Anticoagulant compositions containing antiplatelet agents and anti-inflammatory agents, as well as methods and devices for the use thereof.

Abstract

Devices, systems, methods, and compositions are provided herein, each comprising a composition for coupling to the surface of an implantable article, wherein the composition comprises an anticoagulant comprising a direct factor Xa inhibitor, and at least one of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine. The disclosed technology provides compositions for coupling to the surface of an implantable article, typically a vascular implant, such as a stent, stent-graft, prosthetic valve, or occlusion device.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Application No. 63 / 502,527, filed on 16 May 2023 (Agent Reference No. 32016-736.101), and U.S. Provisional Application No. 63 / 592,857, filed on 24 October 2023 (Agent Reference No. 32016-736.102), the full disclosures thereof, which are incorporated herein by reference. [Background technology]

[0002] background Area of ​​Disclosure: This disclosure relates generally to medical devices and methods, and more particularly to the coating of implantable devices and other devices with anticoagulant compositions.

[0003] Blood clotting, commonly referred to as "coagulation," is a process designed to stop bleeding from damaged blood vessels. Mammals cannot survive long without clotting to stop bleeding after injury, but clotting in blood vessels after stent placement and other intravascular interventions can lead to serious complications that can be fatal, including hyperplasia, restenosis, and vascular calcification.

[0004] The blood coagulation process requires coagulation factors, calcium, and phospholipids. It is initiated by exogenous tenase, formed when factor VIIa binds to tissue factor. Exogenous tenase activates factors IX and X. In the presence of calcium, factor IXa binds to a negatively charged phospholipid surface, where it interacts with factor VIIIa to form endogenous tenase, a complex that efficiently activates factor X. Factor Xa binds to factor Va on the negatively charged phospholipid surface to form prothrombinase, a complex that activates prothrombin (factor II) to thrombin (factor IIa). Thrombin then converts fibrinogen to fibrin. Activated platelets or monocytes provide the negatively charged phospholipid surface on which these coagulation reactions occur. The endogenous pathway is initiated by the negatively charged surface-mediated activation of factor XII (FXII). Such contact activation further propagates thrombin formation through the sequential activation of FXI, FIX, FX, and prothrombin. Importantly, thrombin can further activate FXI in a feedback mechanism. Thrombin also activates platelets, which can then support FXI activation. Activation of FXI leads to enhanced thrombin formation, thus forming a positive feedback loop and enhanced coagulation for thrombin formation. Coagulation disorders can result in obstructive coagulation (thrombosis) or vascular occlusion.

[0005] Damage to blood vessels can be caused, for example, by adverse contact with or intervention by devices used in surgical procedures (e.g., scalpels used to cut tissue containing blood vessels, or deployable stents embedded in the walls of blood vessels). Damage to blood vessels can lead to abnormal or undesirable recruitment, activation, and / or proliferation of proteins (e.g., fibrin) and cells (e.g., platelets) involved in the coagulation process and other processes at the site of injury, which can result in occlusive coagulation or occlusion of blood vessels.

[0006] Following vascular injury, von Willebrand factor acts as a crosslink between endothelial collagen and platelet surface receptor GpIb, promoting platelet adhesion. After adhesion, degranulation from both types of granules occurs, accompanied by the release of various factors. Calcium release occurs simultaneously here. Calcium binds to phospholipids that appear secondarily to platelet activation, providing a surface for the assembly of various coagulation factors.

[0007] Calcium ions play a crucial role in the strict regulation of the coagulation cascade, which is paramount in maintaining hemostasis. Calcium ions are essential in the coagulation cascade because they are cofactors for membrane-bound complexes, including the endogenous tenase complex (FIXa-FVIIIa), the exogenous tenase complex (FVIIa-TF), and the prothrombinase complex (FXa-FVa).

[0008] Under normal physiological conditions, healthy vascular endothelium minimizes contact between tissue factor (TF) and plasma procoagulants. However, vascular injury exposes tissue factor, which binds to factor VIIa and calcium, facilitating the conversion of factor X to factor Xa.

[0009] In addition to platelet activation, calcium ions are involved in the complete activation of several coagulation factors, including coagulation factor XIII (FXIII). FXIII is involved in the covalent crosslinking of pre-formed fibrin clots, preventing their premature fibrinolysis by maintaining the structure and strength of the clots. The time lag in the generation of the first FXIIIa molecules is approximately 10 to 20 minutes. This 10 to 20-minute period is crucial for preventing premature fibrin clot crosslinking.

[0010] Anticoagulants can be used to prevent the formation of blood clots. Some are used to prevent or treat disorders characterized by abnormal blood clots and embolus. By reducing blood clotting, anticoagulants can prevent deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke.

[0011] The blood clotting process requires clotting factors, calcium, and phospholipids. There are three strategies to prevent clotting: (1) inhibiting clotting factors, (2) removing free calcium from the blood, and (3) changing the negatively charged phospholipid surface to neutral or positively charged, so that the clotting reaction cannot occur, as these clotting factors can only bind to the negatively charged phospholipid surface provided by activated platelets or monocytes. Some anticoagulants work by inactivating thrombin and several other clotting factors necessary for clotting. Other anticoagulants work by removing free calcium ions or inhibiting phospholipids such as platelet-activating factor. Removal of free calcium ions can be achieved by the chelating agents EDTA, citrate, or oxalate. EDTA inhibits the initial stage of the clotting cycle by inhibiting the activation of endogenous XII, XI, IX, X and exogenous VIIa / TF clotting factors and depleting / chelating free calcium ions. This is important for the exogenous pathway, which is the only step involved in the coagulation cascade (VIIa / TF activated by Ca2+). The mechanism of EDTA as an anticoagulant for drug-induced coagulation is that its inhibition of adenosine, epinephrine, and thrombin-induced platelet aggregation may be more effective than mechanisms that inhibit platelet aggregation more narrowly, such as clopidogrel, which inhibits only adenosine-induced aggregation.

[0012] Direct factor XIa inhibitors are active-site inhibitors that achieve antithrombotic effects without increasing the risk of bleeding. They also delay the time to clot formation, reduce fibrin uptake into clots, and decrease the resistance of clots to fibrinolysis.

[0013] Systemic administration of anticoagulants may be ineffective in preventing or treating coagulation-related disorders. For example, the concentration of anticoagulants at or near the site of injury may be insufficient for an appropriate time to prevent or treat coagulation-related disorders. Furthermore, the shortcomings of systemic administration of anticoagulants may be exacerbated if the patient has conditions that make them more susceptible to vascular occlusive events (e.g., cardiovascular disease, hypercholesterolemia, or diabetes).

[0014] Previous attempts to provide topical anticoagulants have been limited to the unsuccessful prevention of coagulation disorders and / or thrombus (clot) formation, particularly after local tissue injury. Furthermore, local tissue injury generally involves additional injury to tissue adjacent to the site of the initial injury (e.g., proximal, distal, etc.).

[0015] Stents or drug-coated balloons may be used in arteries to maintain arterial openness in order to reduce partial or complete occlusion of arteries by plaque, or collapse of the arterial wall, and to reduce the chance of restenosis. Unfortunately, drugs coated on stents or balloons can delay the healing period of damaged tissue, increasing tissue factor that can generate or amplify thrombin, fibrin, and / or clot formation, especially within the first 3 to 72 hours or longer; however, the time lag to the generation of the first molecule FXIIIa, which causes covalent crosslinking of early fibrin clots and is activated by calcium ions, is approximately 10 to 20 minutes. This 10 to 20-minute window is crucial to prevent the crosslinking of early fibrin clots.

[0016] Anticoagulants can be used to prevent the formation of blood clots. Some are used to prevent or treat disorders characterized by abnormal blood clots and embolus. By reducing blood clotting, anticoagulants can prevent deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke.

[0017] The purpose of adding implanted medication to a stent is to prevent thrombin accumulation and restenosis. However, due to increased thrombosis at the stent site, the risk of death and myocardial infarction (MI) has increased. Long-term treatment with clopidogrel disulfate and aspirin for at least 12 months has been suggested as a preventive measure, but there is no evidence that this treatment is effective for longer than 6 months. Clopidogrel also increases the risk of massive bleeding episodes.

[0018] There remains a need to develop specialized therapeutic compositions for medical devices that can rapidly deliver therapeutic agents, drugs, or bioactive materials directly to local tissue areas during or after medical procedures to treat or prevent vascular and nonvascular diseases or conditions such as restenosis or thrombosis. The device must release the therapeutic agent in an effective and efficient manner at the desired target site, so the therapeutic agent must rapidly penetrate the target tissue at a topical therapeutic level that inhibits one or more of thrombin, fibrin, and / or clot formation before amplification of coagulation factors.

[0019] Therefore, it would be desirable to provide a device for locally delivering thrombin / clot formation inhibitors, and optionally other types of biologically active agents (e.g., antiproliferative agents, anti-inflammatory agents, etc.) to the site of injury on a body part or to areas adjacent thereto, before, during, and / or after the injury.

[0020] One approach to inhibit hyperplasia and associated adverse events after stent placement was to coat the stent with immunosuppressants and antiproliferative agents, such as paclitaxel (Taxol), sirolimus (rapamycin), and everolimus. Each of these drugs has found broad clinical use.

[0021] Colchicine is a small molecule anti-inflammatory (anti-mitotic) drug that blocks mitotic cells in metaphase. Colchicine is orally administered for the systemic treatment of inflammatory diseases such as gout and pericarditis, and its systemic use has been proposed for treating restenosis (O’Keefe (1992) JACC 19:1597-1600). Systemic colchicine, however, requires treatment at lower doses and / or for shorter durations, and has side effects including toxicity that reduce its efficacy and prevent its widespread adoption for treating restenosis. Other anti-inflammatory agents such as NSAIDs (non-steroidal) and steroids are used as anti-inflammatory drugs for treating restenosis, but colchicine has the advantages of inhibiting endothelial cell dysfunction and inflammation, inhibiting vascular inflammation, inhibiting inflammation in blood vessels after injury such as PCI, inhibiting inflammation from vascular plaques or disease states, inhibiting inflammation from implantable materials, inhibiting or reducing cardiovascular chest pain (angina), reducing hsCRP (an inflammation marker), and inhibiting one or more of NLRP3 inflammasome, IL-1β, IL-18, and / or IL-6. As a result, this would be useful for providing improved formulations for using colchicine to treat restenosis in the vasculature after stent placement and other vascular interventions.

[0022] Coating stents with colchicine in a polymeric carrier has been proposed as an alternative to oral administration (see, e.g., US5,776,184), but colchicine has not been clinically adopted for such use.

[0023] Therefore, it would be desirable to provide improved drug coatings for stents and other implantable devices using colchicine as the primary active agent. In particular, it would be desirable to identify other drugs (or more) that can be combined with colchicine or other immunosuppressants, e.g., sirolimus, or other antiplatelet agents, e.g., tirofiban, ticagrelor, aspirin, in drug coatings for stents and other implantable devices, such that the combination achieves a higher synergistic inhibitory effect than that achieved by coatings using either drug alone. At least some of these objectives are described herein and fulfilled by the present disclosure in the claims.

[0024] This disclosure also provides methods of using such devices and other forms of treatment in the treatment of coagulation at or adjacent to the injury site and in improving or accelerating wound healing. List of background technologies. Related background technologies are US9,770,349; US9,901,663; US6,500,855; US8,409,272; US8,946,219; US2003 / 0158120; US2005004663; US2005 / 0064006; US2009 / 0075949; US2010 / 0003542; US2010 / 0130543; US2010 / 0184729; US2010 / 049328; US2013 / 189329; US2015 / 1 Including 57771;US2018 / 0000490;EP1849434;CA2464290;WO2013 / 007840;WO2013 / 056060;WO2020 / 210613;WO2020 / 210629;US8617104;US8715771;US9066990;US9439792;US9492294;US9656003;US10278839;US20070043418;and US202000384246;O'Keefe (1992) JACC 19:1597-1600 and US5,776,184 as described above. The subject matter of the present application also relates to the subject matter of the following co-pending applications: International Patent Application No. PCT / US2022 / 50099, filed on November 16, 2022, with the title "Anticoagulant Compounds Containing Chelating Agents and Cationic Anticoagulation Enhancers, and Methods and Devices for Their Use" (Attorney Docket No. 32016-729.601); International Patent Application No. PCT / US2021 / 034108, filed on May 25, 2021, with the title "Anticoagulant Compositions, and Methods and Devices for Their Use" (Attorney Docket No. 32016-720.601); International Patent Application No. PCT / US2021 / 044414, filed on August 3, 2021, with the title "Anticoagulant Compositions, and Methods and Devices for Their Pulmonary Use" (Attorney Docket No. 32016-730.601); International Patent Application No. PCT / US2021 / 049964, filed on September 10, 2021, with the title "Anticoagulant Compositions, and Methods and Devices for Their Ophthalmic Use" (Attorney Docket No. 32016-720.601); International Patent Application No. PCT / US2007 / 078317, filed on September 12, 2007, with the title "Macrocyclic Lactone Compounds and Methods for Their Use" (Attorney Docket No. 32016-704.601); International Patent Application No. PCT / US2008 / 056501, filed on March 11, 2008, with the title "Macrocyclic Lactone Compounds and Methods for Their Use" (Attorney Docket No. 32016-704.602); International Patent Application No. PCT / US2009 / 059396, filed on October 2, 2009, with the title "Macrocyclic Lactone Compounds and Methods for Their Use" (Attorney Docket No. 32016-709.601); International Patent Application No. PCT / US2011 / 054637, filed on October 3, 2011, with the title "Macrocyclic Lactone Compounds and Methods for Their Use" (Attorney Docket No. 32016-711.601), each of which is hereby incorporated by reference in its entirety for all purposes.

PRIOR ART DOCUMENTS

PATENT DOCUMENTS

[0025] [Patent Document 1] U.S. Publication No. 9,770,349 [Non-patent literature]

[0026] [Non-Patent Document 1] O'Keefe (1992) JACC 19:1597-1600 [Overview of the project] [Means for solving the problem]

[0027] Summary of Disclosure The disclosed technology provides compositions for coupling to the surface of implantable articles, typically vascular implants, such as stents, stent-grafts, prosthetic valves, and occlusion devices. The use of the compositions is, however, not limited to vascular implants but extends to various other prosthetic implants, diagnostic implants, and other implants further described below herein. Such implants typically include a base structure, such as an expandable scaffold in the case of a stent, and a stent-graft or housing in the case of other implants. The implants typically have an outer surface and / or surface or internal cavity suitable for coating or other deposition of the compositions described herein and claimed herein.

[0028] The terms “coupling” and “to couple,” as used herein and in the claims, broadly represent the fact that the disclosed composition and / or any component thereof is coated, attached, isolated, loaded, coupled, or otherwise fixed onto the surface of a base structure of a surgical article, such as a scaffold, stent, stent-graft, artificial valve, orthopedic implant, or electrical stimulator, such as a pacemaker or nerve stimulator. In other cases, the surface may be on a catheter and other surgical tool that is temporarily introduced into a patient’s vascular structure or vascularized space, such as a vascular catheter, guidewire, guide catheter, or sheath. In some examples, the disclosed composition and / or any component thereof may be loaded and isolated on or in a receptacle or depot formed on or over the surface of the base structure of the surgical article.

[0029] The coupling surface may be any surface on a surgical article, more specifically, often an external surface, and sometimes an internal surface, that is directly or indirectly exposed to the patient's blood. For example, on stents and other scaffolds, a composition and / or any component thereof may be coupled to an external surface, an internal (lumen) surface, and / or an end. In a catheter, a composition and / or any component thereof may be coupled to an external balloon surface, an external shaft surface, and so on. In more complexly structured surgical articles, such as artificial heart valves, the surface may be on an external base or anchor feature, as well as on an internal valve and other mechanical components.

[0030] The disclosed compositions and / or their components may be coated directly and / or indirectly onto the surface of a surgical article in one, two, three, or more layers, or otherwise coupled, where the individual layers may be homogeneous or heterogeneous. The continuous layers of compositions may be formed directly or indirectly with respect to one another, and may be interposed between continuous "active" layers (containing the drugs of the disclosed technology), such as barrier layers, rate control layers, permeable and semipermeable membranes, etc.

[0031] In a first embodiment, the composition comprises an anticoagulant comprising a direct factor Xa inhibitor, and at least one of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine, more often comprising at least two of (a) an antiplatelet agent, (b) a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine, and more frequently comprising all three of (a) an antiplatelet agent, (b) a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine.

[0032] In some cases, direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The drug comprises at least one drug selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). For example, the direct factor Xa inhibitor may include rivaroxaban, apixaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0033] In some examples, the composition comprises at least one antiplatelet agent selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, and P2Y12 inhibitors, or salts or analogs thereof. For example, the antiplatelet agent may comprise tirofiban, its salts, analogs, or metabolites. In further examples, the antiplatelet agent may comprise ticagrelor, its salts, isomers, solvates, derivatives, metabolites, or prodrugs. In yet another example, the antiplatelet agent may comprise acetylsalicylic acid (aspirin, a Cox1 / 2 inhibitor). In an additional example, the antiplatelet agent may comprise clopidogrel or its active metabolite, its salts, isomers, solvates, prodrugs, metabolites, or derivatives.

[0034] In some cases, at least one direct factor IIa inhibitor may be selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine. For example, the direct factor IIa inhibitor drug may include argatroban, its salts, solvates, isomers, derivatives, or metabolites, or prodrugs.

[0035] In a second embodiment, the composition may contain an anticoagulant comprising a direct factor IIa inhibitor, and at least one of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine, and in many cases, at least two of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine, and more frequently, all three of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine.

[0036] In some cases, direct factor IIa inhibitors are selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine. For example, direct factor IIa inhibitor drugs may include rivaroxaban, argatroban, or its salts, analogs, or metabolites.

[0037] In some examples, the composition may include an antiplatelet agent selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, and P2Y12 inhibitors, or salts or analogs thereof. For example, the antiplatelet agent may include tirofiban, ticagrelor, or salts, analogs, or metabolites thereof; acetylsalicylic acid (a Cox1 / 2 inhibitor); or clopidogrel or its active metabolite, or salts, solvates, isomers, derivatives, prodrugs, or metabolites thereof.

[0038] In some cases, direct factor XIIa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The drug may contain at least one selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). For example, a direct factor Xa inhibitor may contain apixaban, its salts, isomers, solvates, isomers, derivatives, metabolites, or prodrugs, and / or rivaroxaban, its salts, solvates, isomers, derivatives, or metabolites.

[0039] In a third embodiment, the composition for coupling to the surface of an implantable article may comprise a direct factor Xa inhibitor, and at least two, often three, of the following: (a) a direct factor IIa inhibitor, (b) an antiplatelet agent selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, and P2y12 inhibitors, and (c) an anti-inflammatory agent.

[0040] In some cases, direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), or a salt, analog, or metabolite thereof may be included. For example, a direct factor Xa inhibitor may include rivaroxaban, or apixaban, a salt, isomer, solvate, derivative, metabolite, or prodrug thereof, and / or rivaroxaban, a salt, isomer, derivative, solvate, metabolite, or prodrug thereof, or argatroban, or a salt, isomer, derivative, solvate, prodrug, or metabolite thereof.

[0041] In some cases, the antiplatelet agent may include at least one drug selected from the group consisting of tyrofiban, ticagrelor, Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, and P2Y12 inhibitors, or their salts, isomers, solvates, derivatives, prodrugs, or metabolites.

[0042] In some cases, the anti-inflammatory agent may include colchicine, its isomer (n isomer), derivative metabolites, or prodrugs.

[0043] In a fourth embodiment, the composition for coupling to the surface of an embeddable article may include apixaban, rivaroxaban, or a salt, isomer, solvate, derivative prodrug, or metabolite thereof; argatroban, or a salt, isomer, derivative, solvate, prodrug, or metabolite thereof; tyrofiban, or a salt, analog, or metabolite thereof; and colchicine.

[0044] In some examples, the composition may further include an additional anti-platelet drug.

[0045] In some examples, the composition may further contain additional anti-inflammatory agents.

[0046] In a fifth aspect, the disclosed technology provides a surgical article comprising a base structure, wherein a disclosed composition and / or one or more components thereof are coupled to the surface or interior of the base structure.

[0047] In some examples, a composition, and / or its individual components, are coupled to a surface in a single layer, and the single layer may be homogeneous or heterogeneous. "Homogeneous" means that the drug components of the composition are mixed and distributed relatively uniformly in the individual layers. "Heterogeneous" means that the drug components of the composition are distributed unevenly in the individual layers.

[0048] In some examples, the composition and / or its individual components are coupled to the surface in two layers of the composition. In such examples, each layer may contain some or all of the drug components of the composition, and the drug components of each layer may exist as a homogeneous or heterogeneous mixture.

[0049] In addition to the “active” layer containing some or all of the drug components of the disclosed composition, the surface may be covered, in whole or in part, directly or indirectly, by an intermediate layer, typically an “inactive” layer, which does not contain an active amount of the composition and / or its drug components. Exemplary intermediate layers include barrier layers, rate control layers, permeable and semipermeable membranes, etc., and may be located between continuous active layers. The intermediate layer may cover and / or be located between other adjacent layers and may contain drugs in addition to the drugs in the composition.

[0050] Drugs in compositions coupled to the surface of surgical articles typically have release rates ranging from 1 day to 1 year, and often have release rates ranging from 1 to 3 days, 1 to 30 days, or 1 to 90 days.

[0051] This disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to expand within a patient's body. A therapeutic composition comprising at least one chelating agent is present on the surface of the scaffold, wherein the therapeutic composition is formulated for the rapid release of the chelating agent into the environment surrounding the scaffold upon implantation of the scaffold structure in the environment.

[0052] The disclosure also provides a therapeutic composition comprising colchicine and / or tyrofiban and at least one antiproliferative agent. The colchicine and / or tyrofiban is present in a carrier configured to release colchicine and / or tyrofiban for a period of at least one week in an amount sufficient to inhibit inflammation resulting from scaffold implantation. The at least one antiproliferative agent is present in the same or a different carrier and is configured to release the antiproliferative agent for a period of at least one week in an amount sufficient to inhibit smooth cell muscle (SMC) proliferation.

[0053] At least one antiproliferative agent typically includes an mTOR inhibitor, usually selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotarolimus, and their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, and more usually sirolimus or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0054] The disclosure also provides a therapeutic composition comprising colchicine and / or tyrofiban and at least one antiproliferative agent. The colchicine and / or tyrofiban is present in a carrier configured to release colchicine and / or tyrofiban for a period of at least one week in an amount sufficient to inhibit inflammation resulting from scaffold implantation. The at least one antiproliferative agent is present in the same or a different carrier and is configured to release the antiproliferative agent for a period of at least one week in an amount sufficient to inhibit smooth cell muscle (SMC) proliferation.

[0055] At least one antiproliferative agent typically includes an mTOR inhibitor, usually selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotarolimus, and their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, and more usually sirolimus or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0056] This disclosure provides devices, compositions, and methods for their use. Devices include implantable scaffolds and other structures having one or more surfaces configured for internal use within a patient's body, most commonly including implantable stents and grafts, but also including vascular, coronary, orthopedic, and other articles intended for long-term and short-term implantation. Coatings are configured to completely or partially cover the surfaces of a device, including outer and inner device surfaces, and are typically deposited on, covering, or within one or more surfaces, including on the surface or within depots formed by the surfaces.

[0057] The coating comprises a composition having one or more drugs or other active substances, such as anticoagulants, antiplatelet agents, antiproliferative agents, colchicine, and chelating agents. The composition is formulated to release one or more drugs into an embedded environment, such as a vascular lumen, coronary valve, or solid tissue, inhibit clot formation, promote clot dissolution, inhibit inflammation, inhibit vascular injury, increase precoagulation time, and / or inhibit cell proliferation. The composition is typically formulated to provide delayed or controlled release of drugs from the structure to the embedded environment.

