or the connecting regions 140. In some cases, the support 110 may be formed by cutting (e.g., laser cutting) the tube. In this case, the structural arrangement of the vertex regions, connecting regions 140, and / or intermediate regions 142 may be determined by the cutting pattern. It is understood that a wide variety of patterns / arrangements may be used for the support 110. In other cases, the support 110 may be a woven or braided support, a support formed from a flat sheet of material that is rolled into a support mold, molded, cast, etc.

[0071] The drug coating or paint composition 134 may be disposed along the support frame 136. For example, Figure 5 A drug coating 134 is schematically depicted along the outer surface or distal lumen side surface 144 of the stent 110 (e.g., along the outer surface or distal lumen side surface 144 of the strut frame 136). Figure 6 A drug coating 134 is schematically depicted along the inner surface or near-nuclear side surface 146 of the stent 110 (e.g., along the inner surface or near-nuclear side surface 146 of the strut frame 136). Figure 7 A drug coating 134 is schematically depicted along both the outer surface or distal lumen side surface 144 of the stent 110 and the inner surface or proximal lumen side surface 146 of the stent 110 (e.g., along both the outer surface or distal lumen side surface 144 and the inner surface or proximal lumen side surface 146 of the strut frame 136). Although not explicitly shown, in some examples, the drug coating 134 may additionally or alternatively be disposed along the lateral side of the strut frame 136, the lateral side extending between the outer surface or distal lumen side surface 144 and the inner surface or proximal lumen side surface 146. It should be noted that Figure 5-7 Cross-sectional views are intended to schematically represent a portion (e.g., a single region or section of the strut) of the strut frame 136. In these views, the strut frame 136 is drawn in a partially arcuate shape. This is intended to correspond to the generally cylindrical shape of the stent 110, for example, when the stent 110 is in an expanded configuration. In some cases, the drug coating 134 may include a DOAC, such as, but not limited to, rivaroxaban, as will be described in more detail herein. The drug coating 134 disposed on the strut frame 136 may have an average thickness, for example, ranging from about 1 μm to about 50 μm.

[0072] The terms “therapeutic agent,” “drug,” “bioactive agent,” “pharmaceutical,” “pharmaceutical active agent,” and other related terms are used interchangeably herein and include genetic therapeutic agents, non-genetic therapeutic agents, and cells. Therapeutic agents can be used alone or in combination. The devices of the present invention can use various therapeutic agent loadings, wherein the pharmaceutically effective amount is readily determined by those skilled in the art and ultimately depends on, for example, the condition to be treated, the nature of the therapeutic agent itself, the tissue to which the dosage form is introduced, etc.

[0073] Drug coatings 34 and 134 may include therapeutic agents containing DOACs, such as, but not limited to, apixaban, rivaroxaban, edoxaban, dabigatran, betroxaban, and argatroban. However, other beneficial therapeutic agents may include, but are not limited to, antithrombotic agents, antiproliferative agents, anti-inflammatory agents, antimigration agents, agents affecting extracellular matrix production and tissues, antitumor agents, antimitotic agents, anesthetics, anticoagulants, angiocyte growth promoters, angiocyte growth inhibitors, cholesterol lowering agents, vasodilators, and agents that interfere with endogenous vasoactivity mechanisms.

[0074] More specific drugs or therapeutic agents include paclitaxel, rapamycin, sirolimus, everolimus, tacrolimus, heparin, diclofenac, aspirin, Epo D, dexamethasone, estradiol, halofoponone, cilostazol, geldmycin, ABT-578 (Abbott Laboratories), tramidil, liprostin, actinomycin D, Resten-NG, Ap-17, abciximab, clopidogrel, lidogre, beta-blockers, bARKct inhibitors, phospholamban inhibitors and SERCA 2 gene / protein, imiquimod, imiquimod (and other imidazoquinoline immunomodulators), human apolipoproteins (e.g., AI, AII, AIII, AIV, AV, etc.), vascular endothelial growth factor (e.g., VEGF-2), and derivatives thereof, and / or combinations thereof.

