Anticoagulant compositions comprising Anti-platelet and Anti-inflammatory drugs and methods and devices for their use

Abstract

Devices, systems, methods, and compositions are provided herein including a composition for coupling to a surface of an implantable article, said composition comprising: an anti-coagulant comprising a direct factor Xa inhibitor and at least one of (a) an anti-platelet drug, (b) anti-coagulant comprising a direct factor IIa inhibitor, and (c) an anti-inflammatory drug comprising colchicine.

Description

ANTICOAGULANT COMPOSITIONS COMPRISING ANTI-PLATELET AND ANTI¬INFLAMMATORY DRUGS AND METHODS AND DEVICES FOR THEIR USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 63 / 502,527 (Attorney Docket No. 32016-736.101), filed on May 16, 2023, and of U.S. Provisional Application 63 / 592,857 (Attorney Docket No. 32016-736.102), filed on October 24, 2023, the full disclosures of which are incorporated herein by reference.BACKGROUND

[0002] Field of the Disclosure: The present disclosure relates generally to medical devices and methods and more particularly to the coating of implantable and other devices with anticoagulant compositions.

[0003] Blood coagulation, commonly referred to as “clotting,” is a process designed to stop bleeding from damaged blood vessels. While mammals could not long survive without coagulation to staunch bleeding after injury, clotting in blood vessels after stenting and other intravascular interventions can cause hyperplasia, restenosis, and vessel calcification which are serious complications that can lead to death.

[0004] The blood coagulation process requires coagulation factors, calcium, and phospholipids. It is initiated by extrinsic tenase, which forms when factor Vila binds to tissue factor. Extrinsic tenase activates factors IX and X. In the presence of calcium, factor IXa binds to negatively charged phospholipid surfaces where it interacts with factor Villa to form intrinsic tenase, a complex that efficiently activates factor X. Factor Xa binds to factor Va on negatively charged phospholipid surfaces to form prothrombinase, the complex that activates prothrombin (factor II) to thrombin (factor Ila). Thrombin then converts fibrinogen to fibrin. Activated platelets or monocytes provide negatively charged phospholipid surfaces on which these clotting reactions occur. The intrinsic pathway is initiated by negatively charged surfaces-mediated activation of factor XII (FXII). Such contact activation further propagates thrombin generation by sequential activation of FXI, FIX, FX, and prothrombin. Importantly, thrombin can further activate FXI in a feedback mechanism. Thrombin also activates platelets, which can subsequently support FXI activation. Activation of FXI leads to enhanced thrombin formation, thus forming a positive feedback loop for thrombin formation and consolidation of coagulation. Disorders of coagulation can lead to obstructive clotting (thrombosis) or occlusion of the blood vessel.

[0005] Damage to a blood vessel can be caused by, e.g., injurious contact of a device employed in a surgery or intervention with the blood vessel (e.g., a surgical knife cutting a tissue containing the blood vessel, or a deployed stent embedding into the wall of the blood vessel). Damage to the blood vessel can lead to abnormal or undesired 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 obstructive clotting or occlusion of the blood vessel.

[0006] After vascular injury von Willebrand factor acts as a bridge between endothelial collagen and platelet surface receptors Gplb and promotes platelet adhesion. After adhesion, degranulation from both types of granules takes place with the release of various factors. Release of calcium occurs here simultaneously. Calcium binds to the phospholipids that appear secondary to the platelet activation and provides a surface for assembly of various coagulation factors.

[0007] Calcium ions play an important role in the tight regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Calcium ions are essential in coagulation cascade as it is a cofactor for membrane-bound complexes, including intrinsic tenase (FIXa-FVIIIa), extrinsic tenase (FVIIa-TF) and prothrombinase (FXa-FVa) complex.

[0008] Under normal physiological conditions, normal vascular endothelium minimizes contact between tissue factor (TF) and plasma procoagulants, but vascular insult expose tissue factor which binds with factor Vila and calcium to promote the conversion of factor X to Xa.

[0009] Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII (FXIII). FXIII is responsible for covalently cross-linking preformed fibrin clots preventing their premature fibrinolysis, by maintaining the clot architecture and strength. The time lag in generation of first FXIIIa molecule is about 10 minutes to 20 minutes. To prevent the crosslinking of premature fibrin clot, this 10 minutes to 20 minutes is highly critical.

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

[0011] The blood coagulation process requires coagulation factors, calcium, and phospholipids. There are three strategies to prevent coagulation: (1) inhibit the clotting factors, (2) removal of free calcium in the blood, and (3) change of negatively charged phospholipid surfaces as neutral or positive charged such that the clotting reactions cannot occur because these clotting factors can only bind to a negatively charged phospholipid surface which is provided by activatedplatelets or monocytes. Some anticoagulant drugs act by inactivating thrombin and several other clotting factors that are required for a clot to form. There are other anticoagulant drugs act by removal free calcium ions or inhibit phospholipid such as platelet activating factor. Removal of free calcium ions can be accomplished by the chelating agent EDTA, citate or oxalate. EDTA inhibits the clotting factors intrinsic XII, XI, IX, X and extrinsic VIIa / TF activation and inhibit initial the clotting cycles by depleting / chelating free calcium ions. This is critical for extrinsic pathway, which is the only step (VIIa / TF activated by Ca2+) involved in the cascade of coagulation. The mechanism of EDTA as an agent to prevent clotting induced by a medicated stent is that its inhibition of adenosine, epinephrine, and thrombin-induced platelet aggregation might be more effective than mechanisms that inhibit platelet aggregation more narrowly, as is the case of clopidogrel, which inhibits only adenosine-induced aggregation.

[0012] Direct Factor Xia inhibitor is an active-site inhibitor, and it achieves antithrombotic activity without increasing bleeding risk. It also delays the time to clot formation, decreases fibrin incorporation into the clot, and reduces the resistance of clots to fibrinolysis.

[0013] Systemic administration of an anticoagulant may be ineffective in preventing or treating disorders associated with coagulation. For example, the concentration of the anticoagulant at or adjacent the site of injury may be insufficient at the appropriate time to prevent or treat disorders associated with coagulation. Furthermore, deficiencies of systemic administration of an anticoagulant can be exacerbated where the patient has a condition (e.g., cardiovascular disease, hypercholesterolemia, or diabetes) that renders the patient more susceptible to a vaso-occlusive event.

[0014] Previous attempts to provide local administration of an anticoagulant have had limited to no success in preventing coagulation disorders and / or preventing thrombus (clot) formation particularly after local tissue injury. Furthermore, local injury to a tissue is commonly associated with additional injury to the tissue adjacent (e.g., proximal, distal, etc.) the site of the first injury.

[0015] To reduce the partial or total occlusion of the artery by plaque or the collapse of the arterial lining and to reduce the chance of restenosis, a stent or drug coated balloon may be used in the artery to keep the artery open. The agents coated on stent or balloon unfortunately may delay the healing period of the injured tissue, increase tissue factor which may generate or amplify thrombin, fibrin, and / or clot formation, especially within the first 3 hours to 72 hours or more; however, the time lag to generate the first molecule FXIIIa, which is responsible for covalently cross-linking pre-matured fibrin clots and activated by calcium ions is about 10 minutes to 20 minutes. To prevent the crosslinking of premature fibrin clot, this 10 minutes to 20 minutes is highly critical.

[0016] Anticoagulants can be used to prevent the formation of blood clots. Some are used for the prevention or treatment of disorders characterized by abnormal blood clots and emboli. 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 an increase in thrombosis at the site of the stent, the risk of death and the risk of myocardial infarction (MI) increased. Although long term treatment with clopidogrel bisulfate plus aspirin for at least 12 months has been suggested as a preventive treatment, there is no evidence that this treatment is effective for more than six months. Clopidogrel also increases the risk of major bleeding episodes.

[0018] There is still a need to develop specialized therapeutic compositions for medical devices that can rapidly deliver therapeutic agents, drugs, or bioactive materials directly into a localized tissue area during or following a medical procedure, so as to treat or prevent vascular and nonvascular diseases or conditions such as restenosis or thrombosis. The device should release the therapeutic agent in an effective and efficient manner at the desired target location, where the therapeutic agent should rapidly permeate the target tissue at a local therapeutic level to inhibit one or more of thrombin, fibrin, and / or clot formation prior to amplification of the clotting factors.

[0019] It would therefore be desirable to provide devices that locally deliver thrombin / clot formation-inhibiting agents, and optionally other kinds of biologically active agents (e.g., antiproliferative agents, anti-inflammatory agents, etc.), to the site of injury of a body part or to an area adjacent thereto before, during, and / or after injury.

[0020] One approach for inhibiting hyperplasia and related adverse events after stenting has been to coat the stents with immunosuppressive and antiproliferative drugs, such as paclitaxel (taxol), sirolimus (rapamycin) and everolimus. Each of these drugs has found widespread clinical use.

[0021] Colchicine is a small molecule anti-inflammatory (anti -mitotic) drug which blocks mitotic cells in metaphase. Colchicine is administered orally for the systemic treatment of inflammatory disease, 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, has side effects including toxicity which require treatment at lower doses and / or for short durations, reducing its effectiveness and preventing widespread adoption for the treatment of restenosis. Other antiinflammatory agents, such NSAIDs (nonsteroidal) and steroids, are used as anti-inflammatories for treating restenosis, but colchicine has advantages such as inhibiting endothelial cell dysfunction and inflammation, inhibiting vascular inflammation, inhibiting vascularinflammation after injury such as PCI, inflammation from vascular plaque or disease condition, inhibiting inflammation from implantable material, inhibiting or reducing cardiovascular chest pain (angina), reducing hsCRP (an inflammation marker), inhibiting one or more of NLRP3 inflammasome, ip, IL- 18, and / or IL-6, so it would be useful to provide improved formulations for using colchicine to treat restenosis in the vasculature after stenting and other vascular interventions.

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

[0023] It would therefore be desirable to provide improved drug coatings for stents and other implantable devices that employ colchicine as a primary active agent. In particular, it would be desirable to identify other drug(s) which could be combined with colchicine or other immunosuppressive drugs such as sirolimus, or other antiplatelet drugs such as tirofiban, ticagrelor, aspirin in drug coatings for stents and other implantable devices where the combination achieves a synergistic inhibitory effect greater than achieved by coatings employing either drug alone. At least some of these objectives will be met by the disclosures described and claimed herein.

[0024] The disclosure also provides methods of using such devices and other forms of therapy in treating clotting, and in improving or promoting wound healing, at the injury site or at an area adjacent thereto.

[0025] Listing of Background Art. Relevant background art includes 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 / 157771; US2018 / 0000490; EP1849434; CA2464290; WO2013 / 007840; WO2013 / 056060; W02020 / 210613; W02020 / 210629; US8617104; US8715771; US9066990; US9439792; US9492294; US9656003; US10278839; US20070043418; and US202000384246; O’Keefe (1992) JACC 19: 1597-1600 and US5, 776, 184 have been described above.

[0026] The subject matter of this application is also related to that of the following commonly owned applications: International Patent Application PCT / US2022 / 50099 filed November 16, 2022, entitled “Anticoagulant compounds comprising chelating agents and cationic anticoagulation enhancers and methods and devices for their use” (Attorney Docket No. 32016- 729.601); International Patent Application PCT / US2021 / 034108 filed May 25, 2021, entitled “Anticoagulant compositions and methods and devices for their use” (Attorney Docket No.32016-720.601); International Patent Application PCT / US2021 / 044414 filed August 3, 2021, entitled “Anticoagulant compositions and methods and devices for their pulmonary use” (Attorney Docket No. 32016-730.601); International Patent Application PCT / US2021 / 049964 filed September 10, 2021, entitled “Anticoagulant compositions and methods and devices for their ophthalmic use” (Attorney Docket No. 32016-720.601); International Patent Application No. PCT / US2007 / 078317, filed September 12, 2007, entitled “Macrocyclic lactone compounds and methods for their use” (Attorney Docket No. 32016-704.601); International Patent Application No. PCT / US2008 / 056501, filed March 11, 2008, entitled “Macrocyclic lactone compounds and methods for their use” (Attorney Docket No. 32016-704.602); International Patent Application No. PCT / US2009 / 059396, filed October 2, 2009, entitled “Macrocyclic lactone compounds and methods for their use” (Attorney Docket No. 32016-709.601); International Patent Application No. PCT / US2011 / 054637, filed October 3, 2011, entitled “Macrocyclic lactone compounds and methods for their use” (Attorney Docket No. 32016- 711.601); each of which are incorporated herein by reference for all purposes in their entireties.SUMMARY OF THE DISCLOSURE

[0027] The disclosed technology provides a composition for coupling to a surface of an implantable article, typically a vascular implant, such as stent, a stent-graft, a prosthetic valve, an occlusion device, or the like. Use of the compositions, however, in not limited to vascular implants and extends to a variety of other prosthetic, diagnostic, and other implants as described further hereinbelow. Such implants will usually comprise base structure, such as an expandable scaffold in the case of stents and stent-grafts or housings in the case of other implants. The implants will typically have an outer surface and / or surface or internal cavities, suitable to coating or other deposition of the compositions described and claimed herein.

[0028] The terms “coupling” and “couple” as used to herein and in the claims broadly denote that the disclosed compositions and / or any components thereof are coated, attached, sequestered, loaded, linked, or otherwise immobilized on a surface of a base structure of a surgical article, including permanently implantable articles such as scaffolds, stents, stent-grafts, prosthetic valves, orthopedic implants, electrical stimulators, such as pacemakers, nerve stimulators, and the like. In other cases, the surfaces may be on a catheters and other surgical tools that are temporarily introduced into a patient’s vasculature or vascularized space, such as vascular catheters, guidewires, guide catheters, sheaths, and the like. In some instances, the disclosed compositions and / or any components may be sequestered otherwise loaded into receptacles or depots formed in or on a surface of the base structure of the surgical article.

[0029] The coupling surface can be any surface on the surgical article, particularly those which are exposed directly or indirectly to patient blood, often being an external surface and at other times being an internal surface. For example, on stents and other scaffolds, the compositions and / or any components thereof may be coupled to outer surfaces, inner (luminal) surfaces, and / or edges. On catheters, the compositions and / or any components thereof may be coupled to an outer balloon surface, an outer shaft surface, or the like. On more complexly structured surgical articles, such as prosthetic heart valves, the surfaces may be on an outer base or anchor feature as well as on internal valve and other mechanical components.

[0030] The disclosed compositions and / or components thereof may be coated or otherwise coupled to the surgical article surface directly and / or indirectly and in one, two, three, or more layers, where individual layers may be homogeneous or non-homogenous. Successive layers of the composition may be formed directly or indirectly over one another, and intermediate “nonactive” layers (not containing drugs of the disclosed technology), such as barrier layers, ratecontrolling layers, permeable and semi-permeable membranes, and the like, may be disposed between successive “active” layers (containing drugs of the disclosed technology).

[0031] In a first aspect, the compositions comprise an anti-coagulant comprising a direct factor Xa inhibitor and at least one of (a) an anti-platelet drug, (b) anti-coagulant comprising a direct factor Ila inhibitor, and (c) an anti-inflammatory drug comprising colchicine, often including at least at least two of (a) the anti-platelet drug, (b) the direct factor Ila inhibitor, and (c) the antiinflammatory drug comprising colchicine, and frequently, including all three of (a) an antiplatelet drug, (b) a direct factor Ila inhibitor, and (c) anti-inflammatory drug comprising colchicine.

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

[0033] In some instances, the compositions comprise at least one an anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibitor, and a P2Y12 inhibitor, or a salt or analog thereof. For example, the anti-platelet drug may comprisetirofiban, a salt, analog, or metabolite thereof. In further examples, the anti-platelet drug may comprise ticagrelor, a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In still further examples, the anti-platelet drug may comprise acetylsalicylic acid (aspirin, a Coxl / 2 inhibitor). In additional examples, the antiplatelet drug may comprise clopidogrel or an active metabolite of clopidogrel, salt, isomer, solvate, prodrug, metabolites, or derivative thereof.

[0034] In some instances, the at least one direct factor Ila inhibitor may be selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. For example, the direct factor Ila inhibitor drug may comprise argatroban, a salt, solvate, isomer, derivative, or metabolite, or prodrug thereof.

[0035] In a second aspect, the compositions may comprise an anti-coagulant comprising a direct factor Ila inhibitor and at least one of (a) an anti-platelet drug, (b) an anti-coagulant comprising a direct factor Ila inhibitor, and (c) an anti-inflammatory drug comprising colchicine, often including at least two of (a) the anti-platelet drug, (b) the anti -coagulant comprising the direct factor Ila inhibitor, and (c) the anti-inflammatory drug comprising colchicine, and frequently including all three of (a) an anti-platelet drug, (b) the anti-coagulant comprising the direct factor Ila inhibitor, and (c) the anti-inflammatory drug comprising colchicine.

[0036] In some instances, the direct factor Ila inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. For example, the direct factor Ila inhibitor drug may comprise rivaroxaban, argatroban, or a salt, analog, or metabolite thereof.

[0037] In some instances, the compositions may comprise an anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibitor, and a P2Y12 inhibitor, or a salt or analog thereof. For example, the anti-platelet drug may comprise tirofiban, ticagrelor, or a salt, analog, or metabolite thereof; acetylsalicylic acid (a Coxl / 2 inhibitor); or clopidogrel or the active metabolite of clopidogrel, or a salt, solvate, isomer, derivative, prodrug, or metabolite thereof.

[0038] In some instances, the direct factor Xlla inhibitor may comprise at least one drug selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). For example, the direct factor Xa inhibitor may comprise apixaban, a salt, isomer, solvate, isomer, derivative metabolite, or prodrug thereof and / or rivaroxaban, a salt, solvate, isomer, derivative, or metabolite thereof.

[0039] In a third aspect, the composition for coupling to a surface of an implantable article may comprise a direct factor Xa inhibitor and at least two and often three of (a) a direct factor Ila inhibitor, (b) an anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibit, and a P2yl2 inhibitor, and (c) an anti-inflammatory drug.

[0040] In some instances, the direct factor Xa inhibitor may comprise at least one drug selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), or a salt, analog or metabolite thereof. For example, the direct factor Xa inhibitor may comprise rivaroxaban, or apixaban, a salt, isomer, solvate, derivative, metabolite, or prodrug thereof or an analog thereof and / or rivaroxaban, or a salt, isomer, derivative solvate, metabolite, or prodrug thereof or may comprise argatroban, or a salt, isomer, derivative, solvate, prodrug, or metabolite thereof.

[0041] In some instances, the anti-platelet drug may comprise at least one drug selected from the group consisting of tirofiban, ticagrelor, a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibitor, and a P2Y12 inhibitor, or a salt, isomer, solvate, derivative, prodrug, or metabolite thereof.

[0042] In some instances, the anti-inflammatory drug may comprise colchicine or n isomer, derivative metabolite, or prodrug thereof.

[0043] In a fourth aspect, the composition for coupling to a surface of an implantable article may comprise apixaban, rivaroxaban or a salt, isomer, solvate, derivative prodrug, or metabolite thereof, argatroban, or a salt, isomer, derivative, solvate, prodrug, or metabolite thereof, tirofiban, or a salt, analog or metabolite thereof, and colchicine.

[0044] In some instances, the compositions may further comprise an additional an anti-platelet drug,

[0045] In some instances, the compositions may further comprise an additional antiinflammatory drug.

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

[0047] In some instances, the composition, and / or individual components thereof, is / are coupled to the surface in a single layer, where the single layer may be homogeneous or non-non- homogeneous. By “homogeneous,” it is meant that the drug components of the composition are mixed and distributed relatively uniformly in the individual layer. By “non-homogeneous,” it is meant that the drug components of the composition are distributed non-uniformly in the individual layer.

[0048] In some instances, the composition, and / or individual components thereof, is / are coupled to the surface in two layers of the composition. In such instances, each layer may comprise some or all drug components of the composition, and the drug components of each layer may be present in homogenous or non-homogeneous mixtures.

[0049] In addition to “active” layers comprising some or all drug components of the disclosed compositions, the surfaces may be directly or indirectly cover, in whole or in part, by intermediate, typically “inactive,” layers which do not carry active amounts of the compositions and / or drug components thereof. Exemplary intermediate layers comprise barrier layers, ratecontrolling layers, permeable and semi-permeable membranes, and the like, and may be disposed between successive active layers. Intermediate layer may be disposed over and / or between other adjacent layer and may comprise a drug in addition to the drugs in the composition.

[0050] The drugs in the composition coupled to the surface of the surgical article typically have a release rate in a range from 1 day to one year, often having a release rate in a range from 1 day to 3 days, from 1 day to 30 days, or 1 day to 90 days.

[0051] The present disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to be expanded in a patient’s body. A therapeutic composition, comprising at least one chelating agent is present on a surface of the scaffold, where the therapeutic composition is formulated for a rapid release of the chelating agent into an environment surrounding the scaffold upon implantation of the scaffold structure in said environment.

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

[0053] The at least one antiproliferative drug typically comprises an mTOR inhibitor, usually being selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, and salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof, more usually comprising sirolimus, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

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

[0055] The at least one antiproliferative drug typically comprises an mTOR inhibitor, usually being selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, and salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof, more usually comprising sirolimus, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0056] The present disclosure provides devices, compositions, and methods for their use. The devices comprise implantable scaffolds and other structures having one or more surfaces configured for internal use within a patient’s body most commonly implantable stents and grafts, but also vascular, coronary, orthopedic, and other articles intended for long-term and short-term implantation. The coatings are configured for fully or partially covering the surfaces of the devices, including outer and inner device surfaces, typically being deposited on, over, or in one or more of the surfaces, including within depots formed on or by the surfaces.