[0058] The composition may provide all the drugs, excipients, binders, and other components as a single formulation intended for simultaneous coating on the surface of an article, but more often, it is proven as multiple separate components to allow for sequential application or deposition on the article so that the composition is formed in situ on the article.

[0059] In some examples, the scaffold structure may be configured to expand in a vascular lumen or any other target site within the patient's body. The therapeutic composition may, at least in part, be present on the surface of the scaffold structure, or at least in part, be present within a cavity or reservoir within the scaffold structure.

[0060] In further embodiments, the Disclosure provides compositions suitable for coating on or within the surfaces of various embeddable articles described herein. The compositions comprise several drugs or other active and inactive components, where the active components are classified as anticoagulants, antiplatelet agents, antiproliferative agents, colchicine, and chelating agents. The compositions are typically formulated to provide delayed or controlled release of the drug from the structure into the embedded environment, inhibiting clot formation, promoting clot dissolution, inhibiting inflammation, inhibiting vascular injury, increasing precoagulation time, and / or inhibiting cell proliferation, both upon release and over time. While the compositions may provide all drugs, additives, binders, and other components as a single formulation intended for simultaneous coating on the surface of an article, in more cases, they are proven as several separate components to allow for sequential application or deposition on the article, so that the composition forms in situ on the article.

[0061] A first composition relating to the principles of this disclosure comprises a first antiplatelet agent comprising (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, (b) colchicine, and (c) tirofiban. The first antiplatelet agent is formulated to be released from the surface of an implantable article in an amount sufficient to inhibit inflammation and / or thrombosis resulting from injury.

[0062] In some cases, the first composition (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, (b) colchicine, and (c) the first antiplatelet agent are formulated to treat injuries resulting from the implantation of an article.

[0063] In some cases, the first composition (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, (b) colchicine, and (c) the first antiplatelet agent are formulated to treat injury without causing one or more of the following: bleeding, a risk of bleeding risk, and bleeding associated with the administration of a systemic antithrombotic agent.

[0064] In some examples, the first composition comprises at least one factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, wherein the at least one direct factor IIa inhibitor may include argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0065] In some cases, the first composition is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The formulation includes at least one factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). For example, the direct factor Xa inhibitor includes apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. For example, the direct factor Xa inhibitor includes rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0066] In some examples, the first composition comprises at least a second antiplatelet agent distinct from the first antiplatelet agent, wherein the second antiplatelet agent may comprise one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0067] In some examples, the first composition comprises at least a third antiplatelet agent distinct from the first and second antiplatelet agents, wherein the third antiplatelet agent may comprise one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0068] In some examples, the first composition includes a chelating agent, where the chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimethyl Captopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives may be selected from the group.

[0069] In some examples, the first composition comprises at least one antiproliferative agent, which may include an mTOR inhibitor.

[0070] A second composition for coating the surface of an embeddable article according to the principles of the present disclosure comprises a first antiplatelet agent comprising (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, and (c) a glycoprotein IIb / IIIa inhibitor, wherein (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, and (c) the first antiplatelet agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation and / or thrombosis resulting from injury.

[0071] In some cases, (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, and (c) a second antiplatelet agent of the first composition are formulated to treat injuries resulting from the implantation of an article.

[0072] In some cases, the first composition (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, and (c) a second antiplatelet agent are formulated to treat injury without causing one or more of the following: bleeding, a risk of bleeding risk, and bleeding associated with the administration of systemic antithrombotic agents.

[0073] In some examples, the second composition further comprises (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, and (c) colchicine, formulated to be released from the surface of an article in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury in combination with the first antiplatelet agent.

[0074] In some examples, the direct factor IIa inhibitor of the second composition is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, where the direct factor IIa inhibitor typically includes argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0075] In some cases, the direct factor Xa inhibitor of the second composition is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The group is selected from 0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). For example, direct factor Xa inhibitors include apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. For example, direct factor Xa inhibitors include rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0076] In some cases, the glycoprotein IIb / IIIa inhibitor of the second composition is selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0077] In some examples, the second composition further comprises at least a second antiplatelet agent different from the first antiplatelet agent, wherein the second antiplatelet agent may comprise one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0078] In some examples, the second composition further comprises at least a third antiplatelet agent different from the first and second antiplatelet agents, wherein the third antiplatelet agent may comprise one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0079] In some examples, the second composition further comprises a chelating agent, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-di The following may be selected: mercaptopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives.

[0080] In some examples, the second composition further comprises at least one antiproliferative agent, wherein the antiproliferative agent may include an mTOR inhibitor.

[0081] A third composition for coating the surface of an implantable article according to the principles of the present disclosure comprises a first antiplatelet agent comprising (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a glycoprotein IIb / IIIa inhibitor, and (d) a second antiplatelet agent comprising an NSAID, wherein (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) the first antiplatelet agent, and (d) the second antiplatelet agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0082] In some cases, the third composition (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat injuries resulting from the implantation of an article.

[0083] In some cases, the third composition (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat injury without causing one or more of the following: bleeding, a risk of bleeding risk, and bleeding associated with the administration of systemic antithrombotic agents.

[0084] In some examples, the third composition further comprises (e) colchicine, formulated to be released from the surface of an article in combination with (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury.

[0085] In some examples, the direct factor IIa inhibitor of the third composition of the present disclosure comprises at least one factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, and typically comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0086] In some examples, the direct factor Xa inhibitors of the third composition of this disclosure are apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD A selection from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), typically comprising (a) apixaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, and / or (b) rivaroxaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0087] In some examples, the glycoprotein IIb / IIIa inhibitor of the third composition of the present disclosure is selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0088] In some cases, the NSAID of the third composition contains a salicylate.

[0089] In some examples, the third composition further comprises at least a third antiplatelet agent different from the first and second antiplatelet agents, wherein the third antiplatelet agent may comprise one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0090] In some examples, the third composition further comprises a chelating agent, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-di The following may be selected: mercaptopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives.

[0091] In some examples, the third composition of the present disclosure further comprises at least one antiproliferative agent, wherein the antiproliferative agent may comprise an mTOR inhibitor.

[0092] A fourth composition according to this disclosure for coating the surface of an implantable article comprises a first antiplatelet agent comprising (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a glycoprotein IIb / IIIa inhibitor, and (d) a second antiplatelet agent comprising an ADP receptor / P2Y12 inhibitor, wherein (a) a direct factor IIa inhibitor, (b) a factor Xa inhibitor, (c) the first antiplatelet agent, and (d) the second antiplatelet agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0093] In some cases, the fourth composition (a) a direct factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat injuries resulting from the implantation of an article.

[0094] In some cases, the fourth composition (a) a direct factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of systemic antithrombotic agents.

[0095] In some examples, the fourth composition of the present disclosure further comprises (e) colchicine, formulated to be released from the surface of an article in combination with (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury.

[0096] In some examples, the fourth composition of the present disclosure further comprises (f) a third antiplatelet agent comprising aspirin and / or another NSAID, formulated to be released from the surface of an article in combination with (a) a direct factor IIa inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury, wherein the direct factor IIa inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, and typically comprises argatroban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0097] In some cases, the direct factor Xa inhibitors of the fourth composition of this disclosure are apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052) may be selected. For example, direct factor Xa inhibitors may include apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. For example, direct factor Xa inhibitors may include rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0098] In some examples, the glycoprotein IIb / IIIa inhibitor of the fourth composition may be selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0099] In some examples, the ADP receptor / P2Y12 inhibitor of the fourth composition may be selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor.

[0100] In some examples, the fourth composition of the present disclosure further comprises at least a third antiplatelet agent distinct from the first and second antiplatelet agents, wherein the third antiplatelet agent may comprise one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors. For example, the third antiplatelet agent may comprise a salicylate, e.g., aspirin, or another NSAID.

[0101] In some examples, the fourth composition of the present disclosure further comprises a chelating agent, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3 -The following may be selected from the group consisting of dimercaptopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactants, EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, salts thereof, analogs, solvates, hydrates and derivatives.

[0102] In some examples, the fourth composition of the present disclosure further comprises at least one antiproliferative agent, such as an mTOR inhibitor.

[0103] A fifth composition for coating the surface of an implantable article according to the principles of the present disclosure comprises a direct factor Xa inhibitor, and one or more of the following: (a) colchicine, (b) a first antiplatelet agent comprising a glycoprotein IIb / IIIa inhibitor, (c) a second antiplatelet agent comprising an NSAID, and (d) a third antiplatelet agent comprising an ADP inhibitor, wherein the direct factor Xa inhibitor, and one or more of the following are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0104] In some cases, the direct factor Xa inhibitor of the fifth composition of the present disclosure, as well as one or more of the first antiplatelet agents comprising (a) colchicine, (b) glycoprotein IIb / IIIa inhibitors, (c) a second antiplatelet agent comprising an NSAID, and (d) an ADP inhibitor, are formulated to treat injuries resulting from article implantation.

[0105] In some examples, the direct factor Xa inhibitor of the fifth composition of the present disclosure, as well as one or more of the first antiplatelet agents comprising (a) colchicine, (b) glycoprotein IIb / IIIa inhibitors, (c) a second antiplatelet agent comprising an NSAID, and (d) an ADP inhibitor, are formulated to treat injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of systemic antithrombotic agents.

[0106] In some examples, the fifth composition of the present disclosure further comprises a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, the direct factor IIa inhibitor may include argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0107] In some cases, the factor Xa inhibitor of the fifth composition is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052) may be selected. For example, direct factor Xa inhibitors may include apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. For example, direct factor Xa inhibitors may include rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0108] In some examples, the glycoprotein IIb / IIIa inhibitor of the composition of the present disclosure may be selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0109] In some examples, the ADP receptor / P2Y12 inhibitor of the composition of the present disclosure may be selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor.

[0110] In some examples, the fifth composition of the present disclosure further comprises at least a fourth antiplatelet agent distinct from the first and second antiplatelet agents, wherein the fourth antiplatelet agent may comprise one or more of prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0111] In some examples, the fifth composition of the present disclosure further comprises a chelating agent, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3 -The following may be selected from the group consisting of dimercaptopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactants, EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, salts thereof, analogs, solvates, hydrates and derivatives.

[0112] In some examples, the fifth composition of the present disclosure further comprises at least one antiproliferative agent, such as an mTOR inhibitor.

[0113] A sixth composition for coating the surface of an implantable article according to the principles of the present disclosure comprises a direct factor IIa inhibitor and one or more of the following: (a) colchicine, (b) glycoprotein IIb / IIIa inhibitor; (c) an NSAID; and (d) an ADP inhibitor, wherein the direct factor Xa inhibitor and one or more of the following are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0114] In some examples, the sixth composition of this disclosure, a direct factor IIa inhibitor, as well as a first antiplatelet agent comprising (a) colchicine, (b) a glycoprotein IIb / IIIa inhibitor, a second antiplatelet agent comprising (c) an NSAID, and a third antiplatelet agent comprising (d) an ADP inhibitor, are formulated to treat injuries resulting from article implantation.

[0115] In some examples, the sixth composition of the present disclosure, a direct factor IIa inhibitor, as well as a first antiplatelet agent comprising (a) colchicine, (b) a glycoprotein IIb / IIIa inhibitor, a second antiplatelet agent comprising (c) an NSAID, and a third antiplatelet agent comprising (d) an ADP inhibitor, are formulated to treat injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of systemic antithrombotic agents.

[0116] In some examples, the direct factor IIa inhibitor of the sixth composition of the present disclosure may be selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, and typically comprises argatroban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0117] In some examples, the sixth composition of this disclosure is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The present invention further comprises a direct factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), the direct factor Xa inhibitor typically comprises (a) apixaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, or (b) rivaroxaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0118] In some examples, the glycoprotein IIb / IIIa inhibitor of the sixth composition of the present disclosure may be selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0119] In some examples, the ADP receptor / P2Y12 inhibitor of the sixth composition of the present disclosure may be selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor.

[0120] In some examples, the sixth composition of the present disclosure further comprises at least a fourth antiplatelet agent distinct from the first and second antiplatelet agents, wherein the fourth antiplatelet agent may comprise one or more of prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0121] In some examples, the sixth composition of the present disclosure further comprises a chelating agent, typically ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3- The following are selected from the group consisting of dimercaptopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives.

[0122] In some examples, the sixth composition of the present disclosure further comprises at least one antiproliferative agent, typically an mTOR inhibitor.

[0123] A seventh composition for coating the surface of an implantable article according to the principles of the present disclosure comprises (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, (b) at least one antiplatelet agent selected from (i) a first antiplatelet agent comprising a COX-1 inhibitor, (ii) a second antiplatelet agent comprising a glycoprotein IIb / IIIa (2a / 3b) inhibitor, and (iii) a third antiplatelet agent comprising an adenosine diphosphate (ADP) / P2Y12 inhibitor, wherein (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, and (b) at least one antiplatelet agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0124] In some examples, the seventh composition of the present disclosure comprises a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, the direct factor IIa inhibitor typically comprises argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0125] In some examples, the seventh composition of this disclosure is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The present invention comprises a direct factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), the direct factor Xa inhibitor typically comprises (a) apixaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, or (b) rivaroxaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0126] In some examples, the seventh composition of this disclosure comprises a COX-1 inhibitor, typically a salicylate or other NSAID.

[0127] In some examples, the seventh composition of the present disclosure comprises a glycoprotein IIb / IIIa inhibitor selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0128] In some examples, the seventh composition of the present disclosure comprises an ADP receptor / P2Y12 inhibitor selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor.

[0129] In some examples, the seventh composition of the present disclosure comprises at least one of a prostaglandin analog, a thromboxane inhibitor, and a phosphodiesterase inhibitor.

[0130] In some examples, the seventh composition of the present disclosure comprises a chelating agent, typically ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-di The following are selected from the group consisting of mercaptopropanesulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives.

[0131] In some examples, the seventh composition of the present disclosure comprises at least one antiproliferative agent, typically an mTOR inhibitor.

[0132] An eighth composition for coating the surface of an implantable article according to the principles of the present disclosure comprises (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, (b) at least one of (i) colchicine, (ii) a first antiplatelet agent, and (iii) a chelating agent, wherein (a) at least one of a direct factor IIa inhibitor and a direct factor Xa inhibitor, and (b) at least one of (i) colchicine, (ii) a first antiplatelet agent, and a chelating agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0133] In some examples, the eighth composition of the present disclosure comprises a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, wherein the direct factor IIa inhibitor includes argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0134] In some examples, the eighth composition of this disclosure is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The present invention comprises a direct factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), the direct factor Xa inhibitor typically comprises (a) apixaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, or (b) rivaroxaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0135] In some examples, the eighth composition of this disclosure comprises colchicine.

[0136] In some examples, the eighth composition of the present disclosure comprises one or more antiplatelet agents selected from the group consisting of glycoprotein IIb / IIIa inhibitors, ADP receptor / P2Y12 inhibitors, COX-1 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0137] In some examples, the eighth composition of this disclosure is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropane sulfoacetic acid The product contains EDTA acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives, as well as chelating agents selected from the group.

[0138] In some examples, the eighth composition of the present disclosure comprises at least one antiproliferative agent, typically an mTOR inhibitor.

[0139] In another example, the therapeutic composition comprises, in an implantable device, one or two antiplatelet agents selected from glycoprotein IIb / IIIa inhibitors, P2Y12 inhibitors, and aspirin, plus additional optional anti-inflammatory agents selected from colchicine, and optionally an anti-proliferation agent, such as mTOR, or a microtubule inhibitor, such as paclitaxel, in combination with one or more agents selected from the group consisting of direct factor Xa inhibitors and direct factor IIa inhibitors, where this combination achieves a higher synergistic inhibitory effect than that achieved by coating with any of the drugs alone.

[0140] In some cases, therapeutic compositions were formulated to combine colchicine with other drugs, such as rivaroxaban, argatroban, and tirofiban, which achieved a higher synergistic inhibitory effect than any of the drugs alone could achieve.

[0141] In some cases, therapeutic compositions were further formulated to combine colchicine with other drugs, such as rivaroxaban, argatroban, tirofiban, ticagrelor, and mTOR, and these combinations achieved higher synergistic inhibitory effects than any of the drugs alone could achieve.

[0142] In other examples, therapeutic compositions include a combination of a direct factor Xa inhibitor and two, three, or more other therapeutic agents selected from the group consisting of glycoprotein IIb / IIIa inhibitors, P2Y12 inhibitors, and aspirin, as well as an anti-inflammatory agent selected from colchicine, in drug coatings for stents and other implantable devices, where the combination achieves a higher synergistic inhibitory effect than that achieved by coatings using any one of the drugs alone.

[0143] In other examples, the therapeutic composition may include a combination of a direct factor IIa inhibitor and two, three, or more other therapeutic agents selected from the group consisting of glycoprotein IIb / IIIa inhibitors, P2Y12 inhibitors, and aspirin, as well as an anti-inflammatory agent selected from colchicine, in a drug coating for stents and other implantable devices, wherein the combination achieves a higher synergistic inhibitory effect than that achieved by coating with any of the drugs alone.

[0144] In other examples, the therapeutic composition may include, in drug coatings for stents and other implantable devices, a combination of a direct factor Xa inhibitor and an antiplatelet substance selected from glycoprotein IIb / IIIa inhibitors, P2Y12 inhibitors, and aspirin, where this combination achieves a higher synergistic inhibitory effect than that achieved by coatings using any one of the drugs alone.

[0145] In other examples, the therapeutic composition may include a combination of a direct factor IIa inhibitor and an antiplatelet substance selected from glycoprotein IIb / IIIa inhibitors, P2Y12 inhibitors, and aspirin in a drug coating for stents and other implantable devices, where this combination achieves a higher synergistic inhibitory effect than that achieved by coating with any of the drugs alone.

[0146] The compositions of this disclosure are typically coated onto articles configured to be implanted in a patient's body. For example, an implantable article may consist of a body having a surface configured for implantation in a patient, the surface being coated at least partially with one of the compositions described above.

[0147] In some examples, the article includes an expandable scaffold configured for implantation in the patient's vascular system.

[0148] In some examples, the article consists of a non-expandable body.

[0149] In some cases, the composition is formulated to be released from the article over a period of at least one week, one month, or one year.

[0150] In some cases, at least the components of the composition may be formulated in one or more carriers that degrade when implanted in a patient.

[0151] In some cases, the composition may be formulated to release 90%, 75%, 50%, 25%, or 10% or less of its weight within one week, one month, three months, six months, or one year of implantation.

[0152] The exemplary chelating agents in the therapeutic composition may be formulated to deplete calcium in the environment surrounding the scaffold, during the embedding of the scaffold structure in the said environment.

[0153] In specific examples, the therapeutic composition may be formulated to release at least 50% by weight, preferably at least 75% by weight, of at least one chelating agent into the vascular environment within 72 hours of implantation, preferably within 24 hours of implantation, more preferably within 6 hours of implantation, and even more preferably within 4 hours of implantation.

[0154] In additional examples, the therapeutic composition may be formulated to release an additional amount of at least one chelating agent into the environment for at least 3 days, preferably at least 7 days, more preferably 21 days, and more preferably at least 28 days, even more preferably at least 3 months, and often 6 months or longer, after implantation. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, and magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), and 2,3-dimercaptopropane sulfopropyl alcohol. The following may be selected from the group consisting of EDTA acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives.

[0155] In certain cases, the chelating agent is essentially derived from ethylenediaminetetraacetic acid (EDTA).

[0156] A therapeutic composition that may contain, essentially consist of, or otherwise contain a chelating agent, wherein the chelating agent may be present in the therapeutic composition in a weight percentage of 10% to 100%. In a specific example, the therapeutic composition consists essentially of a chelating agent, wherein the sole active component in the therapeutic composition is the chelating agent, which is present together with other inactive components and ingredients as needed. In another example, the therapeutic composition contains a chelating agent in combination with additional active and / or inactive substances. In such an example, the additional active and / or inactive substances may be present in the therapeutic composition in a weight percentage of 20% to 90%.

[0157] In some examples, the therapeutic compositions of the present disclosure may further comprise a cationic anticoagulant, which may be selected from the group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salts, toridodecylmethylammonium salts, other benzalkonium compounds, their analogues, solvates, hydrates, and derivatives. Alternatively, or in addition, the cationic anticoagulant may be selected from the group consisting of cationic polymers or compounds, which include, but are not limited to, poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branched polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, polybetaaminoesters (PBAEs), histones, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, their analogues, solvates, hydrates, and derivatives.

[0158] In specific examples, the cationic anticoagulant enhancer may contain, be essentially, or be derived from benzyldimethyltetradecylammonium chloride.

[0159] In specific examples, the cationic anticoagulant enhancer may contain, be essentially, or be composed of linear polyethyleneimine (PEI).

[0160] Any of the therapeutic compositions described above may further contain at least one anticoagulant. In such an example, the therapeutic composition may be formulated to release at least one anticoagulant at a rate equal to the rate of the chelating agent. Alternatively, the therapeutic composition may be formulated to release at least one anticoagulant at a rate slower than the rate of the chelating agent. Alternatively, the therapeutic composition may be formulated to release at least one anticoagulant at a rate faster than the rate of the chelating agent.

[0161] In specific examples, the anticoagulant may be selected from the group consisting of direct factor IIa inhibitors and direct factor Xa inhibitors. Exemplary direct factor IIa inhibitors may be selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine. Preferred direct factor IIa inhibitors include argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0162] Examples of direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052) may be selected. The first preferred direct factor Xa inhibitor comprises apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. The second preferred direct factor Xa inhibitor comprises rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0163] Any of the therapeutic compositions described above may further contain an mTOR inhibitor selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotalolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. Preferred MTOR inhibitors include sirolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.

[0164] Any of the therapeutic compositions described above may further comprise paclitaxel, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0165] Any of the therapeutic compositions described above may further contain an antiplatelet agent. Any of the therapeutic compositions described above may further contain an antiproliferative agent selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, and azathioprine.

[0166] The implantable scaffolds of this disclosure may have any one of a wide variety of known structures suitable for implantation and expansion at a target site on a patient's body. In many cases, the scaffold has at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces. In such examples, at least a portion of the outer surface may be coated with a therapeutic composition. In other examples, at least a portion of the inner surface may be coated with a therapeutic composition. In yet another example, a portion of the end surface may be coated with a therapeutic composition. As an alternative to, or in addition to, surface coating, at least a portion of the surface may have a container formed therein, and at least a portion of the container may contain a therapeutic agent. For example, the container may include one or more of wells, channels, pores, and surface textures.

[0167] In a second aspect, the present disclosure provides a method for treating vascular tissue injury in a patient. The method comprises implanting a scaffold structure at a target site in the patient's vascular structure adjacent to the tissue injury, and releasing a drug composition comprising at least one chelating agent from the implanted scaffold structure into the vascular structure, wherein the chelating agent is released into the vascular structure sufficiently rapidly to prevent blood coagulation and inhibit fibrin formation.

[0168] In certain cases, at least 75% by weight of at least one chelating agent is released into the vascular structure within 72 hours of implantation, preferably within 24 hours, more preferably within 6 hours, and even more preferably within 4 hours, typically within 10 minutes to 4 hours.

[0169] Further examples of the methods described herein include ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopro The chelating agent may be selected from the group consisting of pansulfonic acid (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives. In a specific example, the chelating agent is essentially ethylenediaminetetraacetic acid (EDTA).

[0170] In some examples, the therapeutic composition further comprises a cationic anticoagulant enhancer. For example, the cationic anticoagulant enhancer may be selected from the group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salts, toridodecylmethylammonium salts, other benzalkonium compounds, their analogs, solvates, hydrates, and derivatives.

