ANTICOAGULANT COMPOUNDS COMPRISING CHELATING AGENTS AND CATIONIC ANTI-COAGULATION ENHANCERS AND METHODS AND DEVICES FOR THEIR USE

BACKGROUND
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.

Blood coagulation is a process designed to stop bleeding from a damaged blood vessel. This process requires coagulation factors, calcium and phospholipids. It is initiated by extrinsic tenase, which forms when factor VIIa 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 VIIIa 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 IIa). 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.

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.

After vascular injury von Willebrand factor acts as a bridge between endothelial collagen and platelet surface receptors GpIb 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.

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.

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 VIIa and calcium to promote the conversion of factor X to Xa.

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.

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.

Blood coagulation process requires coagulation factors, calcium and phospholipids. There are three strategies to prevent coagulation. (1) inhibits the clotting factors. (2) removal of free calcium in the blood. (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 activated platelets 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.

FXIa 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.

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.

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.

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.

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.

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.

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., anti-proliferative 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. 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.

Listing of Background Art

Relevant background art includes U.S. Pat. Nos. 9,770,349; 9,901,663; 6,500,855; 8,409,272; 8,946,219; US2003/0158120; US2005004663; US2005/0064006; US2009/0075949; US2010/0003542; US2010/0130543; US2010/0184729; US2010/049328; US2013/189329; US2015/157771; US2018/0000490; EP 1849434; CA2464290; WO2013/007840; WO2013/056060; WO2020/210613; and WO2020/210629.

The subject matter of this application is also related to that of the following commonly owned applications: 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 Aug. 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 Sep. 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 Sep. 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 Mar. 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 Oct. 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 Oct. 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 INVENTION

In a first aspect, the present invention 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.

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.

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.

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.

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 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA). 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt. EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

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

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%.

In some instances, the therapeutic compositions of the present invention 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 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 poly betaaminoester (PBAE). Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof.

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

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

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.

In specific examples, the anti-coagulant may be selected from the group consisting of a direct factor IIa inhibitor and a direct factor Xa inhibitor. Exemplary direct factor IIa 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 IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

Exemplary direct factor Xa inhibitors may be selected from the group consisting of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban. (r)-n-(2-(4-(1-methylpiperidin-4-yl) piperazin-1-v1)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribavaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-1-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.

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.

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

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.

The implantable scaffolds of present invention 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 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.

In a second aspect, the present invention 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.

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.

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 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA). 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, 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).

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,

- 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 of benzyldimethyltetradecylammonium chloride. In another specific instance, the cationic anti-coagulation enhancer consists essentially of linear polyethyleneimine (PEI).

The therapeutic composition delivered by the methods of the present invention 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 IIa inhibitor and a direct factor Xa inhibitor. Alternatively, the at least one anti-coagulant may comprise a direct factor IIa 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 IIa inhibitor may comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

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-(1-methylpiperidin-4-yl) piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-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.

The therapeutic composition delivered by the methods of the present invention 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.

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

The therapeutic composition delivered by the methods of the present invention may further comprise further comprises an antiplatelet drug.

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.

The methods of the present invention 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.

In a third aspect, the present invention 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 IIa inhibitor, an 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.

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.

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.

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.

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.

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, more preferably within 6 hours of implantation, and even more preferably within 4 hour of implantation.

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.

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 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA), deferoxamine (DFO), a surfactant-EDTA complex, 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).

In some instances, the therapeutic composition may further comprise 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 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 of benzyldimethyltetradecylammonium chloride. In another specific instance, the cationic anti-coagulation enhancer consists essentially of linear polyethyleneimine (PEI).

In some instances, the at least one drug may comprise a direct factor IIa 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 IIa inhibitor may comprise argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

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)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-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.

In some examples, the at least one drug may comprise a factor XI/XIa inhibitor selected from the group consisting of protein Z-dependent protease inhibitors (ZPI).