[0057] The coatings include compositions having one or more drugs or other active substances such, as anti-coagulant drugs, antiplatelet drugs, antiproliferative drugs, colchicine, and chelating agents. The compositions are formulated to release one or more of the drugs into an implanted environment, such as a blood vessel lumen, a coronary valve, or solid tissue, to inhibit clot formation, promote clot dissolution, inhibit inflammation, inhibit vessel injury, increase time before clotting, and / or inhibit cell proliferation. The compositions will typically be formulated to provide delayed or controlled release of the drugs from the structure into the implanted environment.

[0058] The compositions may provide all drugs, excipients, binders, and other components as a single formulation intended for simultaneous coating onto a surface of an article but will moreoften be proved as a plurality of separate components to allow sequential application or deposition onto the article so that the composition is formed in situ on the article.

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

[0060] In further aspects, the present disclosure provides compositions suitable for coating on or in surfaces of the various implantable articles described herein. The compositions will each include a plurality of drugs or other active and inactive components, where the active components are classified as anti-coagulant drugs, antiplatelet drugs, antiproliferative drugs, colchicine, and chelating agents. The compositions will typically be formulated to provide delayed or controlled release of the drugs from the structure into an implanted environment and, upon release and over time, to inhibit clot formation, promote clot dissolution, inhibit inflammation, inhibit vessel injury, increase time before clotting, and / or inhibit cell proliferation. The compositions may provide all drugs, excipients, binders, and other components as a single formulation intended for simultaneous coating onto a surface of an article but will more often be proved as a plurality of separate components to allow sequential application or deposition onto the article so that the composition is formed in situ on the article.

[0061] A first composition in accordance with the principles of the present disclosure comprises (a) at least one of a direct factor Ila inhibitor and a direct factor Xa inhibitor, (b) colchicine, and (c) a first antiplatelet drug comprising tirofiban. The (a) at least one of a direct factor Ila inhibitor and a direct factor Xa inhibitor, (b) colchicine, and (c) first antiplatelet drug are formulated to release from the surface of an implanatble article in amounts sufficient to inhibit inflammation and / or thrombosis resulting from an injury.

[0062] In some instances, the (a) at least one of a direct factor Ila inhibitor and a direct factor Xa inhibitor, (b) colchicine, and (c) first antiplatelet drug of the first composition are formulated to treat an injury that resulted from implantation of the article.

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

[0064] In some instances, the first composition comprises at least one factor Ila inhibitor selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, andlepirudin, where the at least one direct factor Ila inhibitor may comprise argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0065] In some instances, the first composition comprises at least one factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). For example, the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. For example, the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0066] In some instances, the first composition comprises at least a second antiplatelet drug different from the first antiplatelet drug, where the second antiplatelet drug may comprise one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0067] In some instances, the first composition comprises at least a third antiplatelet drug different than the first and second antiplatelet drugs, wherein the third antiplatelet drug may comprise one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0068] In some instances, the first composition comprises a chelating agent, where the chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3- dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0069] In some instances, the first composition comprises at least one antiproliferative drug, where the antiproliferative drug may comprise an mTOR inhibitor.

[0070] A second composition for coating a surface of an implantable article in accordance with the principles of the present disclosure comprises (a) a direct factor Ila inhibitor, (b) a direct factor Xa inhibitor, and (c) a first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, where (a) the direct factor Ila inhibitor, (b) the direct factor Xa inhibitor, and (c) the first antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation and / or thrombosis resulting from an injury.

[0071] In some instances, the (a) factor Ila inhibitor, (b) factor Xa inhibitor, and (c) first antiplatelet drug of the second composition are formulated to treat an injury that resulted from implantation of the article.

[0072] In some instances, the (a) factor Ila inhibitor, (b) factor Xa inhibitor, and (c) first antiplatelet drug of the second composition are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0073] In some instances, the second composition further comprises (d) colchicine which in combination with (a) the direct factor Ila inhibitor, (b) the direct factor Xa inhibitor, and (c) first antiplatelet drug is formulated to release from the surface of the article in an amount sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0074] In some instances, the direct factor Ila inhibitor of the second composition is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, where the direct factor Ila inhibitor typically comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0075] In some instances, the direct factor Xa inhibitor the second composition is selected from a group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n- (2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6- carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). For example, the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. For example, the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0076] In some instances, the glycoprotein Ilb / IIIa inhibitor of the second composition is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0077] In some instances, the second composition further comprises at least a second antiplatelet drug different than the first antiplatelet drug, wherein the second antiplatelet drug may comprise one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0078] In some instances, the second composition further comprises at least a third antiplatelet drug different than the first and second antiplatelet drugs, where the third antiplatelet drug may comprise one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0079] In some instances, the second composition further comprises a chelating agent, where the chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3- dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0080] In some instances, the second composition further comprises at least one antiproliferative drug, wherein the antiproliferative drug may comprise an mTOR inhibitor.

[0081] A third composition for coating a surface of an implantable article in accordance with the principles of the present disclosure comprising (a) a direct factor Ila inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, and (d) a second antiplatelet drug comprising an NSAID, wherein (a) the direct factor Ila inhibitor, (b) the direct factor Xa inhibitor, (c) the first antiplatelet drug and (d) the second antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0082] In some instances, the (a) a direct factor Ila inhibitor, (b) a direct factor Xa inhibitor, (c) first antiplatelet drug, and (d) second antiplatelet drug of the third composition are formulated to treat an injury that resulted from implantation of the article.

[0083] In some instances, the (a) a direct factor Ila inhibitor, (b) a direct factor Xa inhibitor, (c) first antiplatelet drug, and (d) second antiplatelet drug of the third composition are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0084] In some instances, the third composition further comprises (e) colchicine which in combination with (a) the direct factor Ila inhibitor, (b) the direct factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug is formulated to release from the surface of the article in amounts sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0085] In some instances, the direct factor Ila inhibitor of the third compositions of the present disclosure is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, typically comprising argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0086] In some instances, the direct factor Xa inhibitor of the third compositions of the present disclosure is selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 - phenylethyl)-lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), typically comprising (a) apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof, and / or (b) rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0087] In some instances, the glycoprotein Ilb / IIIa inhibitor of the third compositions of the present disclosure is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0088] In some instances, the NSAID of the third compositions comprises a salicylate.

[0089] In some instances, the third compositions further comprise at least a third antiplatelet drug different than the first and second antiplatelet drugs, where the third antiplatelet drug may comprise one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADPreceptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0090] In some instances, the third compositions further comprises a chelating agent, wherein the chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3- dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0091] In some instances, the third compositions of the present disclosure further comprise at least one antiproliferative drug, where the antiproliferative drug may comprise an mTOR inhibitor.

[0092] A fourth composition according to the present disclosure for coating a surface of an implantable article comprises (a) a direct factor Ila inhibitor, (b) a direct factor Xa inhibitor, (c) a first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, and (d) a second antiplatelet drug comprising an ADP receptor / P2Y12 inhibitors, where the (a) a direct factor Ila inhibitor, (b) factor Xa inhibitor, (c) first antiplatelet drug and (d) second antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0093] In some instances, the (a)a direct factor Ila inhibitor, (b) factor Xa inhibitor, (c) first antiplatelet drug, and (d) second antiplatelet drug of the fourth compositions are formulated to treat an injury that resulted from implantation of the article.

[0094] In some instances, the (a) a direct factor Ila inhibitor, (b) factor Xa inhibitor, (c) first antiplatelet drug, and (d) second antiplatelet drug of the fourth compositions are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0095] In some instances, the fourth compositions of the present disclosure further comprise ((e) colchicine which in combination with (a) the direct factor Ila inhibitor, (b) the direct factor Xainhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug is formulated to release from the surface of the article in amounts sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0096] In some instances, the fourth compositions of the present disclosure further comprise (f) a third antiplatelet drug comprising aspirin and / or another NSAID which in combination with (a) the direct factor Ila inhibitor, (b) the direct factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug is formulated to release from the surface of the article in amounts sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury, wherein the direct factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, typically comprising argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0097] In some instances, the direct factor Xa inhibitor of the fourth compositions of the present disclosure may be selected from a group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). For example, the direct factor Xa inhibitor may comprise apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. For example, the direct factor Xa inhibitor may comprise rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0098] In some instances, the glycoprotein Ilb / IIIa inhibitor of the fourth compositions may be selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0099] In some instances, the ADP receptor / P2Y12 inhibitor of the fourth compositions may be selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor.

[0100] In some instances, the fourth compositions of the present disclosure further comprise at least a third antiplatelet drug different than the first and second antiplatelet drugs, where the third antiplatelet drug may comprise one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and aphosphodiesterase inhibitor. For example, the third antiplatelet drug may comprises a salicylate such as aspirin or another NS AID.

[0101] In some instances, the fourth compositions of the present disclosure further comprise a chelating agent, where the chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0102] In some instances, the fourth compositions of the present disclosure further comprise at least one antiproliferative drug, such as an mTOR inhibitor.

[0103] A fifth composition for coating a surface of an implantable article in accordance with the principles of the present disclosure comprises a direct factor Xa inhibitor and one or more of (a) colchicine, (b) a first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, (c) a second antiplatelet drug comprising an NSAID, and (d) a third antiplatelet drug comprising an ADP inhibitor, where the direct factor Xa inhibitor and the one or more of (a) the colchicine, (b) the first antiplatelet drug, (c) the second antiplatelet drug and (d) the third antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0104] In some instances, the direct factor Xa inhibitor and the one or more of the (a) colchicine, (b) first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, (c) second antiplatelet drug comprising an NSAID, and (d) third antiplatelet drug comprising an ADP inhibitor of the fifth compositions of the present disclosure are formulated to treat an injury that resulted from implantation of the article.

[0105] In some instances, the direct factor Xa inhibitor and the one or more of the (a) colchicine, (b) first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, (c) second antiplatelet drug comprising an NSAID, and (d) third antiplatelet drug comprising an ADP inhibitor of the fifth compositions of the present disclosure are formulated to treat the injury without causing any oneor more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0106] In some instances, the fifth compositions of the present disclosure further comprise a direct factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, where the direct factor Ila inhibitor may comprise argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0107] In some instances, factor Xa inhibitor of the fifth compositions may be selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n- (2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6- carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). For example, the direct factor Xa inhibitor may comprise apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. For example, the direct factor Xa inhibitor may comprise rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0108] In some instances, the glycoprotein Ilb / IIIa inhibitor of the present disclosure may be selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0109] In some instances, the ADP receptor / P2Y12 inhibitors of the present disclosure may be selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor.

[0110] In some instances, the fifth compositions of the present disclosure further comprise at least a fourth antiplatelet drug different than the first and second antiplatelet drugs, where the fourth antiplatelet drug may comprises one or more of a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.[OHl] In some instances, the fifth compositions of the present disclosure further comprise a chelating agent, wherein the chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid(EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0112] In some instances, the fifth compositions of the present disclosure further comprise at least one antiproliferative drug, such as an mTOR inhibitor.

[0113] A sixth composition for coating a surface of an implantable article in accordance with the principles of the present disclosure comprises a direct factor Ila inhibitor and one or more of (a) colchicine, (b) a first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor; (c) a second antiplatelet drug comprising an NSAID, and (d) a third antiplatelet drug comprising an ADP inhibitor, where the direct factor Xa inhibitor and the one or more of (a) the colchicine, (b) the first antiplatelet drug, (c) the second antiplatelet drug and (d) the third antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0114] In some instances, the direct factor Ila inhibitor and the (a) colchicine, (b) first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, (c) second antiplatelet drug comprising an NSAID, and (d) third antiplatelet drug comprising an ADP inhibitor of the sixth compositions of the present disclosure are formulated to treat an injury that resulted from implantation of the article.

[0115] In some instances, the direct factor Ila inhibitor and the (a) colchicine, (b) first antiplatelet drug comprising a glycoprotein Ilb / IIIa inhibitor, (c) second antiplatelet drug comprising an NSAID, and (d) third antiplatelet drug comprising an ADP inhibitor of the sixth compositions of the present disclosure are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0116] In some instances, the direct factor Ila inhibitor of the sixth compositions of the present disclosure may be selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, typically comprising argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0117] In some instances, the sixth compositions of the present disclosure further comprise a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban,otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), wherein the direct factor Xa inhibitor typically comprises (a) apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof or (b) rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0118] In some instances, the glycoprotein Ilb / IIIa inhibitor of the sixth compositions of present may be selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0119] In some instances, the ADP receptor / P2Y12 inhibitors of the sixth compositions of the present disclosure may be selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor.

[0120] In some instances, the sixth compositions of the present disclosure further comprise at least a fourth antiplatelet drug different than the first and second antiplatelet drugs, where the fourth antiplatelet drug may comprise one or more of a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0121] In some instances, the sixth compositions of the present disclosure further comprise a chelating agent, typically being selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3- dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0122] In some instances, the sixth compositions of the present disclosure further comprise at least one antiproliferative drug, typically comprising an mTOR inhibitor.

[0123] A seventh composition for coating a surface of an implantable article in accordance with the principles of the present disclosure comprising (a) at least one of a direct factor Ila inhibitor and a direct factor Xa inhibitor, (b) at least one antiplatelet drug selected from (i) a first antiplatelet drug comprising a COX-1 inhibitor and (ii) a second antiplatelet drug comprising a glycoprotein Ilb / IIIa (2a / 3b) inhibitor, and (iii) a third antiplatelet drug comprising an adenosine diphosphate (ADP) / P2Y 12 inhibitor, where the (a) at least one of the direct factor Ila inhibitor and the direct factor Xa inhibitor, and (b) at least one antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0124] In some instances, the seventh compositions of the present disclosure comprise a direct factor Ila inhibitor selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, where the direct factor Ila inhibitor typically comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0125] In some instances, the seventh compositions of the present disclosure comprise a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), wherein the direct factor Xa inhibitor typically comprises (a) apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof or (b) rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0126] In some instances, the seventh compositions of the present disclosure comprise a COX-1 inhibitor, typically a salicylate or other NSAID.

[0127] In some instances, the seventh compositions of the present disclosure comprise a glycoprotein Ilb / IIIa inhibitor selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0128] In some instances, the seventh compositions of the present disclosure comprise an ADP receptor / P2Y12 inhibitors is selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor.

[0129] In some instances, the seventh compositions of the present disclosure comprise at least one of a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0130] In some instances, the seventh compositions of the present disclosure comprise a chelating agent, typically being selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3- dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0131] In some instances, the seventh compositions of the present disclosure comprise at least one antiproliferative drug, typically an mTOR inhibitor.

[0132] An eighth composition for coating a surface of an implantable article, in accordance with the principles of the present disclosure comprising (a) at least one of a direct factor Ila inhibitor and a direct factor Xa inhibitor, (b) at least one of (i) colchicine, (ii) a first antiplatelet drug, and (iii) a chelating agent, where the (a) at least one of a direct factor Ila inhibitor and a direct factor Xa inhibitor and (b) the at least one of (i) colchicine (ii) the first antiplatelet drug, and the chelating agent are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0133] In some instances, the eighth compositions of the present disclosure comprise a direct factor Ila inhibitor selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, where the direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0134] In some instances, the eighth compositions of the present disclosure comprise a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), where the direct factor Xa inhibitor typically comprises (a) apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof or (b) rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0135] In some instances, the eighth compositions of the present disclosure comprises colchicine.

[0136] In some instances, the eighth compositions of the present disclosure comprise one or more antiplatelet drugs selected from the group consisting of a glycoprotein Ilb / IIIa inhibitor, an ADP receptor / P2Y12 inhibitor, a COX-1 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitor.

[0137] In some instances, the eighth compositions of the present disclosure comprise a chelating agent selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxy ethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0138] In some instances, the eighth compositions of the present disclosure comprise at least one antiproliferative drug, typically an mTOR inhibitor.

[0139] In still other examples, the therapeutic composition comprises one or more agents selected from the group consisting of direct factor Xa inhibitor, direct factor Ila inhibitor, in combination with one or two antiplatelet selected from glycoprotein Ilb / IIIa inhibitor, P2Y12 inhibitor and aspirin, and additional optional an anti-inflammatory selected from colchicine, and optionally an anti-proliferation such as mTOR, or a microtubule inhibitor such as Paclitaxel in implantable devices where the combination achieves a synergistic inhibitory effect greater than achieved by coatings employing either drug alone.

[0140] In some examples, the therapeutic composition is formulated to combine colchicine with other drug(s) such as rivaroxaban, argatroban, tirofiban and the combination achieved a synergistic inhibitory effect greater than achieved by either drug alone.

[0141] In some examples, the therapeutic composition is further formulated to combine of colchicine with other drug(s) such as rivaroxaban, argatroban, tirofiban, ticagrelor and mTOR, and the combination achieved a synergistic inhibitory effect greater than achieved by either drug alone.

[0142] In still other examples, the therapeutic composition comprises a combination of direct factor Xa inhibitor with two, three or more other therapeutic agent selected from the group consisting antiplatelets selected from glycoprotein Ilb / IIIa inhibitor, P2Y12 inhibitor and aspirin, and anti-inflammatory agents selected from colchicine in drug coatings for stents and other implantable devices where the combination achieves a synergistic inhibitory effect greater than achieved by coatings employing either drug alone.

[0143] In still other examples, the therapeutic composition may comprise a combination of direct factor Ila inhibitor with two, three or more other therapeutic agent selected from the group consisting of antiplatelets selected from glycoprotein Ilb / IIIa inhibitor, P2Y12 inhibitor and aspirin, and anti-inflammatory agents selected from colchicine in drug coatings for stents and other implantable devices where the combination achieves a synergistic inhibitory effect greater than achieved by coatings employing either drug alone.

[0144] In still other examples, the therapeutic composition may comprise a combination of direct factor Xa inhibitor, antiplatelets selected from glycoprotein Ilb / IIIa inhibitor, P2Y12 inhibitor and aspirin, in drug coatings for stents and other implantable devices where the combination achieves a synergistic inhibitory effect greater than achieved by coatings employing either drug alone.

[0145] In still other examples, the therapeutic composition may comprise a combination of direct factor Ila inhibitor, antiplatelets selected from glycoprotein Ilb / IIIa inhibitor, P2Y12 inhibitor and aspirin, in drug coatings for stents and other implantable devices where the combination achieves a synergistic inhibitory effect greater than achieved by coatings employing either drug alone.

[0146] The compositions of the present disclosure are typically coated on articles configured to be implanted in a patient’s body. For example, the implantable article may comprise a body having a surface configured for implantation in a patient, wherein the surface is at least partially coated with any of compositions described above.

[0147] In some instances, the article comprises an expandable scaffold configured for implantation in the patient’s vascular system.

[0148] In some instances, the article comprises a non-expandable body.

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

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

[0151] In some instances, the composition may be formulated to release no greater than 90%, 75%, 50%. 25%, or 10% of its weight of within one week, one month, three months, six months, or one year of implantation.

[0152] Exemplary chelating agents in the therapeutic composition may be formulated to deplete calcium in the environment surrounding the scaffold upon implantation of the scaffold structure in said environment.

[0153] In specific instances, the therapeutic composition may be formulated to release at least 50%, preferably at least 75%, by weight of the 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 hour of implantation.

[0154] In additional instances, the therapeutic composition may be formulated to release additional amounts of the at least one chelating agent into the environment for a period of at least 3 days, preferably at least 7 days, more preferably 21 days, still more preferably at least 28 days, even more preferably at least 3 months, and often 6 months or more after implantation. Exemplary chelating agents may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, and magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0155] In particular instances, the chelating agent consists essentially of ethylenediaminetetraacetic acid (EDTA).

[0156] The therapeutic composition that may comprise, consist essentially of, or consist of chelating agent, where the chelating agent may be present in the therapeutic composition at a weight percent from 10% to 100%. In specific instances, the therapeutic composition consists essentially of chelating agent, where the only active ingredient in the therapy composition will be the chelating agent optionally present with other inactive components and ingredients. In other instances, the therapeutic composition comprises the chelating agent in combination with additional active and / or inactive substances. In such instances, the additional active and / or inactive substances may be present in the therapeutic composition at a weight percent from 20% to 90%.

[0157] In some instances, the therapeutic compositions of the present disclosure may further comprise a cationic anti-coagulation enhancer, where the cationic anti-coagulation enhancer may selected from a group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salts, tridodecylmethylammonium salt, other benzalkonium, analogue, solvate, hydrate and derivatives thereof. Alternatively or additionally, the cationic anticoagulation enhancer may be selected from a group consisting of cationic polymer or compounds including but not limit to poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branch polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, a polybetaaminoester (PBAE), Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof.

[0158] In specific examples, the cationic anti-coagulation enhancer may comprise, consist essentially of, or consist of benzyldimethyltetradecylammonium chloride.

[0159] In specific examples, the cationic anti-coagulation enhancer may comprise, consist essentially of, or consist of linear polyethyleneimine (PEI).