[0171] Cationic anticoagulant enhancers may be selected from the group consisting of cationic polymers or compounds, but are not limited to, poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branched polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, polybeta-aminoester (PBAE), histones, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, their analogs, solvates, hydrates, and derivatives. In a specific example, the cationic anticoagulant enhancer essentially consists of benzyldimethyltetradecylammonium chloride. In another specific example, the cationic anticoagulant enhancer essentially consists of linear polyethyleneimine (PEI).

[0172] The therapeutic composition delivered by the method of the present disclosure may further comprise at least one anticoagulant. For example, at least one anticoagulant may be selected from the group consisting of direct factor IIa inhibitors and direct factor Xa inhibitors. Alternatively, at least one anticoagulant may comprise a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine. Exemplary direct factor IIa inhibitors may comprise argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0173] Other examples of the methods herein include at least one anticoagulant such as apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The direct factor Xa inhibitor may be selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). In one example, the direct factor Xa inhibitor may include apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. In another example, the direct factor Xa inhibitor may include rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0174] The therapeutic composition delivered by the method of the present disclosure may further comprise an mTOR inhibitor selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotalolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. An example of an mTOR inhibitor is sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0175] The therapeutic composition delivered by the method of this disclosure may further comprise paclitaxel, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0176] The therapeutic composition delivered by the method of this disclosure may further comprise an antiplatelet agent.

[0177] In all of the methods described herein, the therapeutic composition may be placed on at least one of the internal and external surfaces of the implantable scaffold, and / or on both the external and internal surfaces of the implantable scaffold.

[0178] The method of this disclosure is generally suitable for treating tissue damage caused by extending scaffolding in place, but is also useful for treating pre-existing tissue damage by deploying a structure in place.

[0179] In a third aspect, the disclosure provides an implant comprising a body structure having a surface configured to be embedded in a patient's body. A therapeutic composition is present on the surface of the body structure, wherein the therapeutic composition comprises at least one drug selected from the group consisting of chelating agents, direct factor IIa inhibitors, and direct factor Xa inhibitors, wherein the therapeutic composition is formulated for delayed release into the environment surrounding the body structure upon implantation of the body structure into the environment.

[0180] In some cases, the therapeutic composition may be formulated for rapid release into the environment surrounding the main structure during a pre-selected period after the main structure has been embedded in the environment.

[0181] An implant may be any type of therapeutic, diagnostic, or other structure intended for implantation in a patient's body, and is typically an expandable scaffold, such as a vascular stent, artificial heart valve, patent foramen ovale (PFO) occlusion device, atrial septal defect (ASD) occlusion device, left atrial appendage (LAA) occlusion device, or similar expandable structure, or an orthopedic implant.

[0182] In such examples, the therapeutic composition may be present, at least in part, on the surface of the main structure. Alternatively, or in addition, the therapeutic composition may be present, at least in part, within cavities or reservoirs within the main structure.

[0183] The therapeutic composition may be formulated to inhibit the release of at least one drug into the environment surrounding the main structure for a period of time having a lower limit selected from 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 45 minutes, and an upper limit selected from 1 hour, 2 hours, 3 hours, and 4 hours, as well as all combinations thereof.

[0184] The therapeutic composition may be formulated to release at least 50% by weight, preferably at least 75% by weight, of at least one drug into the environment surrounding the main body structure within 72 hours of implantation, preferably within 24 hours of implantation, more preferably within 6 hours of implantation, and even more preferably within 4 hours of implantation.

[0185] The therapeutic composition may be formulated to release an additional amount of at least one drug into the environment for at least 3 days, preferably at least 7 days, more preferably 21 days, and even more preferably at least 28 days, and even more preferably at least 3 months, and often 6 months or longer, after implantation.

[0186] In some examples, the drug in the therapeutic composition may include a chelating agent in the therapeutic composition that is formulated to deplete calcium in the environment surrounding the main structure, upon embedding the main structure in the environment. Such chelating agents include ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), and 2,3-dimercaptopropane sulfone. The group may be selected from acids (DMPS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactants-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives. A specific example of a chelating agent is essentially ethylenediaminetetraacetic acid (EDTA).

[0187] In some examples, the therapeutic composition may further contain a cationic anticoagulant enhancer. For example, the cationic anticoagulant enhancer may be selected from the group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salts, toridodecylmethylammonium salts, other benzalkonium compounds, their analogues, solvates, hydrates, and derivatives. Alternatively, or in addition, the cationic anticoagulant enhancer may be selected from the group consisting of cationic polymers or compounds, including, but not limited to, poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branched polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, polybetaaminoesters (PBAEs), histones, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, their analogues, solvates, hydrates, and derivatives. In a specific example, a cationic anticoagulant enhancer essentially consists of benzyldimethyltetradecylammonium chloride. In another specific example, a cationic anticoagulant enhancer essentially consists of linear polyethyleneimine (PEI).

[0188] In some examples, at least one drug may include a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine. For example, at least one direct factor IIa inhibitor may include argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0189] In some cases, at least one drug is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The formulation may include a direct factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). For example, the direct factor Xa inhibitor may include apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. In another example, the direct factor Xa inhibitor may include rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0190] In some cases, at least one drug is an antisense oligonucleotide, including, but not limited to, IONIS-FXI and fesomersen; a monoclonal antibody (mAb), including, but not limited to, osocimab, avelacimab, xisomab (AB023), REGN9933 and MK-2060; a monoclonal antibody (mAb), including, but not limited to, milbexian, asundexian, SHR2285, BMS-262084, BMS-654457, BMS-986177, BMS-962212, ONO-5450598, ONO-7684 and BAY The formulation may include small molecule and protein Z-dependent protease inhibitors (ZPIs), including 2433334 and frunexian (EP-7041), as well as factor XI / XIa inhibitors selected from the group consisting of all of the above analogs, solvates, hydrates, or derivatives.

[0191] In specific examples, a ZPI-containing cationic anticoagulant enhancer may contain, be essentially, or be derived from asundexian or milbexian, which are small molecule factor XIa inhibitors having the formula [(6r,10s)-10-{4-[5-chloro-2-(4-chloro-1h-1,2,3-triazole-1-yl)phenyl]-6-oxo-1(6h)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(methano)pyrazolo[4,3-b][1,7]diazacyclotetradecine-5(6h)-one], and whose full disclosure is incorporated herein by reference in WO2020 / 210613 and WO2020 / 210629.

[0192] In some cases, the therapeutic composition is formulated to release one or more active substances at a rate sufficient to produce tissue concentrations of at least one active ingredient at the injury site within the range of at least about 0.05 ng / m², at least about 0.15 ng / m², or at least about 0.3 ng / m² within approximately 3 hours, 6 hours, 12 hours, 1 day, 3 days, 7 days, 30 days, or 6 months. The resulting concentrations of at least one active ingredient may be found at the injury site, adjacent to the implantable device containing the active ingredient, at the terminal end of the implantable device, and on the body lumen sides of the implantable device.

[0193] In some cases, the therapeutic composition was found to be effective within approximately 3 hours, 6 hours, 12 hours, 1 day, 3 days, 7 days, 30 days, or 6 months, at concentrations of approximately 0.05 ng / tissue mg to approximately 100 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 50 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 25 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 10 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 7 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 5 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 2 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 1 ng / tissue mg, approximately 0.05 ng / tissue mg to approximately 0.75 ng / tissue mg, approximately 0.15 ng / tissue mg to approximately 100 ng / tissue mg, and approximately 0.15 ng / tissue mg. The formulation is designed to release at least one or more active substances at a rate sufficient to produce tissue concentrations of at least one active ingredient at the site of injury, within the ranges of g / tissue mg to approximately 50 ng / tissue mg, approximately 0.15 ng / tissue mg to approximately 25 ng / tissue mg, approximately 0.15 ng / tissue mg to approximately 10 ng / tissue mg, approximately 0.3 ng / tissue mg to approximately 100 ng / tissue mg, approximately 0.3 ng / mg to approximately 50 ng / tissue mg, approximately 0.3 ng / tissue mg to approximately 25 ng / tissue mg, approximately 0.3 ng / tissue mg to approximately 10 ng / tissue mg, approximately 0.3 ng / tissue mg to approximately 5 ng / tissue mg, and approximately 0.3 ng / tissue mg to approximately 1 ng / tissue mg.

[0194] The active ingredients of the therapeutic composition may be formulated in varying amounts relative to each other. In some examples, the active ingredients are formulated to provide equal tissue concentrations of each active ingredient, amounts that provide twice the tissue concentration of one active ingredient compared to others, amounts that provide three times the tissue concentration of one active ingredient compared to others, or amounts that provide four times the tissue concentration of one active ingredient compared to others, within 3 hours, 6 hours, 7 hours, 12 hours, 1 day, 3 days, 7 days, 30 days, or 6 months. By utilizing these ranges of active ingredients for providing the tissue concentrations disclosed herein, and the proportions of each active ingredient described, a remarkably synergistic result of increased blood clotting time is obtained.

[0195] The amounts of active ingredients may vary relative to each other. It is possible within this disclosure to use two, three, four or more active ingredients to achieve synergistic results resulting in a reduction of clotting time. For example, a combination of anticoagulants (or) and antiplatelet agents produces a synergistic effect. A combination of anticoagulants (or) and colchicine produces a synergistic effect. A combination of anticoagulants (or), antiplatelet agents, and anti-inflammatory agents, such as colchicine, produces a synergistic effect. When using anticoagulants, such as direct factor Xa inhibitors and direct factor IIa inhibitors, either inhibitor can be used in relation to other inhibitors in a weight composition ratio of approximately 0.5:1 to approximately 5:1. When using anticoagulants, for example, a direct factor Xa inhibitor or a direct factor IIa inhibitor, alone or together, and an antiplatelet agent, for example, tirofiban or ticagrelor, the weight composition ratio may be approximately 0.5:1 to 5:1 for either or both anticoagulants, compared to a weight composition ratio of approximately 0:5:1 to 5:1 for the antiplatelet agent, or approximately 0:5:1 to 2:1, or approximately 0.5:1 to 3:1 for either or both anticoagulants. When using anticoagulants, for example, a direct factor Xa inhibitor or a direct factor IIa inhibitor, and an anti-inflammatory agent, for example, colchicine, the weight composition ratio may be approximately 0.5:1 to 5:1 for either or both anticoagulants, compared to a weight composition ratio of approximately 0:5:1 to 5:1 for the anti-inflammatory agent, or approximately 0:5:1 to 2:1, or approximately 0.5:1 to 3:1 for either or both anticoagulants. These weight composition ratios may be used for compositions containing direct factor Xa inhibitors, direct factor IIa inhibitors, antiplatelet agents, and anti-inflammatory agents, such as colchicine. Surprisingly, the synergistic effect results in a reduction in clotting time compared to controls from these compositions.

[0196] In some embodiments, the therapeutic compositions of the present disclosure may contain two, three, four, or more active ingredients. In some examples, the active ingredients are formulated in varying amounts relative to one another. For example, a first active ingredient may be defined by the weight composition ratio of the first active ingredient to the remainder of the active ingredients. In some cases, the ratio may be approximately 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, or any ratio within the range between any two preceding values.

[0197] For example, the first and second active ingredients may be defined by the weight composition ratio of the first and second active ingredients to the remainder of the active ingredients. In some cases, the ratio may be about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 100:1, or any ratio within the range between any two preceding values.

[0198] For example, the first, second, and third active ingredients may be defined by the weight composition ratio of the first, second, and third active ingredients to the remainder of the active ingredients. In some cases, the ratio may be about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 100:1, or any ratio within the range between any two preceding values.

[0199] For example, the first, second, third, and fourth active ingredients may be defined by the weight composition ratio of the first, second, third, and fourth active ingredients to the remainder of the active ingredients. In some cases, the ratio may be about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 100:1, or any ratio within the range between any two preceding values.

[0200] In other examples, the therapeutic composition may further comprise an mTOR inhibitor selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotalolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. In specific examples, the mTOR inhibitor comprises sirolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.

[0201] In other examples, the composition may further comprise paclitaxel, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. In other examples, the therapeutic composition may further comprise an antiplatelet agent. In other examples, the therapeutic composition may further comprise an antiproliferative agent selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, and azathioprine.

[0202] In preferred embodiments, the therapeutic composition is formulated to release 90% by weight, 75% by weight, 50% by weight, 25% by weight, or less than 10% by weight of colchicine and / or tyrofiban from the scaffold to the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0203] In preferred embodiments, the therapeutic composition is formulated to release 90% by weight, 75% by weight, 50% by weight, 25% by weight, or 10% by weight or less of the antiproliferative substance from the scaffold to the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0204] In a preferred embodiment, the scaffold structure is loaded with colchicine and / or tyrofiban in amounts ranging from 1.7 μg to 170 μg, 1.7 μg to 85 μg, 2.5 μg to 40 μg, or 3.4 μg to 20 μg per 1 mm of length of the scaffold structure.

[0205] In a preferred embodiment, the scaffold structure is loaded with an amount of antiproliferative agent in the range of 2 μg to 200 μg, 2 μg to 100 μg, 3 μg to 50 μg, or 4 μg to 20 μg per 1 mm of length of the scaffold structure.

[0206] In preferred embodiments, the carrier comprises a biodegradable polymer. For example, the biodegradable polymer may be selected from the group consisting of polyesters, e.g., polylactic acid, polyglycolic acid, polylactic acid-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol-block-polycaprolactone, and polyurethane; poly(methyl methacrylate) (PMMA); poly-N-(2-hydroxypropyl)methacrylamide; polyethyleneimine (PEI), dextran, dextrin, chitosan, poly(L-lysine); poly(aspartamide), polyethylene; polypropylene; polyamide; polyethylene glycol (PEG); silicone; poly(acid anhydride); and polyorthoesters.

[0207] In some cases, the therapeutic composition may further include at least one anticoagulant. For example, the at least one anticoagulant may be a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0208] Other examples include at least one anticoagulant such as apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD It may also be a direct factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0209] In some cases, the therapeutic composition may further contain an antiplatelet agent. For example, the antiplatelet agent may include, but is not limited to, absiximab, eptifivatide, orbofivan, roxifivan, sibrafivan, and tyrofivan, which are glycoprotein IIb / IIIa inhibitors; but is not limited to, clopidogrel, prasugrel, ticlopidine, cangrelor (cCangrelor), erinogrel, and ticagrelor, which are ADP receptor / P2Y12 inhibitors; but is not limited to, beraprost, iloprost, prostacyclin, and treprostinil, which are prostaglandin analog (PGI2) inhibitors; but is not limited to, acetylsalicylic acid / aspirin, alloxipurine, and carbasalate calcium (cCarbasalate COX inhibitors, including calcium, indobufen, triflusal, and dipyridamole; thromboxane inhibitors, including but not limited to picotamide, tervogrel, tertroban, aspirin, lidogrel, and ramatroban; phosphodiesterase inhibitors, including but not limited to cilostazol, dipyridamole, triflusal, and milrinone; other inhibitors, including but not limited to chloricromene, ditasol, and borapaxar; PAR / PAR-1 antagonists, e.g., SCH530348, Atopaxor, borapaxar, and E-5555; GPIa / IIa inhibitors, e.g., EMS16; adhesion antagonists, e.g., DZ-697b and RG12986; or derivatives, analogs, or salts thereof.

[0210] In preferred examples, the antiplatelet agent is a glycoprotein IIb / IIIa platelet inhibitor, such as tirofiban, or its derivatives, analogues, or salts. Particularly useful formulations, when used in combination, include colchicine and / or tirofiban along with sirolimus or another mTOR inhibitor.

[0211] In some cases, the therapeutic composition may further include a second antiproliferative agent. For example, the second antiproliferative agent may be selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, and azathioprine.

[0212] In some examples, the therapeutic composition may further comprise a factor XI / XIa inhibitor. Examples of factor XI / XIa inhibitors include, but are not limited to, antisense oligonucleotides, including IONIS-FXI and fesomersene; but are not limited to, monoclonal antibodies (mAbs), including osocimab, avelacimab, xisomab (AB023), REGN9933 and MK-2060; but are not limited to, small molecules, including milbexian, asundexian, SHR2285, BMS-262084, BMS-654457, BMS-986177, BMS-962212, ONO-5450598, ONO-7684, and BAY 2433334 and flunexian (EP-7041); protein Z-dependent protease inhibitors, and all of the above analogs, solvates, hydrates or derivatives.

[0213] In some examples, the therapeutic composition may further comprise thrombin, a thrombotic agent, and a specific inhibitor of factor IXa, factor XI, factor XIa, factor XII, factor XIIa, factor XIII, factor XIIIa, factor VIIa, or factor VIIIa.

[0214] In some cases, the therapeutic composition may further include a chelating agent formulated to deplete calcium in the environment surrounding the scaffold, during the embedding of the scaffold structure in the said environment.

[0215] A delayed composition release embeddable scaffold may have at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces, wherein at least a portion of the outer surface may be coated with the therapeutic composition. In addition, or / or, at least a portion of the inner surface may be coated with the therapeutic composition. In addition, or / or, at least a portion of the end surface may be coated with the therapeutic composition. In addition, or / or, at least a portion of the surface may have a container formed therein, and at least a portion of the container may contain the therapeutic agent. For example, the container may include one or more of wells, channels, pores, and surface textures.

[0216] In another embodiment, the disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to expand within a patient's body. The first therapeutic composition comprises a first drug formulation which is coated, layered, bonded, or otherwise attached to the scaffold and comprises at least one drug selected from the group consisting of calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors. The second therapeutic composition also comprises a second drug formulation which is coated, layered, bonded, or otherwise attached to the scaffold structure and / or the first therapeutic composition and comprises at least one drug selected from the group consisting of calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors. The first therapeutic composition is formulated for rapid release of the first drug formulation into the vascular environment, and the second therapeutic composition is formulated for extended release of the second drug formulation into the vascular environment.

[0217] The implantable scaffold may have any conventional or novel structure intended for implantation in the patient's vascular structure, including coronary arteries and veins, peripheral and central vascular structures. The scaffold may be intended for direct implantation, for example, by including or consisting of a vascular stent intended to maintain patency in a vascular lumen. In addition, the scaffold may be part of an assembly that includes additional components, such as vascular grafts, prosthetic valves, etc. Depending on the intended purpose, the scaffold may be non-degradable in the vascular environment, for example, by being formed from or otherwise containing a metal or polymer that is non-degradable in the vascular environment. In other examples, the scaffold may be degradable in the vascular environment, for example, by being formed from or otherwise containing a metal or polymer that is degradable in the vascular environment.

[0218] In addition to such implantable scaffolds, the therapeutic compositions and drug formulations described below may also find applications using a wide variety of other implantable and non-implantable devices, as well as tools that can be used for unwanted coagulation, as described elsewhere in this specification.

[0219] The rapid release of the first drug formulation and the prolonged release of the second drug formulation typically act in combination to accelerate the resolution of one or more of the following: inflammation, cell proliferation, internal lamina elastica (IEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or to inhibit one or more of the following: inflammation, cell proliferation, internal lamina elastica (IEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or to increase or prolong the time before blood clots or thrombi form.

[0220] In specific examples, at least one of the first, second, and third drug formulations may contain a calcium chelating agent, a direct factor IIa inhibitor, and a direct factor Xa inhibitor. In other examples, the first, second, and third drug formulations may each contain a calcium chelating agent, a direct factor IIa inhibitor, and a direct factor Xa inhibitor, respectively.

[0221] In a specific example, at least one drug of the first (rapid-release) drug formulation is released from the first therapeutic composition over a first period (duration) which is typically in the range of 5 minutes to 28 days after implantation, usually 5 minutes to 3 days after implantation, preferably 5 minutes to 1 day after implantation. The first therapeutic composition is typically configured to release at least one drug of the first drug formulation at an average rate in the range of 2 μg / hour to 40 μg / hour, usually 2 μg / hour to 30 μg / hour, preferably 2 μg / hour to 10 μg / hour, over a period of 24 hours after exposure to the vascular environment, where the average rate may be determined based on the amount (weight) of drug released over the total duration of release.

[0222] In a specific example, at least one drug of the second drug formulation (sustained-release) is released from the second therapeutic composition over a second period ranging from 30 days to 12 months after implantation, typically from 30 days to 9 months, preferably from 30 days to 6 months after implantation. The second therapeutic composition is typically configured to delay the release of at least one drug of the second drug formulation for at least one 24-hour period after exposure to the vascular environment. The second therapeutic composition is typically configured to release at least one drug of the second drug formulation at an average rate not exceeding 2 μg / hour, typically 1 μg / hour, preferably 0.5 μg / hour, and more preferably 0.1 μg / hour, after a 24-hour period after exposure to the vascular environment, where the average rate may be determined based on the amount (weight) of drug released over the total duration of release.

[0223] The first and second therapeutic compositions typically contain, but not always contain, polymers, and typically contain, but not necessarily, carriers, matrices, or coatings to isolate and control the rate and duration of drug release. In some examples, the drug may be without polymers or other carriers, but may be coated, layered, or otherwise deposited on or within a surface or container in an embeddable structure using additives, coatings, and other common drug coating materials, as needed.

[0224] In some examples, one of the first and second therapeutic compositions may contain a polymer, while the other does not. For example, the first therapeutic (rapid-release) composition may not contain a polymer, while the second (sustained-release) therapeutic composition may contain a polymer to maintain or control the release rate and duration. For example, the first therapeutic composition may be coated onto a scaffold structure or over the second therapeutic composition to influence burst release.

[0225] In examples where the first and second therapeutic compositions each contain a polymer, the first therapeutic composition has a first drug-to-polymer weight ratio, and the second therapeutic composition has a second drug-to-polymer weight ratio. The ratios may be the same, but more often they are different. For example, the first drug-to-polymer weight ratio may be in the range of 5:1 to 1:3, usually 5:2 to 1:2, preferably 5:3 to 1:1, and the second drug-to-polymer weight ratio may be in the range of 5:2 to 1:5, usually 5:3 to 2:5, preferably 1:1 to 1:2. The first drug-to-polymer weight ratio is usually greater than the second drug-to-polymer weight ratio (higher loading may enhance the burst effect in the first therapeutic composition), but in some examples, the first drug-to-polymer weight ratio may be smaller than the second drug-to-polymer weight ratio (higher loading may also enhance the duration of release).

[0226] The drug release from the first and second therapeutic compositions may begin simultaneously, but in many examples, the first and second therapeutic compositions are configured to delay the start of the release of the second drug formulation for a certain period after the start of the release of the first drug formulation. For example, the first therapeutic composition may be layered over the second therapeutic composition to delay the release of the second drug formulation. For instance, the first therapeutic composition may initially cover at least a portion of the second therapeutic composition and then dissolve in the vascular environment over that period, exposing the second therapeutic composition and enabling the release of the second drug formulation.

[0227] Alternatively, the sacrificial layer may be present over at least one of the first and second therapeutic compositions, or between them, to delay the release of one or more drugs from either or both of the first and second therapeutic compositions.

[0228] Alternatively, the diffusion rate control layer may be located over at least one of the first and second therapeutic compositions, or between them, to control the release rate of one or more drugs from either or both of the first and second therapeutic compositions.

[0229] The polymer(s) may be configured to release the first and / or second drug formulation, at least partially, by dissolution of the polymer when exposed to the vascular environment. For example, the polymer of the first therapeutic composition may dissolve in the vascular environment at a faster rate than the dissolution of the second therapeutic composition. Alternatively, the polymer may be configured to release the first and / or second drug formulation, at least partially, by a diffusion mechanism through the polymer when exposed to the vascular environment. Alternatively, the polymer may be configured to release the first and / or second drug formulation, at least partially, by a combination of dissolution and diffusion through the polymer when exposed to the vascular environment.