In specific examples, a ZPI-containing cationic anti-coagulation enhancer may comprise, consist essentially of, or consist of milvexian, a small molecule factor XIa inhibitor having the formula [(6r,10s)-10-{4-[5-chloro-2-(4-chloro-1h-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 (6h)-pyrimidinyl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(metheno) pyrazolo [4,3-b][1,7] diazacyclotetradecin-5 (6h)-one] and described in WO2020/210613 and WO2020/210629, the full disclosures of which are incorporated herein by reference.

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.

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.

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.

In another aspect, the present invention 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 IIa 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 IIa 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.

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.

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.

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 (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.

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 IIa 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 IIa inhibitor, and a direct factor Xa inhibitor.

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 μg/hour to 40 μg/hour, usually from 2 μg/hour to 30 μg/hour, preferably from 2 μg/hour to 10 μg/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.

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 μg/hour, usually 1 μg/hour, preferably 0.5 μg/hour, and more preferably 0.1 μg/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.

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.

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 composition may 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.

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).

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.

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.

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.

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. For example, 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.

Usually, but not necessarily, one or more polymer 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.

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.

In preferred instances, the implantable scaffold of the present invention 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 anti-proliferative drug may present in a third therapeutic composition formulated to release the anti-proliferative drug into a vascular environment when the scaffold is present in the vascular environment.

The first, second, and optionally third or additional therapeutic compositions of the present invention 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.

Exemplary calcium chelating agents of the present invention 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA). 1,2-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.

Exemplary of EDTA complex the present invention 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.

Exemplary direct factor IIa inhibitors of the present invention 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 IIa inhibitors comprise argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

Exemplary direct factor Xa inhibitors of the present invention include apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban. (r)-n-(2-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052), which may be used individually or in combination. Preferred direct factor Xa 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.

Exemplary anti-proliferative agents of the present invention 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.

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

In addition to the first, second, and optional third therapeutic compositions as discuss above, the implantable scaffolds of the present invention 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.

In specific examples of the present invention, the direct factor IIa inhibitor comprises argatroban and the direct factor Xa inhibitor comprises apixaban or rivaroxaban. In other specific examples of the present invention, the direct factor IIa 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.

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.

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 IIa 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.

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.

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.

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.

In yet another aspect, the present invention 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.

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(aspartamides), polyethylenes; polypropylenes; polyamides; polyethylene glycols (PEG); silicones; poly(anhydrides); and poly ortho esters.

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

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, poly(ethylene glycol), polyethylene oxide (PEO), polydimethylsiloxane, polyvinylpyrrolidone, ethylene-vinyl acetate, phosphorylcholine-containing polymers, poly(2-methacryloyloxyethylphosphorylcholine), poly(2-methacryloyloxyethylphosphorylcholine-co-butyl methacrylate), and copolymers thereof.

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.

In a particular example, (1) a calcium chelating agent may be present in the first therapeutic composition at a concentration in a range from 2 μg to 15 μg per mm of scaffold structure length, the argatroban may be present in the first therapeutic composition at a concentration in a range from 0.5 μg to 3 μg 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 0.5 μg to 3 μg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 0.5 μg to 3 μg 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 2 μg to 10 μg 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 2 μg to 10 μg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 2 μg to 10 μg per mm of scaffold structure length in the second therapeutic composition.

In a particular example, (1) the argatroban may be present in the first therapeutic composition at a concentration in a range from 0.5 μg to 3 μg 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 0.5 μg to 3 μg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 0.5 μg to 3 μg 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 2 μg to 15 μg per mm of scaffold structure length, the argatroban may be present at a concentration in a range from 2 μg to 10 μg 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 2 μg to 10 μg per mm of scaffold structure length, and the sirolimus may be present at a concentration in a range from 2 μg to 10 μg per mm of scaffold structure length in the second therapeutic composition.

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 at least 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.

In a still further aspect, the present invention 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 IIa 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 IIa 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.