[0160] Any of the above-described therapeutic compositions may further comprise at least one anti-coagulant. In such instances, the therapeutic composition may be formulated to release at least one anti-coagulant at a rate equal to that of the chelating agent. Alternatively, the therapeutic composition may be formulated to release at least one anti-coagulant at a rate slower than that of the chelating agent. Alternatively, the therapeutic composition may be formulated to release at least one anti-coagulant at a rate faster than that of the chelating agent.

[0161] In specific examples, the anti -coagulant may be selected from the group consisting of a direct factor Ila inhibitor and a direct factor Xa inhibitor. Exemplary direct factor Ila inhibitors may be selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. A preferred, direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0162] Exemplary direct factor Xa inhibitors may be selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l- methylpiperidin-4-yl)piperazin-l-yl)-2-oxo-l -phenylethyl)- lh-indole-6-carboxamide(LY- 517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l- ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). A first preferred direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. A second preferred direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0163] Any of the above-described therapeutic compositions may further comprise an mTOR inhibitor selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. A preferred MTOR inhibitor comprises sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0164] Any of the above-described therapeutic compositions may further comprise paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

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

[0166] The implantable scaffolds of present disclosure may have anyone of a wide variety of known structures suitable for implantation and expansion at a target site in the patient’s body. Often, the scaffold will have at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces. In such instances, at least a portion of the outer surface may be coated with the therapeutic compositions. In other instances, at least a portion of the inner surface may be coated with the therapeutic compositions. In still other instances, a portion of the edge surfaces may be coated with the therapeutic compositions. As an alternativeor in addition to surface coating, at least some of the surfaces may have receptacles formed therein and at least some of said receptacles have therapeutic agent therein. For example, the receptacles comprise one or more of wells, channels, holes, and surface texture.

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

[0168] In particular examples, at least 75% by weight of the at least one chelating agent is released into the vasculature within 72 hours of implantation, preferably within 24 hours of implantation, more preferably within 6 hours of implantation, and even more preferably within 4 hour of implantation, and usually between 10 minutes and 4 hours.

[0169] In the further examples of the methods herein, the chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivative thereof. In one specific instance, the chelating agent consists essentially of ethylenediaminetetraacetic acid (EDTA).

[0170] In some instances, therapeutic composition further comprises a cationic anti-coagulation enhancer. For example, the cationic anti-coagulation enhancer may be selected from a group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salt, triammonium salt, benzyldimethyltetradecylammonium salt, tridodecylmethylammonium salt, other benzalkonium, analogue, solvate, hydrate and derivatives thereof. In another example,

[0171] the cationic anti-coagulation enhancer may be selected from a group consisting of cationic polymer or compounds including but not limit to poly (L-ly sine) (PLL), linearpolyethyleneimine (PEI), branch polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, a polybetaaminoester (PBAE), Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof. In a specific instance, the cationic anti-coagulation enhancer consists essentially of benzyldimethyltetradecylammonium chloride. In another specific instance, the cationic anticoagulation enhancer consists essentially of linear polyethyleneimine (PEI).

[0172] The therapeutic composition delivered by the methods of the present disclosure may further comprise at least one anti-coagulant. For example, the at least one anti -coagulant may be selected from the group consisting of a direct factor Ila inhibitor and a direct factor Xa inhibitor. Alternatively, the at least one anti-coagulant may comprise a direct factor Ila inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. An exemplary direct factor Ila inhibitor may comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0173] In other examples of the methods herein, the at least one anti-coagulant may comprise a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). In one instance, the direct factor Xa inhibitor may comprise apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. In another instance, the direct factor Xa inhibitor may comprise rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

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

[0175] The therapeutic composition delivered by the methods of the present disclosure may further comprise paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0176] The therapeutic composition delivered by the methods of the present disclosure may further comprise further comprises an antiplatelet drug.

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

[0178] The methods of the present disclosure are generally suitable for treating tissue injury caused by expanding the scaffold at the location but are also useful for treating tissue injury that preexists deploying the structure at the location.

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

[0180] In some examples, the therapeutic composition may be formulated for a rapid release into the environment surrounding the body structure a preselected time period after implantation of the body structure into said environment.

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

[0182] In such instances, the therapeutic composition may be present at least partly on the surface of the body structure. Alternatively or additionally, the therapeutic composition may be present at least partly within a cavity or reservoir within the body structure.

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

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

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

[0186] In some examples, the drug in the therapeutic composition may comprise at least a chelating agent in the therapeutic composition is formulated to deplete calcium in the environment surrounding the body structure upon implantation of the body structure in said environment. Such a chelating agent may be selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof. A specific instance, the chelating agent consists essentially of ethylenediaminetetraacetic acid (EDTA).

[0187] In some instances, the therapeutic composition may further comprise a cationic anticoagulation enhancer. For example, the cationic anti-coagulation enhancer may be selected from a group consisting of magnesium stearate and other magnesium salts, monoammonium salts, diammonium salts, triammonium salts, benzyldimethyltetradecylammonium salts, tridodecylmethylammonium salts, other benzalkonium, analogue, solvate, hydrate and derivatives thereof. Alternatively or additionally, the cationic anti-coagulation enhancer may be selected from a group consisting of cationic polymer or compounds including but not limit to poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branch polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, a polybetaaminoester (PBAE), Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof. In a specific instance, the cationic anti-coagulation enhancer consists essentially ofbenzyldimethyltetradecylammonium chloride. In another specific instance, the cationic anticoagulation enhancer consists essentially of linear polyethyleneimine (PEI).

[0188] In some instances, the at least one drug may comprise a direct factor Ila inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. For example, the at least one direct factor Ila inhibitor may comprise argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0189] In some examples, the at least one drug may comprise a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). For example, the direct factor Xa inhibitor may comprise apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. In another example, the direct factor Xa inhibitor may comprise rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0190] In some examples, the at least one drug may comprise a factor Xl / XIa inhibitor selected from the group consisting of antisense oligonucleotides including but not limit to IONIS-FXI and fesomersen; monoclonal antibodies (mAbs) including but not limit to osocimab, abelacimab, xisomab(AB023), REGN9933 and MK-2060; small molecules including but not limit to milvexian, asundexian, SHR2285, BMS-262084, BMS-654457, BMS-986177, BMS-962212, ONO-5450598, ONO-7684, and BAY 2433334 and frunexian (EP-7041) and a protein Z- dependent protease inhibitors (ZPI), and all above analogue, solvate, hydrate or derivatives thereof.

[0191] In specific examples, a ZPI-containing cationic anti -coagulation enhancer may comprise, consist essentially of, or consist of Asundexian, or milvexian, a small molecule factor Xia inhibitor having the formula [(6r,10s)-10-{4-[5-chloro-2-(4-chloro-lh-l,2,3-triazol-l-yl)phenyl]- 6-oxo-l(6h)- pyrimidinyl}- l-(difluoromethyl)-6-methyl-l,4,7,8,9,10-hexahydro-l 1,15 - (metheno)pyrazolo [4,3-b] [1,7] diazacyclotetradecin-5(6h)-one] and described in W02020 / 210613 and W02020 / 210629, the full disclosures of which are incorporated herein by reference.

[0192] In some examples, the therapeutic composition is formulated to release the one or more active substances at a rate sufficient to generate a tissue concentration of at least one activeingredient at the injury site within a range of at least about 0.05 ng / mg of tissue, at least about 0.15 ng / mg of tissue, at least about 0.3 ng / mg of tissue within about 3 hours, 6 hours, 12 hours, one day, 3 days, 7 days, 30 days, or 6 months. The resulting concentration of the at least one active ingredient can be found at the injury site, adjacent to the implantable device containing the active ingredients, at the ends of the implantable device and on the body lumen sides of the implantable device.

[0193] In some examples, the therapeutic composition is formulated to release at least one or more active substances at a rate sufficient to generate a tissue concentration at the injury site of the at least one active ingredients within a range of about 0.05 ng / mg of tissue to about 100 ng / mg of tissue, about 0.05 ng / mg of tissue to about 50 ng / mg of tissue, about 0.05 ng / mg of tissue to about 25 ng / mg of tissue, about 0.05 ng / mg of tissue to about 10 ng. mg of tissue, about 0.05 ng / mg of tissue to about 7 ng / mg of tissue, about 0.05 ng / mg of tissue to about 5 ng / mg of tissue, about 0.05 ng / mg of tissue to about 2 ng / mg of tissue, about 0.05 ng / mg of tissue to about 1 ng / mg of tissue, about 0.05 ng / mg of tissue to about 0.75 ng / mg of tissue, about 0.15 ng / mg of tissue to about 100 ng / mg of tissue, about 0.15 ng / mg of tissue to about 50 ng / mg of tissue, about 0.15 ng / mg of tissue to about 25 ng / mg of tissue, about 0.15 ng / mg of tissue to about 10 ng / mg of tissue, about 0.15 ng / mg of tissue to about 1 ng / mg of tissue, about 0.3 ng / mg of tissue to about 100 ng / mg of tissue, about 0.3 ng / mg to about 50 ng / mg of tissue, about 0.3 ng / mg of tissue to about 25 ng / mg of tissue, about 0.3 ng / mg of tissue to about 10 ng / mg of tissue, about 0.3 ng / mg of tissue to about 5 ng. mg of tissue, about 0.3 ng / mg of tissue to about 1 ng / mg of tissue within about 3 hours, 6 hours, 12 hours, one day, 3 days, 7 days, 30 days, or 6 months.

[0194] The active ingredients of the therapeutic compositions may be formulated in varying amounts relative each other. In some examples, the active ingredients are formulated to provide equal tissue concentrations of each active ingredients, amounts to provide double tissue concentrations of some active ingredients compared to the other active ingredients, amounts to provide triple tissue concentrations of some active ingredients compared to the other active ingredients, or amounts provide four times the tissue concentrations of some active ingredients compared to the other active ingredients within 3 hours, 6 hours, 7 hours, 12 hours, one day, 3 days, 7 days, 30 days, or 6 months. Utilizing these ranges of active ingredients to provide the tissue concentrations disclosed herein and the proportions of each active ingredient as described, surprisingly results in a synergistic result of increased blood clotting time.

[0195] The amounts of active ingredients can vary from one to another. It is possible within the disclosure to use two, three, four or more active ingredients and achieve synergistic results in a decreased clotting time. For example, combinations or anticoagulant(s) and anti-platelet drugsresult in synergism. Combinations of anticoagulant(s) and colchicine result in synergism. Combinations of anticoagulant(s), anti-platelet drug and anti-inflammatory drug, such as colchicine result in synergism. When utilizing anticoagulants, such as direct Factor Xa inhibitor and direct Factor Ila inhibitor, one can use either inhibitor in relationship to the other inhibitor in a weight compositional ratio of about 0.5:1 to about 5:1. When utilizing an anticoagulant, such as direct Factor Xa inhibitor or direct Factor Ila inhibitor alone or together, and an anti-platelet drug, such as tirofiban or ticagrelor, the weight compositional ratios may be about 0.5: 1 to about 5: 1, of either or both of the anticoagulants compared to a weight compositional ratio of about 0:5:1 to about 5:1, or about 0:5:1 to about 2:1, or about 0.5 :1 to about 3:1 of the anti-platelet drug compared to either or both anticoagulants. When utilizing an anticoagulant, such as direct Factor Xa inhibitor or direct Factor Ila inhibitor and an anti-inflammatory drug, such as colchicine, the weight compositional ratios may be about 0.5: 1 to about 5: 1, of either or both of the anticoagulants compared to a weight compositional ratio of about 0:5:1 to about 5: 1, or about 0:5:1 to about 2:1, or about 0.5:1 to about 3:1 of the anti-inflammatory drug compared to either or both anticoagulants. These weight compositional ratios may be used for compositions comprising direct Factor Xa inhibitor, direct Factor Ila inhibitor, an anti-platelet drug and an antiinflammatory drug, such as colchicine. Surprisingly, synergism results in a decrease in clotting time compared to a control from these compositions.

[0196] In some embodiments, there may be two, three, four, or more active ingredients in the therapeutic compositions of the present disclosure. 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 a weight compositional ratio of the first active ingredient relative to the rest 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 a range between any two preceding values.

[0197] For example, a first active ingredient and a second active ingredient may be defined by a weight compositional ratio of the first and the second active ingredient relative to the rest 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 a range between any two preceding values.

[0198] For example, a first active ingredient, a second active ingredient, and a third active ingredient may be defined by a weight compositional ratio of the first, the second, and the third active ingredient relative to the rest 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 a range between any two preceding values.

[0199] For example, a first active ingredient, a second active ingredient, a third active ingredient, and a fourth active ingredient may be defined by a weight compositional ratio of the first, the second, the third, and the fourth active ingredient relative to the rest 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 a range between any two preceding values.

[0200] In other examples, therapeutic composition may further comprise an mTOR inhibitor selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. The particular instance, the mTOR inhibitor comprises sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0201] In still other examples, the composition may further comprise paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof. In still other examples, the therapeutic composition may further comprise an antiplatelet drug. In still other examples, the therapeutic composition may further comprise an antiproliferative agent selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, azathioprine.

[0202] In preferred embodiments, the therapeutic composition is formulated to release no greater than 90%, 75%, 50%. 25%, or 10% by weight of the colchicine and / or tirofiban from the scaffold into a 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 no greater than 90%, 75%, 50%. 25%, or 10% by weight of the antiproliferative from the scaffold into the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0204] In preferred embodiments, the scaffold structure is loaded with an amount of the colchicine and / or tirofiban in a range from 1.7 pg to 170pg, 1.7 pg to 85pg, 2.5 pg to 40pg, or 3.4 pg to 20pg per mm of length of the scaffold structure.

[0205] In preferred embodiments, the scaffold structure is loaded with an amount of the antiproliferative drug in a range from 2 pg to 200pg, 2 pg to lOOpg, 3 pg to 50pg, or 4 pg to 20pg per 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 a group consisting of polyesters, including polylactic acids, polyglycolic acids, polylactic acid-co-glycolic acids, polylactic acid-co- caprolactones, polyethylene glycol-block-poly caprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly N-(2 -Hydroxypropyl) methacrylamides; polyethylenimine (PEI), dextran, dextrin, chitosans, poly(L-lysine); poly(aspartamides), polyethylenes; polypropylenes; polyamides; polyethylene glycols (PEG); silicones; poly(anhydrides); and poly ortho esters.

[0207] In some instances, the therapeutic composition may further comprise at least one anticoagulant agent. For example, the at least one anti-coagulant may be a direct factor Ila inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0208] In other examples, the at least one anti-coagulant may be a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0209] In some instances, the therapeutic composition may further comprise an antiplatelet drug. For example, the antiplatelet drug may be selected from a group consisting of Glycoprotein Ilb / IIIa inhibitors including but not limit to abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, tirofiban; ADP receptor / P2Y12 inhibitors including but not limit to clopidogrel, prasugrel, ticlopidine, cCangrelor, elinogrel, ticagrelor; prostaglandin analogue (PGI2) inhibitors including but not limit to beraprost, iloprost, prostacyclin, treprostinil; COX inhibitors including but not limit to acetylsalicylic acid / aspirin, aloxiprin, cCarbasalate calcium, indobufen, tTriflusal, dipyridamole; thromboxane inhibitors including but not limit to picotamide, terbogrel, Terutroban, aspirin, ridogrel, ramatroban; phosphodiesterase inhibitors including but not limit tocilostazol, dipyridamole, triflusal, milrinone; other inhibitors including but not limit to cloricromen, ditazole, vorapaxar; PAR / PAR-1 antagonists such as SCH530348, atopaxar, vorapaxar and E-5555; GPIa / IIa inhibitor such as EMS16; adhesion antagonists such as DZ-697b and RG12986; or a derivative, analogue, or salt thereof.

[0210] In a preferred instance, the antiplatelet drug will be a glycoprotein Ilb / IIIa platelet inhibitor, such as tirofiban or a derivative, analogue, or salt thereof. Particularly useful formulations will comprise colchicine and / or tirofiban and sirolimus or another mTOR inhibitor in combination with using .

[0211] In some instances, the therapeutic composition may further comprise a second antiproliferative drug. For example, the second antiproliferative drug may be selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, azathioprine.

[0212] In some instances, the therapeutic composition may further comprise a factor Xl / XIa inhibitor. Examples of factor Xl / XIa inhibitors are selected from antisense oligonucleotides including but not limit to IONIS-FXI and fesomersen; monoclonal antibodies (mAbs) including but not limit to osocimab, abelacimab, xisomab(AB023), REGN9933 and MK-2060; small molecules including but not limit to milvexian, asundexian, SHR2285, BMS-262084, BMS- 654457, BMS-986177, BMS-962212, ONO-5450598, ONO-7684, and BAY 2433334 and frunexian (EP-7041); a protein Z-dependent protease inhibitor, and all above analogue, solvate, hydrate or derivatives thereof.

[0213] In some instances, the therapeutic composition may further comprise specific inhibitors of thrombin, thrombotic agents, factor IXa, factor XI, factor Xia, factor XII, factor Xlla, factor XIII, factor Xllla, factor Vila or factor Villa.

[0214] In some instances, the therapeutic composition may further comprise a chelating agent formulated to deplete calcium in the environment surrounding the scaffold upon implantation of the scaffold structure in said environment.

[0215] The delayed composition release implantable scaffolds may have at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces, where at least a portion of the outer surface may be coated with the therapeutic compositions. Additionally or alternatively, at least a portion of the inner surface may be coated with the therapeutic compositions. Additionally or alternatively, at least a portion of the edge surfaces may be coated with the therapeutic compositions. Additionally or alternatively, at least some of the surfaces may have receptacles formed therein and at least some of said receptacles have therapeutic agent therein. For example, the receptacles comprise one or more of wells, channels, holes, and surface texture.

[0216] In another aspect, the present disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to be expanded in the patient’s body. A first therapeutic composition is coated, layered, bonded, or otherwise affixed to the scaffold and comprises a first drug formulation including at least one drug selected from the group consisting of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor. A second therapeutic composition is also coated, layered, bonded, or otherwise affixed to the scaffold structure and or the first therapeutic composition and comprises a second drug formulation including at least one drug selected from the group consisting of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor. The first therapeutic composition is formulated for a rapid release of the first drug formulation into a vascular environment and the second therapeutic composition is formulated for an 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 a patient’s vasculature, including, the arterial and venous coronary, peripheral and cerebral vasculature. The scaffolds may be intended for direct implantation, for example comprising or consisting of vascular stents intended to maintain patency in in a vascular lumen. Additionally, the scaffolds may be part of assemblies including additional components, such as vascular grafts, prosthetic valves, and the like. Depending on the intended purpose, the scaffold may be non-degradable in the vascular environment, for example being formed from or otherwise comprising a metal or a polymer which is non-degradable in the vascular environment. In other instances, the scaffold may be degradable in the vascular environment, for example being formed from or otherwise comprising a metal or polymer which is degradable in the vascular environment.

[0218] In addition to such implantable scaffolds, the therapeutic compositions and drug formulations described below may also find use with a wide variety of other implantable and non-implantable devices and tools which may be subject to unwanted clotting, as described elsewhere herein.

[0219] The rapid release of the first drug formulation and extended release of the second drug formulation will typically act in combination to accelerate dissolution of one or more of inflammation, cell proliferation, internal elastic lamina (TEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or inhibit one or more of inflammation, cell proliferation, internal elastic lamina (TEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or increase or prolong time before blood forms clot or thrombus.

[0220] In specific instances, at least one of the first drug formulation, the second drug formulation, and the third drug formulation may comprise a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor. In other instances, the first drug formulation, the second drug formulation, and the third drug formulation may each comprise a calcium chelating agent, a direct factor Ila inhibitor, and a direct factor Xa inhibitor.

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

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

[0223] The first and second therapeutic composition will typically but not necessarily comprise a carrier, matrix, or coating, usually but not always including a polymer, to sequester and control the release rate and duration of the drugs. In some instances, the drugs may be coated, layered, or otherwise deposited on or in surfaces or receptacles on the implantable structure without a polymer or other carrier but optionally with excipients, coating agents, and other conventional drug coating materials.

[0224] In some instances, one of the first and second therapeutic compositions may comprise a polymer while the other is free from polymer. For example, the first therapeutic (rapid release) composition may free from polymer and the second (sustained release) therapeutic compositionmay comprises a polymer to maintain or control the release rate and duration. For example, the first therapeutic composition may be coated on the scaffold structure or over the second therapeutic composition to affect a burst release.

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

[0226] While drug release from the first and second therapeutic compositions may commence simultaneously, in many instances the first therapeutic composition and the second therapeutic composition are configured to delay start of release of the second drug formulation for a time period after release of the first drug formulation has started. For example, the first therapeutic composition may be layered over the second therapeutic composition to delay release of the second drug formulation, e.g., the first therapeutic composition may initially cover at least a portion of the second therapeutic composition and may be configured to dissolve over the time period in the vascular environment to expose the second therapeutic composition and allow release of the second drug formulation.

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

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

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

[0230] Usually, but not necessarily, one or more polymers will be porous where the first and / or second drug formulation are sequestered in pores of the polymer(s). Often, a release rate of the first and / or second drug formulation may at least partly be determined by a pore size of the polymer. In some instances, the polymers of the first and second drug formulations may have different pore sizes which provide different release rates.

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

[0232] In preferred instances, the implantable scaffold of the present disclosure will further comprise an anti-proliferative drug. The anti-proliferative drug is present in either or both of the first and second drug formulations or may be present in a third drug formulation or may be separately coated, coupled, bonded, or attached to the scaffold. For example, the antiproliferative drug may present in a third therapeutic composition formulated to release the antiproliferative drug into a vascular environment when the scaffold is present in the vascular environment.