[0075] In some embodiments, the drug may be a macrolide immunosuppressant (mustard). In some embodiments, the macrolide immunosuppressant is rapamycin, biolimus A9, 40-O-(2-hydroxyethyl)rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl)benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4(S)-yl)-propyl-2'-en-1'-yl]-rapamycin, (2':E,4'S)-40-O-(4',5'-dihydroxypentan-2'-en-1'-yl)-rapamycin, 40-O-(2-hydroxy)ethoxycarbonylmethyl -Rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-(6-hydroxy)hexyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-dimethyldioxolane-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxypropyl-1-yl]-rapamycin, 40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2-nicotinoxy)ethyl-rapamycin, 40-O-(2-(N-morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-imidazole (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin, 42-O-demethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-methylrapamycin, 40-O-(2-aminoethyl)-rapamycin, 40-O-(2-ethylaminoethyl)-rapamycin, 40-O-(2-nicotinamide ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazol-2'-methylformamide)ethyl)-rapamycin, 40-O-(2-ethylaminoethyl)-rapamycin, 40-O-(2-ethylaminoethyl)-rapamycin, 40-O-(2-nicotinamide ethyl)-rapamycin, 40-O-(2-ethylamino ... (Oxycarbonylaminoethyl)-rapamycin, 40-O-(2-toluenesulfonylaminoethyl)-rapamycin, 40-O-[2-(4',5'-diethoxycarboxyl-1',2',3'-triazol-1'-yl)-ethyl]-rapamycin, 42-epi-(tetrazolyl)rapamycin (tacrolimus) and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropionate]rapamycin (tesimolimus), (42S)-42-deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotamox), or derivatives thereof, isomers, racemates, diastereomers, prodrugs, hydrates, esters or analogs thereof.Other medications may include anti-inflammatory agents such as dexamethasone, prednisolone, corticosteroids, budesonide, estrogens, sulfasalazine, mesalazine, and their analogues; antitumor / antiproliferative / antimiotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vincristine, epoch-forming alkaloids, endostatin, angiostatin, thymidine kinase inhibitors, and their analogues; anesthetics such as lidocaine, bupivacaine, ropivacaine, and their analogues; anticoagulants; and growth factors.

[0076] In some cases, drug-coated medical devices 10, 110 with a localized, continuous delivery of a drug coating 34, 134 providing a direct anticoagulant can reduce the risk of venous occlusion (e.g., but not limited to thrombosis) and can block the stimulation of inflammatory cytokines, which can reduce fibrosis and intimal thickening. For example, the drug-coated medical devices 10, 110 described herein use direct oral anticoagulants (DOACs) (which are typically administered orally and systemically) and deliver them only to the surface of the device where they are needed, thus providing the advantage of reducing the potential side effects of systemic OAC therapy. Drug-coated medical devices 10, 110 with a drug coating 34, 134 can be used to treat persistent venous occlusion by preventing thrombosis and intimal thickening. It is anticipated that drug-coated medical devices 10, 110 can be delivered to the treatment site immediately after DVT removal, to the site of persistent venous occlusion, etc.

[0077] In some cases, rivaroxaban can be the drug used. Rivaroxaban, also known as (S)-5-chloro-N-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide, has the following chemical structure:

[0078] In some cases, drug coatings 34, 134 may comprise individual drug particles encapsulated with one or more excipients. For example, the drug particles may comprise crystals of a drug. Drug crystals can be formed in various ways. In some cases, the drug or other therapeutic agent may be obtained in an amorphous form, and various methods may be used to convert amorphous drugs or other therapeutic agents into crystalline drugs or other therapeutic agents. In other examples, the therapeutic agent may be obtained in crystalline form. In still other examples, the therapeutic agent may be transformed into crystals during the preparation and application of drug coatings 34, 134. However, in some cases, individual drug particles do not need to be encapsulated.