In different instances of the methods of the present invention, 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.

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.

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 IIa inhibitor and a direct factor Xa inhibitor.

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 μg/hour to 10 μg/hour, usually from 1 μg/hour to 5 μg/hour, preferably from 2 μg/hour to 4 μg/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.

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 second therapeutic composition is typically configured to release the at least one drug of the second drug formulation for at a mean rate not exceeding 2 μg/hour, usually 1 μg/hour, preferably 0.5 μg/hour, and more preferably 0.1 μg/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.

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.

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.

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

In another aspect, the present invention 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 IIa 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.

Often, the drug formulation includes a calcium chelating agent, a direct factor IIa 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.

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.

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.

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.

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 μg/hour, usually 1 μg/hour, preferably 0.5 μg/hour, and more preferably 0.1 μg/hour following exposure to the vascular environment.

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.

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)-1h-indole-6-carboxamide (LY-517717), Daraxaban (YM-150)). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052) or others; and/or a direct IIa 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. REGI, 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 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA). 1,2-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 FX/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 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. Argatroban or its analogue, and one of Taxol or sirolimus or an analogue thereof analogues.

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. In some examples, the therapeutic composition is formulated to locally release the one or more active substances to the injury site at a rate sufficient to generate a tissue concentration of about 2 ng/mg tissue to about 50 ng/mg tissue of the one or more active substances at the injury site within about 3 hours after the external surface of the structure is positioned adjacent the injury site.

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 IIa 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. In some examples, the therapeutic composition is formulated to locally release the one or more active substances to the injury site at a rate sufficient to generate a tissue concentration of about 2 ng/mg tissue to about 200 ng/mg tissue of the one or more active substances at the injury site within about 3 hours after the external surface of the structure is positioned adjacent the injury site.

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.

While the drug carriers of the present invention 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.

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.

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

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.

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.

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.

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.

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.

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 in unbuffered water of less than 40 mg/mL are selected from the group consisting of asparagine, aspartic acid, cystine, eptifibatide, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, and 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(ornithine), 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 (EPA), docosahexanoic acid (DHA), palmitoleic acid and myristoleic acid.

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 two hydroxyl 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.

For example, the therapeutic composition is preferably formulated to locally release the one or more active substances to the injury site at a rate sufficient to generate a tissue concentration of about 20 ng/mg tissue to about 200 ng/mg tissue, or more preferably about 40) ng/mg tissue to about 200 ng/mg tissue, of the one or more active substances at the injury site within about 3 hours after the external surface of the structure is positioned adjacent the injury site. In another example of this aspect, the medical device structure has an internal (inner) surface, wherein one or more agents are coated on at least one region of the inner structure surface, preferably coated on the entire inner structure surfaces. In yet another example of this aspect, the medical device structure has more than two surfaces, and wherein the one or more agents are coated on all or some of these surfaces. In yet another example of this aspect, the coating thickness may be uniform between surfaces or vary between surfaces of the structure. In yet another example of this aspect, the device may have a partial or full covering or a sleeve on one or more surfaces of the device (such as PTFE. Dacron, or other type material) wherein said material comprises the one or more agents. In some examples, the therapeutic composition is formulated to release substantially all of the one or more active substances within about 1 to about 90 days. In some examples, the therapeutic composition is formulated to release substantially all of the one or more active substances about 90 to about 180 days or more. In some examples, the therapeutic composition is formulated to locally release the one or more active substances to the injury site at a rate sufficient to generate a tissue concentration of 0.1 ng/mg or more for a period ranging from 3 hours to 90 days, 3 hours to 180 days, or 3 hours to 270) days or more.

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.

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.

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 IIa 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.

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 at the injury site within a range of about 2 ng/mg to about 100 ng/mg within about 24 hours. 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 at the injury site within a range of about 3 ng/mg to about 50) ng/mg within about 24 hours. 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 at the injury within a range of about 4 ng/mg to about 25 ng/mg within about 24 hours.