[0233] The first, second, and optionally third or additional therapeutic compositions of the present disclosure may be positioned on an external, internal, edge, and / or other surface of the implantable scaffold. Optionally but not necessarily, the scaffold surfaces will be roughened, scored, etched, or otherwise treated to enhance attachment of the therapeutic compositions. In some instances, the therapeutic compositions may be sequestered in wells, indentations or other receptacles formed on or in the scaffold surfaces.

[0234] Exemplary calcium chelating agents of the present disclosure is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate to calcium disodium edetate, magnesium dipotassium edetate, magnesium disodium edetate, disodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt,tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxy ethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid (BAPTA), citrate, oxalate, the surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivative thereof.

[0235] Exemplary of EDTA complex the present disclosure include monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, and any chemical could complex with EDTA.

[0236] Exemplary direct factor Ila inhibitors of the present disclosure include argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin, which may be used individually or in combination. Preferred direct factor Ila inhibitors comprise argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0237] Exemplary direct factor Xa inhibitors of the present disclosure include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4- yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6-carboxamide(L Y -517717), daraxaban (YM- 150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperi din-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), which may be used individually or in combination. Preferred direct factor Xa inhibitor comprise (1) apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof and (2) rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0238] Exemplary anti-proliferative agents of the present disclosure include mycophenolate mofetil, mycophenolate sodium, azathioprine, mTOR inhibitors selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof, which may be used individually or in combination. Preferred anti-mTOR proliferative agents comprise sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0239] Exemplary anti-proliferative agents of the present disclosure also include paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0240] In addition to the first, second, and optional third therapeutic compositions as discuss above, the implantable scaffolds of the present disclosure may further comprise at least one additional drug, typically an antiplatelet drug. The additional drug will not necessarily be incorporated as a drug formulation or as part of a therapeutic composition.

[0241] In specific examples of the present disclosure, the direct factor Ila inhibitor comprises argatroban and the direct factor Xa inhibitor comprises apixaban or rivaroxaban. In other specific examples of the present disclosure, the direct factor Ila inhibitor comprises argatroban or an analogue of argatroban, the direct factor Xa inhibitor comprises apixaban or rivaroxaban or an analogue of apixaban or rivaroxaban, and the anti-proliferative agent comprises sirolimus or an analogue of sirolimus.

[0242] In some instances, at least one of the therapeutic compositions may comprises an excipient, an adjuvant, a carrier, a wetting agent. In some instances, the first and second therapeutic compositions may be formed contiguously. In some instances, the first and second therapeutic compositions are separated by barrier, for example a polymer layer.

[0243] In some examples, a third therapeutic composition comprises a third drug formulation including at least one drug selected from the group consisting of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor. The third drug formulation may comprise any one of the previously discussed drugs and / or an additional drug. The third therapeutic composition may be disposed at least partially over the first therapeutic composition which may disposed at least partially over the second therapeutic composition, where the third therapeutic composition may be configured to effect a burst release which is more rapid than the release of either the first or second therapeutic compositions.

[0244] In specific examples, the first and second therapeutic compositions may comprise polymer and the third therapeutic composition may be free from polymer and coated or otherwise deposited over at least a portion of the first therapeutic composition.

[0245] In other examples, the third drug formulation may comprise at least one polymer, where at least one polymer in the third formulation may be the same and / as or different from 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 provided by at least one polymer in the first and second drug formulations. In other examples, the at least one polymer in the third formulation provides substantially the same release rate as provided by at least one polymer in the first and second drug formulations.

[0246] In specific instances, the first, second, or optional third therapeutic compositions may comprise a plurality of drug different formulations for at least one drug. For example, a single drug type may be sequestered in formulations with polymers have different release rates and / or drug loadings, allowing further control of the drug release characteristics.

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

[0248] Carriers will typically comprise polymers, usually biodegradable polymers, more usually but not always being synthetic polymers synthesized from petroleum and other hydrocarbon feedstocks. Exemplary biodegradable, synthetic polymers are selected from the group consisting of polyesters, including polylactic acids, polyglycolic acids, polylactic acid-co-glycolic acids, polylactic acid-co-caprolactones, polyethylene glycol-block-poly caprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly N-(2 -Hydroxypropyl) methacrylamides; polyethylenimine (PEI), dextran, dextrin, chitosans, poly(L-lysine); poly (aspartami des), polyethylenes; polypropylenes; polyamides; polyethylene glycols (PEG); silicones; poly(anhydrides); and poly ortho esters.

[0249] An exemplary biodegradable polymer comprises poly(lactic-co-glycolic acid) (PLGA), where the PLGA is present at 5 pg to 15 g per mm of scaffold structure length in the first therapeutic composition and from and from 5 pg to 20 pg per mm of scaffold structure length in the second therapeutic composition.

[0250] Alternatively, the polymer may comprises a non-degradable polymer, for example being selected from the group consisting of polyacrylates, polymethacrylates, poly(n-butyl methacrylate), poly(hydroxyethylmethacrylate), polyamides, nylons, nylon 12, Dacron, polyethylene terephthalate, polyethylene glycol), polyethylene oxide (PEO), polydimethylsiloxane, polyvinylpyrrolidone, ethylene-vinyl acetate, phosphorylcholine- containing polymers, poly(2-methacryloyloxyethylphosphorylcholine), poly(2- methacryloyloxyethylphosphorylcholine-co-butyl methacrylate), and copolymers thereof.

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

[0252] In a particular example, (1) a calcium chelating agent may be present in the first therapeutic composition at a concentration in a range from 2pg to 15 pg per mm of scaffold structure length, the argatroban may be present in the first therapeutic composition at a concentration in a range from 0.5pg to 3pg per mm of scaffold structure length, the direct factor Xa inhibitor including at least one of apixaban and rivaroaxaban may be present at a concentration in a range from 0.5pg to 3pg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 0.5 g to 3 pg per mm of scaffold structure length in the first therapeutic composition and (2) the argatroban may be present at a concentration in a range from 2pg to lOpg per mm of scaffold structure length, the direct factor Xa inhibitor including at least one of apixaban and rivaroxaban may be present at a concentration in a range from 2pg to lOpg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 2pg to lOpg per mm of scaffold structure length in the second therapeutic composition.

[0253] In a particular example, (1) the argatroban may be present in the first therapeutic composition at a concentration in a range from 0.5 pg to 3 pg per mm of scaffold structure length, the direct factor Xa inhibitor including at least one of apixaban and rivaroaxaban may be present at a concentration in a range from 0.5pg to 3pg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 0.5 pg to 3 pg per mm of scaffold structure length in the first therapeutic composition and (2) a calcium chelating agent may be present in the first therapeutic composition at a concentration in a range from 2pg to 15 pg per mm of scaffold structure length, the argatroban may be present at a concentration in a range from 2pg to lOpg per mm of scaffold structure length, the direct factor Xa inhibitor including at least one of apixaban and rivaroxaban may be present at a concentration in a range from 2pg to lOpg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 2pg to lOpg per mm of scaffold structure length in the second therapeutic composition.

[0254] In other examples, the first therapeutic composition may be coated on one or more surfaces of the scaffold structure and the second therapeutic composition may be coated over atleast a portion of the first therapeutic composition. For example, the first and second therapeutic compositions cover at least 75% of the area of inner and outer surfaces of the scaffold structure.

[0255] In a still further aspect, the present disclosure comprises a method for treating a vascular tissue injury in a patient. The method comprises expanding a scaffold structure at a target location in the patient’s vasculature proximate a tissue injury. A first drug formulation including at least one of a drug selected from the group consisting of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa is released from a first therapeutic composition on the scaffold, and a second drug formulation including at least one drug selected from the group consisting of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa is released from a second therapeutic composition on the scaffold to the location of injury. The first therapeutic composition may be formulated to rapidly release the first drug formulation into a vascular environment, and the second therapeutic composition may be formulated to provide an extended release of the second drug formulation into the vascular environment.

[0256] In different instances of the methods of the present disclosure, the therapeutic compositions may be positioned on an external surface of the implantable scaffold, on an internal surface of the implantable scaffold, or on both external and internal surfaces of the implantable scaffold.

[0257] While the tissue injury will frequently be caused by expanding the scaffold at the location, in other cases the tissue injury may preexist, deploying the structure at the location.

[0258] In specific instances, at least one of the first drug formulation and the second drug formulation may comprise either or both or three of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor.

[0259] In specific instances, the first (rapid release) drug formulation may release drug from the first therapeutic composition over a first time period is in a range from 3 hours to 28 days after implantation, usually from 3 hours to 7 days after implantation, preferably from 3 hours to 3 days after implantation, where the at least one drug of the first drug formulation is typically at a mean rate in the range from 1 pg / hour to 1 Opg / hour, usually from 1 pg / hour to 5pg / hour, preferably from 2 pg / hour to 4 pg / hour over a 24 hour period following exposure to the vascular environment, where the mean rate may be determined based on the amount (weight) of drug released over the total duration of the release.

[0260] In specific instances, the at least one drug of the second drug formulation is released from the second (sustained release) therapeutic composition over a second time period is in a range from 30 days to 12 months after implantation, usually from 30 days to 9 months after implantation, preferably from 30 days to 6 months after implantation, where the secondtherapeutic composition is typically configured to release the at least one drug of the second drug formulation for at a mean rate not exceeding 2 pg / hour, usually 1 pg / hour, preferably 0.5 pg / hour, and more preferably 0.1 pg / hour after the 24 hour period following exposure to the vascular environment, where the mean rate may be determined based on the amount (weight) of drug released over the total duration of the release.

[0261] In preferred instances, the therapeutic compositions are formulated to locally release the first and second drug formulation of a calcium chelating agent to the injury site at a rate or a concentration sufficient to begin to inhibit one or more of inflammation, cell proliferation, internal elastic lamina (IEL) injury, fibrin formation, and clot formation within about 1 hours to about 7 days after the structure is deployed.

[0262] In preferred instances, the therapeutic compositions are formulated to locally release the first and second drug formulation Xa to the injury site at a rate or a concentration sufficient to begin to inhibit one or more of inflammation, cell proliferation, internal elastic lamina (IEL) injury, fibrin formation, and clot formation within about 3 hours to about 7 days after the structure is deployed.

[0263] In other instances, the methods may further comprise releasing an antiplatelet drug from at least one of the first and second therapeutic compositions.

[0264] In another aspect, the present disclosure provides an implantable scaffold comprising a scaffold structure having a surface configured to be expanded in the patient’s body. At least one therapeutic composition comprising a drug formulation including at least one drug selected from the group consisting of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor s coated, layered, or otherwise bonded or affixed to the scaffold, wherein the therapeutic composition is formulated for an extended release of the drug formulation into a vascular environment.

[0265] Often, the drug formulation includes a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor, and in some instances, the drug formulation may include one or more additional drugs as described elsewhere herein.

[0266] Usually, the drug formulation comprises a polymer, and the drug(s) are incorporated into the polymer. The polymer is typically non-degradable in the vascular environment, where the drugs are loaded into a porous structure of the polymer and released by diffusion over an extended period. Alternatively, the polymer may be degradable in the vascular environment, and the drugs may be released by a combination of diffusion through and dissolution of the polymer.

[0267] Typically, the scaffold comprises a metal or a polymer which is non-degradable in the vascular environment, but in other instances the scaffold may be partly of wholly degradable, particularly when the polymer of the drug formulation is also degradable.

[0268] In specific examples, at least one drug of the drug formulation is released from the therapeutic composition over a time period of at least 28 days after implantation, usually at least 3 months after implantation, and preferably at least one year after implantation.

[0269] In other examples the therapeutic composition may be configured to release the at least one drug of the drug formulation at a mean rate not exceeding 2 pg / hour, usually 1 pg / hour, preferably 0.5 pg / hour, and more preferably 0.1 pg / hour following exposure to the vascular environment.

[0270] In many or all instances, the extended release of the drug formulation acts to accelerate dissolution of one or more of inflammation, cell proliferation, internal elastic lamina (IEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or inhibit one or more of inflammation, cell proliferation, internal elastic lamina (IEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and / or increase or prolong time before blood forms clot or thrombus.

[0271] In one aspect, a medical device may comprise 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 include but not limited to a direct factor Xa inhibitor such as Apixaban, Betrixaban, Edoxaban, Otamixaban, Rivaroxaban, Razaxaban, (r)-n- (2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6- carboxamide(LY-517717), Daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), or 2-(5-carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl- piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052) or others; and / or a direct Ila inhibitor such as Hirudin, Bivalirudin such as Angiomax, Desirudin, Lepirudin, atecegatran metoxil (AZD-0837), Argatroban, Dabigatran, Efegatran, Inogatran, Melagatran, Ximelagatran, or others; Vitamin K antagonist such as Acenocoumarol, Coumatetralyl, Dicoumarol, Ethyl biscoumacetate, Phenprocoumon, Warfarin, Clorindione, Diphenadione, Phenindione, Tioclomarol, or others; and / or other anti-coagulant drug such as Antithrombin III, Defibrotide, Protein C (Drotrecogin alfa), Ramatroban, REG1, or others; and / or an antiplatelet drug such as Abciximab, Eptifibatide, Orbofiban, Roxifiban, Sibrafiban, Tirofiban, Clopidogrel, Prasugrel, Cangrelor, Elinogrel, Ticagrelor, Beraprost, Iloprost, Prostacyclin, Treprostinil, Acetylsalicylic acid / Aspirin, Aloxiprin, Carbasalate calcium, Indobufen, Triflusal,Dipyridamole / aspirin, Picotamide, Terbogrel, Terutroban, Cilostazol, Dipyridamole, Triflusal, Cloricromen, Ditazole, Vorapaxar, Ticlopidine, or others; and / or thrombolytic drugs / fibrinolytics drug such as Plasminogen activators r-tPA, Alteplase, Reteplase, Tenecteplase, Desmoteplase, Saruplase, Urokinase, Anistreplase, Monteplase, Streptokinase, Ancrod, Brinase, Fibrinolysin, or others; and / or Ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, Di sodium edetate, Tetrasodium edetate, Trisodium edetate, monoammonium EDTA salt, Diammonium EDTA salt, Triammonium EDTA salt, Benzyldimethyltetradecylammonium EDTA salt, Tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), citrate, oxalate, the surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivative thereof; and / or an inhibitor for intrinsic pathway of coagulation and thrombosis such as a FXI / FXIa inhibitor, protein Z- dependent protease inhibitor; and / or anti-proliferative drug such as Paclitaxel (Taxol), or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs, and / or an m-TOR inhibitor such as sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs,, and combinations thereof. In a preferred example, a medical device comprising 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 the one or more active substances comprises one of apixaban, rivaroxaban, or argatroban. In a preferred example, a medical device comprising 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 the one or more active substances comprises apixaban and argatroban, apixaban and an anti-platelet agent, Rivaroxaban, and an anti-platelet agent, or argatroban and an anti-platelet agent. In a preferred example, a medical device comprising 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 the one or more active substances comprises one of apixaban or rivaroxaban or an analogue thereof, and argatroban or an analogue of it. In another preferred example, a medical device comprising a structure having at least one surface configured for internal use within a patient’s body and a therapeuticcomposition comprising one or more active substances, wherein the one or more active substances comprises one of apixaban or rivaroxaban or an analogue thereof, argatroban or its analogue, and one of taxol or sirolimus or an analogue thereof analogues.

[0272] In one aspect, a medical device may comprise 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 including a calcium chelating agent disposed on at least one surface, 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 an injury site in the patient’s body, preferably expanding such site to a larger configuration.

[0273] In one aspect, a medical device may comprise 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 including a direct factor Ila inhibitor disposed on at least one surface, 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 an injury site in the patient’s body, preferably expanding such site to a larger configuration.

[0274] In some examples, the therapeutic composition is formulated to reduce, inhibit, and / or maintain reduced cell inflammatory at implantation injury site for an extended period, usually at least about 28 days after the external surface of the structure is positioned adjacent the injury site, typically from 1 month to about 12 months.

[0275] While the drug carriers of the present disclosure will often be synthetic, biodegradable polymers, as described above, in other examples, the drug carrier may be formulated with other biocompatible, biodegradable, or non-biodegradable materials, including non-synthetic polymers, such as biological polymers, such as proteins, polypeptides, nucleic acids, carbohydrates, and the like, formulated in coating or other sequestration materials.

[0276] Such biological and other biocompatible coatings can reduce the foreign body inflammatory response induced by the intraluminal device. In some examples, such biocompatible drug carriers can deliver effective drug concentration within the vessel walls, provide a reservoir for abluminal drug elution, direct a drug toward a vessel wall, enable enhanced drug-tissue permeation to achieve enhanced drug bioavailability, improve homogeneous drug distribution, and / or improve drug stability.

[0277] In some examples, the therapeutic composition is formulated to improve drug delivery to target cells, such as diabetic cells.

[0278] In some examples, the therapeutic composition is formulated to improve drug lipophilicity and carrier hydrophobicity to facility drug effective delivery to vessel wall and extend drug release rate.

[0279] In some examples, instead of being a component of the coating, the therapeutic agent may also be chemically combined with the coating, carrier, or matrix by any chemical combination technique.

[0280] In some examples, the therapeutic composition is formulated with a biocompatible carrier having a surface-binding cell adhesion polypeptide deposited on the stent surface forming an amino-containing hydrophobic bond by binding moiety included but not limit to 3,4- dihydroxyphenylalanine (DOPA) or having adhesives peptide or polypeptide such as in the form of L-DOPA-containing proteins. These positive charged amino-terminal region polypeptides inhibit platelet activation and degranulation and limit platelet adhesion in the stent surface.

[0281] In some examples, the therapeutic composition is formulated with a biocompatible carrier deposited on the surface, forming a hydrophobic coating to enhance the corrosion resistance, avoiding the aggregation of platelets in the blood vessels and appropriate proliferation of endothelial cells and controlled proliferation of smooth muscle cells, which reduces the development of pathology, such as neointimal hyperplasia, thrombosis, and restenosis.

[0282] In some examples, the therapeutic composition is formulated with a biocompatible carrier with “mussel-inspired,” catechol-functionalized hydrogels. In some examples, the therapeutic composition is formulated with a biocompatible hydrogel or soft gel carrier when it contacted with body fluid, the coating will reduce, inhibit, and / or maintain reduced cell inflammatory at the injury site and extend drug release rate. In some examples, the therapeutic composition is formulated with polyunsaturated fatty acids (PUFAs) such as Omega-3 or Omega-6 to modify platelet responsiveness with anticoagulants.

[0283] The biocompatible drug carriers include but not limit to low water solubility amino acid, peptide, polypeptide, modified peptide conjugated with a linker or a spacer, modified polypeptide conjugated with a linker or a spacer, fatty acid including Omega-3 or Omega-6 polyunsaturated fatty acids, crosslinked fatty acid, crosslinked oil, including fish oil, Vitamin E, hazelnut oil, avocado oil, macadamia nut oil, grapeseed oil, groundnut 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, and derivatives and combinations thereof. Exemplary low-solubility amino acid having a solubility inunbuffered 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 combinations thereof. Exemplary of peptides include but not limit to lysine, ornithine, arginine, histidine, glutamic acid, aspartic acid, histidine, polyornithine, serine, threonine, tyrosine, leucine, analogues including D and L isomers, oligomers, copolymers, block polymers, derivatives, and any peptide with different amino acid sequence. Exemplary of peptides include but not limit to signaling peptides, carrier peptides, enzyme-inhibiting peptides, neurotransmitter-inhibiting peptides, antimicrobial peptides, analogs, derivatives, and combinations thereof. Exemplary of polypeptides include but not limit to poly(lysine), poly(omithine), poly(arginine), poly(histidine), poly(glutamic acid), poly(aspartic acid), poly(histidine), poly(ornithine), poly(serine), poly(threonine), poly (tyrosine), poly(leucine), analogues including D and L isomers, copolymers, block polymers, derivatives, and combinations thereof. Exemplary of cell adhesion polypeptides include but not limit to fibronectin, vitronectin, laminin, elastin, fibrinogen, and collagens, such as types I, II, and V, and any peptide derived from any of the peptides, including a cell adhesive peptide fragment having the amino acid sequence, and any peptide with different amino acid sequence. Exemplary of drug carries are containing at least one multiple bonds, i.e. preferably one unsaturated fatty acid moiety, fatty acids, cross-linked fatty acid, fatty acid esters, fatty acid derivatives, ethers, diethers, tetraethers, lipids, oils, fats, glycerides, tri-glycerides, glycol esters, glycerin esters, fish oil or derivatives thereof, vitamin E or derivatives thereof, peanut oil, cotton-seed oil, oleic acid or combinations thereof as well as mixtures of the aforementioned substances. Suitable saturated fatty acids include but not limited to, those 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 not limited to those selected from the group consisting of arachidonic acid, oleic acid, erucic acid, nervonic acid, linolenic acid, arachidonic acid, eicosapentanoic acid (EP A), docosahexanoic acid (DHA), palmitoleic acid, and myristoleic acid.