[0079] Medical devices 10, 110, or portions thereof, may be coated with therapeutic compositions 34, 134. As an example, the therapeutic composition may include one or more therapeutic agents, such as, but not limited to, rivaroxaban. Rivaroxaban crystals may be mixed with, dispersed in, or coated with excipients or mixtures of excipients. Excipients may be used to enhance the durability of the drug coatings 34, 134, facilitate drug transfer to the treatment site, and / or control drug dissolution. In some embodiments, one or more additional therapeutic agents may be provided in addition to rivaroxaban. For example, paclitaxel may be added to the therapeutic composition. In other examples, paclitaxel may be provided as a separate therapeutic composition in a separate layer. In some cases, medical devices 10, 110, or portions thereof may be contacted with the coating composition to form a coating on the medical device. In some cases, medical devices 10, 110, or portions thereof may be immersed in the coating composition. In some cases, vapor deposition may be used to transfer the coating composition to medical devices 10, 110. In some cases, a roller coating process can be used to transfer the coating composition to medical devices 10, 110. These are just examples. In some cases, the coating composition can be sprayed onto medical devices 10, 110, or onto specific portions or areas of medical devices 10, 110.

[0080] For example, when the medical device 10 includes an inflatable balloon 14, the coating composition can be sprayed onto at least a portion of the outer surface of the inflatable balloon 14 to enable subsequent transfer of at least a portion of the drug coating 34 to the vessel wall. Alternative coating methods, such as dip coating, roller coating, syringe coating, vapor deposition, etc., and / or other suitable coating methods, can be used. Applying the coating composition to other parts of the medical device (e.g., the balloon catheter shaft) may offer little or no benefit, as the balloon catheter shaft, for example, may at most come into accidental contact with the vessel wall.

[0081] For example, when the medical device 10 is or includes an expandable stent 110, a coating composition can be sprayed onto at least a portion of the outer surface 144 of the expandable stent 110 to enable subsequent direct delivery of at least a portion of the medication to the vessel wall. When the coating composition 134 is deposited on the outer surface of the expandable stent 110, it can remain in apposition to the tissue to be treated. It may be beneficial to elute at least a portion of the medication into the blood flowing through the expandable stent, as this can provide a local therapeutic dose of medication across the vessel wall between the stent struts and downstream of the deployment location of the expandable stent 110. Therefore, the coating composition can be applied to the inner surface 146 and / or the lateral sidewalls of the expandable stent 110.

[0082] In addition to the therapeutic agent, the coating compositions 34 and 134 may also include one or more excipients. Excipients may be used to enhance the durability of the drug coatings 34 and 134, facilitate drug delivery to the lesion, and / or control drug dissolution. It is anticipated that the inflatable balloon 14 and stent 110 may require different excipients due to differences in use. For example, the inflatable balloon 14 may require an excipient that facilitates the transfer of the coating composition 34 from the balloon 14 to the vessel wall, while the coating composition 134 of the stent 110 can be retained thereon. Exemplary excipients may include poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP), which can be formed as a porous membrane. PVDF-HFP has the following chemical structure:

[0083] Another exemplary excipient may include acetylacetic acid tributyl ester (ATBC), which in some cases may be referred to by its IUPAC name 2-acetoxypropane-1,2,3-tricarboxylic acid tributyl ester. ATBC has the following chemical structure:

[0084] Another exemplary excipient may include polylactic acid (PLA). PLA has the following chemical structure:

[0085] Other exemplary excipients may include, but are not limited to, tributyl acetylglucosyl citrate (ATHC), poly-DL-lactide (PDLLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly(lactic-co-glycolic acid) (PLGA), etc. The expected release rate of rivaroxaban may increase or decrease based on the degradation rate of the excipient. For example, PLGA may degrade faster than PLA. The release rate of rivaroxaban can be increased by using a faster-degrading polylactide / glycolic acid copolymer (PLGA). Release from PLGA can be controlled by adjusting the ratio of lactide to glycolide and the polymer molecular weight.

[0086] ATBC can be a plasticizer or phthalate that helps retain drug particles on balloon 14 before deployment, facilitates translocation to blood vessels during balloon deployment, and slows the dissolution of the therapeutic agent. In some examples, additional components may also be used in coating compositions 34, 134. In some cases, antioxidants, such as, but not limited to, butylated hydroxytoluene (BHT), may be used in the composition.