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 at the injury site within a range of about 1 ng/mg to about 30 ng/mg within about 7 days. 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 at the injury site within a range of about 1.5 ng/mg to about 20 ng/mg within about 7 days. 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 at the injury site within a range of about 2 ng/mg to about 25 ng/mg within about 7 days.

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 at the injury site within a range of about 0.5 ng/mg to about 30 ng/mg within about 28 days. 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 at the injury site within a range of about 1 ng/mg to about 20 ng/mg within about 28 days. 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 at the injury site within a range of about 1.5 ng/mg to about 25 ng/mg within about 28 days.

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 at a location proximal or distal a proximal end of the structure or a distal end of the structure, respectively, within a range of about 0.5 ng/mg to about 500 ng/mg within about 3 hours. 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 at the location proximal or distal the proximal end of the structure or the distal end of the structure, respectively, within a range of about 1 ng/mg to about 35 ng/mg within about 3 hours. 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 at the location proximal or distal the proximal end of the structure or the distal end of the structure, respectively, within a range of about a range of about 1.5 ng/mg to about 30 ng/mg within about 3 hours. In some examples, the therapeutically effective dose is sufficient to generate a tissue concentration of the direct factor IIa inhibitor of about 0.001 ng/g tissue to about 100 mg/g tissue, preferably, the therapeutically effective dose is sufficient to generate a tissue concentration of the direct factor IIa inhibitor of about 0.01 ng/g tissue to about 100 mg/g tissue, more preferably, the therapeutically effective dose is sufficient to generate a tissue concentration of the direct factor IIa inhibitor of about 0.1 ng/g tissue to about 100 mg/g tissue. For example, the therapeutically effective dose may be sufficient to generate a tissue concentration of the direct factor IIa inhibitor of about 0.2 ng/g tissue to about 100 mg/g tissue, about 0.5 ng/g tissue to about 100 mg/g tissue, about 1 ng/g tissue to about 100 mg/g tissue, about 10 ng/g tissue to about 100 mg/g tissue, or about 100 ng/g tissue to about 100 mg/g tissue: in about 1 day. 30 days. 60 days, 90 days, or 120 days after introducing the therapeutically effective dose. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor IIa inhibitor which is less than about 200 ng/ml. 100 ng/ml. 50 ng/ml 25 ng/ml, or 10 ng/ml. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor IIa inhibitor which is less than a systemic therapeutic concentration of the direct factor IIa inhibitor for any systemic indication. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor IIa inhibitor which is smaller than a median maximum serum concentration (Cmax) of the direct factor IIa inhibitor generated by systemic delivery of the direct factor IIa 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 IIa inhibitor which does not exceed a median maximum serum concentration (Cmax) of the direct factor IIa inhibitor generated by systemic delivery of the direct factor IIa 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 IIa inhibitor of about 0.1 ng/g tissue to about 100 mg/g tissue for about 1 day to about 120 days, 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 therapeutic composition comprises at least three therapeutic active substances comprising a calcium chelating agent, a direct factor Xa inhibitor and a direct factor IIa inhibitor.