[0230] While not always the case, typically one or more polymers are porous, where the first and / or second drug formulations are sequestered within the pores of the polymer. In many cases, the release rate of the first and / or second drug formulations can be determined, at least in part, by the pore size of the polymer. In some examples, the polymers of the first and second drug formulations may have different pore sizes, providing different release rates.

[0231] In other examples, the first and second drug formulations may be separated, at least partially, into different regions within the porous polymer. Alternatively, or in addition, the first and second drug formulations may be present, at least partially, within overlapping regions of the porous polymer.

[0232] In a preferred example, the embeddable scaffold of the present disclosure further comprises an antiproliferative agent. The antiproliferative agent may be present in either or both of the first and second drug formulations, or in the third drug formulation, or separately, it may coat, couple, bind to, or adhere to the scaffold. For example, if the scaffold is present in the vascular environment, the antiproliferative agent may be present in a third therapeutic composition formulated to release the antiproliferative agent into the vascular environment.

[0233] The first, second, and optionally third or additional therapeutic compositions of this disclosure may be placed on the exterior, interior, edges, and / or other surfaces of an implantable scaffold. Optionally, but not necessarily, the scaffold surface may be roughened, incised, etched, or otherwise treated to enhance adhesion of the therapeutic composition. In some examples, the therapeutic composition may be isolated in wells, indentations, or other containers formed on or within the scaffold surface.

[0234] Examples of calcium chelating agents in this disclosure include ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate to calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiaminetetraacetic acid The following are selected from the group consisting of hydroxyfluryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), citrates, oxalates, surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates, and derivatives.

[0235] Examples of EDTA complexes in this disclosure include EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, and other EDTA benzalkonium salts, and any chemical substance can form a complex with EDTA.

[0236] Examples of direct factor IIa inhibitors of this disclosure include argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine, which may be used individually or in combination. Preferred direct factor IIa inhibitors include argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0237] Examples of direct factor Xa inhibitors in this disclosure include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD Examples include (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), which may be used individually or in combination. Preferred direct factor Xa inhibitors include (1) apixaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, and (2) rivaroxaban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0238] Examples of antiproliferative agents of this disclosure include mTOR inhibitors selected from the group consisting of mycophenolate mofetil, sodium mycophenolate, azathioprine, sirolimus, biolimus, everolimus, myolimus, noborimus, ridafololimus, temsirolimus, and zotarolimus, or their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, which may be used individually or in combination. Preferred anti-mTOR proliferative agents include sirolimus, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0239] Examples of antiproliferative agents in this disclosure include paclitaxel, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0240] In addition to the first, second, and optionally third therapeutic compositions discussed above, the implantable scaffolds of this disclosure may further include at least one additional drug, typically an antiplatelet agent. The additional drug is not necessarily incorporated as a drug formulation or as part of a therapeutic composition.

[0241] In specific examples of this disclosure, direct factor IIa inhibitors include argatroban, and direct factor Xa inhibitors include apixaban or rivaroxaban. In other specific examples of this disclosure, direct factor IIa inhibitors include argatroban or an analog of argatroban, direct factor Xa inhibitors include apixaban or rivaroxaban, or an analog of apixaban or rivaroxaban, and antiproliferative agents include sirolimus or an analog of sirolimus.

[0242] In some examples, at least one of the therapeutic compositions may contain additives, adjuvants, carriers, or wetting agents. In some examples, the first and second therapeutic compositions may be formed in close proximity. In some examples, the first and second therapeutic compositions are separated by a barrier, such as a polymer layer.

[0243] In some examples, the third therapeutic composition comprises a third drug formulation comprising at least one drug selected from the group consisting of calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors. The third drug formulation may comprise any one of the drugs discussed previously and / or additional drugs. The third therapeutic composition may be arranged at least partially covering the first therapeutic composition, the first therapeutic composition may be arranged at least partially covering the second therapeutic composition, wherein the third therapeutic composition may be configured to produce a burst release more rapidly than the release of either the first or second therapeutic composition.

[0244] In specific examples, the first and second therapeutic compositions may contain polymers, and the third therapeutic composition may not contain polymers, and may be a coating over or deposited on at least a portion of the first therapeutic composition.

[0245] In other examples, the third drug formulation may contain at least one polymer, where the at least one polymer in the third formulation may be the same as and / or different from the at least one polymer in the first and second drug formulations. For example, the at least one polymer in the third formulation may provide a different release rate than that provided by the at least one polymer in the first and second drug formulations. In other examples, the at least one polymer in the third formulation may provide substantially the same release rate as that provided by the at least one polymer in the first and second drug formulations.

[0246] In specific examples, the first, second, or optionally third therapeutic composition may comprise multiple different formulations of at least one drug. For example, a single drug type may be isolated in formulations having polymers with different release rates and / or drug loadings, allowing for further control of drug release characteristics.

[0247] In yet another embodiment, the disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to expand within the patient's body. A first therapeutic composition comprising a first drug formulation comprising at least one of a calcium chelating agent or EDTA complex, argatroban, apixaban, and rivaroaxaban, and sirolimus, is contained in a polymer configured to rapidly release the first drug formulation into the vascular environment. A second therapeutic composition comprises a second drug formulation comprising at least one of argatroban, apixaban, and rivaroaxaban, and sirolimus, contained in a polymer or other carrier configured for extended release of the second drug formulation into the vascular environment.

[0248] The carriers typically include polymers, usually biodegradable polymers, and more commonly, but not always, biodegradable polymers, which are synthetic polymers synthesized from petroleum and other hydrocarbon supply materials. Exemplary biodegradable synthetic polymers are selected from the group consisting of polyesters, e.g., polylactic acid, polyglycolic acid, polylactic acid-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol-block-polycaprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly-N-(2-hydroxypropyl)methacrylamide; polyethyleneimine (PEI), dextran, dextrin, chitosan, poly(L-lysine); poly(aspartamide), polyethylene; polypropylene; polyamide; polyethylene glycol (PEG); silicone; poly(acid anhydride); and polyorthoesters.

[0249] An example of a biodegradable polymer is poly(lactic acid-co-glycolic acid) (PLGA), where PLGA is present in the first therapeutic composition at a concentration of 5 μg to 15 μg per 1 mm of scaffold structure length, and in the second therapeutic composition at a concentration of 5 μg to 20 μg per 1 mm of scaffold structure length.

[0250] Alternatively, the polymer may include, for example, a non-degradable polymer selected from the group consisting of polyacrylate, polymethacrylate, poly(n-butyl methacrylate), poly(hydroxyethyl methacrylate), polyamide, nylon, nylon 12, dacron, polyethylene terephthalate, poly(ethylene glycol), polyethylene oxide (PEO), polydimethylsiloxane, polyvinylpyrrolidone, ethylene-vinyl acetate, phosphorylcholine-containing polymers, poly(2-methacryloyloxyethyl phosphorylcholine), poly(2-methacryloyloxyethyl phosphorylcholine-co-butyl methacrylate), and copolymers thereof.

[0251] In specific examples, at least one of argatroban, apixaban, and rivaroxaban, as well as sirolimus, may be sequestered within the porous structure of PLGA, and the release of direct factor Xa inhibitors, including at least one of argatroban, apixaban, and rivaroxaban, as well as sirolimus, into the vascular environment occurs through a combination of diffusion and dissolution.

[0252] In certain cases, (1) a calcium chelating agent may be present in the first therapeutic composition at a concentration ranging from 2 μg to 15 μg per 1 mm of scaffold structure length, argatroban may be present in the first therapeutic composition at a concentration ranging from 0.5 μg to 3 μg per 1 mm of scaffold structure length, a direct factor Xa inhibitor comprising at least one of apixaban and rivaroxaban may be present at a concentration ranging from 0.5 μg to 3 μg per 1 mm of scaffold structure length, and sirolimus may be present in the first therapeutic composition (1) The material may contain a concentration of 0.5 μg to 3 μg per 1 mm of length of the scaffold structure, (2) Argatroban may contain a concentration of 2 μg to 10 μg per 1 mm of length of the scaffold structure, a direct factor Xa inhibitor containing at least one of apixaban and rivaroxaban may contain a concentration of 2 μg to 10 μg per 1 mm of length of the scaffold structure, and sirolimus may contain a concentration of 2 μg to 10 μg per 1 mm of length of the scaffold structure in the second therapeutic composition.

[0253] In certain cases, (1) argatroban may be present in the first therapeutic composition at a concentration ranging from 0.5 μg to 3 μg per 1 mm of scaffold structure length, a direct factor Xa inhibitor comprising at least one of apixaban and rivaroxaban may be present at a concentration ranging from 0.5 μg to 3 μg per 1 mm of scaffold structure length, sirolimus may be present in the first therapeutic composition at a concentration ranging from 0.5 μg to 3 μg per 1 mm of scaffold structure length, and (2) a calcium chelating agent may be present in the scaffold structure Argatroban may be present in the first therapeutic composition at a concentration ranging from 2 μg to 15 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure, a direct factor Xa inhibitor comprising at least one of apixaban and rivaroxaban may be present at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure5 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10 μg per 1 mm of length of the scaffold structure at a concentration ranging from 2 μg to 10

[0254] In other examples, the first therapeutic composition may be a coating on one or more surfaces of the scaffolding structure, and the second therapeutic composition may be a coating covering at least a portion of the first therapeutic composition. For example, the first and second therapeutic compositions cover at least 75% of the inner and outer surface areas of the scaffolding structure.

[0255] In further embodiments, the disclosure includes a method for treating vascular tissue injury in a patient. The method includes extending a scaffold structure at a target site in the patient's vascular structure adjacent to the tissue injury. A first drug formulation comprising at least one drug selected from the group consisting of calcium chelators, direct factor IIa inhibitors, and direct factor Xa is released from a first therapeutic composition on the scaffold, and a second drug formulation comprising at least one drug selected from the group consisting of calcium chelators, direct factor IIa inhibitors, and direct factor Xa is released at the site of injury from a second therapeutic composition on the scaffold. The first therapeutic composition may be formulated to rapidly release the first drug formulation into the vascular environment, and the second therapeutic composition may be formulated to provide extended release of the second drug formulation into the vascular environment.

[0256] In different examples of the methods of this disclosure, the therapeutic composition may be placed on the outer surface of the implantable scaffold, on the inner surface of the implantable scaffold, or on both the outer and inner surfaces of the implantable scaffold.

[0257] Tissue damage is frequently caused by extending scaffolding in place, but in other cases, tissue damage may be present beforehand and the structure may be deployed in place.

[0258] In specific examples, at least one of the first and second drug formulations may contain a calcium chelating agent, a direct factor IIa inhibitor, a direct factor Xa inhibitor, or both, or all three.

[0259] In a specific example, the first (rapid-release) drug formulation may release the drug from the first therapeutic composition over a first period ranging from 3 hours to 28 days after implantation, typically from 3 hours to 7 days after implantation, preferably from 3 hours to 3 days after implantation, where at least one drug of the first drug formulation typically has an average rate of 1 μg / hour to 10 μg / hour, typically from 1 μg / hour to 5 μg / hour, preferably from 2 μg / hour to 4 μg / hour, over a period of 24 hours after exposure to the vascular environment, where the average rate may be determined based on the amount (weight) of drug released over the total duration of release.

[0260] In a specific example, at least one drug of the second drug formulation is released from the second (sustained-release) therapeutic composition over a second period ranging from 30 to 12 months after implantation, typically from 30 to 9 months, preferably from 30 to 6 months, where the second therapeutic composition is typically configured to release at least one drug of the second drug formulation at an average rate not exceeding 2 μg / hour, typically 1 μg / hour, preferably 0.5 μg / hour, and more preferably 0.1 μg / hour, after a period of 24 hours following exposure to the vascular environment, where the average rate may be determined based on the amount (weight) of drug released over the total duration of release.

[0261] In a preferred example, the therapeutic composition is formulated to locally release first and second drug formulations of calcium chelating agents to the injury site at a rate or concentration sufficient to initiate inhibition of one or more of the following: inflammation, cell proliferation, internal elastic lamina (IEL) injury, fibrin formation, and clot formation, approximately 1 hour to 7 days after the structure is deployed.

[0262] In a preferred example, the therapeutic composition is formulated to locally release Xa of the first and second drug formulations to the injury site at a rate or concentration sufficient to initiate inhibition of one or more of the following: inflammation, cell proliferation, internal elastic lamina (IEL) injury, fibrin formation, and clot formation, approximately 3 hours to 7 days after the structure is deployed.

[0263] In other examples, the method may further include releasing an antiplatelet agent from at least one of the first and second therapeutic compositions.

[0264] In another embodiment, the disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to expand within the body of a patient. At least one therapeutic composition comprising a drug formulation comprising at least one drug selected from the group consisting of calcium chelators, direct factor IIa inhibitors and direct factor Xa inhibitors is coated, layered, or otherwise bound to or attached to the scaffold, wherein the therapeutic composition is formulated for extended release of the drug formulation into the vascular environment.

[0265] In many cases, the drug formulation includes a calcium chelating agent, a direct factor IIa inhibitor, and a direct factor Xa inhibitor, and in some examples, the drug formulation may include one or more additional drugs as described elsewhere in this specification.

[0266] Typically, drug formulations contain a polymer, and the drug(s) are incorporated into the polymer. The polymer is usually non-degradable in the vascular environment, where the drug is loaded into the polymer's porous structure and released by diffusion over a long period. Alternatively, the polymer may be degradable in the vascular environment, and the drug may be released by a combination of diffusion and dissolution through the polymer.

[0267] Typically, scaffolds contain metals or polymers that are non-degradable in the vascular environment, but in other cases, scaffolds may be partially or entirely degradable, especially if the polymers in the drug formulation are also degradable.

[0268] In a specific example, at least one drug in the drug formulation is released from the therapeutic composition for at least 28 days after implantation, usually at least 3 months after implantation, and preferably at least 1 year after implantation.

[0269] In other examples, the therapeutic composition may be configured to release at least one drug of the drug formulation at an average rate not exceeding 2 μg / hour, typically 1 μg / hour, preferably 0.5 μg / hour, and more preferably 0.1 μg / hour, after exposure to the vascular environment.

[0270] In many or all cases, extended release of a drug formulation acts to accelerate the resolution of one or more of the following: inflammation, cell proliferation, internal lamina elasticum (IEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or to inhibit one or more of the following: inflammation, cell proliferation, internal lamina elasticum (IEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or to increase or prolong the time before blood clots or thrombi form.

[0271] In one embodiment, the medical device may include a structure having at least one surface configured for internal use within a patient's body, and a therapeutic composition comprising one or more active substances. These active substances are not limited to, but include direct factor Xa inhibitors such as apixaban, betrixaban, edoxaban, otamixaban, rivaroxaban, razakisaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), or 2-(5-carbamimidyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), etc.; and / or direct IIa inhibitors, such as hirudin, bivalirudine, deciludine, repirudine, atesegatran methoxyl (AZD-0837), argatroban, dabigatran, etc. , efegatran, inogatran, melagatran, xymelagatran, etc.; vitamin K antagonists, e.g., asenocumarol, coumatetralyl, dicumarol, biscoma ethyl acetate, fenprocumone, warfarin, chlorindione, diphenadione, phenindione, thiochromatol, etc.; and / or other anticoagulants, e.g., antithrombin III, defibrotide, protein C (drolecogin alfa), ramatroban, REG1, etc.;And / or antiplatelet agents, e.g., absiximab, eptifivatide, orvofivan, roxifivan, sibrafivan, tirofivan, clopidogrel, prasugrel, cangrelor, erinogrel, ticagrelor, beraprost, iloprost, prostacyclin, treprostinil, acetylsalicylic acid / aspirin, alloxiprine, carbasalate calcium, indobufen, triflusal, dipyridamole / aspirin, picotamide, tervogrel, tertroban, cilostazol, dipyridamole Triflusal, Chloricromene, Ditasol, Volapaxar, Ticlopidine, etc.; and / or thrombolytics / fibrinolytics, such as plasminogen activator r-tPA, alteplase, reteplase, tenecteplase, desmoteplase, salplase, urokinase, anistreplase, monteplase, streptokinase, Ankrod, brinase, fibrinolysin, etc.; and / or ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium edetate Potassium umen, disodium magnesium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, toridodecylmethylammonium EDTA salt, other benzalkonium EDTA salts, tetraacetoxymethyl EDTA, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiaminetetrahydrochloride Friyl disulfide (TTFD), dimercaptosuccinate (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), citrates, oxalates, surfactants - EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, their salts, analogs, solvates, hydrates and derivatives;And / or inhibitors of the endogenous pathways of coagulation and thrombosis, e.g., FXI / FXIa inhibitors, protein Z-dependent protease inhibitors; and / or antiproliferative agents, e.g., paclitaxel (Taxol), or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs; and / or m-TOR inhibitors, e.g., sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs, and combinations thereof. In a preferred example, a medical device comprises a structure having at least one surface configured for internal use in the body of a patient, and a therapeutic composition comprising one or more active substances, wherein one or more active substances include one of apixaban, rivaroxaban, or argatroban. In a preferred example, the medical device comprises a structure having at least one surface configured for internal use within a patient's body, and a therapeutic composition comprising one or more active substances, wherein one or more active substances include apixaban and argatroban, apixaban and an antiplatelet agent, rivaroxaban and an antiplatelet agent, or argatroban and an antiplatelet agent. In another preferred example, the medical device comprises a structure having at least one surface configured for internal use within a patient's body, and a therapeutic composition comprising one or more active substances, wherein one or more active substances include one of apixaban or rivaroxaban, or an analogue thereof, argatroban or an analogue thereof, and one of taxol or sirolimus or an analogue thereof.

[0272] In one embodiment, the medical device may include a structure having an external surface configured for internal use within a patient's body, and a therapeutic composition comprising one or more active substances, preferably a calcium chelating agent, disposed on at least one surface, or preferably disposed on the entire external surface of the structure. In some examples, the external surface of the structure is configured to be positioned adjacent to a site of injury on the patient's body, preferably extending such site to a larger structure.

[0273] In one embodiment, the medical device may include a structure having an external surface configured for internal use within a patient's body, and a therapeutic composition comprising one or more active substances, preferably a direct factor IIa inhibitor, disposed on at least one surface, preferably on the entire external surface of the structure. In some examples, the external surface of the structure is configured to be located adjacent to a site of injury in the patient's body, preferably extending such site to a larger structure.

[0274] In some cases, therapeutic compositions are formulated to reduce, inhibit, and / or maintain cellular inflammation at the implantation site for an extended period, typically at least about 28 days, usually 1 to about 12 months, after the external surface of the structure is positioned adjacent to the injury site.

[0275] The drug carriers of this disclosure are often synthetic biodegradable polymers, as described above, but in other examples, the drug carriers may be formulated with other biocompatible, biodegradable, or non-biodegradable materials, including non-synthetic polymers, such as biomacromolecules, such as proteins, polypeptides, nucleic acids, and carbohydrates, formulated in a coating or other isolation material.

[0276] Such biological and other biocompatible coatings can reduce the foreign body inflammatory response induced by intraluminal devices. In some cases, such biocompatible drug carriers can deliver effective drug concentrations within the vascular wall, provide a reservoir for anti-luminal drug elution, direct the drug toward the vascular wall, enable enhanced drug-tissue permeability, achieve enhanced drug bioavailability, improve homogeneous drug distribution, and / or improve drug stability.

[0277] In some cases, therapeutic compositions are formulated to improve drug delivery to target cells, such as diabetic cells.

[0278] In some cases, therapeutic compositions are formulated to improve the lipophilicity of the drug and the hydrophobicity of the carrier in order to facilitate effective delivery of the drug to the vascular wall and extend the drug release rate.

[0279] In some cases, instead of being a component of the coating, the therapeutic agent may also be chemically bonded to the coating, support, or matrix by any chemical bonding technique.

[0280] In some cases, therapeutic compositions are formulated using biocompatible carriers having surface-bound cell adhesion polypeptides deposited on the stent surface, which form amino-containing hydrophobic bonds, by having a 3,4-dihydroxyphenylalanine (DOPA)-containing moiety or adhesion peptides or polypeptides in the form of L-DOPA-containing proteins. These positively charged amino-terminal polypeptides inhibit platelet activation and degranulation, limiting platelet adhesion to the stent surface.

[0281] In some cases, therapeutic compositions are formulated using biocompatible carriers deposited on the surface to form a hydrophobic coating that enhances corrosion resistance, prevents platelet aggregation in blood vessels, and promotes proper endothelial cell proliferation and controlled smooth muscle cell proliferation, thereby reducing the development of conditions such as neointima hyperplasia, thrombosis, and restenosis.

[0282] In some cases, therapeutic compositions are formulated using biocompatible carriers having catechol-functionalized hydrogels "inspired by mussels." In some cases, therapeutic compositions are formulated using biocompatible hydrogels or soft gel carriers when in contact with body fluids, and the coating reduces, inhibits, and / or maintains reduced cellular inflammation and prolonged drug release rates at the injury site. In some cases, therapeutic compositions are formulated with polyunsaturated fatty acids (PUFAs), such as omega-3 or omega-6, to modify platelet responsiveness to anticoagulants.

[0283] Examples of biocompatible drug carriers include, but are not limited to, low water-soluble amino acids, peptides, polypeptides, modified peptides conjugated with linkers or spacers, modified polypeptides conjugated with linkers or spacers, fatty acids, such as omega-3 or omega-6 polyunsaturated fatty acids, cross-linked fatty acids, cross-linked oils, such as fish oil, vitamin E, hazelnut oil, avocado oil, macadamia nut oil, grape seed oil, peanut oil, sesame oil, corn oil, almond oil, sunflower oil, hemp oil, tea oil (camellia), pectin, and gelatin. Exemplary amino acids are selected from the group consisting of phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, histidine, arginine, cysteine, glycine, glutamine, proline, tyrosine, alanine, aspartic acid, asparagine, glutamic acid, serine, and selenocysteine, as well as their derivatives and combinations. Exemplary low-solubility amino acids having a solubility in unbuffered water of less than 40 mg / mL are selected from the group consisting of asparagine, aspartic acid, cystine, eptifibatide, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, and their combinations. Examples of peptides include, but are not limited to, lysine, ornithine, arginine, histidine, glutamic acid, aspartic acid, histidine, polyornithine, serine, threonine, tyrosine, leucine, analogs, such as D and L isomers, oligomers, copolymers, block polymers, derivatives, and any peptide having different amino acid sequences. Examples of peptides include, but are not limited to, signaling peptides, carrier peptides, enzyme inhibitory peptides, neurotransmitter inhibitory peptides, antimicrobial peptides, their analogs, derivatives, and combinations.Examples of polypeptides include, but are not limited to, poly(lysine), poly(ornithine), poly(arginine), poly(histidine), poly(glutamic acid), poly(aspartic acid), poly(histidine), poly(ornithine), poly(serine), poly(threonine), poly(tyrosine), poly(leucine), their analogs, e.g., D and L isomers, copolymers, block polymers, derivatives, and combinations. Examples of cell adhesion polypeptides include, but are not limited to, fibronectin, vitronectin, laminin, elastin, fibrinogen, and collagen such as type I, II, and V, as well as any peptide derived from any of these peptides, e.g., cell adhesion peptide fragments having an amino acid sequence, and any peptide having a different amino acid sequence. Examples of drug carriers include those comprising at least one multiple bond, preferably one unsaturated fatty acid moiety, fatty acid, cross-linked fatty acid, fatty acid ester, fatty acid derivative, ether, diether, tetraether, lipid, oil, fat, glyceride, triglyceride, glycol ester, glycerin ester, fish oil or its derivatives, vitamin E or its derivatives, peanut oil, cottonseed oil, oleic acid or a combination thereof, and mixtures of the aforementioned substances. Suitable saturated fatty acids include, but are not limited to, but are selected from the group consisting of butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, linoleic acid, oleic acid, and stearic acid. Suitable unsaturated fatty acids include, but are not limited to, those selected from the group consisting of arachidonic acid, oleic acid, erucic acid, nervonic acid, linolenic acid, arachidonic acid, eicosapentanoic acid (EPA), docosahexaenoic acid (DHA), palmitoleic acid, and myristoleic acid.