[0087] One challenge in formulating rivaroxaban-based drug-coated balloons is the relatively high water solubility of rivaroxaban compared to paclitaxel and olimus-based drug-coated balloons. Crystalline paclitaxel and everolimus are both soluble in water, ranging from approximately 0.2–0.5 micrograms (μg) of drug per milliliter (mL) of water. Crystalline rivaroxaban is soluble in water, ranging from approximately 3 μg of drug per mL of water. It can be seen that the water solubility of crystalline rivaroxaban is approximately 10 times that of paclitaxel and everolimus. This may pose a challenge to formulating rivaroxaban-based drug-coated balloons with sustained tissue release using excipients used in many existing drug-coated balloons.14 For example, rivaroxaban drug-coated balloons using ATBC or ethyl cellulose as excipients have shown rapid drug dissolution in in vitro drug release tests.

[0088] In one illustrative example, the drug coating 34 may include PLA as an excipient. A therapeutic agent (e.g., but not limited to, an anticoagulant, such as a direct oral anticoagulant (DOAC) (e.g., rivaroxaban)) may be contained within microspheres of PLA or another biodegradable polymer. The size of the microspheres may range from about 1 μm to about 20 μm in diameter. The microspheres may contain about 5% to about 45% by weight of the therapeutic agent and about 55% to about 95% by weight of PLA. In some examples, ATBC may be provided in the drug coating as an additional excipient to help anchor the microspheres to the vessel wall during deployment of the inflatable balloon 14. In other examples, polydopamine may be provided as an additional excipient in the drug coating 34 to help anchor the microspheres to the vessel wall during device placement of the inflatable balloon 14. For example, the microspheres may be coated with polydopamine. Exemplary polydopamine coatings are described in commonly assigned U.S. Patent Publication No. 2016 / 0331564 entitled DRUG COATED MEDICAL DEVICES, the disclosure of which is incorporated herein by reference.

[0089] In another example, the drug coating 134 may include a blood-compatible polymer, such as, but not limited to, poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP), and a therapeutic agent, such as an anticoagulant, like a direct oral anticoagulant (DOAC). In some examples, the PVDF-HFP may have an 85 / 15 VDF to HFP ratio. However, this is not required. Other ratios may be used as needed. The therapeutic agent may form crystalline particles within the continuous PVDF-HFP matrix. The resulting drug coating 134 may be applied to the surface of the stent 110 to act as a drug depot for sustained local release.

[0090] The expected surface area of ​​stent 110 and / or the duration of in-situ placement of device 110 can at least partially determine the time it takes for the drug coating 134 to release the drug. For example, a stent 110 implanted in the body can release the drug for a longer period than a balloon that temporarily inflates and transfers the drug coating 34 to the vessel wall. In some cases, the surface area of ​​devices 14, 110 can be adjusted to provide the desired duration of drug release. For example, the number of struts in strut frame 136 can be increased to increase the surface area of ​​stent 110, thereby increasing the volume of the drug coating (and therefore the drug) that can be placed on stent 110. Alternatively or additionally, the surface area of ​​stent 110 can be increased by providing a stent cover on the outer and / or inner surface of stent 110. If provided in this way, the stent cover can cover the entire stent 110 or one or more portions thereof. In some examples, the size and shape of stent 110 can be designed to provide the ability to be constructed in a drug reservoir to provide long-duration (e.g., about 1 year) release of DOACs and other drugs for local treatment of PTS and other vascular diseases.

[0091] In one embodiment, the polymer coating (e.g., PVDF-HFP) and one or more DOACs are dissolved in a solvent suitable for dissolving the polymer and the drug. In some examples, the solvent may be a blend of acetone and N,N-dimethylformamide (DMF). However, other solvents may be used, such as, but not limited to, N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP). The solution may be applied directly to the stent 110 by dip coating or spray coating processes. Spray coating may result in the drug coating 134 being applied to only one surface of the stent 110, although this is not necessary. It is anticipated that the entire stent 110 may be coated with the drug coating 134. In other examples, less than the entire stent 110 may be coated with the drug coating 134. The drug coating 134 may be applied to achieve 100-4000 nanograms (ng) of drug per square millimeter (mm) on the surface of the stent 110. 2The drug coating density (based on vessel surface area) is specified. The drug coating may comprise approximately 5% to approximately 45% by weight of a therapeutic agent and approximately 55% to approximately 95% by weight of PVDF-HFP. It is anticipated that a significantly thicker coating compared to the coated balloon 14 can be achieved when the drug coating 134 is disposed on the stent 110. The thickness of the drug coating 34 on the balloon 14 may be limited due to the effects of folding and deployment of the balloon 14 during loading and deployment. A thicker drug coating 34 on the balloon 14 may rupture and peel off or hinder the folding and deployment process. The drug coating 134 on the stent 110 can have a thickness of up to 10 μm and can achieve an anticoagulant content in the range of approximately 100-300 micrograms (μg) on ​​the stent 110. The significantly thicker coating on the stent 110 and the increased contact time compared to the balloon 14 or the thinner drug coating 34, 134, can result in a longer drug release time. In another example, the amount of drug contained in the coated or stent 110 device may be approximately 100-4000 ng / mm². 2 The drug coating 134, which includes PVDF-HFP and DOAC (such as rivaroxaban), is expected to release approximately 40-80% of the therapeutic agent within approximately 7-60 days after implantation of the device 110.