[0284] In some examples, the biocompatible carrier comprises polypeptides conjugated with an adhesive moiety and / or a linker to enhance hydrophobicity and ease drug delivery. Adhesive moieties, including but not limited to catechol moieties and L-DOPA-containing proteins, may be joined to each other and to cell adhesive polypeptides by linkers including but not limit to hyaluronic acid, polyethylene glycol / poly lysine, dopamine, 1,6-diaminohexane, 1,5- diaminopentane, 1,4-diaminobutane, or 1,3-diaminopropane or any compound having at least twohydroxyl group or two amine group that could reacted with polypeptide amnio acid group. In some examples, the biocompatible carrier is peptides and conjugated with a spacer and / or a linker to make peptide more hydrophobic and having controlled delivery of therapeutic compounds or an extended-release rate of therapeutic compounds. In some examples, the biocompatible carrier is a controlled release layer contains one or more matrix forming gelling agents selected from group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, carbomer, carboxy methylcellulose, gum tragacanth, gum acacia, guar gum, pectin, modified starch derivatives, xanthan gum, locusta bean gum, sodium alginate, which on contact with gastric fluid swells and gels, forming matrix structure that entraps the gas released and also releases the active agent in a controlled manner. In some examples, the biocompatible carrier is an absorption promoter 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 comprises a coating disposed on the external surface of the structure, and the coating comprises plasmid DNA loaded biodegradable polymer such as Polylactic-polyglycolic acid (PLGA) as stent coating. This gene therapy on the vessel wall by effective transfection of neointimal cells by local delivery of DNA. The carriers include but not limit to DNA fragments, nucleic acids, genetic material, oligonucleotides, radioisotopes, or combinations of these classes of compounds.

[0285] In some examples, the therapeutic composition is formulated to release the one or more agents, configured to release the two or more agents, or is configured to release the three or more agents, in one or more of the following: a burst release phase and an extended-release phase, wherein the release of a first phase comprises a faster release rate than a second release phase, or other.

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

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

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

[0289] In some examples, the therapeutic composition comprising a direct factor Xa inhibitor further comprises at least one additional therapeutically active substance. In some examples, the at least one additional therapeutically active substance comprises a direct factor Ila inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, or lepirudin. In some examples, the direct factor Ila inhibitor comprises argatroban. or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. In some examples, the direct factor Xa inhibitor comprises apixaban and the direct factor Ila inhibitor comprises argatroban. In some examples, the therapeutically effective dose of the direct factor Ila inhibitor is within a range of about 50 micrograms to about 10 mg. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor Ila inhibitor which is smaller than a median maximum serum concentration (Cmax) of the direct factor Ila inhibitor generated by systemic delivery of the direct factor Ila inhibitor to achieve the same tissue concentration at the site of the inflammatory ophthalmic condition or disease. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor Ila inhibitor which does not exceed a median maximum serum concentration (Cmax) of the direct factor Ila inhibitor generated by systemic delivery of the direct factor Ila inhibitor to achieve the same tissue concentration at the site of the inflammatory ophthalmic condition or disease for more than about 6 hours to about 3 days. In some examples, the therapeutically effective dose is sufficient to maintain a tissue concentration of the direct factor Ila 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 compositional ratio of the direct factor Xa inhibitor to the direct factor Ila inhibitor in the therapeutic composition is within a range of about 3: 1 to about 1 :3. For example, the weight compositional ratio of the direct factor Xa inhibitor to the direct factor Ila inhibitor in the therapeutic composition may be about 1 : 1.

[0290] In some examples, the therapeutic composition comprises one or more anticoagulant agents that has an IC50 to inhibit factor Xa and factor II at a dose ranging from O.OOOlnM tolOOOnM, preferably at a dose ranging from O.OOOlnM to lOOnM, more preferably at a dose ranging from O.OOOlnM to lOnM, and most preferably at a dose ranging from O.OOOlnM to InM.

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

[0292] In some examples, the release rate ratio of the direct factor Xa inhibitor to the antiproliferative agent is within a range of about 1 :6 to about 6: 1, or about 1 :3 to about 6: 1, or about 2.5:2 to about 6: 1. In some examples, the release rate ratio of the direct factor Xa inhibitor to the anti-proliferative agent is within a range of about 1 :2 to about 6: 1, about 1 :3 to about 6: 1, or about 2.5:2 to about 6: 1 within about 3 hours, about 24 hours, about 7 days, or about 28 days. In some examples, the release rate ratio of the direct factor Xa inhibitor to the anti-proliferative agent is within a range of about 3:2 to about 6: 1, or about 2.2:2 to about 6: 1, or about 2.5:2 to about 6: 1. In some examples, the release rate ratio of the direct factor Xa inhibitor to the antiproliferative agent is within a range of about 3 :2 to about 6: 1, about 2.2:2 to about 6: 1, or about 2.5:2 to about 6: 1 within about 3 hours, about 24 hours, about 7 days, or about 28 days. In some other examples, the release rate ratio of the direct factor Xa inhibitor to the anti -proliferative agent is within a range of about 1 : 1 to about 2: 1 within about 3 hours, 1 day, about 3 days, about 7 days, or about 28 days.

[0293] In some examples, the therapeutic composition is formulated to release the antiproliferative agent at a rate of about Ipg / second / mm device to about 50pg / day / mm device, of about Ipg / min / mm device to about lOpg / day / mm device, or of about Ipg / hour / mm device to about 7pg / day / mm device within about 3 hours, about 1 day, or about 3 days.

[0294] In some examples, the therapeutic composition is formulated to release the antiproliferative agent at a rate of about 1 pg / hour / mm device to about 4 pg / day / mm device.

[0295] In some examples, the weight compositional ratio of the direct factor Xa inhibitor to the anti-proliferative agent in the therapeutic composition is about 5:2, about 2:1, about 1.25: 1, or about 1 : 1. In some examples, the weight compositional ratio of the direct factor Xa inhibitor to the anti-proliferative agent in the therapeutic composition is within a range of about 5: 1 to about 3 : 1 or about 5 : 1 to about 1 : 1.

[0296] In some examples, the therapeutic composition comprises a coating disposed on one or more surfaces of the device structure, and the coating comprises a first layer and a second layer. In some examples, the first layer comprises the direct factor Xa inhibitor. In some examples, the first layer comprises the anti-proliferative agent and the second layer comprises the direct factor Xa inhibitor. In some examples, the therapeutic composition further comprises a top layer or coat of the same or different material as the first layer or the second layer. In some examples, the first layer comprises the direct factor Xa inhibitor and the anti-proliferative agent. In some examples, the second layer comprises a top layer or coat of the same or different material as the first layer. In some examples, the therapeutic composition comprises a coating disposed on one or more surfaces the device structure, and the coating further comprises a biodegradable polymer carrier. In some examples, the first and / or second layer comprise a drug / polymer matrix of the one or more agents. In one example, the first layer is configured for a burst release of the one or more agents, while the second layer is configured for an extended release of the one or more agents. In yet another example, the first and / or second layer are topcoat covering one or more drug agents wherein the one or more drug agents are formulated with an excipient or are formulated in a drug polymer matrix under said first and / or second layer coating. The coating of the matrix and the first or second layers maybe the same or different.

[0297] In some examples, the weight compositional ratio of the biodegradable polymer carrier to the 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 a preferred example, the polymer is biodegradable.

[0298] In some other examples, the weight compositional ratio of the carrier to the 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 carrier is one or more excipients.

[0299] In some examples, the therapeutic composition is disposed on at least one surface of the device, preferably on at least the external and / or the inner surfaces of the structure. In some examples, the therapeutic composition is disposed on the external surface (abluminal) of the structure, on the interior surface (luminal) of the structure, and on the side surfaces of the structure. In yet other examples, the therapeutic composition is disposed on one or more surfaces of the structure. In yet other examples, the therapeutic composition is disposed on all surfaces of the structure. In yet other examples, the therapeutic composition is disposed in a reservoir on or in the structure. In some examples, the therapeutic composition is disposed on the external surface of the structure.

[0300] In some examples, the therapeutic composition comprises a coating disposed on the external surface of the structure, and the coating further comprises a non-degradable polymercarrier. In some examples, the therapeutic composition comprises a coating disposed on the external surface of the structure, and the coating comprises at least one layer of a polymeric material containing the direct factor Xa inhibitor. In some examples, the therapeutic composition comprises a coating disposed on the external surface of the structure, and the coating consists of a single layer of a polymeric material which releasably contains the direct factor Xa inhibitor. In some examples, the therapeutic composition further comprises a top layer or coat comprising the same or different polymeric material. In some examples, the direct factor Xa inhibitor is uniformly distributed in the polymeric material. In some examples, the direct factor Xa inhibitor is non-uniformly distributed in the polymeric material.

[0301] In some examples, the therapeutic composition comprises a coating disposed on at least on surface of the structure, and the coating comprises at least one layer of a polymeric material holding one or more of the direct factor Xa inhibitor and the anti-proliferative agent. In some examples, the therapeutic composition comprises a coating disposed on the external surface of the structure, and the coating consists of a single layer of a polymeric material which releasably contains the direct factor Xa inhibitor and the anti-proliferative agent. In some examples, the therapeutic composition further comprises a top layer or coat comprising the same or different polymeric material. In some examples, the direct factor Xa inhibitor, and the anti-proliferative agent are uniformly distributed in the polymeric material. In some examples, the direct factor Xa inhibitor, and the anti-proliferative agent are non-uniformly distributed in the polymeric material. In some examples, the one or more active substances is present in the polymeric material at weight ratios within a range of about 1 : 1 to about 6: 1 of direct factor Xa inhibitor to antiproliferative agent.

[0302] In some examples, the polymeric material is porous. In some examples, the polymeric material has a porosity within a range of about lOnm to about 10pm. In some examples, the polymeric material is non-degradable. In some examples, the polymeric material is biodegradable. In some examples, the polymeric material has a degradation rate within a range of about 1 month to about 36 months. In some examples, the polymeric material comprises a material selected from a group consisting of polyesters, polylactide, polyglycolide, poly(s- caprolactone), polydioxanone, poly(hydroxyalkanoates), poly(L-lactide-co-D-lactide), poly(L- lactide-co-D,L-lactide), poly(D-lactide-co-D,L-lactide), poly(lactide-co-glycolide) (including 70:30 to 99: 1 PLA-co-PGA, such as 85: 15 PLA-co-PGA), poly(lactide-co-s-caprolactone) (including 70:30 to 99: 1 PLA-co-PCL, such as 90: 10 PLA-co-PCL), poly(glycolide-co-s- caprolactone), poly(lactide-co-dioxanone), poly(glycolide-co-dioxanone), poly(lactide-co- trimethylene carbonate), poly(glycolide-co-trimethylene carbonate), poly(lactide-co-ethylenecarbonate), and copolymers and combinations thereof, wherein lactide includes L-lactide, D- lactide and D, L-lactide. In some examples, the polymeric material comprises a material selected from a group of non-degradable polymeric materials consisting of polyacrylates, polymethacrylates, poly(n-butyl methacrylate), poly(hydroxyethylmethacrylate), polyamides, nylons, nylon 12, Dacron, Polyethylene terephthalate, polyethylene glycol), polyethylene oxide (PEO), polydimethylsiloxane, polyvinylpyrrolidone, ethylene-vinyl acetate, phosphorylcholine- containing polymers, poly(2-methacryloyloxyethylphosphorylcholine), poly(2- methacryloyloxyethylphosphorylcholine-co-butyl methacrylate), and copolymers and combinations thereof.

[0303] In some examples, the therapeutic composition is disposed within a drug reservoir fluidly coupled to the external surface of the structure.

[0304] In another aspect, a medical device may comprise 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 chelating agent, a direct factor Xa inhibitor and a direct factor Ila inhibitor. In some examples, the at least one surface of the structure is configured to be positioned adjacent an injury site in the patient’s body. In some examples, the therapeutic composition is formulated to locally release the two or more active substances to the injury site at a rate or a concentration sufficient to reduce cell proliferation at the injury site within about 3 hours to about 7 days, or within about 28 days to about 12 months, after the external surface of the structure is positioned adjacent the injury site.

[0305] In some examples, the therapeutic composition further comprises an anti-proliferative agent. In some examples, the direct factor Ila inhibitor comprises argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, or lepirudin. In some examples, the direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof. In some examples, the direct factor Ila inhibitor comprises dabigatran, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof.

[0306] In some examples, the direct factor Xa inhibitor comprises apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l- yl)-2-oxo-l-phenylethyl)-lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), or 2- (5-carbamimidoyl-2-hydroxy -phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052). In some examples, the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof. In some examples, the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof. In some examples, the anti-proliferative agent comprises Paclitaxel (Taxol), or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. In some examples, the anti-proliferative agent comprises an m-TOR inhibitor. In some examples, the anti-proliferative agent comprises sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs (including deuterated analogs), derivatives, metabolites, or prodrugs thereof. In some examples, the anti-proliferative agent comprises sirolimus, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof.

[0307] In some examples, the direct factor Ila inhibitor comprises Argatroban and the direct factor Xa inhibitor comprises apixaban. In some examples, the direct factor Ila inhibitor comprises Argatroban, the direct factor Xa inhibitor comprises apixaban, and the antiproliferative agent comprises sirolimus. In yet another examples the therapeutic composition comprises one of Apixaban, Rivaroxaban, or an analogue thereof, and one of Sirolimus or an analogue of Sirolimus.

[0308] In some examples, the therapeutic composition of a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor is formulated to reduce cell proliferation compared to either the direct factor Ila inhibitor or the direct factor Xa inhibitor alone. In some examples, the therapeutic composition is formulated to reduce, inhibit, and / or maintain reduced cell proliferation at the injury site at about 28 days after the external surface of the structure is positioned adjacent the injury site to about 12 months. 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 a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor and an antiproliferative is formulated to reduce cell proliferation compared to an antiproliferative alone. In some examples, the therapeutic composition is formulated to reduce, inhibit, and / or maintain reduced cell proliferation at the injury site at about 28 days after the external surface of the structure is positioned adjacent the injury site to about 12 months.

[0309] In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor is formulated to release said agents at a rate and / or concentration sufficient to accelerate dissolution or to inhibit one or more ofinflammation, smooth muscle cell proliferation, cell proliferation, thrombin formation, fibrin formation, platelet aggregation, platelet activation, vessel 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, the therapeutic composition comprising a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor is formulated to release said agents to accelerate dissolution of or to inhibit one or more of inflammation, smooth muscle cell proliferation, cell proliferation, thrombin formation, fibrin formation, platelet aggregation, platelet activation, vessel 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.

[0311] In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor formulated to have a weight composition ratio of factor Xa inhibitor to factor Ila inhibitor in the ratio ranging from about 1 : 1 : 1 to about 10: 1 : 1 In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor formulated to have a weight composition ratio of factor Xa inhibitor to factor Ila inhibitor in the ratio ranging from about 0.5 : 1 to about 5: 1.

[0312] In some examples, the therapeutic composition is formulated to reduce one or more of cell proliferation or fibrin formation within 7 days or longer.

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

[0314] In some examples, the release rate ratio of the direct factor Ila inhibitor to the direct factor Xa inhibitor to the anti-proliferative agent is within a range of about 1 : 1 : 1 to about 4:4: 1. In some examples, the therapeutic composition is formulated to release the direct factor Ila inhibitor at a rate of about 4pg / hour / mm device to about 14pg / day / mm device. In some examples, the therapeutic composition is formulated to release the direct factor Xa inhibitor at a rate of about 4pg / hour / mm device to about 14pg / day / mm device. In some examples, the therapeutic composition is formulated to release the anti-proliferative agent at a rate of about Ipg / hour / mm device to about 4pg / day / mm device.

[0315] In some examples, the weight compositional ratio of the direct factor Ila inhibitor to the direct factor Xa inhibitor in the therapeutic composition is about 1 : 1. In some examples, the weight compositional ratio of the direct factor Ila inhibitor to the direct factor Xa inhibitor in the therapeutic composition is within a range of about 3 : 1 to about 1 : 3, for example about 1 : 1. In some examples, the weight compositional ratio of the direct factor Ila inhibitor to the direct factor Xa inhibitor to the anti-proliferative agent in the therapeutic composition is about 5:5:2. In some examples, the weight compositional ratio of the direct factor Ila inhibitor to the direct factor Xa inhibitor to the anti-proliferative agent in the therapeutic composition is within a range of about 6:6: 1 to about 1 :3: 1.

[0316] In some other examples, the weight compositional ratio of the carrier to the two or more active substances is about 1 :5 to about 3: 1, about 0.5: 1 to about 1 : 1, or about 1 :5 to about 1.25: 1. In one example the carrier is one or more excipients.

[0317] In some examples, the therapeutic composition is disposed on the external surface of the structure and on the internal (inner) surface of the structure. In some examples, the therapeutic composition is disposed on the external surface (abluminal) of the structure, on the interior surface (luminal) of the structure, and on the side surfaces of the structure. In yet other examples, the therapeutic composition is disposed on one or more surfaces of the structure. In yet other examples, the therapeutic composition is disposed on all surfaces of the structure. In yet other examples, the therapeutic composition is disposed in a reservoir on or in the structure. In some examples, the therapeutic composition is disposed on the external surface of the structure.

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

[0319] In some examples, the therapeutic composition comprises a coating disposed on at least one surface of the structure, and the coating comprises a first layer and a second layer. In some examples, the first layer comprises the anti-proliferative agent, the direct factor Ila inhibitor, and the direct factor Xa inhibitor. In some examples, the second layer comprises a top layer or coat of the same or different material as the first layer. In some examples, the first layer comprises the anti-proliferative agent and the second layer comprises the direct factor Ila inhibitor and the direct factor Xa inhibitor. In some examples, the first layer comprises the anti-proliferative agent and the direct factor Xa inhibitor and the second layer comprises the direct factor Ila inhibitor. In some examples, the first layer comprises the direct factor Ila inhibitor and the direct factor Xa inhibitor and the second layer comprises the anti-proliferative agent. In some examples, the first layer comprises apixaban and argatroban and the second layer comprises sirolimus. In some examples, the therapeutic composition further comprises a top layer or coat of the same or different material as the first layer or the second layer.

[0320] In some examples, the coating further comprises a third layer. In some examples, the first layer comprises the direct factor Ila inhibitor, the second layer comprises the direct factor Xa inhibitor, and the third layer comprises the anti-proliferative agent. In some examples, the therapeutic composition further comprises a top layer or coat of the same or different material as the first layer, the second layer, or the third layer.

[0321] In some examples, the therapeutic composition comprises a coating disposed on at least one surface of the structure, and the coating further comprises a biodegradable polymer carrier. In some examples, the weight compositional ratio of the biodegradable polymer carrier to the two or more active substances is about 1 :5 to about 3:2. In some examples, the therapeutic composition comprises a coating disposed on the external surface of the structure, and the coating comprises at least one layer of a polymeric material holding one or more of the direct factor Ila inhibitor and the direct factor Xa inhibitor.

[0322] In some examples, the therapeutic composition comprises a coating disposed on at least one surface of the structure, and the coating consists of a single layer of a polymeric material which releasably holds each of the direct factor Ila inhibitor and the direct factor Xa inhibitor. In some examples, the therapeutic composition further comprises a top layer or coat comprising thesame or different polymeric material. In some examples, the direct factor Ila inhibitor and the direct factor Xa inhibitor are uniformly distributed in the polymeric material. In some examples, the direct factor Ila inhibitor and the direct factor Xa inhibitor are non-uniformly distributed in the polymeric material.

[0323] In some examples, the therapeutic composition comprises a coating disposed on at least one surface of the structure, and the coating comprises at least one layer of a polymeric material holding one or more of the direct factor Ila inhibitor, the direct factor Xa inhibitor, and the antiproliferative agent. In some examples, the therapeutic composition comprises a coating disposed on at least one surface of the structure, and the coating consists of a single layer of a polymeric material which releasably holds each of the direct factor Ila inhibitor, the direct factor Xa inhibitor, and the anti-proliferative agent. In some examples, the therapeutic composition further comprises a top layer or coat comprising the same or different polymeric material. In some examples, the direct factor Ila inhibitor, the direct factor Xa inhibitor, and the anti-proliferative agent are uniformly distributed in the polymeric material. In some examples, the direct factor Ila inhibitor, the direct factor Xa inhibitor, and the anti-proliferative agent are non-uniformly distributed in the polymeric material.

[0324] In some examples, the two or more active substances are present in the polymeric material at weight ratios of about 4: 1 :3: 1; about 5:3:2:1; about 4: 2:2: 1; about 5:2:3 : 1; about 6:3 :3 : 1 ; about 10:5:5: 1; or about 12:6:6: 1 of a calcium chelating agent, direct factor Ila inhibitor to direct factor Xa inhibitor to anti-proliferative agent.

[0325] In another aspect, a method of treating one or more of inflammation, cell proliferation, smooth muscle cell proliferation, or clotting in a patient may comprise providing a structure having an external surface; deploying the structure at a target location in the patient’s body so as to cause an injury at the location; and releasing from at least one surface of the deployed structure to the location of injury in the patient’s body therapeutically effective amounts of a therapeutic composition including at least a calcium chelating agent, a direct factor Ila inhibitor, a direct factor Xa inhibitor, and an anti-proliferative agent.