[0284] In some examples, the biocompatible carrier includes a polypeptide conjugated with an adhesion moiety and / or linker to enhance hydrophobicity and facilitate drug delivery. The adhesion moiety, which includes, but is not limited to, a catechol moiety and an L-DOPA-containing protein, may be conjugated to each other and to the cell adhesion polypeptide by a linker, which includes, but is not limited to, hyaluronic acid, polyethylene glycol / polylysine, dopamine, 1,6-diaminohexane, 1,5-diaminopentane, 1,4-diaminobutane, or 1,3-diaminopropane, or any compound having at least two hydroxyl groups or two amine groups that can react with the amino acid groups of the polypeptide. In some examples, the biocompatible carrier is a peptide and is conjugated with a spacer and / or linker to make the peptide more hydrophobic and to have controlled delivery of the therapeutic compound or an extended release rate of the therapeutic compound. In some examples, the biocompatible carrier is a controlled-release layer containing one or more matrix-forming gelling agents selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, carbomer, carboxymethylcellulose, tragacanth gum, acacia gum, guar gum, pectin, modified starch derivatives, xanthan gum, locusta bean gum, and sodium alginate, which, upon contact with gastric juice, swells, gels, encapsulates the released gas, and also releases the active agent in a controlled manner, forming a matrix structure. In some examples, the biocompatible carrier is an absorption enhancer selected from the group consisting of propylene glycol, propylene glycol monolaurate, isopropyl palmitate, 1,2,6-hexanetriol, polyethylene glycol, diisopropyl adipate, polyethylene glycol 400 acetate, and ethylene glycol monoether. In some examples, the therapeutic composition includes a coating placed on the outer surface of the structure, and the coating, as a stent coating, contains plasmid DNA loaded onto a biodegradable polymer, such as polylactic acid-polyglycolic acid (PLGA).This gene therapy for the vascular wall is by effective transfection of neointimal cells by local delivery of DNA. Carriers include, but are not limited to, DNA fragments, nucleic acids, genetic materials, oligonucleotides, radioisotopes, or combinations of compounds of these classes.

[0285] In some examples, the therapeutic composition is formulated to release one or more agents in one or more of a burst release phase and an extended release phase, such that the release rate of the first stage of release is faster than the second release stage, or is configured to release two or more agents, or is configured to release three or more agents.

[0286] In some examples, the therapeutic composition is formulated to release one or more agents, wherein the therapeutic composition comprises a first therapeutic composition formulated to release the agent at a faster rate and a second therapeutic composition formulated to release the agent at a slower release rate.

[0287] In some examples, the device comprises one therapeutic composition formulated to release one or more of a calcium chelating agent, such as a calcium chelating agent, a direct factor Xa inhibitor, a direct factor IIa inhibitor, and / or an antiproliferative agent, wherein the formulation is formulated to release the drug over a long period ranging from 7 days to 6 months, preferably from 14 days to 6 months, more preferably from 21 days to 6 months, and most preferably from 30 days to 1 year, upon exposure to the vascular environment. Optionally, the formulation is configured to have a bolus drug release rate within the first hour, 3 hours, or first 24 hours upon exposure to the vascular environment.

[0288] In some examples, the therapeutic composition comprises at least three therapeutic active substances including a calcium chelating agent, a direct factor Xa inhibitor and a direct factor IIa inhibitor.

[0289] In some examples, a therapeutic composition comprising a direct factor Xa inhibitor further comprises at least one additional therapeutic active substance. In some examples, the at least one additional therapeutic active substance comprises a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, or lepirudin. In some examples, the direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof. In some examples, the direct factor Xa inhibitor comprises apixaban and the direct factor IIa inhibitor comprises argatroban. In some examples, the therapeutically effective dose of the direct factor IIa inhibitor is in the range of about 50 micrograms to about 10 mg. In some examples, the therapeutically effective dose is sufficient to produce a blood concentration of the direct factor IIa inhibitor that is lower than the median maximum serum concentration (Cmax) of the direct factor IIa inhibitor produced by systemic delivery of the direct factor IIa inhibitor to reach the same tissue concentration at the site of the inflammatory ocular condition or disease. In some examples, the therapeutically effective dose is sufficient to produce a blood concentration of the direct factor IIa inhibitor that is longer than about 6 hours to about 3 days and does not exceed the median maximum serum concentration (Cmax) of the direct factor IIa inhibitor produced by systemic delivery of the direct factor IIa inhibitor to reach the same tissue concentration at the site of the inflammatory ocular condition or disease. In some examples, the therapeutically effective dose is sufficient to maintain a tissue concentration of the direct factor IIa inhibitor of about 0.1 ng / g tissue to about 100 mg / g tissue for about 1 day to about 1 year, 30 days to about 1 year, 3 months to about 1 year, or 6 months to about 1 year. In some examples, the weight composition ratio of the direct factor Xa inhibitor to the direct factor IIa inhibitor in the therapeutic composition is in the range of about 3:1 to about 1:3. For example, the weight composition ratio of the direct factor Xa inhibitor to the direct factor IIa inhibitor in the therapeutic composition may be about 1:1.

[0290] In some examples, the therapeutic composition comprises one or more anticoagulants having an IC50 that inhibits factor Xa and factor II at doses in the range of 0.0001 nM to 1000 nM, preferably in the range of 0.0001 nM to 100 nM, more preferably in the range of 0.0001 nM to 10 nM, and most preferably in the range of 0.0001 nM to 1 nM.

[0291] In some cases, the therapeutic composition is formulated to release the direct factor Xa inhibitor and the antiproliferative agent at the same rate. In some cases, the therapeutic composition is formulated to release the direct factor Xa inhibitor and the antiproliferative agent at different rates. In other cases, the therapeutic composition is formulated to release the direct factor Xa inhibitor at a faster rate than the antiproliferative agent within the first 3 hours, 1 day, or 72 hours. In yet another case, the therapeutic composition is formulated to release the direct factor Xa inhibitor at a slower rate than the antiproliferative agent within the first 3 hours, 1 day, or 72 hours.

[0292] In some cases, the release rate ratio of direct factor Xa inhibitors to antiproliferative agents is within the range of approximately 1:6 to 6:1, or approximately 1:3 to 6:1, or approximately 2.5:2 to 6:1. In some cases, the release rate ratio of direct factor Xa inhibitors to antiproliferative agents is within the range of approximately 1:2 to 6:1, approximately 1:3 to 6:1, or approximately 2.5:2 to 6:1 within approximately 3 hours, approximately 24 hours, approximately 7 days, or approximately 28 days. In some cases, the release rate ratio of direct factor Xa inhibitors to antiproliferative agents is within the range of approximately 3:2 to 6:1, or approximately 2.2:2 to 6:1, or approximately 2.5:2 to 6:1. In some cases, the release rate ratio of direct factor Xa inhibitors to antiproliferative agents is within the range of approximately 3:2 to 6:1, approximately 2.2:2 to 6:1, or approximately 2.5:2 to 6:1 within approximately 3 hours, approximately 24 hours, approximately 7 days, or approximately 28 days. In some other cases, the release rate ratio of direct factor Xa inhibitors to antiproliferative agents is within the range of approximately 1:1 to 2:1 within approximately 3 hours, 1 day, approximately 3 days, approximately 7 days, or approximately 28 days.

[0293] In some cases, therapeutic compositions are formulated to release the antiproliferative agent at a rate of approximately 1 μg / sec / mm device to approximately 50 μg / day / mm device, approximately 1 μg / min / mm device to approximately 10 μg / day / mm device, or approximately 1 μg / hour / mm device to approximately 7 μg / day / mm device over approximately 3 hours, approximately 1 day, or approximately 3 days.

[0294] In some cases, therapeutic compositions are formulated to release the antiproliferative agent at a rate of approximately 1 μg / hour / mm device to approximately 4 μg / day / mm device.

[0295] In some cases, the weight ratio of the direct factor Xa inhibitor to the antiproliferative agent in the therapeutic composition is approximately 5:2, approximately 2:1, approximately 1.25:1, or approximately 1:1. In some cases, the weight ratio of the direct factor Xa inhibitor to the antiproliferative agent in the therapeutic composition is in the range of approximately 5:1 to approximately 3:1 or approximately 5:1 to approximately 1:1.

[0296] In some examples, the therapeutic composition includes a coating disposed on one or more surfaces of a device structure, the coating comprising a first layer and a second layer. In some examples, the first layer comprises a direct factor Xa inhibitor. In some examples, the first layer comprises an antiproliferative agent, and the second layer comprises a direct factor Xa inhibitor. In some examples, the therapeutic composition further comprises a top layer or topcoat of the same or different material as the first or second layer. In some examples, the first layer comprises a direct factor Xa inhibitor and an antiproliferative agent. In some examples, the second layer comprises a top layer or topcoat of the same or different material as the first layer. In some examples, the therapeutic composition includes a coating disposed on one or more surfaces of a device structure, the coating further comprising a biodegradable polymer carrier. In some examples, the first and / or second layer comprises a drug / polymer matrix of one or more drugs. In one example, the first layer is configured for burst release of one or more drugs, while the second layer is configured for extended release of one or more drugs. In yet another example, the first and / or second layer is a topcoat covering one or more drug agents, which are formulated with additives or in a drug polymer matrix beneath the coating of the first and / or second layer. The matrix and the coating of the first or second layer may be the same or different.

[0297] In some examples, the weight composition ratio of the biodegradable polymer carrier to one or more active substances is about 1:5 to about 3:2, about 0.5:1 to about 1:1, or about 1:5 to about 1.25:1. In preferred examples, the polymer is biodegradable.

[0298] In some other examples, the weight composition ratio of the support to one or more active substances is about 1:5 to about 3:2, about 0.5:1 to about 1:1, or about 1:5 to about 1.25:1. In one example, the support is one or more additives.

[0299] In some examples, the therapeutic composition is placed on at least one surface of the device, preferably at least the external and / or internal surfaces of the structure. In some examples, the therapeutic composition is placed on the external surface (anti-luminal side), the internal surface (luminal side), and the side surfaces of the structure. In yet another example, the therapeutic composition is placed on one or more surfaces of the structure. In yet another example, the therapeutic composition is placed on all surfaces of the structure. In yet another example, the therapeutic composition is placed on or within a reservoir of the structure. In some examples, the therapeutic composition is placed on the external surface of the structure.

[0300] In some examples, the therapeutic composition includes a coating placed on the outer surface of a structure, the coating further comprising a non-degradable polymer carrier. In some examples, the therapeutic composition includes a coating placed on the outer surface of a structure, the coating comprising at least one layer of polymer material containing a direct factor Xa inhibitor. In some examples, the therapeutic composition includes a coating placed on the outer surface of a structure, the coating consisting of a single layer of polymer material containing a direct factor Xa inhibitor in a releaseable manner. In some examples, the therapeutic composition further comprises a top layer or top coat composed of the same or different polymer material. In some examples, the direct factor Xa inhibitor is uniformly distributed in the polymer material. In some examples, the direct factor Xa inhibitor is non-uniformly distributed in the polymer material.

[0301] In some examples, the therapeutic composition includes a coating placed on at least the surface of the structure, the coating comprising at least one layer of polymer material holding one or more of the direct factor Xa inhibitor and the antiproliferative agent. In some examples, the therapeutic composition includes a coating placed on the outer surface of the structure, the coating consisting of a single layer of polymer material containing the direct factor Xa inhibitor and the antiproliferative agent in a releaseable manner. In some examples, the therapeutic composition further includes a top layer or topcoat composed of the same or different polymer material. In some examples, the direct factor Xa inhibitor and the antiproliferative agent are uniformly distributed in the polymer material. In some examples, the direct factor Xa inhibitor and the antiproliferative agent are non-uniformly distributed in the polymer material. In some examples, one or more active substances are present in the polymer material in a weight ratio of the direct factor Xa inhibitor to the antiproliferative agent ranging from about 1:1 to about 6:1.

[0302] In some cases, the polymer material is porous. In some cases, the polymer material has porosity in the range of approximately 10 nm to approximately 10 μm. In some cases, the polymer material is non-degradable. In some cases, the polymer material is biodegradable. In some cases, the polymer material has a degradation rate in the range of approximately 1 month to approximately 36 months. In some examples, polymer materials include polyester, polylactide, polyglycolide, poly(ε-caprolactone), polydioxanone, poly(hydroxyalkanoate), poly(L-lactide-co-D-lactide), poly(L-lactide-co-D,L-lactide), poly(D-lactide-co-D,L-lactide), poly(lactide-co-glycolide) (PLA-co-PGA in a ratio of 70:30 to 99:1, e.g., including PLA-co-PGA in a ratio of 85:15), and poly(lactide-co-ε-caprolactone) (PLA-co-Glycolide in a ratio of 70:30 to 99:1). The material comprises materials selected from the group consisting of LA-co-PCL (e.g., including 90:10 PLA-co-PCL), poly(glycolide-co-ε-caprolactone), poly(lactide-co-dioxanone), poly(glycolide-co-dioxanone), poly(lactide-co-trimethylene carbonate), poly(glycolide-co-trimethylene carbonate), poly(lactide-co-ethylene carbonate), and copolymers and combinations thereof, wherein lactide includes L-lactide, D-lactide, and D,L-lactide. In some examples, the polymer material includes materials selected from the group of non-degradable polymer materials consisting of polyacrylates, polymethacrylates, poly(n-butyl methacrylate), poly(hydroxyethyl methacrylate), polyamides, nylon, nylon 12, dacron, polyethylene terephthalate, poly(ethylene glycol), polyethylene oxide (PEO), polydimethylsiloxane, polyvinylpyrrolidone, ethylene vinyl acetate, phosphorylcholine-containing polymers, poly(2-methacryloyloxyethyl phosphorylcholine), poly(2-methacryloyloxyethyl phosphorylcholine-co-butyl methacrylate), and copolymers and combinations thereof.

[0303] In some cases, the therapeutic composition is placed in a drug reservoir that is fluidly coupled to the outer surface of the structure.

[0304] In another embodiment, the medical device may include a structure having at least one surface configured for internal use within a patient's body, and a therapeutic composition comprising two or more active substances, including a calcium chelator, a direct factor Xa inhibitor, and a direct factor IIa inhibitor. In some examples, at least one surface of the structure is configured to be positioned adjacent to a site of injury in the patient's body. In some examples, the therapeutic composition is formulated to locally release two or more active substances to the injury site at a rate or concentration sufficient to reduce cell proliferation at the injury site within about 3 hours to about 7 days, or about 28 days to about 12 months, after the external surface of the structure is positioned adjacent to the injury site.

[0305] In some cases, the therapeutic composition further comprises an antiproliferative agent. In some cases, the direct factor IIa inhibitor includes argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, decildin, or repirudine. In some cases, the direct factor IIa inhibitor includes argatroban, or its salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs. In some cases, the direct factor IIa inhibitor includes dabigatran, or its salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs.

[0306] In some cases, direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD This includes 0348292), or 2-(5-carbamimidyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). In some examples, direct factor Xa inhibitors include rivaroxaban, or its salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs. In some examples, direct factor Xa inhibitors include apixaban, or its salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs. In some examples, antiproliferative agents include paclitaxel (Taxol), or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. In some examples, antiproliferative agents include m-TOR inhibitors. In some cases, the antiproliferative agent includes sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotalolimus, or their salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs.

[0307] In some examples, the direct factor IIa inhibitor includes argatroban, and the direct factor Xa inhibitor includes apixaban. In some examples, the direct factor IIa inhibitor includes argatroban, the direct factor Xa inhibitor includes apixaban, and the anti-proliferative agent includes sirolimus. In yet another example, the therapeutic composition includes one of apixaban, rivaroxaban, or an analog thereof, and sirolimus or an analog of sirolimus.

[0308] In some examples, the therapeutic composition of the calcium chelating agent, direct factor IIa inhibitor and direct factor Xa inhibitor is formulated to reduce cell proliferation as compared to either the direct factor IIa inhibitor or the direct factor Xa inhibitor alone. In some examples, the therapeutic composition is formulated to reduce, inhibit, and / or maintain the reduction of cell proliferation at the injury site for about 28 days to about 12 months after the outer surface of the structure is disposed adjacent to the injury site. In some examples, the therapeutic composition is formulated to reduce smooth muscle cell proliferation at the injury site. In some examples, the therapeutic composition of the calcium chelating agent, direct factor IIa inhibitor, direct factor Xa inhibitor and anti-proliferative substance is formulated to reduce cell proliferation as compared to the anti-proliferative substance alone. In some examples, the therapeutic composition is formulated to reduce, inhibit, and / or maintain the reduction of cell proliferation at the injury site for about 28 days to about 12 months after the outer surface of the structure is disposed adjacent to the injury site.

[0309] In other examples, the therapeutic composition comprising a calcium chelating agent, direct factor IIa inhibitor and direct factor Xa inhibitor is formulated to release the agents at a sufficient rate and / or concentration to accelerate dissolution or to inhibit one or more of inflammation, smooth muscle cell proliferation, cell proliferation, thrombin formation, fibrin formation, platelet aggregation, platelet activation, vascular injury, or clot formation within about 3 hours to about 28 days or longer, or within about 3 hours to about 3 months or longer.

[0310] In other examples, therapeutic compositions comprising calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors are formulated to release the drugs to accelerate dissolution or to inhibit one or more of the following: inflammation, smooth muscle cell proliferation, cell proliferation, thrombin formation, fibrin formation, platelet aggregation, platelet activation, vascular injury, or clot formation, within approximately 3 hours to approximately 28 days or longer, or within approximately 3 hours to approximately 3 months or longer.

[0311] In other examples, therapeutic compositions comprising calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors are formulated to have a weight composition ratio of factor Xa inhibitor to factor IIa inhibitor in the range of about 1:1:1 to about 10:1:1. In other examples, therapeutic compositions comprising calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors are formulated to have a weight composition ratio of factor Xa inhibitor to factor IIa inhibitor in the range of about 0.5:1 to about 5:1.

[0312] In some cases, therapeutic compositions are formulated to reduce one or more of the following: cell proliferation or fibrin formation, within 7 days or longer.

[0313] In some cases, the therapeutic composition is formulated to release two or more active substances at a rate of 1 μg / sec / mm device to about 50 μg / day / mm device, preferably at a rate of 1 μg / min / mm device to about 30 μg / day / mm device, more preferably at a rate of 1 μg / hour / mm device to about 30 μg / day / mm device. In some cases, the therapeutic composition is formulated to begin releasing two or more active substances before the device is placed adjacent to the injury site, or immediately after at least one surface of the structure is placed adjacent to the injury site, or within about 5, about 15, or about 30 minutes thereafter. In some cases, the therapeutic composition is formulated to begin releasing two or more active substances before the outer surface of the structure is placed adjacent to the injury site. In some cases, the therapeutic composition is formulated to release substantially all of the two or more active substances within about 1 to about 90 days or longer. In some cases, the therapeutic composition is formulated to release substantially all of two or more active substances within approximately 90 to approximately 180 days or longer. In some cases, the therapeutic composition is formulated to release substantially all of two or more active substances within approximately 7 days or approximately 28 days. In some cases, the therapeutic composition is formulated to release substantially all of two or more active substances within approximately 3 hours, or approximately 6 hours, or approximately 12 hours, or approximately 1 day, or approximately 3 days. In some cases, the therapeutic composition is formulated to release at least 50%, at least 60%, or at least 70% of two or more active substances within approximately 3 hours, or approximately 6 hours, or approximately 12 hours, or approximately 1 day, or approximately 3 days, or approximately 7 days, or approximately 28 days.

[0314] In some cases, the release rate ratio of direct factor IIa inhibitors to direct factor Xa inhibitors and antiproliferative agents is in the range of approximately 1:1:1 to approximately 4:4:1. In some cases, the therapeutic composition is formulated to release direct factor IIa inhibitors at a rate of approximately 4 μg / hour / mm device to approximately 14 μg / day / mm device. In some cases, the therapeutic composition is formulated to release direct factor Xa inhibitors at a rate of approximately 4 μg / hour / mm device to approximately 14 μg / day / mm device. In some cases, the therapeutic composition is formulated to release antiproliferative agents at a rate of approximately 1 μg / hour / mm device to approximately 4 μg / day / mm device.

[0315] In some cases, the weight composition ratio of the direct factor IIa inhibitor to the direct factor Xa inhibitor in the therapeutic composition is approximately 1:1. In some cases, the weight composition ratio of the direct factor IIa inhibitor to the direct factor Xa inhibitor in the therapeutic composition is in the range of approximately 3:1 to approximately 1:3, for example, approximately 1:1. In some cases, the weight composition ratio of the direct factor IIa inhibitor to the direct factor Xa inhibitor and the antiproliferative agent in the therapeutic composition is approximately 5:5:2. In some cases, the weight composition ratio of the direct factor IIa inhibitor to the direct factor Xa inhibitor and the antiproliferative agent in the therapeutic composition is in the range of approximately 6:6:1 to approximately 1:3:1.

[0316] In some other examples, the weight composition ratio of the support to two or more active substances is approximately 1:5 to 3:1, approximately 0.5:1 to 1:1, or approximately 1:5 to 1.25:1. In one example, the support is one or more additives.

[0317] In some examples, the therapeutic composition is placed on the external and internal (inner) surfaces of the structure. In some examples, the therapeutic composition is placed on the external surface (anti-luminal side), the internal surface (luminal side), and the side surfaces of the structure. In yet another example, the therapeutic composition is placed on one or more surfaces of the structure. In yet another example, the therapeutic composition is placed on all surfaces of the structure. In yet another example, the therapeutic composition is placed on or within a reservoir of the structure. In some examples, the therapeutic composition is placed on the external surface of the structure.

[0318] In some examples, the therapeutic composition includes a coating disposed on at least one surface of a structure, the coating comprising a first layer and a second layer. In some examples, the first layer contains a direct factor IIa inhibitor and a direct factor Xa inhibitor. In some examples, the first layer contains a direct factor IIa inhibitor and the second layer contains a direct factor Xa inhibitor. In some examples, the therapeutic composition further includes a top layer or topcoat of the same or different material as the first or second layer.

[0319] In some examples, the therapeutic composition includes a coating disposed on at least one surface of a structure, the coating comprising a first layer and a second layer. In some examples, the first layer comprises an antiproliferative agent, a direct factor IIa inhibitor, and a direct factor Xa inhibitor. In some examples, the second layer comprises a top layer or topcoat of the same or different material as the first layer. In some examples, the first layer comprises an antiproliferative agent, and the second layer comprises a direct factor IIa inhibitor and a direct factor Xa inhibitor. In some examples, the first layer comprises an antiproliferative agent and a direct factor Xa inhibitor, and the second layer comprises a direct factor IIa inhibitor. In some examples, the first layer comprises a direct factor IIa inhibitor and a direct factor Xa inhibitor, and the second layer comprises an antiproliferative agent. In some examples, the first layer comprises apixaban and argatroban, and the second layer comprises sirolimus. In some examples, the therapeutic composition further includes a top layer or top coat made of the same or different material as the first or second layer.

[0320] In some examples, the coating further comprises a third layer. In some examples, the first layer contains a direct factor IIa inhibitor, the second layer contains a direct factor Xa inhibitor, and the third layer contains an antiproliferative agent. In some examples, the therapeutic composition further comprises a top layer or topcoat of the same or different material as the first layer, the second layer, or the third layer.