[0092] In another example, a DOAC (e.g., rivaroxaban) can be dissolved in a solvent and a polymeric excipient. The subsequent mixture can then be deposited onto the scaffold 110 by spraying or dip coating. A drug-free polymer topcoat can be deposited on the drug coating 110 to further modulate the drug release rate. In some examples, the polymer topcoat may include PVDF-HFP. Increasing the weight percentage of the polymer topcoat relative to the weight of the drug coating 134 is expected to slow the release of the therapeutic agent.

[0093] It is anticipated that when the drug coating 34 is applied to the balloon 14, the DOAC crystal (e.g., rivaroxaban crystal) can embed into the tissue to be treated. Alternatively or additionally, excipients may be selected to help the drug coating 34 adhere to the treatment site. In yet another example, the DOAC (e.g., rivaroxaban) may be incorporated into biodegradable polymer microspheres, wherein the microspheres are embedded in the tissue to be treated, and the biodegradable polymer controls the release of the drug into the tissue. Additionally, other excipients, such as, but not limited to, ATBC, may be selected to help the microspheres adhere to the treatment site.

[0094] It is anticipated that any of the pharmaceutical coating compositions described herein can be disposed above a base coat. The base coat can be applied directly to the balloon 14 and / or stent 110 prior to the application of pharmaceutical coating compositions 34, 134. The base coat can be applied to the balloon 14 and / or stent 110 using coating processes such as spraying, dip coating, roll coating, vapor deposition, etc., and / or other suitable coating processes. In some examples, the base coat can be a polymer dissolved in a solvent or solvent mixture. An exemplary base coat for stent 110 may comprise poly(butyl methacrylate) (PBMA) (2% solids) dissolved in a solvent mixture comprising approximately 70% acetone and 30% cyclohexanone. Methods for forming crystallized RIVAROXABAN

[0095] Crystallized rivaroxaban can be produced by crystallizing rivaroxaban from a solution of a mixture of N,N-dimethylformamide (DMF) and water. Crystallized rivaroxaban can also be produced by slowly adding a solution of rivaroxaban in DMF (1 to 4% by weight solids) to a large excess of deionized (DI) water. Experimental results

[0096] Figure 8 This is a graph of experimental data, providing the relative drug release rate when the stent is coated with a drug-coated undercoat containing 60 wt% PVDF-HFP and 40 wt% rivaroxaban. Each drug coating was applied with a topcoat containing a different weight percentage of PVDF-HFP relative to the drug coating.

[0097] Innova TM Self-expanding brace (8mm x 20mm; available from Boston) (Commercially available) Several PVDF-HFP / rivaroxaban coating formulations were used for spraying. The coating consisted of a base coat made of 60 / 40 (wt / wt) PVDF-HFP / rivaroxaban. A 2% (wt / wt) solution of polymer / drug in 60 / 40 acetone / DMF was sprayed onto the base coat. PVDF-HFP overcoats of varying thicknesses were sprayed onto the base coat. Increasing the thickness of the PVDF-HFP overcoat also increased its weight, as the scaffolds were all of the same size. An overcoat was sprayed onto the top coat from a solution of 2% wt% solids PVDF-HFP in acetone. Table 1 below shows the coated formulations. The scaffolds were tested by incubating them in phosphate-buffered saline (PBS) (pH ~ 7) at 37°C and 120 rpm. In vitro drug release from the coated scaffold was achieved by incubation in 20% phosphate buffer solution on a rocking incubator. Drug elution was quantified by high-performance liquid chromatography (HPLC) analysis of the phosphate buffer solution at different time points. Drug release profiles are shown below. Figure 8 middle. Table 1. Coating formulations for drug-coated stents.