In some examples, the therapeutic composition comprising a 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 IIa 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 IIa 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 IIa inhibitor comprises argatroban. In some examples, the therapeutically effective dose of the direct factor IIa 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 tissue concentration of the direct factor IIa inhibitor of about 0.1 ng/g tissue to about 100 mg/g tissue. For example, the therapeutically effective dose may be sufficient to generate a tissue concentration of the direct factor IIa inhibitor of about 0.2 ng/g tissue to about 100 mg/g tissue, about 0.5 ng/g tissue to about 100 mg/g tissue, about 1 ng/g tissue to about 100 mg/g tissue, about 10 ng/g tissue to about 100 mg/g tissue, or about 100 ng/g tissue to about 100 mg/g tissue. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor IIa inhibitor which is less than about 200 ng/ml. 100 ng/ml. 50 ng/ml 25 ng/ml, or 10 ng/ml. In some examples, the therapeutically effective dose is sufficient to generate a blood concentration of the direct factor IIa inhibitor which is smaller than a median maximum serum concentration (Cmax) of the direct factor IIa inhibitor generated by systemic delivery of the direct factor IIa 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 IIa inhibitor which does not exceed a median maximum serum concentration (Cmax) of the direct factor IIa inhibitor generated by systemic delivery of the direct factor IIa 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 IIa inhibitor of about 0.1 ng/g tissue to about 100 mg/g tissue for about 1 day to about 1 year. 30 days to about 1 year. 3 months to about 1 year, or 6 months to about 1 year. In some examples, the weight compositional ratio of the direct factor Xa inhibitor to the direct factor IIa 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 IIa inhibitor in the therapeutic composition may be about 1:1.

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 0.0001 nM to 1000 nM, preferably at a dose ranging from 0.0001 nM to 100 nM, more preferably at a dose ranging from 0.0001 nM to 10 nM, and most preferably at a dose ranging from 0.0001 nM to 1 nM.

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 about 0.5 ng/mg to about 10 ng/mg of tissue adjacent to the device structure within about 28 days or about 90 days or about 180 days.

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, 1 day, or 72 hour.

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 anti-proliferative 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.

In some examples, the therapeutic composition is formulated to release the anti-proliferative agent at a rate of about 1 μg/second/mm device to about 50 μg/day/mm device, of about 1 μg/min/mm device to about 10 μg/day/mm device, or of about 1 μg/hour/mm device to about 7 μg/day/mm device within about 3 hours, about 1 day, or about 3 days.

In some examples, the therapeutic composition is formulated to release the anti-proliferative agent at a rate of about 1 μg/hour/mm device to about 4 μg/day/mm device.

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.

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.

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.

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.

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.

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 polymer carrier. 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.

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 anti-proliferative agent.

In some examples, the polymeric material is porous. In some examples, the polymeric material has a porosity within a range of about 10 nm to about 10 μm. 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(ε-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-&-caprolactone) (including 70:30 to 99:1 PLA-co-PCL, such as 90:10 PLA-co-PCL), poly(glycolide-co-8-caprolactone), poly(lactide-co-dioxanone), poly(glycolide-co-dioxanone), poly(lactide-co-trimethylene carbonate), poly(glycolide-co-trimethylene carbonate), poly(lactide-co-ethylene carbonate), and copolymers and combinations thereof, wherein lactide includes L-lactide. D-lactide and D,L-lactide. In some examples, the 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, poly(ethylene 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.

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

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 IIa 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. For example, the therapeutic composition is preferably formulated to locally release the two or more active substances to the injury site at a rate sufficient to generate a tissue concentration of about 20 ng/mg tissue to about 200 ng/mg tissue, or more preferably about 40 ng/mg tissue to about 200 ng/mg tissue, of the one or more active substances at the injury site within about 3 hours after the external surface of the structure is positioned adjacent the injury site. In some examples, the therapeutic composition is formulated to locally release the two or more active substances to the injury site at a rate sufficient to generate a tissue concentration of about 2 ng/mg tissue to about 200 ng/mg tissue of the one or more active substances at the injury site within about 3 hours after the external surface of the structure is positioned adjacent the injury site. For example, the therapeutic composition is preferably formulated to locally release the one or more active substances to the injury site at a rate sufficient to generate a tissue concentration of about 20 ng/mg tissue to about 200 ng/mg tissue, or more preferably about 40 ng/mg tissue to about 200 ng/mg tissue, of the one or more active substances at the injury site within about 3 hours after the external surface of the structure is positioned adjacent the injury site.

In some examples, the therapeutic composition further comprises an anti-proliferative agent. In some examples, the direct factor IIa 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 IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof. In some examples, the direct factor IIa inhibitor comprises dabigatran, or a salt, isomer, solvate, analog (including deuterated analog), derivative, metabolite, or prodrugs thereof.