[0321] In some examples, the therapeutic composition includes a coating placed on at least one surface of the structure, the coating further comprising a biodegradable polymer carrier. In some examples, the weight composition ratio of the biodegradable polymer carrier to two or more active substances is about 1:5 to about 3:2. In some examples, the therapeutic composition includes a coating placed on the outer surface of the structure, the coating comprising at least one layer of polymer material holding one or more of direct factor IIa inhibitors and direct factor Xa inhibitors.

[0322] In some examples, the therapeutic composition includes a coating disposed on at least one surface of the structure, the coating consisting of a single layer of polymer material that releases the direct factor IIa inhibitor and the direct factor Xa inhibitor, respectively. In some examples, the therapeutic composition further includes a top layer or topcoat composed of the same or different polymer material. In some examples, the direct factor IIa inhibitor and the direct factor Xa inhibitor are uniformly distributed in the polymer material. In some examples, the direct factor IIa inhibitor and the direct factor Xa inhibitor are non-uniformly distributed in the polymer material.

[0323] In some examples, the therapeutic composition includes a coating disposed on at least one surface of the structure, the coating comprising at least one layer of polymer material having one or more of a direct factor IIa inhibitor, a direct factor Xa inhibitor, and an antiproliferative agent. In some examples, the therapeutic composition includes a coating disposed on at least one surface of the structure, the coating consisting of a single layer of polymer material that releases each of the direct factor IIa inhibitor, the direct factor Xa inhibitor, and the antiproliferative agent. In some examples, the therapeutic composition further includes a top layer or top coat composed of the same or different polymer material. In some examples, the direct factor IIa inhibitor, the direct factor Xa inhibitor, and the antiproliferative agent are uniformly distributed in the polymer material. In some examples, the direct factor IIa inhibitor, the direct factor Xa inhibitor, and the antiproliferative agent are non-uniformly distributed in the polymer material.

[0324] In some cases, two or more active substances are present in the polymer material in weight ratios of approximately 4:1:3:1; approximately 5:3:2:1; approximately 4:2:2:1; approximately 5:2:3:1; approximately 6:3:3:1; approximately 10:5:5:1; or approximately 12:6:6:1 of calcium chelating agents relative to direct factor IIa inhibitors, direct factor Xa inhibitors, and antiproliferative agents.

[0325] In another embodiment, a method for treating one or more of inflammation, cell proliferation, smooth muscle cell proliferation, or coagulation in a patient may include: providing a structure having an external surface; deploying the structure at a target site on the patient's body that causes injury therein; and releasing a therapeutically effective amount of a therapeutic composition comprising at least a calcium chelator, a direct factor IIa inhibitor, a direct factor Xa inhibitor, and an antiproliferative agent from at least one surface of the structure deployed at the site of injury on the patient's body.

[0326] In other examples, therapeutic compositions comprising calcium chelators, direct factor IIa inhibitors and direct factor Xa inhibitors, and antiproliferative agents are formulated to release the agents at a rate sufficient to inhibit one or more of the following: inflammation, smooth muscle cell proliferation, cell proliferation, thrombin formation, fibrin formation, or clot formation, within about 3 hours to about 28 days or longer, or within about 3 hours to about 3 months or longer.

[0327] In another example, the therapeutic composition is formulated to release two or more active substances to the injured site of a body lumen, where two or more substances include a calcium chelator, a direct IIa inhibitor, a direct Xa inhibitor, and an antiproliferative agent. In another example, the therapeutic composition is formulated to release two or more active substances to the injured site of a body lumen, where two or more substances include a calcium chelator, a direct IIa inhibitor, a direct Xa inhibitor, and an antiproliferative agent. In another example, the therapeutic composition is formulated to release two or more active substances to the injured site of a body lumen, where two or more substances include a calcium chelator, a direct IIa inhibitor, and an antiproliferative agent. In another example, the therapeutic composition is formulated to release two or more active substances to the injured site of a body lumen, where two or more substances include a calcium chelator, a direct IIa inhibitor, a direct Xa inhibitor. In another example, a therapeutic composition is formulated to release two or more active substances to the site of injury in a body lumen, where the two or more substances include a calcium chelator, a direct Xa inhibitor, and an antiproliferative agent.

[0328] In some cases involving calcium chelating agents, direct factor IIa inhibitors include argatroban, direct factor Xa inhibitors include apixaban, and antiproliferative agents include sirolimus.

[0329] In some cases involving calcium chelating agents, direct factor IIa inhibitors include argatroban, direct factor Xa inhibitors include rivaroxaban, and antiproliferative agents include sirolimus.

[0330] In some examples, the therapeutic composition comprises a coating on the external surface of the structure or on at least one surface of the structure, and the release of the therapeutic composition comprises the release of the therapeutic composition from the coating. In some examples, the coating comprises one or more layers. In some examples, the coating comprises a biodegradable porous polymer material, a biodegradable polymer material, or a non-biodegradable polymer material. In some examples, calcium chelators, direct factor IIa inhibitors, and direct factor Xa inhibitors are released faster than antiproliferative agents. In some examples, direct factor IIa inhibitors and direct factor Xa inhibitors enhance the antiproliferative effect of antiproliferative agents. In some examples, the therapeutic composition is placed in a drug reservoir fluidly coupled to the external surface of the structure, and the release of the therapeutic composition comprises the delivery of the therapeutic agent from the drug reservoir to the deployed external surface of the structure.

[0331] In some cases, the injury is caused, at least partially, before the deployment of the structure. In some cases, the deployment of the structure causes the injury, and the therapeutic composition is formulated to release a calcium chelator, a direct factor IIa inhibitor, a direct factor Xa inhibitor, or an antiproliferative agent before the injury occurs.

[0332] In some examples, the therapeutic composition comprises a first and / or second layer containing a drug / polymer matrix of one or more drugs. In one example, the first layer is configured for the burst release of one or more drugs, while the second layer is configured for the extended release of one or more drugs. In yet another example, the first and / or second layer is a topcoat covering one or more drugs, where one or more drugs are formulated with additives or are formulated in the drug polymer matrix beneath the coating of the first and / or second layer. The matrix and the coating of the first or second layer may be the same or different.

[0333] In any other example of the examples of this application, a therapeutic composition comprising two or more active substances on at least one surface of a device is configured to be positioned adjacent to a site of injury on a patient's body, where adjacent to is one or more of the following: next to, touching, unfolding at, expanding at, pushing against, placed against, etc. In a preferred example, the active substances are a calcium chelator, a direct factor IIa inhibitor, and a direct factor Xa inhibitor. In another example, the active substances are a calcium chelator, a direct factor IIa inhibitor, a direct factor Xa inhibitor, and an antiproliferative agent. In yet another example, the active substances are one of argatroban, rivaroxaban, or apixaban, and sirolimus or a sirolimus analog.

[0334] The examples described herein are not intended to be limiting. Other examples may be used, modified, or combined in whole or in part without departing from the scope of the subject matter presented herein. The aspects of this disclosure generally described herein, as shown in the figures and detailed descriptions and examples, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly intended herein.

[0335] These and other embodiments are described in further detail in the following description relating to the attached drawings.

[0336] In other examples, the therapeutic compositions of the present disclosure may be formulated to initiate the release of a calcium chelator and a direct factor IIa inhibitor before initiating the release of a direct factor Xa inhibitor. For example, the release of the calcium chelator may begin 1 minute to 3 days, usually 3 hours to 1 day, after the release of the direct factor IIa inhibitor has begun.

[0337] In other examples, the therapeutic compositions of the present disclosure may be formulated to initiate the release of a calcium chelating agent before initiating the release of a direct factor IIa inhibitor and a direct factor Xa inhibitor. For example, the release of the direct factor Xa inhibitor may begin 1 minute to 3 days, usually 3 hours to 1 day, after the release of the direct factor IIa inhibitor and the direct factor IIa inhibitor has begun.

[0338] In other examples, the therapeutic compositions of the present disclosure may be formulated to initiate the release of a direct factor Xa inhibitor before the release of a direct factor IIa inhibitor. For example, the release of the direct factor IIa inhibitor may begin 1 minute to 3 days, usually 3 hours to 1 day, after the release of the direct factor Xa inhibitor has begun.

[0339] Examples of direct factor IIa inhibitors suitable for incorporation into therapeutic compositions of the present disclosure include at least one of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, decildin, and repirudine. Currently, argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, are preferred.

[0340] Examples of direct factor Xa inhibitors suitable for incorporation into therapeutic compositions of the present disclosure include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD At least one of the following is an example: 0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). Currently, rivaroxaban and apixaban, or their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs are preferred.

[0341] Examples of suitable antiproliferative agents for incorporation into therapeutic compositions of the present disclosure include m-tor inhibitors selected from the group consisting of at least sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotalolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. Preferred m-tor inhibitors include sirolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.

[0342] Examples of antiproliferative agents suitable for incorporation into therapeutic compositions of the present disclosure include paclitaxel, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, as well as antiplatelet agents.

[0343] A preferred combination of active agents includes a calcium chelating agent, argatroban as a direct factor IIa inhibitor, and apixaban or rivaroxaban as a direct factor Xa inhibitor.

[0344] In a specific example, the structure may include a scaffold having at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces. In such an example, at least a portion of the outer surface may be coated with the therapeutic composition, at least a portion of the inner surface may be coated with the therapeutic composition, and at least a portion of the end surfaces may be coated with the therapeutic composition, and more often, two or three such surfaces are coated.

[0345] In a specific example, at least a portion of the surface, including the outer, inner, and end surfaces, may have containers formed therein, and at least a portion of these containers may contain a therapeutic agent. The containers may include one or more of the following: wells, channels, pores, surface textures, etc.

[0346] In specific examples, the therapeutic composition may further include additives, adjuvants, polymer carriers, and the like.

[0347] In a specific example, three or more active substances may be uniformly mixed with each other. Alternatively, or in addition, three or more active substances may be layered separately from each other. Each layer may contain additives mixed with the therapeutic agent, where the additive(s) in two or more layers may be the same or different in at least two of the three layers.

[0348] In a specific example, the device may further include a controlled release layer formed by covering at least two, three or more active materials.

[0349] In a specific example, the therapeutic composition may include a base layer formed over the surface of the structure and a top layer formed over the base layer. The base layer and the top layer may differ in at least some properties. For example, the base layer and the top layer may differ in at least one of the following: drug dose, drug release rate, and drug release duration.

[0350] In a preferred example, the top layer of the therapeutic composition is formulated to begin releasing the active substances before the release of the active substances from the base layer. For example, the active substances may be released from the top layer over a period ranging from 1 hour to 7 days after the surface of the structure is positioned adjacent to the injury site, and / or the active substances may be released from the base layer over a period ranging from 7 days to 12 months after the active substances have been substantially released from the top layer. For example, each of the base layer and the top layer may contain at least three active substances mixed in a biodegradable polymer matrix.

[0351] In some cases, the scaffold structure may be configured to expand within the vascular lumen of the patient's body.

[0352] In some cases, the therapeutic composition may be coated, at least partially, onto the surface of the scaffold structure.

[0353] In some cases, the therapeutic composition is present, at least partially, within a cavity or reservoir in the scaffold structure.

[0354] In some examples, the embeddable scaffold has at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces. For example, at least a portion of the outer surface may be coated with a therapeutic composition, at least a portion of the inner surface may be coated with a therapeutic composition, and / or at least a portion of the end surface may be coated with a therapeutic composition.

[0355] In some examples, at least a portion of the surface has a container formed therein, and at least a portion of the container has a therapeutic agent within it. For example, the container may include one or more of wells, channels, pores, and surface textures.

[0356] In a second aspect, the present disclosure provides a method for treating vascular tissue injury in a patient. The method comprises implanting a scaffold structure at a target site in the patient's vascular structure adjacent to the tissue injury. The therapeutic composition on the scaffold comprises colchicine and / or tirofiban and at least one antiproliferative agent. Colchicine and / or tirofiban are released into the vascular tissue from the carrier in the therapeutic composition over a period of at least one week in an amount sufficient to inhibit inflammation resulting from the implantation of the scaffold. At least one antiproliferative agent is released from the same or a different carrier over a period of at least one week in an amount sufficient to inhibit smooth cell muscle (SMC) proliferation.

[0357] The scaffold structures of this disclosure may have any one of a wide variety of known structures suitable for implantation and expansion at a target site on a patient's body. In many cases, the scaffold has at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces. In such examples, at least a portion of the outer surface may be coated with a therapeutic composition. In other examples, at least a portion of the inner surface may be coated with a therapeutic composition. In yet another example, a portion of the end surface may be coated with a therapeutic composition. As an alternative to, or in addition to, surface coating, at least a portion of the surface may have a container formed therein, and at least a portion of the container may contain a therapeutic agent. For example, the container may include one or more of wells, channels, pores, and surface textures.

[0358] In all aspects and examples of this disclosure, the therapeutic composition may be located on at least one of the internal and external surfaces of the implantable scaffold, and / or on both the external and internal surfaces of the implantable scaffold.

[0359] The embeddable scaffolding and methods of this disclosure are generally suitable for mitigating tissue damage caused by extending scaffolding in place, but are also useful for deploying structures in place to address pre-existing tissue damage.

[0360] In some cases, the therapeutic composition may be formulated for an initial rapid release into the environment around the implantable scaffold for a pre-selected period after the implantation of the main structure into the environment, followed by a slower, controlled release over a longer period as described above.

[0361] While the scaffolds of this disclosure are particularly intended for use in vascular stents and grafts, they may also be found to be used in any type of therapeutic, diagnostic, or other structure intended for implantation in a patient's vascular structure or other vascularized area of ​​the patient's body, such as artificial heart valves, patent foramen ovale (PFO) occlusion devices, atrial septal defect (ASD) occlusion devices, left atrial appendage (LAA) occlusion devices, or similar expandable structures, such as orthopedic implants.

[0362] The carriers typically include polymers, usually biodegradable polymers, and more commonly, but not always, biodegradable polymers, which are synthetic polymers synthesized from petroleum and other hydrocarbon supply materials. Exemplary biodegradable synthetic polymers are selected from the group consisting of polyesters, e.g., polylactic acid, polyglycolic acid, polylactic acid-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol-block-polycaprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly-N-(2-hydroxypropyl)methacrylamide; polyethyleneimine (PEI), dextran, dextrin, chitosan, poly(L-lysine); poly(aspartamide), polyethylene; polypropylene; polyamide; polyethylene glycol (PEG); silicone; poly(acid anhydride); and polyorthoesters.

[0363] An example of a biodegradable polymer is poly(lactic acid-co-glycolic acid) (PLGA), where PLGA is present in the first therapeutic composition at a rate of 5 μg to 15 μg per 1 mm of scaffold structure length, and in the second therapeutic composition at a rate of 5 μg to 20 μg per 1 mm of scaffold structure length.

[0364] Alternatively, the polymer may include, for example, a non-degradable polymer selected from the group consisting of polyacrylate, polymethacrylate, poly(n-butyl methacrylate), poly(hydroxyethyl methacrylate), polyamide, nylon, nylon 12, dacron, polyethylene terephthalate, poly(ethylene glycol), polyethylene oxide (PEO), polydimethylsiloxane, polyvinylpyrrolidone, ethylene-vinyl acetate, phosphorylcholine-containing polymers, poly(2-methacryloyloxyethyl phosphorylcholine), poly(2-methacryloyloxyethyl phosphorylcholine-co-butyl methacrylate), and copolymers thereof.

[0365] In another embodiment, the present disclosure provides a method for treating tissue injury in a patient. The method comprises deploying a structure at the site of target tissue injury in a body lumen of the patient. A therapeutic composition is released from the deployed structure to the site of injury, wherein the therapeutic composition comprises at least a calcium chelator, a direct factor IIa inhibitor, a direct factor Xa inhibitor, and optionally an antiproliferative agent.

[0366] The therapeutic composition may be placed on the external surface of the device, on the internal surface of the device, or on both the external and internal surfaces of the device.

[0367] Tissue damage may be caused by deploying a structure at that location, or it may have existed prior to the deployment of the structure at that location.

[0368] In a specific example, body lumens include blood vessels, and the therapeutic composition is formulated to locally release at least two, three, or more active substances to the injury site at a rate or concentration sufficient to initiate the inhibition or resolution of one or more of the following within approximately 3 hours to 7 days after the structure has been deployed: inflammation, cell proliferation, internal elastic lamina (IEL) injury, fibrin formation, platelet aggregation, platelet activation, and clot formation or dissolution.

[0369] In specific examples, at least two, three, or more active substances may be released to the injury site at a rate or concentration sufficient to inhibit one or more of the following: inflammation, cell proliferation, internal elastic lamina (IEL) injury, fibrin formation, platelet aggregation, platelet activation, and clot formation or dissolution, for a period of at least one day, at least one week, at least one month, at least three months, at least six months, or at least one year, after the surface of the structure is positioned adjacent to the injury site.

[0370] In specific examples, two, three, or more active substances are released substantially simultaneously.

[0371] Alternatively, or in addition, the direct factor IIa inhibitor and the direct factor Xa inhibitor may be released substantially simultaneously, and the anti-proliferative agent may be released after the release of the direct factor IIa inhibitor and the direct factor Xa inhibitor has begun. For example, the release of the anti-proliferative agent may begin 1 minute to 3 days, usually 6 hours to 1 day, after the release of the direct factor IIa inhibitor and the direct factor Xa inhibitor has begun.

[0372] Alternatively, or in addition, the therapeutic composition may begin releasing a direct factor IIa inhibitor before the release of the direct factor Xa inhibitor begins. For example, the release of the direct factor Xa inhibitor begins 1 minute to 3 days after the release of the direct factor IIa inhibitor begins, usually 6 hours to 1 day later.

[0373] Alternatively, or in addition, the therapeutic composition may begin releasing a direct factor Xa inhibitor before the release of the direct factor IIa inhibitor begins. For example, here, the release of the direct factor IIa inhibitor begins 1 minute to 3 days after the release of the direct factor Xa inhibitor begins, usually 6 hours to 1 day later.

[0374] In some examples, direct factor IIa inhibitors include at least one of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, decildin, and repirudine. In currently preferred examples, direct factor IIa inhibitors include argatroban, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0375] In some cases, direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The first example includes at least one of the following: (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). In the currently preferred example, the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof. In the second preferred example, the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0376] In some examples, the antiproliferative agent includes an m-Tor inhibitor, which may be selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, nobolimus, ridafololimus, temsirolimus, zotalolimus, or their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs. Currently preferred antiproliferative agents include sirolimus, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0377] In other examples, the antiproliferative agent may include paclitaxel, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0378] In other examples, the antiproliferative agent may also include an antiplatelet agent.

[0379] Preferred combinations and pair formations of active substances in the methods of this specification include (1) a calcium chelating agent, (2) a direct factor IIa inhibitor containing argatroban and a direct factor Xa inhibitor containing apixaban, and (3) an antiproliferative agent containing a direct factor IIa inhibitor containing argatroban, a direct factor Xa inhibitor containing apixaban, and sirolimus.

[0380] In some examples, the structure includes a scaffold having at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces, and deployment includes extending the scaffold in a body lumen. Typically, at least a portion of the outer surface is coated with a therapeutic composition. If necessary, at least a portion of the inner surface is coated with a therapeutic composition. If further necessary, a portion of the end surfaces is coated with a therapeutic composition.

[0381] In some examples, at least a portion of the surface may have containers formed therein, at least a portion of which contain a therapeutic agent, where the containers may include one or more of wells, channels, pores, and surface textures.

[0382] In some cases, the release rate(s) of active substances are controlled. For example, additives with different decomposition or release rates can be added to different layers and / or combined with different active substances. In addition, or / or, a controlled release layer may be formed covering the therapeutic composition to control the release of three or more active substances.

[0383] In some cases, the therapeutic composition may include a base layer formed over a surface and a top layer formed over the base layer, wherein the base layer and the top layer differ in at least some properties. In such examples, the therapeutic composition may be formulated to release the active substance substantially completely from the top layer before releasing it from the base layer. For example, the active substance may be released from the top layer over a period ranging from 1 hour to 7 days after the surface of the structure is positioned adjacent to the injury site, and the active substance may be released from the base layer over a period ranging from 7 days to 12 months after the active substance has been substantially released from the top layer (after the after). In some examples, each of the base layer and the top layer contains at least three active substances mixed in a biodegradable polymer matrix.

[0384] In many cases, injury is caused, at least partially, before the deployment of a structure, but more generally, in arteries, the deployment of a structure, such as stent expansion, causes injury, and therapeutic compositions are formulated to release calcium chelating agents such as EDTA, direct factor IIa inhibitors, direct factor Xa inhibitors, or antiproliferative agents before, during, and / or after the injury occurs. Specific examples include vascular wall injury during vascular interventions, including angioplasty, atherosclerosis, stent placement, and graft placement.

[0385] In other examples, injuries occur during the placement, implantation, or other introduction of temporary or non-temporary devices selected from the group consisting of access devices, injection devices, tools, surgical instruments and tools, implants, body implants, buttock implants, shoulder implants, knee implants, organ implants, luminal implants, vascular implants, stent delivery systems, stents, stent-grafts, catheters, balloons, graft implants, grafts, aneurysm coils, valves, valve implants, shunts, left atrial appendage implants, orifice implants, leads, closure devices, clips, wound closure devices and implants, sutures, patches, injection devices, needles inserted into the body, and needles inserted from outside the body.

[0386] The anticoagulants described herein and of the claims, each of the classes and types of anticoagulants described herein and of the claims, including, but not limited to, inhibitors of the coagulation cascade, such as certain factor IIa inhibitors, factor Xa inhibitors, factor XI inhibitors, and factor XIa inhibitors listed herein, as well as certain chelating agents and certain anticoagulant enhancers, may be combined with one or more of the other classes and types of anticoagulants described herein and of the claims. Furthermore, each of the classes and types of anticoagulants described herein and of the claims may be formulated for any release profile described herein and of the claims, such as bolus release, dual bolus release, and extended release.

[0387] In some embodiments, the Disclosure provides compositions for coupling to the surface of an embeddable article. The compositions may comprise an anticoagulant comprising a direct factor Xa inhibitor, and at least one of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor IIa inhibitor, or (c) an anti-inflammatory agent comprising colchicine.

[0388] In some embodiments, the composition further comprises at least two of the following: (a) an antiplatelet agent, (b) a direct factor IIa inhibitor, or (c) an anti-inflammatory agent comprising colchicine. In some embodiments, the composition further comprises all three of the following: (a) an antiplatelet agent, (b) a direct factor IIa inhibitor, and (c) an anti-inflammatory agent comprising colchicine.

[0389] In some embodiments, the direct factor Xa inhibitor is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), eribaxaban (PD The drug comprises at least one drug selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052), and salts, isomers, solvates, derivatives, metabolites, or prodrugs of any preceding member of the group. In some embodiments, the direct factor Xa inhibitor comprises rivaroxaban, apixaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0390] In some embodiments, the composition further comprises at least one antiplatelet agent selected from the group consisting of a Cox1 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a Cox2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a glycoprotein IIIb / IIIa inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; and a P2Y12 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet agent comprises tirofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet agent comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet agent comprises a Cox1 / 2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, the Cox1 / 2 inhibitor comprises acetylsalicylic acid. In some embodiments, the antiplatelet agent comprises clopidogrel, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0391] In some embodiments, the composition further comprises at least one direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine. In some embodiments, the drug of at least one direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0392] In another embodiment, the Disclosure provides compositions for coupling to the surface of an embeddable article. The compositions may comprise an anticoagulant comprising a direct factor IIa inhibitor, and at least one of (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor Xa inhibitor, or (c) an anti-inflammatory agent comprising colchicine.