[0098] Figure 8 This describes how drug release can be controlled by varying the weight and thickness of the PVDF-HFP topcoat. By customizing the topcoat thickness and / or weight, the duration of drug release can range from approximately 1 day to over 30 days. For example, Figure 8 As can be seen, increasing the weight percentage of the topcoat and thus increasing its thickness slows down the release of rivaroxaban. For example, a sample with a 7 wt% PVDF-HFP topcoat releases approximately 80% rivaroxaban in one day. A sample with a 27 wt% PVDF-HFP topcoat releases approximately 80% rivaroxaban in about 9 days and 90% in about 21 days. A sample with a 29 wt% PVDF-HFP topcoat releases approximately 80% rivaroxaban in about 21 days. A sample with a 47 wt% PVDF-HFP topcoat releases approximately 50% rivaroxaban in about 28 days.

[0099] Figure 9 The study demonstrates drug release from rivaroxaban-coated balloons compared to everolimus-based balloons when ethyl cellulose is used as the excipient. Over 90% of the rivaroxaban was released / dissolved within 22 hours, compared to only approximately 24% released / dissolved using everolimus-based balloons. To obtain longer release / dissolution profiles, the drug was incorporated into a slowly degradable, bioabsorbable polymer matrix, polylactide (PLA), in the form of microspheres. The resulting microspheres were then coated onto balloons using excipients such as ATBC or ethyl cellulose, which act as binders to the balloon surface and also facilitate transfer of the beads to the blood vessel during deployment.

[0100] PLA / rivaroxaban microspheres were prepared as follows: First, PLA10 (purchased from Evonik, Essen, Germany) and rivaroxaban were dissolved in a 9 1 / 9 (wt / wt) ratio in a 7 5 / 25 (wt / wt) mixture of dichloromethane and dimethylformamide. 0.5 mL of the PLA / rivaroxaban solution was added to 10 mL of a 2% polyvinyl alcohol (PVA) aqueous solution (molecular weight (MW) 146,000 to 186,000, 87 to 89% hydrolyzed) while mixing using a homogenizer. Beads were prepared at three different mixer speeds (rpm) to obtain a range of microsphere sizes. For example, slower mixer speeds resulted in larger microsphere (bead) sizes. After mixing for 2 minutes, the bead solution was added to 150 mL of a 0.1% PVA aqueous solution and stirred with a magnetic stir bar for 2 hours. The resulting beads were collected by filtration and vacuum dried at room temperature for 3 days. The drug content (rivaroxaban) in the beads was determined by HPLC. The beads were incubated in phosphate-buffered saline (PBS) (pH ~ 7) at 37°C and 120 rpm. Drug release was determined by incubation in a 20% solution on a rocking incubator. Drug concentration in PBS was measured by HPLC. Table 2 shows the drug content and bead size data. Figure 10 Drug release data for PLA-based beads produced at medium and high mixing rates are shown. Within 6 days, approximately 38% of the drug was released from the smaller microspheres (e.g., formed at high mixing rates), and approximately 27% from the medium-sized microspheres (e.g., formed at medium mixing rates). Therefore, the smaller microspheres initially release the drug at a higher rate. The release rate slows down after approximately 6 days, but the microspheres continue to release the drug. For PLA-based microspheres, it is estimated that the microspheres will release rivaroxaban for more than 45 days. The release rate of rivaroxaban can be improved by using a faster-degrading polylactide / glycolic acid copolymer (PLGA). Release from PLGA can be controlled by adjusting the ratio of lactide to glycolide and the polymer molecular weight. Table 2. PLA / Rivarzaban Microsphere Data bead samples % drug recovery rate Bead size (μm) low mixing speed 81 10-40 medium mixing speed 79 10-20 High mixing speed 85 5-15