[0326] In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor and an anti-proliferative is formulated to release said agents at a rate sufficient to inhibit one or more of 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 the two or more active substances, wherein the two or more substances comprise a calcium chelating agent, adirect Ila inhibitor, a direct Xa inhibitor, and an antiproliferative, to an injury site in a body lumen. In another example, the therapeutic composition is formulated to release the two or more active substances, wherein the two or more substances include of a calcium chelating agent, a direct Ila inhibitor, a direct Xa inhibitor, and an antiproliferative, to an injury site in a body lumen. In another example, the therapeutic composition is formulated to release the two or more active substances, wherein the two or more substances include of a calcium chelating agent, a direct Ila inhibitor, and an antiproliferative, to an injury site in a body lumen. In another example, the therapeutic composition is formulated to release the two or more active substances, wherein the two or more substances include of a calcium chelating agent, a direct Ila inhibitor, a direct Xa inhibitor, to an injury site in a body lumen. In another example, the therapeutic composition is formulated to release the two or more active substances, wherein the two or more substances include of a calcium chelating agent, a direct Xa inhibitor and an anti-proliferative, to an injury site in a body lumen.

[0328] In some examples, include of a calcium chelating agent, the direct factor Ila inhibitor comprises argatroban, the direct factor Xa inhibitor comprises apixaban, and the antiproliferative agent comprises sirolimus.

[0329] In some examples, include of a calcium chelating agent, the direct factor Ila inhibitor comprises argatroban, the direct factor Xa inhibitor comprises rivaroxaban, and the antiproliferative agent comprises sirolimus.

[0330] In some examples, the therapeutic composition comprises a coating on the external surface of the structure or at least one surface of the structure and releasing the therapeutic composition comprises releasing 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 polymeric material, a degradable polymeric material, or a non-degradable polymeric material. In some examples, a calcium chelating agent, the direct factor Ila inhibitor and the direct factor Xa inhibitor are released faster than the anti-proliferative agent. In some examples, the direct factor Ila inhibitor and the direct factor Xa inhibitor enhance an antiproliferative effect of the anti-proliferative agent. In some examples, the therapeutic composition is disposed within a drug reservoir fluidly coupled to the external surface of the structure and releasing the therapeutic composition comprises delivering the therapeutic from the drug reservoir to the external surface of the deployed structure.

[0331] In some examples, the injury is at least partially caused before deployment of the structure. In some examples, deployment of the structure causes the injury, and the therapeuticcomposition is formulated to release a calcium chelating agent, the direct factor Ila inhibitor, the direct factor Xa inhibitor, or the anti-proliferative agent before the injury occurs.

[0332] In some examples, the therapeutic composition comprises a first and / or second layer comprise a drug / polymer matrix of the one or more agents. In one example, the first layer is configured for a burst release of the one or more agents, while the second layer is configured for an extended release of the one or more agents. In yet another example, the first and / or second layer are topcoat covering one or more drug agents wherein the one or more drug agents are formulated with an excipient or are formulated in a drug polymer matrix under said first and / or second layer coating. The coating of the matrix and the first or second layers maybe the same or different.

[0333] In another example of any of the examples in this application, a therapeutic composition comprising two or more active substances on at least one surface of the device is configured to be positioned adjacent to an injury site in the patient’s body, wherein adjacent to comprises one or more of the following: next to, touching, deployed at, expanded at, pushing against, placed against, or other. In a preferred example, the active substances are a calcium chelating agent, a direct factor Ila inhibitor and a direct factor Xa inhibitor. In another example the active substances are a calcium chelating agent, a direct factor Ila inhibitor, a direct factor Xa inhibitor and an anti-proliferative. In yet another example, the active substances are one of Argatroban, Rivaroxaban or Apixaban, and Sirolimus or Sirolimus analogue.

[0334] The illustrative examples described are not meant to be limiting. Other examples may be utilized, and other changes may be made, or combined in whole or in part, without departing from the scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the figures, and detailed description, and in the examples, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0335] These and other embodiments are described in further detail in the following description related to the appended drawing figures.

[0336] In still other instances, the therapeutic compositions of the present disclosure may be formulated to commence release of a calcium chelating agent and the direct factor Ila inhibitor before commencing release of and the direct factor Xa inhibitor. For example, the release of a calcium chelating agent may commence from 1 minute to 3 days, usually 3 hours to 1 day, after release of the direct factor Ila inhibitor has commenced.

[0337] In still other instances, the therapeutic compositions of the present disclosure may be formulated to commence release of a calcium chelating agent before commencing release of the direct factor Ila inhibitor and the direct factor Xa inhibitor. For example, the release of the of the direct factor Xa inhibitor may commence from 1 minute to 3 days, usually 3 hours to 1 day, after release of the direct factor Ila inhibitor and the direct factor Ila inhibitor has commenced.

[0338] In still other instances, the therapeutic compositions of the present disclosure may be formulated to commence release of the direct factor Xa inhibitor before commencing release of the direct factor Ila inhibitor. For example, release of the of the direct factor Ila inhibitor may commence from 1 minute to 3 days, usually 3 hours to 1 day, after release of the direct factor Xa inhibitor has commenced.

[0339] Exemplary direct factor Ila inhibitors suitable for incorporation into the therapeutic compositions of the present disclosure include at least one of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. Presently preferred is argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0340] Exemplary direct factor Xa inhibitors suitable for incorporation into the therapeutic compositions of the present disclosure include at least one of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). Presently preferred are rivaroxaban and apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0341] Exemplary anti-proliferative agents suitable for incorporation into the therapeutic compositions of the present disclosure include at least m-tor inhibitors selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. Preferred m-tor inhibitors include sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0342] Exemplary anti-proliferative agents suitable for incorporation into the therapeutic compositions of the present disclosure also include paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof, as well as antiplatelet drugs.

[0343] Preferred combinations of active agent pairs include a calcium chelating agent, argatroban as the direct factor Ila inhibitor and apixaban or rivaroxaban as the direct factor Xa inhibitor comprises.

[0344] In specific instances, the structure may comprise a scaffold having at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surface. In such instances at least a portion of the outer surface may coated with the therapeutic composition, at least a portion of the inner surface may be coated with the therapeutic composition, at least a portion of the edge surfaces is coated with the therapeutic composition, and frequently two or three of such surfaces will be coated.

[0345] In specific instances, at least some of the surfaces, including the outer, inner, and edge surfaces, may have receptacles formed therein, and at least some of these receptacles may have therapeutic agent(s) therein. The receptacles may comprise one or more of wells, channels, holes, surface texture, and the like.

[0346] In specific instances, the therapeutic compositions may further comprise an excipient, an adjuvant, a polymeric carrier, or the like.

[0347] In specific instances, the three or more active substances may be mixed uniformly with each other. Alternatively or additionally, the three or more active substances may be layered separately from each other. Each layer may comprise an excipient mixed with the therapeutic agent, where the excipient(s) in two or more layers may the same or may be different in at least two of the three layers.

[0348] In specific instances, the, the devices may further comprise a control-release layer formed over the at least two, three or more active substances.

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

[0350] In preferred examples, the top layer of the therapeutic composition will be formulated to commence release of the active substances before commencing of the active substances from the base layer. For example, the active substances may be released from the top layer over a time period in the range from 1 hour to 7 days after the surface of the structure is positioned adjacent the injury site and / or the active substances may be released from the base layer over a time period in the range from 7 days to 12 months after the active substances have been substantially completely released from the top layer. For example, each of the base and top layers may comprise the at least three active substances are mixed in a biodegradable polymeric matrix.

[0351] In some instances, the scaffold structure may be configured to be expanded in a vascular lumen in the patient’s body.

[0352] In some instances, the therapeutic composition may be coated at least partly on the surface of scaffold structure.

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

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

[0355] In some instances, at least some of the surfaces have receptacles formed therein and at least some of said receptacles have therapeutic agent therein. For example, the receptacles may comprise one or more of wells, channels, holes, and surface texture.

[0356] In a second aspect, the preset disclosure provides a method for treating a vascular tissue injury in a patient. The method comprises implanting a scaffold structure at a target location in the patient’s vasculature proximate the tissue injury. A therapeutic composition on the scaffold comprises colchicine and / or tirofiban and at least one antiproliferative drug. The colchicine and / or tirofiban is released from a carrier in the therapeutic composition into the vascular tissue over a period of at least one week in an amount sufficient to inhibit inflammation resulting from the implantation of the scaffold. The at least one antiproliferative drug 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 present disclosure may have anyone of a wide variety of known structures suitable for implantation and expansion at a target site in the patient’s body. Often, the scaffold will have at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces. In such instances, at least a portion of the outer surface may be coated with therapeutic compositions. In other instances, at least a portion of the inner surface may be coated with therapeutic compositions. In still other instances, a portion of the edge surfaces may be coated with therapeutic compositions. As an alternative or in addition to surface coating, at least some of the surfaces may have receptacles formed therein and at least some of said receptacles have therapeutic agent therein. For example, the receptacles comprise one or more of wells, channels, holes, and surface texture.

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

[0359] The implantable scaffolds and methods of the present disclosure are generally suitable for mitigating tissue injury caused by expanding the scaffold at the location but are also useful for treating tissue injury that preexists deploying the structure at the location.

[0360] In some examples, the therapeutic composition may be formulated for an initial rapid release into the environment surrounding the implantable scaffold a preselected time period after implantation of the body structure into said environment followed by a slower controlled release over the extended periods as described above.

[0361] The scaffolds of the present disclosure are particularly intended for use in vascular stents and grafts, but may also find use may be any type of therapeutic, diagnostic, or other structure intended for implantation in the patient’s vasculature or other vascularized regions of the patient’s body, such as prosthetic heart valves, patent foramen ovale (PFO) occlusion devices, atrial septal defect (ASD) occlusion devices, left atrial appendage (LAA) occlusion devices, or similar expandable structure, including an orthopedic implants.

[0362] Carriers will typically comprise polymers, usually biodegradable polymers, more usually but not always being synthetic polymers synthesized from petroleum and other hydrocarbon feedstocks. Exemplary biodegradable, synthetic polymers are selected from the group consisting of polyesters, including polylactic acids, polyglycolic acids, polylactic acid-co-glycolic acids, polylactic acid-co-caprolactones, polyethylene glycol-block-poly caprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly N-(2 -Hydroxypropyl) methacrylamides; polyethylenimine (PEI), dextran, dextrin, chitosans, poly(L-lysine); poly (aspartami des), polyethylenes; polypropylenes; polyamides; polyethylene glycols (PEG); silicones; poly(anhydrides); and poly ortho esters.

[0363] An exemplary biodegradable polymer comprises poly(lactic-co-glycolic acid) (PLGA), where the PLGA is present at 5 pg to 15 g per mm of scaffold structure length in the first therapeutic composition and from and from 5 pg to 20 pg per mm of scaffold structure length in the second therapeutic composition.

[0364] Alternatively, the polymer may comprises a non-degradable polymer, for example being selected from the group consisting of polyacrylates, polymethacrylates, poly(n-butyl methacrylate), poly(hydroxyethylmethacrylate), polyamides, nylons, nylon 12, Dacron, polyethylene terephthalate, polyethylene glycol), polyethylene oxide (PEO),polydimethylsiloxane, polyvinylpyrrolidone, ethylene-vinyl acetate, phosphorylcholine- containing polymers, poly(2-methacryloyloxyethylphosphorylcholine), poly(2- methacryloyloxyethylphosphorylcholine-co-butyl methacrylate), and copolymers thereof.

[0365] In another aspect, the present disclosure provides a method for treating tissue injury in patients. The method comprises deploying a structure at a target tissue injury location in the patient’s body lumen. A therapeutic composition is released from the deployed structure to the location of injury, where the therapeutic composition comprises at least a calcium chelating agent, a direct factor Ila inhibitor, a direct factor Xa inhibitor, and optionally an anti-proliferative agent.

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

[0367] The tissue injury may be caused by deploying the structure at the location or may preexists deploying the structure at the location.

[0368] In specific instances, the body lumen comprises a blood vessel and the therapeutic composition is formulated to locally release the at least two, three or more active substances to the injury site at a rate or a concentration sufficient to begin to inhibit or resolve one or more of inflammation, cell proliferation, internal elastic lamina (TEL) injury, fibrin formation, platelet aggregation, platelet activation, and clot formation or dissolution within about 3 hours to about 7 days after the structure is deployed.

[0369] In specific instances, the at least two, three or more active substances may be released to the injury site at a rate or a concentration sufficient to inhibit one or more of inflammation, cell proliferation, internal elastic lamina (TEL) injury, fibrin formation, platelet aggregation, platelet activation, and clot formation or dissolution for a period of at least 1 day, for a period of at least one week, for a period of at least one month, for a period of at least three months, for a period of at least six months, or for a period of at least one year after the surface of the structure is positioned adjacent the injury site.

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

[0371] Alternatively or additionally, the direct factor Ila inhibitor and the direct factor Xa inhibitor are released substantially simultaneously and the anti-proliferative is released after the release of the direct factor Ila inhibitor and the direct factor Xa inhibitor has commenced. For example, the release of the of the anti -proliferative agent may commence in a period of 1 minute to 3 days, usually 6 hours to 1 day, after release of the direct factor Ila inhibitor and the direct factor Xa inhibitor has commenced.

[0372] Alternatively or additionally, the therapeutic composition may commences release of the direct factor Ila inhibitor before commencing release of the direct factor Xa inhibitor. For example, the release of the of the direct factor Xa inhibitor commences from 1 minute to 3 days, usually 6 hours to 1 day, after release of the direct factor Ila inhibitor has commenced.

[0373] Alternatively or additionally, the therapeutic composition may commence release of the direct factor Xa inhibitor before commencing release of the direct factor Ila inhibitor. For example, wherein the release of the of the direct factor Ila inhibitor commences from 1 minute to 3 days, usually 6 hours to 1 day, after release of the direct factor Xa inhibitor has commenced.

[0374] In some instances, the direct factor Ila inhibitor comprises at least one of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. In presently preferred instances, the direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0375] In some instances, the direct factor Xa inhibitor comprises at least one of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4- yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6-carboxamide(L Y -517717), daraxaban (YM- 150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperi din-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052). In a presently preferred example, the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof. In a second preferred example, the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0376] In some instances, the anti-proliferative agent comprises an m-Tor inhibitor may be selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof. A presently preferred anti-proliferative agent comprises sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0377] In other instances, the anti-proliferative agent may comprise paclitaxel, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0378] In still other instances, the anti-proliferative agent may comprise an antiplatelet drug.

[0379] Preferred combinations and pairings of active substances in the methods herein, comprise: a calcium chelating agent (1), the direct factor Ila inhibitor comprising (2) argatroban and the direct factor Xa inhibitor comprising apixaban and (3) the direct factor Ila inhibitor comprisingargatroban, the direct factor Xa inhibitor comprises apixaban, and the anti-proliferative agent comprising sirolimus.

[0380] In some instances, the structure comprises a scaffold having at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces and wherein deploying comprises expanding the scaffold in the body lumen. Typically, at least a portion of the outer surface is coated with the therapeutic composition. Optionally, at least a portion of the inner surface is coated with the therapeutic composition. Further optionally, a portion of the edge surfaces is coated with the therapeutic composition.

[0381] In some instances, at least some of the surfaces may have receptacles formed therein and at least some of these receptacles have therapeutic agent therein wherein the receptacles may comprise one or more of wells, channels, holes, and surface texture.

[0382] In some instances, the release rate(s) of the active substances will be controlled. For example, excipients with different degradation or release rates can be added to different layers and / or combined with different active substances. Additionally or alternatively, a control-release layer may be formed over therapeutic composition to control the release of the three or more active substances.

[0383] In some, the therapeutic composition may include a base layer formed over the surface and a top layer formed over the base layer, wherein the base layer and top layer differ in at least some properties. In such instances, the therapeutic composition may be formulated to release the active substances substantially completely from the top layer before releasing the active substances from the base layer. For example, the active substances may be released from the top layer over a time period in the range from 1 hour to 7 days after the surface of the structure is positioned adjacent the injury site, and the active substances are released from the base layer over a time period in the range from 7 days to 12 months after the after the active substances have been substantially completely released from the top layer. In some instances, each of the base and top layers comprises the at least three active substances are mixed in a biodegradable polymeric matrix.

[0384] Often, the injury is at least partially caused before deployment of the structure, but more commonly deployment of the structure, e.g., stent expansion in an artery, causes the injury and wherein the therapeutic composition is formulated to release the calcium chelating agent EDTA the direct factor Ila inhibitor, the direct factor Xa inhibitor, or the anti-proliferative agent before, during, and / or following the injury occurs. Specific examples include vascular wall injury during vascular interventions, including, angioplasty, atherectomy, stent placement, graft placement, and the like.

[0385] In other instances, injury occurs during placement, implantation, or other introduction of a temporary or non-temporary device which is selected from the group consisting of access devices, infusion devices, tools, surgical instruments and tools, implants, bodily implants, hip 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, foramen implants, leads, closure devices, clips, wound-closure devices and implants, sutures, patches, injection devices, needles inserted in the body, and needles inserted from outside the body.

[0386] Each class and type of anti-coagulation agent described and claimed herein, including but not limited to the inhibitors of the clotting cascade, such as the specific factor Ila inhibitor, factor Xa inhibitor, factor XI inhibitor, and factor Xia inhibitor listed herein, as well as the specific chelating agents and the specific anti-coagulation enhancers, may be combined one or more of the other classes and types of anti-coagulation agents described and claimed herein. Moreover, each class and type of anti-coagulation agent described and claimed herein may be formulated for any release profile as described and claimed such as bolus release, dual bolus release, and extended release.

[0387] In an aspect, the present disclosure provides a composition for coupling to a surface of an implantable article. The composition may comprise: an anti-coagulant comprising a direct factor Xa inhibitor and at least one of (a) an anti-platelet drug, (b) anti-coagulant comprising a direct factor Ila inhibitor, or (c) an anti-inflammatory drug comprising colchicine.

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

[0389] In some embodiments, wherein the direct factor Xa inhibitor comprises at least one drug selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2- yl)methyl-[4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM- 60828), eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl- piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), and a salt, isomer, solvate, derivative, metabolite, or pro-drug 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 an anti-platelet drug selected from the group consisting of: a Cox 1 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a Cox 2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a glycoprotein lllb / 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 anti-platelet drug comprises tirofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the anti-platelet drug comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the anti-platelet drug comprises a Coxl / 2 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, wherein the Coxl / 2 inhibitor comprises acetylsalicylic acid. In some embodiments, the antiplatelet drug 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 Ila inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin. In some embodiments, the at least one direct factor Ila inhibitor drug comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0392] In another aspect, the present disclosure provides a composition for coupling to a surface of an implantable article. The composition may comprise: an anti-coagulant comprising a direct factor Ila inhibitor and at least one of (a) an anti-platelet drug, (b) an anti-coagulant comprising a direct factor Xa inhibitor, or (c) an anti-inflammatory drug comprising colchicine.

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

[0394] In some embodiments, the direct factor Ila inhibitor is selected from the group consisting of: argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, lepirudin, and a salt, isomer, solvate, derivative, metabolite, or pro-drug of any preceding member of the group. In someembodiments, the direct factor Ila inhibitor drug comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0395] In some embodiments, the composition further comprises at least one an anti-platelet drug selected from the group consisting of: a Cox 1 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a Cox 2 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a glycoprotein Ilb / 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 anti-platelet drug comprises tirofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the anti-platelet drug comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the anti-platelet drug comprises a Coxl / 2 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, wherein the Coxl / 2 inhibitor comprises acetylsalicylic acid. In some embodiments, the antiplatelet drug comprises: clopidogrel or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; or the active metabolite of clopidogrel or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0396] In some embodiments, the direct factor Xa inhibitor comprises at least one drug selected from the group consisting of: apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2- yl)methyl-[4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM- 60828), eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl- piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), and a salt, isomer, solvate, derivative, metabolite, or pro-drug of any preceding member of the group. In some embodiments, the direct factor Xa inhibitor comprises: apixaban, or a salt or an analog thereof; and / or rivaroxaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

[0397] In another aspect, the present disclosure provides a composition for coupling to a surface of an implantable article. The composition may comprise: a direct factor Xa inhibitor; and at least two of (a) a direct factor Ila inhibitor, (b) an anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibit, and a P2yl2 inhibitor; or (c) an antiinflammatory drug. In some embodiments, the composition further comprises all three of (a) the direct factor Ila inhibitor, (b) the anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, and a Ilb / IIIa inhibitor; and (c) the anti-inflammatory drug.

[0398] The composition of claim 25 or 26, wherein the direct factor Xa inhibitor comprises at least one drug selected from the group consisting of: apixaban, betrixaban, edoxaban,otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l-yl)-2-oxo- 1 -phenylethyl)- lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), and a salt, isomer, solvate, derivative, metabolite or prodrug 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 the direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof. In some embodiments, the antiplatelet drug comprises at least one drug selected from the group consisting of tirofiban, ticagrelor, a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibitor, a P2Y12 inhibitor, and a salt, analog, or metabolite of any preceding member of the group. In some embodiments, the antiinflammatory drug comprises colchicine.

[0400] In another aspect, the present disclosure provides a composition for coating a surface of an implantable article. The composition 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; tirofiban 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 an anti-platelet drug. In some embodiments, the composition of any aspect or embodiment further comprises an additional anti-inflammatory drug.

[0402] In another aspect, the present disclosure provides a surgical article comprising a base structure, wherein the composition of any aspect or embodiment and / or one or more components thereof are coupled to a 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 non- homogeneous. 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 comprises an intermediate layer over and / or between said at least two layers. In some embodiments, the intermediate layer comprises a drug in addition to drugs on the composition. In some embodiments, the drugs in the composition coupled to the surface have a release rate in a range from 1 day to one year. In some embodiments, the drugs in the composition coupled to thesurface have a release rate in a range from 1 day to 3 days, from 1 day to 30 days, or 1 day to 90 days.