[0393] In some embodiments, the composition further comprises at least two of the following: (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor Xa inhibitor, or (c) an anti-inflammatory agent comprising colchicine. In some embodiments, the composition further comprises all three of the following: (a) an antiplatelet agent, (b) an anticoagulant comprising a direct factor Xa inhibitor, and (c) an anti-inflammatory agent comprising colchicine.

[0394] In some embodiments, the composition is a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, repirudine, and salts, isomers, solvates, derivatives, metabolites, or prodrugs of any preceding member of the group. In some embodiments, the drug of the direct factor IIa inhibitor includes argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0395] In some embodiments, the composition further comprises at least one antiplatelet agent selected from the group consisting of a Cox1 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a Cox2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a glycoprotein IIb / IIIa inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; and a P2Y12 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet agent comprises tirofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet agent comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet agent comprises a Cox1 / 2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, the Cox1 / 2 inhibitor comprises acetylsalicylic acid. In some embodiments, the antiplatelet agent includes clopidogrel, or its salts, isomers, solvates, derivatives, metabolites, or prodrugs; or active metabolites of clopidogrel, or its salts, isomers, solvates, derivatives, metabolites, or prodrugs.

[0396] In some embodiments, the direct factor Xa inhibitor is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), eribaxaban (PD The drug comprises at least one drug selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052), and salts, isomers, solvates, derivatives, metabolites, or prodrugs of any preceding member of the group. In some embodiments, the direct factor Xa inhibitor comprises apixaban, or a salt or analog thereof; and / or rivaroxaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0397] In another embodiment, the Disclosure provides compositions for coupling to the surface of an embeddable article. The compositions may comprise a direct factor Xa inhibitor; and at least two of the following: (a) a direct factor IIa inhibitor; (b) an antiplatelet agent selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, and P2y12 inhibitors; or (c) an anti-inflammatory agent. In some embodiments, the compositions further comprise all three of the following: (a) a direct factor IIa inhibitor; (b) an antiplatelet agent selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, and IIb / IIIa inhibitors; and (c) an anti-inflammatory agent.

[0398] Direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The composition according to claim 25 or 26, comprising (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052), and at least one drug selected from the group consisting of salts, isomers, solvates, derivatives, metabolites or prodrugs of any preceding member of the group.

[0399] In some embodiments, the direct factor Xa inhibitor comprises rivaroxaban, apixaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the composition further comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the composition comprises an antiplatelet agent comprising at least one drug selected from the group consisting of tirofiban, ticagrelor, Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, P2Y12 inhibitors, and salts, analogs, or metabolites of any preceding member of the group. In some embodiments, the composition comprises an anti-inflammatory agent comprising colchicine.

[0400] In another embodiment, the Disclosure provides compositions for coating the surface of an embeddable article. The compositions may comprise apixaban, or a salt, analog, or metabolite thereof; rivaroxaban, or a salt, analog, or metabolite thereof; argatroban, or a salt, analog, or metabolite thereof; tyrofiban, or a salt, analog, or metabolite thereof; and colchicine, or a salt, analog, or metabolite thereof.

[0401] In some embodiments, the composition of any aspect or embodiment further comprises an additional antiplatelet agent. In some embodiments, the composition of any aspect or embodiment further comprises an additional anti-inflammatory agent, according to any one of the preceding claims.

[0402] In another aspect, the disclosure provides a surgical article comprising a base structure, wherein a composition and / or one or more components thereof of any aspect or embodiment are coupled to the surface or interior of the base structure.

[0403] In some embodiments, the composition is coupled to the surface in a single layer. In some embodiments, the single layer is homogeneous. In some embodiments, the single layer is heterogeneous. In some embodiments, at least two layers of the composition and / or one or more components are coupled to the surface. In some embodiments, the surgical article further includes intermediate layers covering and / or between at least two layers. In some embodiments, one or more intermediate layers contain a drug in addition to the drug on the composition. In some embodiments, the drug in the surface-coupled composition has a release rate in the range of 1 day to 1 year. In some embodiments, the drug in the surface-coupled composition has a release rate in the range of 1 day to 3 days, 1 day to 30 days, or 1 day to 90 days.

[0404] Item 1. A scaffold structure having a surface configured to be embedded in a patient's vascular structure; an implantable scaffold comprising a therapeutic composition configured to be released from the surface of the scaffold, wherein the therapeutic composition comprises colchicine and / or tirofiban and at least one antiproliferative agent, wherein the colchicine and / or tirofiban is present in a carrier configured to release colchicine and / or tirofiban in an amount sufficient to inhibit inflammation arising from the embedding of the scaffold for a period of at least one week; and at least one antiproliferative agent is present in the same or a different carrier configured to release the antiproliferative agent in an amount sufficient to inhibit smooth cell muscle (SMC) proliferation for a period of at least one week.

[0405] Item 2. An implantable scaffold according to Item 1, wherein at least one antiproliferative agent comprises an mTOR inhibitor.

[0406] Item 3. An implantable scaffold according to Item 2, wherein the mTOR inhibitor comprises one or more drugs selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotarolimus, and their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0407] Item 4. An implantable scaffold as described in Item 3, comprising sirolimus or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0408] Item 5. An implantable scaffold according to items 1-4, wherein the therapeutic composition is formulated to release 90% by weight, 75% by weight, 50% by weight, 25% by weight, or 10% by weight or less of colchicine and / or tyrofiban from the scaffold to the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0409] Item 6. An implantable scaffold according to Item 5, wherein the therapeutic composition is formulated to release 90% by weight, 75% by weight, 50% by weight, 25% by weight, or 10% by weight or less of the antiproliferative agent from the scaffold to the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0410] Item 7. An embeddable scaffold as described in Items 1-5, wherein the scaffold structure is loaded with colchicine in amounts ranging from 1.7 μg to 170 μg, 1.7 μg to 85 μg, 2.5 μg to 40 μg, or 3.4 μg to 20 μg per 1 mm of length of the scaffold structure.

[0411] Item 8. An implantable scaffold as described in Items 1-6, wherein the scaffold structure is loaded with an amount of antiproliferative agent in the range of 2 μg to 200 μg, 2 μg to 100 μg, 3 μg to 50 μg, or 4 μg to 20 μg per 1 mm of length of the scaffold structure.

[0412] Item 9. An embeddable scaffold according to items 1 to 8, wherein the carrier comprises a biodegradable polymer.

[0413] Item 10. An embeddable scaffold as described in Item 9, wherein the biodegradable polymer is selected from the group consisting of polyesters, e.g., polylactic acid, polyglycolic acid, polylactic acid-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol-block-polycaprolactone, and polyurethane; poly(methyl methacrylate) (PMMA); poly-N-(2-hydroxypropyl)methacrylamide; polyethyleneimine (PEI), dextran, dextrin, chitosan, poly(L-lysine); poly(aspartamide), polyethylene; polypropylene; polyamide; polyethylene glycol (PEG); silicone; poly(acid anhydride); and polyorthoesters.

[0414] Item 11. An implantable scaffold according to items 1 to 10, wherein the therapeutic composition further comprises at least one anticoagulant.

[0415] Item 12. The implantable scaffold according to Item 11, wherein at least one anticoagulant is selected from the group consisting of direct factor IIa inhibitors and direct factor Xa inhibitors.

[0416] Item 13. An implantable scaffold according to Item 12, wherein at least one anticoagulant comprises a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0417] Item 14. An implantable scaffold according to Item 13, comprising at least one direct factor IIa inhibitor, argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0418] Item 15. At least one anticoagulant is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD An implantable scaffold according to any one of items 11 to 14, comprising a direct factor Xa inhibitor selected from the group consisting of (0348292) and (carbamimidyl-2-hydroxy-phenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0419] Item 16. An implantable scaffold as described in Item 15, comprising apixaban or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0420] Item 17. An implantable scaffold according to Item 16, comprising a direct factor Xa inhibitor, rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0421] Item 18. An implantable scaffold according to any one of items 1 to 17, wherein the therapeutic composition further comprises an antiplatelet agent.

[0422] Item 19. The method according to any one of Item 18, wherein the antiplatelet agent is selected from the group consisting of absiximab, eptifivatide, orvofivan, roxifivan, sibrafivan, tirofivan, clopidogrel, prasugrel, cangrelor, erinogrel, ticagrelor, beraprost, iloprost, prostacyclin, treprostinil, acetylsalicylic acid / aspirin, alloxiprine, carbasalate calcium, indobufen, triflusal, dipyridamole / aspirin, picotamide, tervogrel, tertroban, cilostazol, dipyridamole, triflusal, chloricromene, ditasol, borapaxar, and ticlopidine.

[0423] Item 20. An implantable scaffold according to items 1 to 19, wherein the therapeutic composition further comprises a second antiproliferative agent.

[0424] Item 21. The implantable scaffold according to item 20, wherein the second antiproliferative agent is selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, and azathioprine.

[0425] Item 22. An implantable scaffold according to items 1 to 21, wherein the therapeutic composition further comprises a cationic anticoagulant enhancer.

[0426] Item 23. An embeddable scaffold according to Item 22, wherein the cationic anticoagulant enhancer is selected from a first group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salt, toridodecylmethylammonium salt, benzalkonium, its analogs, solvates, hydrates and derivatives, or from a second group consisting of poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branched polyethyleneimine (PEI), chitosan, PAMAM dendrimers and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, polybetaaminoester (PBAE), histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, its analogs, solvates, hydrates and derivatives.

[0427] Item 24. An implantable scaffold according to items 1 to 23, wherein the therapeutic composition further comprises a factor XI / XIa inhibitor.

[0428] Item 25. An embeddable scaffold according to Item 24, wherein the factor XI / XIa inhibitor comprises a protein Z-dependent protease inhibitor, its analog, solvate, hydrate, or derivative.

[0429] Item 26. An embeddable scaffold according to items 1 to 25, wherein the therapeutic composition further comprises a chelating agent formulated to deplete calcium in the environment surrounding the scaffold, upon embedding the scaffold structure in the environment.

[0430] Item 27. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS). An embeddable scaffold as described in item 26, selected from the group consisting of thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinate (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0431] Item 28. An implantable scaffold as described in items 1-27, wherein the scaffold structure is configured to expand in the vascular lumen of the patient's body.

[0432] Item 29. An embeddable scaffold according to items 1 to 28, wherein the therapeutic composition is coated on the surface of the scaffold structure in at least part of the manner.

[0433] Item 30. An implantable scaffold according to items 1 to 29, wherein the therapeutic composition is present in at least part within a cavity or reservoir within the scaffold structure.

[0434] Item 31. An embeddable scaffold according to items 1 to 30, wherein the embeddable scaffold has at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces.

[0435] Item 32. The implantable scaffold according to Item 31, wherein at least a portion of the outer surface is coated with a therapeutic composition.

[0436] Item 33. An implantable scaffold according to item 30 or 31, wherein at least a portion of the inner surface is coated with a therapeutic composition.

[0437] Item 34. An embeddable scaffold according to any one of items 31 to 33, wherein a portion of the end surface is coated with a therapeutic composition.

[0438] Item 35. An embeddable scaffold according to any one of items 31 to 34, wherein at least a portion of the surface has a container formed therein, and at least a portion of the container has a therapeutic agent therein.

[0439] Item 36. An embeddable scaffold as described in Item 35, wherein the container includes one or more of wells, channels, holes, and surface textures.

[0440] Items 37-50 have been intentionally left blank.

[0441] Item 51. A method for treating vascular tissue injury in a patient, comprising implanting a scaffold structure at a target site in the patient's vascular structure adjacent to the tissue injury; a therapeutic composition on the scaffold comprising colchicine and / or tirofiban and at least one antiproliferative agent; colchicine and / or tirofiban being released into the vascular tissue from a carrier in the therapeutic composition over a period of at least one week in an amount sufficient to inhibit inflammation arising from the implantation of the scaffold; and at least one antiproliferative agent being released from the same or a different carrier over a period of at least one week in an amount sufficient to inhibit smooth cell muscle (SMC) proliferation.

[0442] 52. The method according to item 51, wherein at least one antiproliferative agent comprises an mTOR inhibitor.

[0443] The method according to item 52, wherein the mTOR inhibitor comprises one or more drugs selected from the group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridafololimus, temsirolimus, zotarolimus, and their salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0444] Item 54. The method according to item 53, wherein the mTOR inhibitor comprises sirolimus, or its salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs.

[0445] Item 55. The method according to items 51-54, wherein the therapeutic composition is formulated to release 90% by weight, 75% by weight, 50% by weight, 25% by weight, or 10% by weight or less of colchicine and / or tyrofiban from the scaffold to the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0446] Item 56. The method according to item 55, wherein the therapeutic composition is formulated to release 90% by weight, 75% by weight, 50% by weight, 25% by weight, or 10% by weight or less of an mTOR inhibitor from the scaffold to the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0447] Item 57. The method according to items 51-55, wherein the scaffold structure is loaded with colchicine and / or tyrofiban in amounts ranging from 1.7 μg to 170 μg, 1.7 μg to 85 μg, 2.5 μg to 40 μg, or 3.4 μg to 20 μg per 1 mm of length of the scaffold structure.

[0448] Item 58. The method according to items 51-56, wherein the scaffold structure is loaded with an amount of antiproliferative agent in the range of 2 μg-200 μg, 2 μg-100 μg, 3 μg-50 μg, or 4 μg-20 μg per 1 mm of length of the scaffold structure.

[0449] Item 59. The method according to items 51-58, wherein the carrier comprises a biodegradable polymer.

[0450] Item 60. The method according to item 59, wherein the biodegradable polymer is selected from the group consisting of polyesters, e.g., polylactic acid, polyglycolic acid, polylactic acid-co-glycolic acid, polylactic acid-co-caprolactone, polyethylene glycol-block-polycaprolactone, and polyurethane; poly(methyl methacrylate) (PMMA); poly-N-(2-hydroxypropyl)methacrylamide; polyethyleneimine (PEI), dextran, dextrin, chitosan, poly(L-lysine); poly(aspartamide), polyethylene; polypropylene; polyamide; polyethylene glycol (PEG); silicone; poly(acid anhydride); and polyorthoesters.

[0451] Item 61. The method according to items 51-60, wherein the therapeutic composition further comprises at least one anticoagulant.

[0452] Item 62. The method according to item 61, wherein at least one anticoagulant is selected from the group consisting of direct factor IIa inhibitors and direct factor Xa inhibitors.

[0453] Item 63. The method according to item 62, wherein at least one anticoagulant comprises a direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0454] Item 64. The method according to item 63, wherein at least one direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0455] Item 65. At least one anticoagulant is apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The method according to any one of items 61 to 64, comprising a direct factor Xa inhibitor selected from the group consisting of (0348292) and (carbamidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0456] Item 66. The method according to Item 65, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0457] Item 67. The method according to Item 66, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0458] Item 68. The method according to any one of items 51 to 67, wherein the therapeutic composition further comprises an antiplatelet agent.

[0459] Item 69. The method according to any one of Item 68, wherein the antiplatelet agent is selected from the group consisting of absiximab, eptifivatide, orvofivan, roxifivan, sibrafivan, tirofivan, clopidogrel, prasugrel, cangrelor, erinogrel, ticagrelor, beraprost, iloprost, prostacyclin, treprostinil, acetylsalicylic acid / aspirin, alloxiprine, carbasalate calcium, indobufen, triflusal, dipyridamole / aspirin, picotamide, tervogrel, tertroban, cilostazol, dipyridamole, triflusal, chloricromene, ditasol, borapaxar, and ticlopidine.

[0460] Item 70. The method according to items 51-69, wherein the therapeutic composition further comprises a second antiproliferative agent.

[0461] Item 71. The method according to item 70, wherein the second antiproliferative agent is selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, and azathioprine.

[0462] Item 72. The method according to items 51 to 71, wherein the therapeutic composition further comprises a cationic anticoagulant enhancer.

[0463] Item 73. The method according to item 72, wherein the cationic anticoagulant enhancer is selected from a first group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salt, toridodecylmethylammonium salt, benzalkonium, its analogs, solvates, hydrates and derivatives, or from a second group consisting of poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branched polyethyleneimine (PEI), chitosan, PAMAM dendrimers and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, polybetaaminoester (PBAE), histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, its analogs, solvates, hydrates and derivatives.

[0464] Item 74. The method according to items 51-73, wherein the therapeutic composition further comprises a factor XI / XIa inhibitor.

[0465] Item 75. The method according to Item 74, wherein the factor XI / XIa inhibitor comprises a protein Z-dependent protease inhibitor, an analog, solvate, hydrate, or derivative thereof.

[0466] Item 76. The method according to items 51-54, wherein the therapeutic composition further comprises a chelating agent formulated to deplete calcium in the environment surrounding the scaffold, during the embedding of the scaffold structure in the environment.

[0467] Item 77. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The method according to claim 76, selected from the group consisting of PS) thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complexes, EDTA quaternary ammonium salts, EDTA benzalkonium salts, EDTA complexes, salts thereof, analogs, solvates, hydrates and derivatives.

[0468] Item 78. The method according to items 51-77, wherein the scaffold structure is configured to expand in the vascular lumen of the patient's body.

[0469] Item 79. The method according to items 51-78, wherein the therapeutic composition is coated in at least part onto the surface of a scaffold structure.

[0470] Item 80. The method according to items 51-79, wherein the therapeutic composition is present in at least part within a cavity or reservoir in a scaffold structure.

[0471] Item 81. The method according to items 51 to 80, wherein the scaffolding has at least an outer surface, an inner surface, and one or more end surfaces between the outer and inner surfaces.

[0472] Item 82. The method according to item 81, wherein at least a portion of the outer surface is coated with a therapeutic composition.

[0473] Item 83. The method according to item 81 or 32, wherein at least a portion of the inner surface is coated with a therapeutic composition.

[0474] Item 84. The method according to any one of items 81 to 83, wherein a portion of the end surface is coated with a therapeutic composition.

[0475] Item 85. The method according to any one of items 81 to 83, wherein at least a portion of the surface has a container formed therein, and at least a portion of the container has a therapeutic agent therein.

[0476] Item 86. The method according to Item 85, wherein the container includes one or more of wells, channels, pores, and surface textures.

[0477] Items 87-100 have been intentionally left blank.

[0478] Item 101. A composition for coating the surface of an embeddable article, wherein the composition comprises a first antiplatelet agent comprising (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor; (b) colchicine; and (c) tirofiban; wherein (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor, (b) colchicine; and (c) the first antiplatelet agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation and / or thrombosis resulting from injury.

[0479] The composition according to item 101, wherein (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor, (b) colchicine, and (c) a first antiplatelet agent is formulated to treat injury resulting from the implantation of an article.

[0480] A composition according to item 101 or 102, wherein (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor, (b) colchicine, and (c) a first antiplatelet agent is formulated to treat an injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of a systemic antithrombotic agent.

[0481] Item 104. A composition according to items 101 to 103, comprising at least one factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0482] Item 105. The composition according to Item 104, wherein at least one direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0483] Item 106. Apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The composition according to items 101 to 105, comprising at least one factor Xa inhibitor selected from the group consisting of (0348292) and (carbamimidyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0484] Item 107. The composition according to Item 106, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0485] Item 108. The composition according to Item 106, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0486] Item 109. The composition according to items 101 to 108, further comprising at least a second antiplatelet agent different from the first antiplatelet agent.

[0487] Item 110. The composition according to Item 109, wherein the second antiplatelet agent comprises one or more of the following: glycoprotein IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0488] Item 111. The compositions according to items 109 and 110, further comprising at least a third antiplatelet agent different from the first and second antiplatelet agents.

[0489] Item 112. The composition according to Item 111, wherein the third antiplatelet agent comprises one or more of the following: factor IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0490] Item 113. The compositions according to items 101 to 112, further comprising a chelating agent.

[0491] Item 114. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 113, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0492] Item 115. The composition according to items 101 to 114, further comprising at least one antiproliferative agent.

[0493] Item 116. The composition according to item 115, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0494] Item 117. The compositions according to items 101 to 116, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0495] Item 118. The compositions according to items 101 to 116, wherein the individual components of the composition are configured to sequentially coat a surface.

[0496] Items 119-200 have been intentionally left blank.

[0497] Item 201. A composition for coating the surface of an embeddable article, wherein the composition comprises a first antiplatelet agent comprising (a) a factor IIa inhibitor; (b) a factor Xa inhibitor; and (c) a factor IIa / IIIb inhibitor; and the composition is formulated so that (a) the factor IIa inhibitor, (b) the factor Xa inhibitor, and (c) the first antiplatelet agent are released from the surface of the article in an amount sufficient to inhibit inflammation and / or thrombosis resulting from injury.

[0498] The composition according to item 201, wherein (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, and (c) a first antiplatelet agent are formulated to treat injury resulting from the implantation of an article.

[0499] A composition according to Section 201 or 202, wherein (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, and (c) a first antiplatelet agent are formulated to treat an injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of a systemic antithrombotic agent.

[0500] A composition according to items 201-203, further comprising (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, and (c) colchicine formulated to be released from the surface of an article in combination with the first antiplatelet agent in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury.

[0501] Item 205. The composition according to items 201 to 204, wherein the factor IIa inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analog, bivalirudine, deciludine, and repirudine.

[0502] Item 206. The composition according to Item 205, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0503] Item 207. Factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD A composition according to items 201 to 206, selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0504] Item 208. The composition according to Item 207, wherein the factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0505] Item 209. The composition according to Item 20, wherein the factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0506] Item 210. The composition according to items 201-209, wherein the factor IIb / IIIa inhibitor is selected from the group consisting of absiximab, eptifivatide, olvofivan, roxifivan, sibrafivan, and tyrofivan.

[0507] Item 211. The composition according to items 201-210, further comprising at least a second antiplatelet agent different from the first antiplatelet agent.

[0508] Item 212. The composition according to Item 211, wherein the second antiplatelet agent comprises one or more of the following: factor IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0509] Item 213. The compositions according to items 211 and 212, further comprising at least a third antiplatelet agent different from the first and second antiplatelet agents.

[0510] Item 214. The composition according to Item 213, wherein the third antiplatelet agent comprises one or more of the following: factor IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0511] Item 215. The compositions according to items 201 to 214, further comprising a chelating agent.

[0512] Item 216. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 215, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0513] Item 217. The composition according to items 201 to 216, further comprising at least one antiproliferative agent.

[0514] Item 218. The composition according to item 217, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0515] Item 219. The compositions according to items 201-218, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0516] Item 220. The compositions according to items 201-218, wherein the individual components of the composition are configured to sequentially coat a surface.

[0517] Items 221-300 have been intentionally left blank.

[0518] Item 301. A composition for coating the surface of an implantable article, wherein the composition comprises (a) a factor IIa inhibitor; (b) a factor Xa inhibitor; (c) a first antiplatelet agent comprising a factor IIa / IIIb inhibitor; and (d) a second antiplatelet agent comprising an NSAID; and the composition is formulated such that (a) the factor IIa inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet agent, and (d) the second antiplatelet agent are released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0519] The composition according to item 301, wherein (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat injury resulting from the implantation of an article.

[0520] A composition according to Section 301 or 302, wherein (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat an injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of a systemic antithrombotic agent.

[0521] A composition according to items 301-303, further comprising (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent, formulated to be released from the surface of an article in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury.

[0522] Item 305. The composition according to items 301 to 304, wherein the factor IIa inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analog, bivalirudine, deciludine, and repirudine.

[0523] Item 306. The composition according to Item 305, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0524] Item 307. Factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD A composition according to items 301 to 306, selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0525] Item 308. The composition according to Item 307, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0526] Item 309. The composition according to Item 30, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0527] Item 310. The composition according to items 301-309, wherein the factor IIb / IIIa inhibitor is selected from the group consisting of absiximab, eptifivatide, olvofivan, roxifivan, sibrafivan, and tyrofivan.

[0528] Item 311. A composition according to items 301-310, wherein the NSAID comprises a salicylate.