[0101] Materials that can be used for various components of the medical devices described herein may include those typically associated with medical devices. The medical devices described herein may include various components that may be made of metals, metal alloys, polymers (some examples of which are disclosed below), metal-polymer composites, ceramics, combinations thereof, or other suitable materials. Some examples of suitable metals and metal alloys include stainless steel, such as 304V, 304L, and 316LV stainless steel; low-carbon steel; nickel-titanium alloys, such as linearly elastic and / or hyperelastic nickel-titanium alloys; other nickel alloys, such as nickel-chromium-molybdenum alloys (e.g., UNS: N06625, such as...). 625, UNS: N06022, such as UNS: N10276, such as other Alloys, etc.), nickel-copper alloys (e.g., UNS: N04400, such as...) 400, 400, 400, etc.), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS: R30035, such as...) (etc.), nickel-molybdenum alloys (e.g., UNS: 10665, such as...) ALLOY Other nickel-chromium alloys, other nickel-molybdenum alloys, other nickel-cobalt alloys, other nickel-iron alloys, other nickel-copper alloys, other nickel-tungsten or tungsten alloys, etc.; cobalt-chromium alloys; cobalt-chromium-molybdenum alloys (e.g., UNS: R30003, for example). (etc.); platinum-rich stainless steel; titanium; combinations thereof; etc.; or any other suitable material.

[0102] As mentioned herein, within the family of commercially available nickel-titanium or nitinol alloys, there is a category designated as “linear elastic” or “non-hyperelastic”, which, while chemically similar to conventional shape memory and hyperelastic varieties, can exhibit distinct and useful mechanical properties. The difference between linear elastic and / or non-hyperelastic nitinol and hyperelastic nitinol lies in the fact that linear elastic and / or non-hyperelastic nitinol does not exhibit a substantial “hyperelastic plateau” or “flag region” in its stress / strain curve as hyperelastic nitinol does. In fact, in linear elastic and / or non-hyperelastic nitinol, stress continues to increase substantially linearly or slightly but not necessarily completely linearly with increasing recoverable strain until plastic deformation begins, or at least with a more linear relationship than the hyperelastic plateau and / or flag region observed in hyperelastic nitinol. Therefore, for the purposes of this disclosure, linear elastic and / or non-hyperelastic nitinol may also be referred to as “substantially” linear elastic and / or non-hyperelastic nitinol.

[0103] In some cases, linear elastic and / or non-hyperelastic nitinol can also be distinguished from hyperelastic nitinol because linear elastic and / or non-hyperelastic nitinol can accept up to about 2-5% strain while remaining essentially elastic (e.g., before plastic deformation), while hyperelastic nitinol can accept up to about 8% strain before plastic deformation. Both materials can also be distinguished from other linear elastic materials such as stainless steel (which can also be distinguished based on its composition), which can accept only about 0.2% to 0.44% strain before plastic deformation.

[0104] In some embodiments, linear elastic and / or non-hyperelastic nickel-titanium alloys are alloys that do not exhibit any martensitic / austenitic phase transformations detectable by differential scanning calorimetry (DSC) and dynamic metallographic analysis (DMTA) over a wide temperature range. For example, in some embodiments, martensitic / austenitic phase transformations detectable by DSC and DMTA may be absent in linear elastic and / or non-hyperelastic nickel-titanium alloys in the range of about -60°C to about 120°C. Therefore, the mechanical bending properties of such materials can generally be inert to temperature effects over this very wide temperature range. In some embodiments, the mechanical bending properties of linear elastic and / or non-hyperelastic nickel-titanium alloys at ambient temperature or room temperature are substantially the same as their mechanical properties at body temperature, for example, they do not exhibit hyperelastic plateaus and / or flag-shaped regions. In other words, linear elastic and / or non-hyperelastic nickel-titanium alloys retain their linear elastic and / or non-hyperelastic properties and / or characteristics throughout the wide temperature range.

[0105] In some embodiments, the linear elastic and / or non-hyperelastic nickel-titanium alloy may be about 50 to about 60 wt% nickel, with the remainder being substantially titanium. In some embodiments, the composition is about 54 to about 57 wt% nickel. An example of a suitable nickel-titanium alloy is the FHP-NT alloy, commercially available from Furukawa Techno Material Co., Kanagawa Prefecture, Japan. Some examples of nickel-titanium alloys are disclosed in U.S. Patent Nos. 5,238,004 and 6,508,803, which are incorporated herein by reference. Other suitable materials may include ULTANIUM. TM (Available from Neo-Metrics) and GUM METAL TM (Available from Toyota). In some other embodiments, a superelastic alloy (e.g., superelastic nitinol) can be used to achieve the desired properties.