[0404] Clause 1. An implantable scaffold comprising: a scaffold structure having a surface configured to be implanted in a patient’s vasculature; a therapeutic composition configured to be released from a surface of the scaffold, said therapeutic composition comprising colchicine and / or tirofiban and at least one antiproliferative drug; wherein the colchicine and / or tirofiban is present in a carrier configured to release the colchicine and / or tirofiban over a period of at least one week in an amount sufficient to inhibit inflammation resulting from the implantation of the scaffold; and wherein the at least one antiproliferative drug is present in the same or a different carrier configured to release the antiproliferative drug over a period of at least one week in an amount sufficient to inhibit smooth cell muscle (SMC) proliferation.

[0405] Clause 2. The implantable scaffold of clause 1, wherein the at least one antiproliferative drug comprises an mTOR inhibitor.

[0406] Clause 3. The implantable scaffold of clause 2, wherein the mTOR inhibitor comprises one or more drugs selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, and salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.

[0407] Clause 4. The implantable scaffold of clause 3, wherein the mTOR inhibitor comprises sirolimus, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0408] Clause 5. The implantable scaffold of clause 1 to 4, wherein the therapeutic composition is formulated to release no greater than 90%, 75%, 50%. 25%, or 10% by weight of the colchicine and / or tirofiban from the scaffold into a vascular environment within one week, one month, three months, six months, or one year of implantation.

[0409] Clause 6. The implantable scaffold of clause 5, wherein the therapeutic composition is formulated to release no greater than 90%, 75%, 50%. 25%, or 10% by weight of the antiproliferative drug from the scaffold into the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0410] Clause 7. The implantable scaffold of clause 1 to 5, wherein the scaffold structure is loaded with an amount of the colchicine in a range from 1.7 pg to 170pg, 1.7 pg to 85pg, 2.5 pg to 40pg, or 3.4 pg to 20pg per mm of the scaffold structure of the length.

[0411] Clause 8. The implantable scaffold of clause 1 to 6, wherein the scaffold structure is loaded with an amount of the antiproliferative drug in a range from 2 pg to 200pg, 2 pg to lOOpg, 3 pg to 50pg, or 4 pg to 20pg per mm of the scaffold structure of the length.

[0412] Clause 9. The implantable scaffold of clause 1 to 8, wherein the carrier comprises a biodegradable polymer.

[0413] Clause 10. The implantable scaffold of clause 9, wherein the biodegradable polymer is selected from a group consisting of polyesters, including polylactic acids, polyglycolic acids, polylactic acid-co-glycolic acids, polylactic acid-co-caprolactones, polyethylene glycol-block- poly caprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly N-(2- Hydroxypropyl) methacrylamides; polyethylenimine (PEI), dextran, dextrin, chitosans, poly(L- lysine); poly(aspartamides), polyethylenes; polypropylenes; polyamides; polyethylene glycols (PEG); silicones; poly(anhydrides); and poly ortho esters.

[0414] Clause 11. The implantable scaffold of clause 1 to 10, wherein the therapeutic composition further comprises at least one anti-coagulant agent.

[0415] Clause 12. The implantable scaffold of clause 11, wherein the at least one anticoagulant is selected from the group consisting of a direct factor Ila inhibitor and a direct factor Xa inhibitor.

[0416] Clause 13. The implantable scaffold of clauses 12, wherein the at least one anticoagulant comprises a direct factor Ila inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0417] Clause 14. The implantable scaffold of clause 13, wherein the at least one direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0418] Clause 15. The implantable scaffold of any one of clauses 11 to 14, wherein the at least one anti-coagulant comprises a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l- methylpiperidin-4-yl)piperazin-l-yl)-2-oxo-l -phenylethyl)- lh-indole-6-carboxamide(LY- 517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l- ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0419] Clause 16. The implantable scaffold of clause 15, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0420] Clause 17. The implantable scaffold of clause 16, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0421] Clause 18. The implantable scaffold of any one of clauses 1 to 17, wherein therapeutic composition further comprises an antiplatelet drug.

[0422] Clause 19. The method of any one of clauses 18, wherein the antiplatelet drug is selected from a group consisting of Abciximab, Eptifibatide, Orbofiban, Roxifiban, Sibrafiban, Tirofiban, Clopidogrel, Prasugrel, Cangrelor, Elinogrel, Ticagrelor, Beraprost, Iloprost, Prostacyclin , Treprostinil, Acetylsalicylic acid / Aspirin, Aloxiprin, Carbasalate calcium, Indobufen, Triflusal, Dipyridamole / aspirin, Picotamide, Terbogrel, Terutroban, Cilostazol, Dipyridamole, Triflusal, Cloricromen, Ditazole, Vorapaxar, and Ticlopidine.

[0423] Clause 20. The implantable scaffold of clause 1 to 19, wherein therapeutic composition further comprises a second antiproliferative drug.

[0424] Clause 21. The implantable scaffold of clause 20, wherein the second antiproliferative drug is selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, azathioprine.

[0425] Clause 22. The implantable scaffold of clause 1 to 21, wherein therapeutic composition further comprises a cationic anti-coagulation enhancer.

[0426] Clause 23. The implantable scaffold of clause 22, wherein the cationic anticoagulation enhancer is selected from a first group consisting of magnesium stearate and other magnesium salts, monoammonium salt, diammonium salt, triammonium salt, benzyldimethyltetradecylammonium salt, tridodecylmethylammonium salt, a benzalkonium, analogue, solvate, hydrate and derivatives thereof or from a second group consisting of poly(L- lysine) (PLL), linear polyethyleneimine (PEI), branch polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2-dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, a polybetaaminoester (PBAE), Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof.

[0427] Clause 24. The implantable scaffold of clause 1 to 23, wherein therapeutic composition further comprises a factor Xl / XIa inhibitor.

[0428] Clause 25. The implantable scaffold of clause 24, wherein factor Xl / XIa inhibitor comprises a protein Z-dependent protease inhibitor, analogue, solvate, hydrate or derivatives thereof.

[0429] Clause 26. The implantable scaffold of clause 1 to 25, wherein the therapeutic composition further comprises a chelating agent formulated to deplete calcium in the environment surrounding the scaffold upon implantation of the scaffold structure in said environment.

[0430] Clause 27. The implantable scaffold of clause 26, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3-dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), diethylenetriaminepentaacetate (DTP A), hydroxy ethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0431] Clause 28. The implantable scaffold of clause 1 to 27, wherein the scaffold structure is configured to be expanded in a vascular lumen in the patient’s body.

[0432] Clause 29. The implantable scaffold of clause 1 to 28, wherein the therapeutic composition is coated at least partly on the surface of scaffold structure.

[0433] Clause 30. The implantable scaffold of clause 1 to 29, wherein the therapeutic composition is present at least partly within a cavity or reservoir within the scaffold structure.

[0434] Clause 31. The implantable scaffold of clause 1 to 30, wherein the implantable scaffold has at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces.

[0435] Clause 32. The implantable scaffold of clause 31, wherein at least a portion of the outer surface is coated with the therapeutic compositions.

[0436] Clause 33. The implantable scaffold of clause 30 or 31, wherein at least a portion of the inner surface is coated with the therapeutic compositions.

[0437] Clause 34. The implantable scaffold of any one of clauses 31 to 33, wherein a portion of the edge surfaces is coated with the therapeutic compositions.

[0438] Clause 35. The implantable scaffold of any one of clauses 31 to 34, wherein at least some of the surfaces have receptacles formed therein and at least some of said receptacles have therapeutic agent therein.

[0439] Clause 36. The implantable scaffold of clause 35, wherein the receptacles comprise one or more of wells, channels, holes, and surface texture.

[0440] Clause 37 - 50 intentionally left blank.

[0441] Clause 51. A method for treating a vascular tissue injury in a patient, the method comprising: implanting a scaffold structure at a target location in the patient’s vasculature proximate the tissue injury; and wherein a therapeutic composition on the scaffold comprises colchicine and / or tirofiban and at least one antiproliferative drug; wherein the colchicine and / or tirofiban is released from a carrier in the therapeutic composition into the vascular tissue over a period of at least one week in an amount sufficient to inhibit inflammation resulting from the implantation of the scaffold; and wherein the at least one antiproliferative drug 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.

[0442] Clause 52. The method of clause 51, wherein the at least one antiproliferative drug comprises an mTOR inhibitor.

[0443] Clause 53. The method of clause 52, wherein the mTOR inhibitor comprises one or more drugs selected from a group consisting of sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, and salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.

[0444] Clause 54. The method of clause 53, wherein the mTOR inhibitor comprises sirolimus, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

[0445] Clause 55. The method of clause 51 to 54, wherein the therapeutic composition is formulated to release no greater than 90%, 75%, 50%. 25%, or 10% by weight of the colchicine and / or tirofiban from the scaffold into a vascular environment within one week, one month, three months, six months, or one year of implantation.

[0446] Clause 56. The method of clause 55, wherein the therapeutic composition is formulated to release no greater than 90%, 75%, 50%. 25%, or 10% by weight of the mTOR inhibitor from the scaffold into the vascular environment within one week, one month, three months, six months, or one year of implantation.

[0447] Clause 57. The method of clause 51 to 55, wherein the scaffold structure is loaded with an amount of the colchicine and / or tirofiban in a range 1.7 pg to 170pg, 1.7 pg to 85pg, 2.5 pg to 40pg, or 3.4 pg to 20pg per mm of the length of the scaffold structure.

[0448] Clause 58. The method of clause 51 to 56, wherein the scaffold structure is loaded with an amount of the antiproliferative drug in a range from 2 pg to 200pg, 2 pg to lOOpg, 3 pg to 50pg, or 4 pg to 20pg per mm of the length of the scaffold structure.

[0449] Clause 59. The method of clause 51 to 58, wherein the carrier comprises a biodegradable polymer.

[0450] Clause 60. The method of clause 59, wherein the biodegradable polymer is selected from a group consisting of polyesters, including polylactic acids, polyglycolic acids, polylactic acid-co-glycolic acids, polylactic acid-co-caprolactones, polyethylene glycol-block-poly caprolactone, and polyurethanes; poly(methyl methacrylate) (PMMA); poly N-(2- Hydroxypropyl) methacrylamides; polyethylenimine (PEI), dextran, dextrin, chitosans, poly(L- lysine); poly(aspartamides), polyethylenes; polypropylenes; polyamides; polyethylene glycols (PEG); silicones; poly(anhydrides); and poly ortho esters.

[0451] Clause 61. The method of clause 51 to 60, wherein the therapeutic composition further comprises at least one anti-coagulant agent.

[0452] Clause 62. The method of clause 61, wherein the at least one anti -coagulant is selected from the group consisting of a direct factor Ila inhibitor and a direct factor Xa inhibitor.

[0453] Clause 63. The method of clauses 62, wherein the at least one anti -coagulant comprises a direct factor Ila inhibitor selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0454] Clause 64. The method of clause 63, wherein the at least one direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0455] Clause 65. The method of any one of clauses 61 to 64, wherein the at least one anticoagulant comprises a direct factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4- yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6-carboxamide(L Y -517717), daraxaban (YM- 150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperi din-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0456] Clause 66. The method of clause 65, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0457] Clause 67. The method of clause 66, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0458] Clause 68. The method of any one of clauses 51 to 67, wherein therapeutic composition further comprises an antiplatelet drug.

[0459] Clause 69. The method of any one of clauses 68, wherein the antiplatelet drug is selected from a group consisting of Abciximab, Eptifibatide, Orbofiban, Roxifiban, Sibrafiban, Tirofiban, Clopidogrel, Prasugrel, Cangrelor, Elinogrel, Ticagrelor, Beraprost, Iloprost, Prostacyclin , Treprostinil, Acetylsalicylic acid / Aspirin, Aloxiprin, Carbasalate calcium, Indobufen, Triflusal, Dipyridamole / aspirin, Picotamide, Terbogrel, Terutroban, Cilostazol, Dipyridamole, Triflusal, Cloricromen, Ditazole, Vorapaxar, and Ticlopidine.

[0460] Clause 70. The method of clause 51 to 69, wherein therapeutic composition further comprises a second antiproliferative drug.

[0461] Clause 71. The method of clause 70, wherein the second antiproliferative drug is selected from the group consisting of my cophenolate mofetil, my cophenolate sodium, azathioprine.

[0462] Clause 72. The method of clause 51 to 71, wherein therapeutic composition further comprises a cationic anti -coagulation enhancer.

[0463] Clause 73. The method of clause 72, wherein the cationic anti-coagulation enhancer is selected from a first group consisting of magnesium stearate and other magnesium salts, monoammonium salt, diammonium salt, triammonium salt, benzyldimethyltetradecylammonium salt, tridodecylmethylammonium salt, a benzalkonium, analogue, solvate, hydrate and derivatives thereof or from a second group consisting of poly(L-lysine) (PLL), linear polyethyleneimine (PEI), branch polyethyleneimine (PEI), chitosan, PAMAM dendrimers, and poly(2- dimethylamino)ethyl methacrylate (pDMAEMA), protamine, polylysine, a polybetaaminoester (PBAE), Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof.

[0464] Clause 74. The method of clause 51 to 73, wherein therapeutic composition further comprises a factor Xl / XIa inhibitor.

[0465] Clause 75. The method of clause 74, wherein factor Xl / XIa inhibitor comprises a protein Z-dependent protease inhibitor, analogue, solvate, hydrate or derivatives thereof.

[0466] Clause 76. The method of clause 51 to 54, wherein the therapeutic composition further comprises a chelating agent formulated to deplete calcium in the environment surrounding the scaffold upon implantation of the scaffold structure in said environment.

[0467] Clause 77. The method of clause 76, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0468] Clause 78. The method of clause 51 to 77, wherein the scaffold structure is configured to be expanded in a vascular lumen in the patient’ s body.

[0469] Clause 79. The method of clause 51 to 78, wherein the therapeutic composition is coated at least partly on the surface of scaffold structure.

[0470] Clause 80. The method of clause 51 to 79, wherein the therapeutic composition is present at least partly within a cavity or reservoir within the scaffold structure.

[0471] Clause 81. The method of clause 51 to 80, wherein the scaffold has at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces.

[0472] Clause 82. The method of clause 81, wherein at least a portion of the outer surface is coated with the therapeutic compositions.

[0473] Clause 83. The method of clause 81 or 32, wherein at least a portion of the inner surface is coated with the therapeutic compositions.

[0474] Clause 84. The method of any one of clauses 81 to 83, wherein a portion of the edge surfaces is coated with the therapeutic compositions.

[0475] Clause 85. The method of any one of clauses 81 to 83, wherein at least some of the surfaces have receptacles formed therein and at least some of said receptacles have therapeutic agent therein.

[0476] Clause 86. The method of clause 85, wherein the receptacles comprise one or more of wells, channels, holes, and surface texture.

[0477] Clause 87 - 100 intentionally left blank.

[0478] Clause 101. A composition for coating a surface of an implantable article, said composition comprising: (a) at least one of a factor Ila inhibitor and a factor Xa inhibitor (b)col chi cine; and (c) a first antiplatelet drug comprising tirofiban; wherein the (a) at least one of a factor Ila inhibitor and a factor Xa inhibitor, (b) colchicine; and (c) first antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation and / or thrombosis resulting from an injury.

[0479] Clause 102. The composition of clause 101, wherein the (a) at least one of a factor Ila inhibitor and a factor Xa inhibitor, (b) colchicine; and (c) first antiplatelet drug are formulated to treat an injury that resulted from implantation of the article.

[0480] Clause 103. The composition of clause 101 or 102, wherein the (a) at least one of a factor Ila inhibitor and a factor Xa inhibitor, (b) colchicine; and (c) first antiplatelet drug are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0481] Clause 104. The composition of clause 101 to 103, comprising at least one factor Ila inhibitor selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0482] Clause 105. The composition of clause 104, wherein the at least one direct factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0483] Clause 106. The composition of clause 101 to 105, comprising at least one factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 - phenylethyl)-lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0484] Clause 107. The composition of clause 106, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0485] Clause 108. The composition of clause 106, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0486] Clause 109. The composition of clause 101 to 108, further comprising at least a second antiplatelet drug different from the first antiplatelet drug.

[0487] Clause 110. The composition of clause 109, wherein the second antiplatelet drug comprises one or more of a glycoprotein Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0488] Clause 111. The composition of clause 109 and 110, further comprising at least a third antiplatelet drug different than the first and second antiplatelet drugs.

[0489] Clause 112. The composition of clause 111, wherein the third antiplatelet drug comprises one or more of a factor Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0490] Clause 113. The composition of clause 101 to 112, further comprising a chelating agent.

[0491] Clause 114. The composition of clause 113, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0492] Clause 115. The composition of clause 101 to 114, , further comprising at least one antiproliferative drug.

[0493] Clause 116. The composition of clause 115, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0494] Clause 117. The composition of clause 101 to 116, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0495] Clause 118. The composition of clause 101 to 116, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0496] Clause 119 to 200 intentionally left blank.

[0497] Clause 201. A composition for coating a surface of an implantable article, said composition comprising: (a) a factor Ila inhibitor; (b) a factor Xa inhibitor; and (c) a firstantiplatelet drug comprising a factor Ila / IIIb inhibitor; wherein (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, and (c) the first antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation and / or thrombosis resulting from an injury.

[0498] Clause 202. The composition of clause 201, wherein (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, and (c) first antiplatelet drug are formulated to treat an injury that resulted from implantation of the article.

[0499] Clause 203. The composition of clause 201 or 202, wherein the (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, and (c) first antiplatelet drug are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0500] Clause 204. The composition of clause 201 to 203, further comprising (d) colchicine which in combination with (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, and (c) first antiplatelet drug is formulated to release from the surface of the article in an amount sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0501] Clause 205. The composition of clause 201 to 204, wherein the factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0502] Clause 206. The composition of clause 205, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0503] Clause 207. The composition of clause 201 to 206, wherein the factor Xa inhibitor is selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0504] Clause 208. The composition of clause 207, wherein the factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0505] Clause 209. The composition of clause 20, wherein the factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0506] Clause 210. The composition of clause 201 to 209, wherein the factor Ilb / IIIa inhibitor is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0507] Clause 211. The composition of clause 201 to 210, further comprising at least a second antiplatelet drug different than the first antiplatelet drug.

[0508] Clause 212. The composition of clause 211, wherein the second antiplatelet drug comprises one or more of a factor Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0509] Clause 213. The composition of clause 211 and 212, further comprising at least a third antiplatelet drug different than the first and second antiplatelet drugs.

[0510] Clause 214. The composition of clause 213, wherein the third antiplatelet drug comprises one or more of a factor Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0511] Clause 215. The composition of clause 201 to 214, further comprising a chelating agent.

[0512] Clause 216. The composition of clause 215, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0513] Clause 217. The composition of clause 201 to 216, further comprising at least one antiproliferative drug.

[0514] Clause 218. The composition of clause 217, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0515] Clause 219. The composition of clause 201 to 218, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0516] Clause 220. The composition of clause 201 to 218, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0517] Clause 221 to 300 intentionally left blank.

[0518] Clause 301. A composition for coating a surface of an implantable article, said composition comprising: (a) a factor Ila inhibitor; (b) a factor Xa inhibitor; (c) a first antiplatelet drug comprising a factor Ila / IIIb inhibitor; and (d) a second antiplatelet drug comprising an NS AID; wherein (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug and (d) the second antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0519] Clause 302. The composition of clause 301, wherein (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug are formulated to treat an injury that resulted from implantation of the article.

[0520] Clause 303. The composition of clause 301 or 302, wherein the (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0521] Clause 304. The composition of clause 301 to 303, further comprising (e) colchicine which in combination with (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug is formulated to release from the surface of the article in amounts sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0522] Clause 305. The composition of clause 301 to 304, wherein the factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0523] Clause 306. The composition of clause 305, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0524] Clause 307. The composition of clause 301 to 306, wherein factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), oreribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0525] Clause 308. The composition of clause 307, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0526] Clause 309. The composition of clause 30, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0527] Clause 310. The composition of clause 301 to 309, wherein the factor Ilb / IIIa inhibitor is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0528] Clause 311. The composition of clause 301 to 310, wherein the NSAID comprises a salicylate.

[0529] Clause 312. The composition of clause 301 to 311, further comprising at least a third antiplatelet drug different than the first and second antiplatelet drugs.

[0530] Clause 313. The composition of clause 311, wherein the third antiplatelet drug comprises one or more of a factor Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0531] Clause 314. The composition of clause 301 to 313, further comprising a chelating agent.

[0532] Clause 315. The composition of clause 314, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0533] Clause 316. The composition of clause 301 to 315, , further comprising at least one antiproliferative drug.

[0534] Clause 317. The composition of clause 316, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0535] Clause 318. The composition of clause 301 to 317, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0536] Clause 319. The composition of clause 301 to 317, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0537] Clause 320 to 350 intentionally left blank.

[0538] Clause 351. A composition for coating a surface of an implantable article, said composition comprising: (a) a factor Ila inhibitor; (b) a factor Xa inhibitor; (c) a first antiplatelet drug comprising a factor Ila / IIIb inhibitor; and (d) a second antiplatelet drug comprising an ADP receptor / P2Y12 inhibitors; wherein (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug and (d) the second antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0539] Clause 352. The composition of clause 351, wherein (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug are formulated to treat an injury that resulted from implantation of the article.