[0529] Item 312. The composition according to items 301 to 311, further comprising at least a third antiplatelet agent different from the first and second antiplatelet agents.

[0530] Item 313. The composition according to Item 311, wherein the third antiplatelet agent comprises one or more of the following: factor IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0531] Item 314. The compositions according to items 301 to 313, further comprising a chelating agent.

[0532] Item 315. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 314, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0533] Item 316. The composition according to items 301 to 315, further comprising at least one antiproliferative agent.

[0534] Item 317. The composition according to item 316, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0535] Item 318. The compositions according to items 301 to 317, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0536] Item 319. The compositions according to items 301 to 317, wherein the individual components of the composition are configured to sequentially coat a surface.

[0537] Items 320-350 have been intentionally left blank.

[0538] Item 351. A composition for coating the surface of an implantable article, wherein the composition comprises (a) a factor IIa inhibitor; (b) a factor Xa inhibitor; (c) a first antiplatelet agent comprising a factor IIa / IIIb inhibitor; and (d) a second antiplatelet agent comprising an ADP receptor / P2Y12 inhibitor; and the composition is formulated such that (a) the factor IIa inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet agent, and (d) the second antiplatelet agent are released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0539] The composition according to item 351, wherein (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat injury resulting from the implantation of an article.

[0540] A composition according to Section 351 or 352, wherein (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent are formulated to treat an injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of a systemic antithrombotic agent.

[0541] A composition according to Sections 351-353, further comprising (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent, formulated to be released from the surface of an article in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury.

[0542] A composition according to items 351-354, further comprising (a) a factor IIa inhibitor, (b) a factor Xa inhibitor, (c) a first antiplatelet agent, and (d) a second antiplatelet agent, formulated to be released from the surface of an article in an amount sufficient to enhance the inhibition of inflammation and / or thrombosis resulting from injury, in combination with (f) an aspirin and / or another NSAID.

[0543] Item 356. The composition according to items 351 to 355, wherein the factor IIa inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analog, bivalirudine, deciludine, and repirudine.

[0544] Item 357. The composition according to Item 356, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0545] Item 358. Factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD A composition according to items 351 to 357, selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0546] Item 359. The composition according to Item 358, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0547] Item 360. The composition according to Item 359, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0548] Item 361. The composition according to items 351-360, wherein the factor IIb / IIIa inhibitor is selected from the group consisting of absiximab, eptifivatide, olvofivan, roxifivan, sibrafivan, and tyrofivan.

[0549] Item 362. The composition according to items 351-361, wherein the ADP receptor / P2Y12 inhibitor is selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor. [Only in SLIDER #1]

[0550] Item 363. The composition according to items 351-362, further comprising at least a third antiplatelet agent different from the first and second antiplatelet agents.

[0551] Item 364. The composition according to Item 363, wherein the third antiplatelet agent comprises one or more of the following: factor IIb / IIIa inhibitors, COX inhibitors, ADP receptor / P2Y12 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0552] Item 365. The composition according to item 364, wherein the third antiplatelet agent comprises aspirin or another NSAID.

[0553] Item 366. The compositions according to items 351 to 365, further comprising a chelating agent.

[0554] Item 367. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 366, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0555] Item 368. The composition according to items 351-367, further comprising at least one antiproliferative agent.

[0556] Item 369. The composition according to item 368, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0557] Item 370. The compositions according to items 351-369, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0558] Item 371. The compositions according to items 351-370, wherein the individual components of the composition are configured to sequentially coat a surface.

[0559] Items 372-400 have been intentionally left blank.

[0560] Item 401. A composition for coating the surface of an implantable article, wherein the composition comprises a factor Xa inhibitor; and one or more of the following: (a) colchicine, (b) a first antiplatelet agent comprising a factor IIa / IIIb inhibitor; (c) a second antiplatelet agent comprising an NSAID; and (d) a third antiplatelet agent comprising an ADP inhibitor; and the factor Xa inhibitor; and one or more of the following: (a) colchicine, (b) a first antiplatelet agent, (c) a second antiplatelet agent, and (d) a third antiplatelet agent, are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0561] Item 402. The composition according to Item 401, wherein a factor Xa inhibitor, and a first antiplatelet agent comprising (a) colchicine, (b) a factor IIa / IIIb inhibitor; a second antiplatelet agent comprising (c) an NSAID; and a third antiplatelet agent comprising an ADP inhibitor are formulated to treat injury resulting from the implantation of an article.

[0562] Section 403. A composition according to Section 401 or 402, wherein a factor Xa inhibitor, and a first antiplatelet agent comprising (a) colchicine, (b) a factor IIa / IIIb inhibitor; a second antiplatelet agent comprising (c) an NSAID; and a third antiplatelet agent comprising an ADP inhibitor are formulated to treat an injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of a systemic antithrombotic agent.

[0563] Item 404. The composition according to items 401-403, further comprising a factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0564] Item 405. The composition according to Item 404, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0565] Item 406. Factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD A composition according to items 401 to 405, selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052).

[0566] Item 407. The composition according to Item 406, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0567] Item 408. The composition according to Item 407, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0568] Item 409. The composition according to items 401-408, wherein the factor IIb / IIIa inhibitor is selected from the group consisting of absiximab, eptifivatide, olvofivan, roxifivan, sibrafivan, and tyrofivan.

[0569] Item 410. The composition according to items 401-409, wherein the ADP receptor / P2Y12 inhibitor is selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor. [Only in SLIDER #1]

[0570] Item 411. The compositions according to items 401 and 410, further comprising at least a fourth antiplatelet agent different from the first and second antiplatelet agents.

[0571] Item 412. The composition according to item 363, wherein the fourth antiplatelet agent comprises one or more of the following: prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0572] Item 413. The compositions according to items 401 to 412, further comprising a chelating agent.

[0573] Item 414. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 413, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0574] Item 415. The composition according to items 401 to 414, further comprising at least one antiproliferative agent.

[0575] Item 416. The composition according to item 415, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0576] Item 417. The compositions according to items 401 to 416, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0577] Item 418. The compositions according to items 401 to 416, wherein the individual components of the composition are configured to sequentially coat a surface.

[0578] Items 419-500 have been intentionally left blank.

[0579] Item 501. A composition for coating the surface of an implantable article, wherein the composition comprises a factor IIa inhibitor; and one or more of the following: (a) colchicine, (b) a first antiplatelet agent comprising a factor IIa / IIIb inhibitor; (c) a second antiplatelet agent comprising an NSAID; and (d) a third antiplatelet agent comprising an ADP inhibitor; and the factor Xa inhibitor; and one or more of the following: (a) colchicine, (b) a first antiplatelet agent, (c) a second antiplatelet agent, and (d) a third antiplatelet agent, are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation arising from the implantation of the article when implanted in a patient.

[0580] Item 502. The composition according to item 501, wherein a factor IIa inhibitor, and a first antiplatelet agent comprising (a) colchicine, (b) a factor IIa / IIIb inhibitor; a second antiplatelet agent comprising (c) an NSAID; and a third antiplatelet agent comprising an ADP inhibitor are formulated to treat injury resulting from the implantation of an article.

[0581] Section 503. A composition according to Section 501 or 502, wherein a factor IIa inhibitor, and a first antiplatelet agent comprising (a) colchicine, (b) a factor IIa / IIIb inhibitor; a second antiplatelet agent comprising (c) an NSAID; and a third antiplatelet agent comprising an ADP inhibitor are formulated to treat an injury without causing one or more of the following: bleeding, risk of bleeding, and bleeding associated with the administration of a systemic antithrombotic agent.

[0582] Item 504. The composition according to items 501 to 503, wherein the factor IIa inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analog, bivalirudine, deciludine, and repirudine.

[0583] Item 505. The composition according to Item 504, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0584] Item 506. Apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The composition according to items 501 to 505, further comprising a factor Xa inhibitor selected from the group consisting of (0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0585] Item 507. The composition according to Item 506, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0586] Item 508. The composition according to Item 507, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0587] Item 509. The composition according to items 501 to 508, wherein the factor IIb / IIIa inhibitor is selected from the group consisting of absiximab, eptifivatide, olvofivan, roxifivan, sibrafivan, and tyrofivan.

[0588] Item 510. The composition according to items 501-509, wherein the ADP receptor / P2Y12 inhibitor is selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor. [Only in SLIDER #1]

[0589] Item 511. The compositions according to items 501 and 510, further comprising at least a fourth antiplatelet agent different from the first and second antiplatelet agents.

[0590] Item 512. The composition according to item 511, wherein the fourth antiplatelet agent comprises one or more of the following: prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0591] Item 513. The compositions according to items 501 to 512, further comprising a chelating agent.

[0592] Item 514. The chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 513, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0593] Item 515. The composition according to items 501 to 514, further comprising at least one antiproliferative agent.

[0594] Item 516. The composition according to item 515, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0595] Item 517. The compositions according to items 501 to 516, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0596] Item 518. The compositions according to items 5101 to 516, wherein the individual components of the composition are configured to sequentially coat a surface.

[0597] Items 519-600 have been intentionally left blank.

[0598] Item 601. A composition for coating the surface of an implantable article, wherein the composition comprises (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor; (b) at least one antiplatelet agent selected from (i) a first antiplatelet agent comprising a COX-1 inhibitor; (ii) a second antiplatelet agent comprising a factor IIa / IIIb (2a / 3b) inhibitor; and (iii) a third antiplatelet agent comprising an adenosine diphosphate (ADP) / P2Y12 inhibitor; and the composition wherein (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor, and (b) at least one antiplatelet agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0599] Item 602. The composition according to item 601, comprising at least one factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0600] Item 603. The composition according to Item 602, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0601] Item 604. Apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The composition according to items 601 to 603, comprising a factor Xa inhibitor selected from the group consisting of (0348292) and (carbamidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0602] Item 605. The composition according to Item 604, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0603] Item 606. The composition according to Item 604, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0604] Item 607. A composition according to items 601 to 606, comprising a COX-1 inhibitor.

[0605] Item 608. The composition according to item 607, wherein the COX-1 inhibitor comprises a salicylate or other NSAID.

[0606] Item 609. A composition according to items 601-607, comprising a factor IIb / IIIa inhibitor selected from the group consisting of absiximab, eptifivatide, olbofivan, roxifivan, sibrafivan, and tyrofivan.

[0607] Item 610. A composition according to items 601-609, comprising an ADP receptor / P2Y12 inhibitor selected from the group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, erinogrel, and ticagrelor. [Only in SLIDER #1]

[0608] Item 611. The composition according to items 601-610, further comprising at least one of a prostaglandin analog, a thromboxane inhibitor, and a phosphodiesterase inhibitor.

[0609] Item 612. The compositions according to items 601 to 610, further comprising a chelating agent.

[0610] Item 613. Chelating agents include ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DM The composition according to item 612, selected from the group consisting of PS), thiaminetetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, salts thereof, analogs, solvates, hydrates and derivatives.

[0611] Item 614. The composition according to items 601 to 613, further comprising at least one antiproliferative agent.

[0612] Item 615. The composition according to item 614, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0613] Item 616. The compositions according to items 601 to 615, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0614] Item 617. The compositions according to items 601 to 615, wherein the individual components of the composition are configured to sequentially coat a surface.

[0615] Items 618-700 have been intentionally left blank.

[0616] Section 701. A composition for coating the surface of an implantable article, wherein the composition comprises (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor, (b) at least one of (i) colchicine, (ii) a first antiplatelet agent, and (iii) a chelating agent; and the composition wherein (a) at least one of a factor IIa inhibitor and a factor Xa inhibitor, and (b) at least one of (i) colchicine, (ii) a first antiplatelet agent, and a chelating agent are formulated to be released from the surface of the article in an amount sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0617] Item 702. The composition according to item 701, comprising at least one factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, and repirudine.

[0618] Item 703. The composition according to Item 702, wherein the factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0619] Item 704. Apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The composition according to items 701 to 703, comprising at least one factor Xa inhibitor selected from the group consisting of (0348292) and (carbamimidyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

[0620] Item 705. The composition according to Item 704, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0621] Item 706. The composition according to Item 704, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0622] Item 707. A composition according to items 701 to 706, comprising colchicine.

[0623] Item 708. A composition according to items 701 to 707, comprising one or more antiplatelet agents selected from the group consisting of factor IIa / IIIb inhibitors, ADP receptor / P2Y12 inhibitors, COX-1 inhibitors, prostaglandin analogs, thromboxane inhibitors, and phosphodiesterase inhibitors.

[0624] Item 709. Ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, EDTA monoammonium salt, EDTA diammonium salt, EDTA triammonium salt, EDTA benzyldimethyltetradecylammonium salt, EDTA toridodecylmethylammonium salt, other EDTA benzalkonium salts, EDTA tetraacetoxymethyl ester, ethylene glycol tetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiamine The composition according to item 708, comprising tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriamine pentaacetate (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, EDTA quaternary ammonium salt, EDTA benzalkonium salt, EDTA complex, its salts, analogs, solvates, hydrates and derivatives, and a chelating agent selected from this group.

[0625] Item 710. The composition according to items 701 to 709, further comprising at least one antiproliferative agent.

[0626] Item 711. The composition according to item 710, wherein the antiproliferative agent comprises an mTOR inhibitor.

[0627] Item 712. The compositions according to items 701 to 711, wherein the individual components of the composition are configured to simultaneously coat a surface.

[0628] Item 713. The compositions according to items 701 to 711, wherein the individual components of the composition are configured to sequentially coat a surface.

[0629] Items 714-800 have been intentionally left blank.

[0630] Item 801. An implantable article comprises a body having a surface configured for implantation in a patient, the surface being at least partially coated with a composition described in any one of items 101 to 713.

[0631] Article 802. An expandable scaffold configured for implantation in a patient's vascular system, as described in Article 801.

[0632] Item 803. Articles as described in Item 801, consisting of a non-expandable body.

[0633] Item 804. An article according to items 801-803, wherein the composition is formulated to be released from the article over a period of at least one week, one month, or one year.

[0634] Article according to Articles 801-804, wherein at least some of the components of the composition are formulated in one or more carriers that degrade when implanted in a patient.

[0635] Articles according to Articles 801-805, wherein the composition is formulated to release 90%, 75%, 50%, 25%, or 10% or less of its weight within one week, one month, three months, six months, or one year of implantation.

[0636] The examples described herein are not intended to be limiting. Other examples may be used, modified, or combined in whole or in part without departing from the scope of the subject matter presented herein. The aspects of this disclosure generally described herein, as shown in the figures and detailed descriptions and examples, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly intended herein.

[0637] These and other embodiments are described in further detail in the following description relating to the attached drawings. Embedding by reference

[0638] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference.

[0639] Novel features of this disclosure are shown in particular in the appended claims. A better understanding of the features and merits of this disclosure is obtained by the following detailed description illustrating exemplary embodiments in which the principles of this disclosure are utilized, and by reference to the following appended drawings. [Brief explanation of the drawing]

[0640] [Figure 1A] Figure 1A shows plots of HAoSMC cell proliferation in the presence of rapamycin and various concentrations of apixaban, according to Example 1.

[0641] [Figure 1B] Figure 1B shows plots of HAoSMC cell proliferation in the presence of rapamycin and various concentrations of argatroban, according to Example 1.

[0642] [Figure 1C] Figure 1C shows a plot of HAoSMC cell proliferation in the presence of rapamycin and various concentrations of apixaban and argatroban, according to Example 1.

[0643] [Figure 1D] Figure 1D shows plots of HAoSMC cell proliferation in the presence of different concentrations of apixaban, according to Example 1.

[0644] [Figure 1E] Figure 1E shows plots of HAoSMC cell proliferation in the presence of different concentrations of argatroban, according to Example 1.

[0645] [Figure 2A] Figure 2A shows a plot of activated clotting time (ACT) against drug concentration, according to the example.

[0646] [Figure 2B] Figure 2B shows a plot of activated clotting time (ACT) against drug concentration, according to Example 2.

[0647] [Figure 2C] Figure 2C shows a plot of activated clotting time (ACT) against drug concentration, demonstrating the synergistic effect of apixaban combined with argatroban, according to Example 2.

[0648] [Figure 2D] ...

Claims

1. A composition for coupling to the surface of an embeddable article, An anticoagulant containing a direct factor Xa inhibitor, and at least one of the following: (a) an antiplatelet agent, (b) an anticoagulant containing a direct factor IIa inhibitor, or (c) an anti-inflammatory agent containing colchicine. A composition containing the following:

2. The composition according to claim 1, comprising at least two of the following: (a) the antiplatelet agent, (b) the direct factor IIa inhibitor, or (c) the anti-inflammatory agent comprising colchicine.

3. The composition according to claim 1, comprising all three of the following: (a) an antiplatelet agent, (b) a direct factor IIa inhibitor, and (c) an anti-inflammatory agent including colchicine.

4. The aforementioned direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), and eribaxaban (PD The composition according to any one of claims 1 to 3, comprising 0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052), and at least one drug selected from the group consisting of salts, isomers, solvates, derivatives, metabolites, or prodrugs of any preceding member of the group.

5. The composition according to claim 4, wherein the direct factor Xa inhibitor comprises rivaroxaban, apixaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

6. Cox1 inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs; Cox2 inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs; Glycoprotein IIIb / IIIa inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs; and P2Y12 inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs. The composition according to any one of claims 1 to 5, comprising at least one antiplatelet agent selected from the group consisting of the following.

7. The composition according to claim 6, wherein the antiplatelet agent comprises tyrofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

8. The composition according to claim 6, wherein the antiplatelet agent comprises ticagrelor, or a salt thereof, isomer, solvate, derivative, metabolite, or prodrug.

9. The composition according to claim 6, wherein the antiplatelet agent comprises a Cox 1 / 2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, the Cox 1 / 2 inhibitor comprises acetylsalicylic acid.

10. The composition according to claim 6, wherein the antiplatelet agent comprises clopidogrel, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

11. The composition according to any one of claims 1 to 10, comprising at least one direct factor IIa inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analog, bivalirudine, deciludine, and repirudine.

12. The composition according to claim 11, wherein the drug of at least one direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

13. A composition for coupling to the surface of an embeddable article, An anticoagulant containing a direct factor IIa inhibitor, and at least one of (a) an antiplatelet agent, (b) an anticoagulant containing a direct factor Xa inhibitor, or (c) an anti-inflammatory agent containing colchicine. A composition containing the following:

14. The composition according to claim 13, comprising at least two of the following: (a) the antiplatelet agent, (b) the anticoagulant comprising the direct factor Xa inhibitor, or (c) the anti-inflammatory agent comprising colchicine.

15. The composition according to claim 13, comprising all three of the following: (a) an antiplatelet agent, (b) the anticoagulant comprising the direct factor Xa inhibitor, and (c) the anti-inflammatory agent comprising colchicine.

16. The composition according to any one of claims 13 to 15, wherein the direct factor IIa inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atesegatran methoxyl (AZD-0837), hirudin, hirudin analogs, bivalirudine, deciludine, repirudine, and salts, isomers, solvates, derivatives, metabolites, or prodrugs of any preceding member of the group.

17. The composition according to claim 16, wherein the direct factor IIa inhibitor drug comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

18. Cox1 inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs; Cox2 inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs; Glycoprotein IIb / IIIa inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs; and P2Y12 inhibitors, or their salts, isomers, solvates, derivatives, metabolites, or prodrugs. The composition according to any one of claims 13 to 17, comprising at least one antiplatelet agent selected from the group consisting of the following.

19. The composition according to claim 18, wherein the antiplatelet agent comprises tyrofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

20. The composition according to claim 18, wherein the antiplatelet agent comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

21. The composition according to claim 18, wherein the antiplatelet agent comprises a Cox 1 / 2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, the Cox 1 / 2 inhibitor comprises acetylsalicylic acid.

22. The aforementioned antiplatelet drug, Clopidogrel, or its salts, isomers, solvates, derivatives, metabolites, or prodrugs; or Clopidogrel, or its salts, isomers, solvates, derivatives, metabolites, or active metabolites of prodrugs The composition according to claim 18, comprising:

23. The aforementioned direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), and eribaxaban (PD The composition according to any one of claims 13 to 22, comprising 0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052), and at least one drug selected from the group consisting of salts, isomers, solvates, derivatives, metabolites, or prodrugs of any preceding member of the group.

24. The aforementioned direct factor Xa inhibitor Apixaban, or its salts or analogues; and / or Rivaroxaban, or its salts, isomers, solvates, derivatives, metabolites, or prodrugs. The composition according to claim 23, comprising:

25. A composition for coupling to the surface of an embeddable article. Direct factor Xa inhibitors; and (a) direct factor IIa inhibitors, (b) antiplatelet agents selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, IIb / IIIa inhibitors, and P2y12 inhibitors; or (c) anti-inflammatory agents A composition comprising at least two of the following.

26. The composition according to claim 25, comprising (a) the direct factor IIa inhibitor, (b) the antiplatelet agent selected from the group consisting of Cox1 inhibitors, Cox2 inhibitors, and IIb / IIIa inhibitors, and (c) all three of the anti-inflammatory agents.

27. The direct factor Xa inhibitors are apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), dalaxaban (YM-150), 2-[(7-carbamimidylnaphthalene-2-yl)methyl-[4-(1-ethaneimidoylpiperidine-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD The composition according to claim 25 or 26, comprising 0348292), carbamimidoyl-2-hydroxyphenyl)4-[5-(2,6-dimethyl-piperidine-1-yl)-pentyl]-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid (PD0313052), and at least one drug selected from the group consisting of salts, isomers, solvates, derivatives, metabolites or prodrugs of any preceding member of the group.

28. The composition according to claim 27, wherein the direct factor Xa inhibitor comprises rivaroxaban, apixaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

29. The composition according to any one of claims 25 to 28, wherein the direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

30. The composition according to any one of claims 25 to 29, wherein the antiplatelet agent comprises at least one drug selected from the group consisting of tyrofiban, ticagrelor, Cox 1 inhibitors, Cox 2 inhibitors, IIb / IIIa inhibitors, P2Y12 inhibitors, and salts, analogs, or metabolites of any preceding member of the group.

31. The composition according to any one of claims 25 to 30, wherein the anti-inflammatory agent comprises colchicine.

32. A composition for coating the surface of an embeddable article, Apixaban, or its salts, analogues, or metabolites; Rivaroxaban, or its salts, analogues, or metabolites; Argatroban, or its salts, analogues, or metabolites; Tyrofiban, or its salts, analogues, or metabolites; and Colchicine, or its salts, analogues, or metabolites A composition containing the following:

33. The composition according to any one of the preceding claims, further comprising an additional antiplatelet agent.

34. The composition according to any one of the preceding claims, further comprising an additional anti-inflammatory agent.

35. A surgical article comprising a base structure, wherein one or more of the compositions and / or components thereof described in any one of claims 1 to 34 are coupled to the surface or interior of the base structure.

36. The surgical article according to claim 35, wherein the composition is coupled to the surface in a single layer.

37. The surgical article according to claim 36, wherein the single layer is homogeneous.

38. The surgical article according to claim 36, wherein the single layer is heterogeneous.

39. The surgical article according to any one of claims 35 to 38, wherein at least two layers of the composition and / or one or more components are coupled to the surface.

40. The surgical article according to claim 39, further comprising an intermediate layer covering and / or between the at least two layers.

41. A surgical article according to any one of claims 35 to 40, wherein one or more intermediate layers contain a drug in addition to the drug on the composition.

42. The surgical article according to any one of claims 35 to 41, wherein the drug in the composition coupled to the surface has a release rate in the range of 1 day to 1 year.

43. The surgical article according to any one of claims 35 to 41, wherein the drug in the composition coupled to the surface has a release rate in the range of 1 to 3 days, 1 to 30 days, or 1 to 90 days.

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