[0106] In at least some embodiments, part or all of the medical device described herein may be doped with, made of, or otherwise include a radiopaque material. A radiopaque material should be understood as a material capable of producing a relatively bright image on a fluorescent screen or other imaging technique during medical procedures. This relatively bright image helps the user of the medical device described herein to determine their location. Some examples of radiopaque materials may include, but are not limited to, gold, platinum, palladium, tantalum, tungsten alloys, polymeric materials loaded with radiopaque fillers, etc. Additionally, other radiopaque marking strips and / or coils may be incorporated into the design of the medical device described herein to achieve the same result.

[0107] In some embodiments, a degree of magnetic resonance imaging (MRI) compatibility is imparted to the medical devices described herein. For example, the medical devices or portions thereof described herein may be made of materials that substantially do not distort images and do not produce significant artifacts (i.e., gaps in the image). For example, certain ferromagnetic materials may be unsuitable because they may produce artifacts in MRI images. The medical devices or portions thereof described herein may also be made of materials that an MRI machine can image. Some materials exhibiting these properties include, for example, tungsten, cobalt-chromium-molybdenum alloys (e.g., UNS: R30003, such as...). (etc.), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS: R30035, such as...) (etc.), nickel-titanium, etc., and other materials.

[0108] It should be understood that this disclosure is merely illustrative in many respects. Changes in detail may be made, particularly in terms of shape, size, and arrangement of steps, without departing from the scope of this disclosure. To the appropriate extent, this may include the use of any feature of an exemplary embodiment used in other embodiments. Of course, the scope of this disclosure is defined by the language of the appended claims.

Claims

1. A pharmaceutical coating composition comprising: Excipients containing polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), or poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP); and Direct oral anticoagulants (DOACs).

2. The pharmaceutical coating composition of claim 1, wherein the DOAC is apixaban, rivaroxaban, or edoxaban.

3. The pharmaceutical coating composition according to any one of claims 1-2, wherein the DOAC is present in the pharmaceutical coating composition in the range of about 5% by weight to about 40% by weight.

4. The pharmaceutical coating composition according to any one of claims 1-3, wherein the DOAC is present in the pharmaceutical coating composition in an amount of 100-4000 nanograms per square millimeter.

5. The pharmaceutical coating composition according to any one of claims 1-4, further comprising an antiproliferative agent.

6. The pharmaceutical coating composition of claim 5, wherein the antiproliferative agent comprises one or more of paclitaxel, everolimus, sirolimus, and rapamycin.

7. The pharmaceutical coating composition according to any one of claims 1-6, further comprising an antioxidant.

8. A method for manufacturing a pharmaceutical coating composition, the method comprising: Polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) is dissolved with rivaroxaban in a mixture of dichloromethane and dimethylformamide to form a first solution; The first solution is added to an aqueous solution of polyvinyl alcohol (PVA) and mixed to form a bead solution; The bead solution is filtered to collect multiple microspheres; and The plurality of microspheres are dried.

9. The method of claim 8, wherein PLA or PLGA and rivaroxaban are dissolved at a ratio of about 85 to 95% by weight of PLA or PLGA to about 5 to about 15% by weight of rivaroxaban.

10. The method of any one of claims 8-9, wherein the mixture of dichloromethane and dimethylformamide is about 75% by weight of dichloromethane and about 25% by weight of dimethylformamide.

11. The method of any one of claims 8-10, wherein the PVA aqueous solution is about 2% PVA.

12. The method of any one of claims 8-11, further comprising adding the bead solution to a 0.1% aqueous PVA solution and mixing for a first time period.

13. The method of claim 12, wherein the first time period is in the range of about 1 hour to about 3 hours.

14. The method of any one of claims 8-13, wherein drying the plurality of microspheres comprises drying the microspheres under vacuum at room temperature for a second time period.

15. The method of claim 14, wherein the second time period is in the range of about 2 days to about 4 days.

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