[0540] Clause 353. The composition of clause 351 or 352, wherein the (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0541] Clause 354. The composition of clause 351 to 353, further comprising (e) colchicine which in combination with (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug is formulated to release from the surface of the article in amounts sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0542] Clause 355. The composition of clause 351 to 354, further comprising (f) a third antiplatelet drug comprising aspirin and / or another NSAID which in combination with (a) the factor Ila inhibitor, (b) the factor Xa inhibitor, (c) the first antiplatelet drug, and (d) the second antiplatelet drug is formulated to release from the surface of the article in amounts sufficient to enhance inhibition of inflammation and / or thrombosis resulting from the injury.

[0543] Clause 356. The composition of clause 351 to 355, wherein the factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran,inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0544] Clause 357. The composition of clause 356, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0545] Clause 358. The composition of clause 351 to 357, wherein factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0546] Clause 359. The composition of clause 358, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0547] Clause 360. The composition of clause 359, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0548] Clause 361. The composition of clause 351 to 360, wherein the factor Ilb / IIIa inhibitor is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0549] Clause 362. The composition of clause 351 to 361, wherein the ADP receptor / P2Y12 inhibitors is selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor. [in SLIDER #1 only]

[0550] Clause 363. The composition of clause 351 to 362, further comprising at least a third antiplatelet drug different than the first and second antiplatelet drugs.

[0551] Clause 364. The composition of clause 363, wherein the third antiplatelet drug comprises one or more of a factor Ilb / IIIa inhibitor, a COX inhibitor, an ADP receptor / P2Y12 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0552] Clause 365. The composition of clause 364, wherein the third antiplatelet drug comprises aspirin or another NS AID.

[0553] Clause 366. The composition of clause 351 to 365, further comprising a chelating agent.

[0554] Clause 367. The composition of clause 366, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodiumedetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0555] Clause 368. The composition of clause 351 to 367, , further comprising at least one antiproliferative drug.

[0556] Clause 369. The composition of clause 368, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0557] Clause 370. The composition of clause 351 to 369, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0558] Clause 371. The composition of clause 351 to 370, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0559] Clause 372 to 400 intentionally left blank.

[0560] Clause 401. A composition for coating a surface of an implantable article, said composition comprising: a factor Xa inhibitor; and one or more of (a) colchicine, (b) a first antiplatelet drug comprising a factor Ila / IIIb inhibitor; (c) a second antiplatelet drug comprising an NSAID, and (d) a third antiplatelet drug comprising an ADP inhibitor; wherein the factor Xa inhibitor and the one or more of (a) the colchicine, (b) the first antiplatelet drug, (c) the second antiplatelet drug and (d) the third antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0561] Clause 402. The composition of clause 401, wherein the factor Xa inhibitor and (a) the colchicine, (b) the first antiplatelet drug comprising a factor Ila / IIIb inhibitor; (c) the second antiplatelet drug comprising an NSAID, and (d) the third antiplatelet drug comprising an ADP inhibitor are formulated to treat an injury that resulted from implantation of the article.

[0562] Clause 403. The composition of clause 401 or 402, wherein the factor Xa inhibitor and (a) the colchicine, (b) the first antiplatelet drug comprising a factor Ila / IIIb inhibitor; (c) the second antiplatelet drug comprising an NSAID, and (d) the third antiplatelet drug comprising an ADP inhibitor are formulated to treat the injury without causing any one or more of bleeding, arisk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0563] Clause 404. The composition of clause 401 to 403, further comprising a factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0564] Clause 405. The composition of clause 404, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0565] Clause 406. The composition of clause 401 to 405, wherein factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0566] Clause 407. The composition of clause 406, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0567] Clause 408. The composition of clause 407, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0568] Clause 409. The composition of clause 401 to 408, wherein the factor Ilb / IIIa inhibitor is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0569] Clause 410. The composition of clause 401 to 409, wherein the ADP receptor / P2Y12 inhibitors is selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor. [in SLIDER #1 only]

[0570] Clause 411. The composition of clause 401 to 410, further comprising at least a fourth antiplatelet drug different than the first and second antiplatelet drugs.

[0571] Clause 412. The composition of clause 363, wherein the fourth antiplatelet drug comprises one or more of a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0572] Clause 413. The composition of clause 401 to 412, further comprising a chelating agent.

[0573] Clause 414. The composition of clause 413, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0574] Clause 415. The composition of clause 401 to 414, , further comprising at least one antiproliferative drug.

[0575] Clause 416. The composition of clause 415, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0576] Clause 417. The composition of clause 401 to 416, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0577] Clause 418. The composition of clause 401 to 416, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0578] Clause 419 to 500 intentionally left blank.

[0579] Clause 501. A composition for coating a surface of an implantable article, said composition comprising: a factor Ila inhibitor; and one or more of (a) colchicine, (b) a first antiplatelet drug comprising a factor Ila / IIIb inhibitor; (c) a second antiplatelet drug comprising an NSAID, and (d) a third antiplatelet drug comprising an ADP inhibitor; wherein the factor Xa inhibitor and the one or more of (a) the colchicine, (b) the first antiplatelet drug, (c) the second antiplatelet drug and (d) the third antiplatelet drug are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0580] Clause 502. The composition of clause 501, wherein the factor Ila inhibitor and (a) the colchicine, (b) the first antiplatelet drug comprising a factor Ila / IIIb inhibitor; (c) the second antiplatelet drug comprising an NSAID, and (d) the third antiplatelet drug comprising an ADP inhibitor are formulated to treat an injury that resulted from implantation of the article.

[0581] Clause 503. The composition of clause 501 or 502, wherein the factor Ila inhibitor and (a) the colchicine, (b) the first antiplatelet drug comprising a factor Ila / IIIb inhibitor; (c) the second antiplatelet drug comprising an NSAID, and (d) the third antiplatelet drug comprising an ADP inhibitor are formulated to treat the injury without causing any one or more of bleeding, a risk of bleeding risk, and bleeding associated with an administration of a systemic antithrombotic drug.

[0582] Clause 504. The composition of clause 501 to 503, wherein the factor Ila inhibitor is selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0583] Clause 505. The composition of clause 504, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0584] Clause 506. The composition of clause 501 to 505, further comprising a factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 - phenylethyl)-lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0585] Clause 507. The composition of clause 506, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0586] Clause 508. The composition of clause 507, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0587] Clause 509. The composition of clause 501 to 508, wherein the factor Ilb / IIIa inhibitor is selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0588] Clause 510. The composition of clause 501 to 509, wherein the ADP receptor / P2Y12 inhibitors is selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor. [in SLIDER #1 only]

[0589] Clause 511. The composition of clause 501 to 510, further comprising at least a fourth antiplatelet drug different than the first and second antiplatelet drugs.

[0590] Clause 512. The composition of clause 511, wherein the fourth antiplatelet drug comprises one or more of a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0591] Clause 513. The composition of clause 501 to 512, further comprising a chelating agent.

[0592] Clause 514. The composition of clause 513, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0593] Clause 515. The composition of clause 501 to 514, further comprising at least one antiproliferative drug.

[0594] Clause 516. The composition of clause 515, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0595] Clause 517. The composition of clause 501 to 516, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0596] Clause 518. The composition of clause5101 to 516, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0597] Clause 519 to 600 intentionally left blank.

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

[0599] Clause 602. The composition of clause 601, comprising a factor Ila inhibitor selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0600] Clause 603. The composition of clause 602, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0601] Clause 604. The composition of clause 601 to 603, comprising a factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole- 6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0602] Clause 605. The composition of clause 604, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0603] Clause 606. The composition of clause 604 wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0604] Clause 607. The composition of clause 601 to 606, comprising a COX-1 inhibitor

[0605] Clause 608. The composition of clause 607, wherein the COX-1 inhibitor comprises a salicylate or other NSAID.

[0606] Clause 609. The composition of clause 601 to 607, comprising a factor Ilb / IIIa inhibitor selected from a group consisting of abciximab, eptifibatide, orbofiban, roxifiban, sibrafiban, and tirofiban.

[0607] Clause 610. The composition of clause 601 to 609, comprising an ADP receptor / P2Y12 inhibitors is selected from a group consisting of clopidogrel, ticlopidine, prasugrel, cangrelor, elinogrel, and ticagrelor. [in SLIDER #1 only]

[0608] Clause 611. The composition of clause 601 to 610, further comprising at least one of a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitors.

[0609] Clause 612. The composition of clause 601 to 610, further comprising a chelating agent.

[0610] Clause 613. The composition of clause 612, wherein the chelating agent is selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodiumedetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0611] Clause 614. The composition of clause 601 to 613, further comprising at least one antiproliferative drug.

[0612] Clause 615. The composition of clause 614, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0613] Clause 616. The composition of clause 601 to 615, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0614] Clause 617. The composition of clause 601 to 615, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0615] Clause 618 to 700 intentionally left blank.

[0616] Clause 701. A composition for coating a surface of an implantable article, said composition comprising: (a) at least one of a factor Ila inhibitor and a factor Xa inhibitor (b) at least one of (i) colchicine, (ii) a first antiplatelet drug, and (iii) a chelating agent; wherein the (a) at least one of a factor Ila inhibitor and a factor Xa inhibitor and (b) the at least one of (i) colchicine (ii) the first antiplatelet drug, and the chelating agent are formulated to release from the surface of the article in amounts sufficient to inhibit inflammation resulting from the implantation of the article when implanted in a patient.

[0617] Clause 702. The composition of clause 701, comprising a factor Ila inhibitor selected from a group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

[0618] Clause 703. The composition of clause 702, wherein the factor Ila inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0619] Clause 704. The composition of clause 701 to 703, comprising a factor Xa inhibitor selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl- [4-(l-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)- pentyl]-3 -oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052).

[0620] Clause 705. The composition of clause 704, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0621] Clause 706. The composition of clause 704 wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

[0622] Clause 707. The composition of clause 701 to 706, comprising colchicine.

[0623] Clause 708. The composition of clause 701 to 707, comprising one or more antiplatelet drugs selected from the group consisting of a factor Ila / IIIb inhibitor, an ADP receptor / P2Y12 inhibitor, a COX-1 inhibitor, a prostaglandin analogue, a thromboxane inhibitor, and a phosphodiesterase inhibitor.

[0624] Clause 709. The composition of clause 708, comprising a chelating agent selected from a group consisting of ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate, magnesium dipotassium edetate, magnesium di sodium edetate, di sodium edetate, tetrasodium edetate, trisodium edetate, monoammonium EDTA salt, diammonium EDTA salt, triammonium EDTA salt, benzyldimethyltetradecylammonium EDTA salt, tridodecylmethylammonium EDTA salt, other benzalkonium EDTA salt, tetra acetoxymethyl ester EDTA, ethyleneglycoltetraacetic acid (EGTA), 2,3 -dimercaptopropanesulfonic acid (DMPS), thiamine tetrahydrofurfuryl disulfide (TTFD), dimercaptosuccinic acid (DMSA), di ethylenetriaminepentaacetate (DTP A), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

[0625] Clause 710. The composition of clause 701 to 709, further comprising at least one antiproliferative drug.

[0626] Clause 711. The composition of clause 710, wherein the antiproliferative drug comprises an mTOR inhibitor.

[0627] Clause 712. The composition of clause 701 to 711, wherein individual components of the composition are configured to be coated on the surface simultaneously.

[0628] Clause 713. The composition of clause 701 to 711, wherein individual components of the composition are configured to be coated on the surface sequentially.

[0629] Clause 714 to 800 intentionally left blank.

[0630] Clause 801. An implantable article comprises a body having a surface configured for implantation in a patient, wherein the surface is at least partially coated with a composition according to any one of clauses 101 to 713.

[0631] Clause 802. The article of clause 801, wherein the article is an expandable scaffold configured for implantation in the patient’s vascular system.

[0632] Clause 803. The article of clause 801, wherein the article comprises a non-expandable body.

[0633] Clause 804. The article of clauses 801 to 803, wherein the composition is formulated to be released from the article over a period of at least of at least one week, one month, or one year.

[0634] Clause 805. The article of clauses 801 to 804, wherein at least some the components of the composition are formulated in one or more carriers which degrade when implanted in the patient.

[0635] Clause 806. The article of clauses 801 to 805, wherein the composition is formulated to release no greater than 90%, 75%, 50%. 25%, or 10% of its weight of within one week, one month, three months, six months, or one year of implantation.

[0636] The illustrative examples described are not meant to be limiting. Other examples may be utilized, and other changes may be made, or combined in whole or in part, without departing from the scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the figures, and detailed description, and in the examples, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0637] These and other embodiments are described in further detail in the following description related to the appended drawing figures.INCORPORATION BY REFERENCE

[0638] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0639] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosurewill be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0640] FIG. 1 A shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of Apixaban, in accordance with example 1.

[0641] FIG. IB shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of Argatroban, in accordance with example 1.

[0642] FIG. 1C shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of Apixaban and Argatroban, in accordance with example 1.

[0643] FIG. ID shows a plot of HAoSMC cell proliferation in the presence of difference concentrations of Apixaban, in accordance with example 1.

[0644] FIG. IE shows a plot of HAoSMC cell proliferation in the presence of difference concentrations of Argatroban, in accordance with example 1.

[0645] FIG. 2A shows a plot of activated clotting time (ACT) versus drug concentration, in accordance with examples.

[0646] FIG. 2B shows a plot of activated clotting time (ACT) versus drug concentration, in accordance with example 2.

[0647] FIG. 2C shows a plot of activated clotting time (ACT) versus drug concentration, showing the synergistic effects of Apixaban in combination with Argatroban, in accordance with example 2.

[0648] FIG. 2D shows a plot of various synergistic effects of drug combination ratios between Apixaban and Argatroban, in accordance with example 2.

[0649] FIG. 3 A shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between rivaroxaban and argatroban, in accordance with example 3.

[0650] FIG. 3B shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between edoxaban and argatroban, in accordance with example 4.

[0651] FIG. 3C shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between betrixaban and argatroban, in accordance with example 5.

[0652] FIG. 4A shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between colchicine, rivaroxaban and argatroban, in accordance with example 6.

[0653] FIG. 4B shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between tirofiban, rivaroxaban and argatroban, in accordance with example 7.

[0654] FIG. 4C shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between ticagrelor, rivaroxaban and Argatroban, in accordance with example 8.

[0655] FIG. 4D shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between tirofiban, colchicine, rivaroxaban and argatroban, in accordance with example 9.

[0656] FIG. 4E shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between rivaroxaban and Tirofiban or colchicine or ticagrelor, in accordance with example 10.

[0657] FIG. 4F shows a plot of net activated clotting time (net ACT) versus drug concentration, showing the synergy effect between argatroban and tirofiban or colchicine or ticagrelor, in accordance with example 11.

[0658] FIG. 5 shows a plot of in-vivo mean tissue concentration vs time of Rapamycin, Rivaroxaban and Argatroban in stented segments, in accordance with example 27.

[0659] FIG. 6 shows a plot of in-vitro average percent of drug released vs time of Colchicine, Tirofiban, Rapamycin, Rivaroxaban and Argatroban in coated stent, in accordance with example45.

[0660] FIG. 7 shows a plot of in-vitro average percent of drug released vs time of Colchicine, Tirofiban, Rapamycin, Rivaroxaban and Argatroban in coated stent, in accordance with example46.

[0661] FIG. 8 shows a plot of in-vitro average percent of drug released vs time of Colchicine, Tiro...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A composition for coupling to a surface of an implantable article, said composition comprising: an anti-coagulant comprising a direct factor Xa inhibitor and at least one of (a) an anti-platelet drug, (b) anti -coagulant comprising a direct factor Ila inhibitor, or (c) an antiinflammatory drug comprising colchicine.

2. The composition of claim 1, including at least two of (a) the anti -platelet drug, (b) the direct factor Ila inhibitor, or (c) the anti-inflammatory drug comprising colchicine.

3. The composition of claim 1, including all three of (a) an anti-platelet drug, (b) a direct factor Ila inhibitor, and (c) anti-inflammatory drug comprising colchicine.

4. The composition of any one of claims 1 to 3, wherein the direct factor Xa inhibitor comprises at least one drug selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l- yl)-2-oxo-l -phenylethyl)- lh-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4- dihydro-quinoxaline-6-carboxylic acid (PD0313052), and a salt, isomer, solvate, derivative, metabolite, or pro-drug of any preceding member of the group.

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

6. The composition of any one of claims 1 to 5, comprising at least one an antiplatelet drug selected from the group consisting of: a Cox 1 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a Cox 2 inhibitor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a glycoprotein lllb / 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.

7. The composition of claim 6, wherein the anti-platelet drug comprises tirofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

8. The composition of claim 6, wherein the anti-platelet drug comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

9. The composition of claim 6, wherein the anti-platelet drug comprises a Coxl / 2 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, wherein the Coxl / 2 inhibitor comprises acetylsalicylic acid.

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

11. The composition of any one of claims 1 to 10, including at least one direct factor Ila inhibitor is selected from the group consisting of argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.

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

13. A composition for coupling to a surface of an implantable article, said composition comprising: an anti-coagulant comprising a direct factor Ila inhibitor and at least one of (a) an anti-platelet drug, (b) an anti-coagulant comprising a direct factor Xa inhibitor, or (c) an antiinflammatory drug comprising colchicine.

14. The composition of claim 13, including at least two of (a) the anti-platelet drug, (b) the anti-coagulant comprising the direct factor Xa inhibitor, or (c) the anti-inflammatory drug comprising colchicine.

15. The composition of claim 13, including all three of (a) an anti-platelet drug, (b) the anti-coagulant comprising the direct factor Xa inhibitor, and (c) the anti-inflammatory drug comprising colchicine.

16. The composition of any one of claims 13 to 15, wherein the direct factor Ila inhibitor is selected from the group consisting of: argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, lepirudin, and a salt, isomer, solvate, derivative, metabolite, or pro-drug of any preceding member of the group.

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

18. The composition of any one of claims 13 to 17, comprising at least one an antiplatelet drug selected from the group consisting of:a Cox 1 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a Cox 2 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; a glycoprotein Ilb / 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.

19. The composition of claim 18, wherein the anti-platelet drug comprises tirofiban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

20. The composition of claim 18, wherein the anti-platelet drug comprises ticagrelor, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

21. The composition of claim 18, wherein the anti-platelet drug comprises a Coxl / 2 inhibitor or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; optionally, wherein the Coxl / 2 inhibitor comprises acetylsalicylic acid.

22. The composition of claim 18, wherein the antiplatelet drug comprises: clopidogrel or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof; or the active metabolite of clopidogrel or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

23. The composition of any one of claims 13 to 22, wherein the direct factor Xa inhibitor comprises at least one drug selected from the group consisting of: apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l- yl)-2-oxo-l -phenylethyl)- lh-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4- dihydro-quinoxaline-6-carboxylic acid (PD0313052), and a salt, isomer, solvate, derivative, metabolite, or pro-drug of any preceding member of the group.

24. The composition of claim 23, wherein the direct factor Xa inhibitor comprises: apixaban, or a salt or an analog thereof; and / or rivaroxaban, or a salt, isomer, solvate, derivative, metabolite, or prodrug thereof.

25. A composition for coupling to a surface of an implantable article, said composition comprising: a direct factor Xa inhibitor; andat least two of (a) a direct factor Ila inhibitor, (b) an anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibit, and a P2yl2 inhibitor; or (c) an anti-inflammatory drug.

26. The composition of claim 25, comprising all three of (a) the direct factor Ila inhibitor, (b) the anti-platelet drug selected from the group consisting of a Cox 1 inhibitor, a Cox 2 inhibitor, and a Ilb / IIIa inhibitor; and (c) the anti-inflammatory drug.

27. The composition of claim 25 or 26, wherein the direct factor Xa inhibitor comprises at least one drug selected from the group consisting of: apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4-yl)piperazin-l- yl)-2-oxo-l-phenylethyl)-lh-indole-6-carboxamide(LY-517717), daraxaban (YM-150), 2-[(7- carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-l-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid(PD0313052), and a salt, isomer, solvate, derivative, metabolite or prodrug of any preceding member of the group.

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

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

30. The composition of any one of claim 25 to 29, wherein the anti-platelet drug comprises at least one drug selected from the group consisting of tirofiban, ticagrelor, a Cox 1 inhibitor, a Cox 2 inhibitor, a Ilb / IIIa inhibitor, a P2Y12 inhibitor, and a salt, analog, or metabolite of any preceding member of the group.

31. The composition of any one of claim 25 to 30, wherein the anti-inflammatory drug comprises colchicine.

32. A composition for coating a surface of an implantable article, said composition comprising: apixaban or a salt, analog, or metabolite thereof; rivaroxaban or a salt, analog, or metabolite thereof; argatroban or a salt, analog, or metabolite thereof; tirofiban or a salt, analog, or metabolite thereof; and colchicine or a salt, analog, or metabolite thereof.

33. The composition of any one of the preceding claims, further comprising an additional an anti -platelet drug.

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

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

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

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

38. The surgical article of claim 36, wherein the single layer is non-homogeneous.

39. The surgical article of 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 of claim 39, further comprising an intermediate layer over and / or between said at least two layers.

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

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

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

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