In some examples, the direct factor Xa inhibitor comprises apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban. (r)-n-(2-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-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.

In some examples, the direct factor IIa inhibitor comprises Argatroban and the direct factor Xa inhibitor comprises apixaban. In some examples, the direct factor IIa inhibitor comprises Argatroban, the direct factor Xa inhibitor comprises apixaban, and the anti-proliferative 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.

In some examples, the therapeutic composition of a calcium chelating agent, a direct factor IIa inhibitor and a direct factor Xa inhibitor is formulated to reduce cell proliferation compared to either the direct factor IIa inhibitor or the direct factor Xa inhibitor alone. In some examples, the therapeutic composition is formulated to reduce, inhibit, and/or maintain 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 IIa 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

In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor IIa 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 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.

In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor IIa 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.

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

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

In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate of 1 μg/second/mm device to about 50 μg/day/mm device, preferably at a rate of 1 μg/min/mm device to about 30 μg/day/mm device, more preferably at a rate of 1 μg/hour/mm device to about 30 μg/day/mm device. In some 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 3 hours 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.

In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 2 ng/mg to about 100 ng/mg within about 24 hours. In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 3 ng/mg to about 50 ng/mg within about 24 hours. In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury within a range of about 4 ng/mg to about 25 ng/mg within about 24 hours.

In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 1 ng/mg to about 30 ng/mg within about 7 days. In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 1.5 ng/mg to about 20 ng/mg within about 7 days. In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 2 ng/mg to about 25 ng/mg within about 7 days.

In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 0.5 ng/mg to about 30 ng/mg within about 28 days. In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 1 ng/mg to about 20 ng/mg within about 28 days. In some examples, the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration at the injury site within a range of about 1.5 ng/mg to about 25 ng/mg within about 28 days.

In some examples, the release rate ratio of the direct factor IIa 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 IIa inhibitor at a rate of about 4 μg/hour/mm device to about 14 μg/day/mm device. In some examples, the therapeutic composition is formulated to release the direct factor Xa inhibitor at a rate of about 4 μg/hour/mm device to about 14 μg/day/mm device. In some examples, the therapeutic composition is formulated to release the anti-proliferative agent at a rate of about 1 μg/hour/mm device to about 4 μg/day/mm device.

In some examples, the weight compositional ratio of the direct factor IIa 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 IIa 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 IIa 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 IIa 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.

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.

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.

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 IIa 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 IIa 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 IIa inhibitor. In some examples, the first layer comprises the direct factor IIa 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.

In some examples, the coating further comprises a third layer. In some examples, the first layer comprises the direct factor IIa 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.

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 IIa inhibitor and the direct factor Xa inhibitor.

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 IIa inhibitor and 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 IIa inhibitor and the direct factor Xa inhibitor are uniformly distributed in the polymeric material. In some examples, the direct factor IIa inhibitor and the direct factor Xa inhibitor are non-uniformly distributed in the polymeric material.

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 IIa inhibitor, the direct factor Xa inhibitor, and the anti-proliferative 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 IIa 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 IIa inhibitor, the direct factor Xa inhibitor, and the anti-proliferative agent are uniformly distributed in the polymeric material. In some examples, the direct factor IIa inhibitor, the direct factor Xa inhibitor, and the anti-proliferative agent are non-uniformly distributed in the polymeric material.

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 IIa inhibitor to direct factor Xa inhibitor to anti-proliferative agent.

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 IIa inhibitor, a direct factor Xa inhibitor, and an anti-proliferative agent.

In other examples, the therapeutic composition comprising a calcium chelating agent, a direct factor IIa 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.

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, a direct IIa 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 IIa 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 IIa 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 IIa 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.

In some examples, include of a calcium chelating agent, the direct factor IIa inhibitor comprises argatroban, the direct factor Xa inhibitor comprises apixaban, and the anti-proliferative agent comprises sirolimus.

In some examples, include of a calcium chelating agent, the direct factor IIa inhibitor comprises argatroban, the direct factor Xa inhibitor comprises Rivaroxaban, and the anti-proliferative agent comprises sirolimus.

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 IIa inhibitor and the direct factor Xa inhibitor are released faster than the anti-proliferative agent. In some examples, the direct factor IIa inhibitor and the direct factor Xa inhibitor enhance an anti-proliferative 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.

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 therapeutic composition is formulated to release a calcium chelating agent, the direct factor IIa inhibitor, the direct factor Xa inhibitor, or the anti-proliferative agent before the injury occurs.

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 may be the same or different.

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 IIa inhibitor and a direct factor Xa inhibitor. In another example the active substances are a calcium chelating agent, a direct factor IIa 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.

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.

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

In still other instances, the therapeutic compositions of the present invention may be formulated to commence release of a calcium chelating agent and the direct factor IIa 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 IIa inhibitor has commenced.

In still other instances, the therapeutic compositions of the present invention may be formulated to commence release of a calcium chelating agent before commencing release of the direct factor IIa 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 IIa inhibitor and the direct factor IIa inhibitor has commenced.

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

Exemplary direct factor IIa inhibitors suitable for incorporation into the therapeutic compositions of the present invention 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.

Exemplary direct factor Xa inhibitors suitable for incorporation into the therapeutic compositions of the present invention include at least one of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-1 (7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD (348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-1-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.

Exemplary anti-proliferative agents suitable for incorporation into the therapeutic compositions of the present invention 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.

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

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

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.

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.

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

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.

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

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.

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.

In another aspect, the present invention 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 IIa inhibitor, a direct factor Xa inhibitor, and optionally an anti-proliferative agent.

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.

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

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 (IEL) 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.

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 (IEL) 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.

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

Alternatively or additionally, the direct factor IIa inhibitor and the direct factor Xa inhibitor are released substantially simultaneously and the anti-proliferative is released after the release of the direct factor IIa 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 IIa inhibitor and the direct factor Xa inhibitor has commenced.

Alternatively or additionally, the therapeutic composition may commences release of the direct factor IIa 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 IIa inhibitor has commenced.

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

In some instances, the direct factor IIa 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 IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some instances, the direct factor Xa inhibitor comprises at least one of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban. (r)-n-(2-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-2-oxo-1-phenylethyl)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD (348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-dimethyl-piperidin-1-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.

In some instances, the anti-proliferative agent comprises an m-Tor inhibitormay 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.

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

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

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

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.

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.

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.

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.

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 IIa 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.

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.

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 IIa 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.

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

INCORPORATION BY REFERENCE

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

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 disclosure will 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:

FIG. 1A shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of Apixaban, in accordance with examples:

FIG. 1B shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of Argatroban, in accordance with examples:

FIG. 1C shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of Apixaban and Argatroban, in accordance with examples:

FIG. 1D shows a plot of HAoSMC cell proliferation in the presence of difference concentrations of Apixaban, in accordance with examples:

FIG. 1E shows a plot of HAoSMC cell proliferation in the presence of difference concentrations of Argatroban, in accordance with examples:

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

FIG. 2B shows a plot of activated clotting time (ACT) versus drug concentration, in accordance with examples:

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 examples; and

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

DETAILED DESCRIPTION OF THE DISCLOSURE

In the following detailed description, reference is made to the accompanying figures, which form a part hereof. In the figures, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative examples described in the detailed description, figures, and claims 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, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

Although certain examples and examples are disclosed below, inventive subject matter extends beyond the specifically disclosed examples to other alternative examples and/or uses, and to modifications and equivalents thereof. Thus, the scope of the claims appended hereto is not limited by any of the particular examples described below. For example, in any method or process disclosed herein, the acts or operations of the method or process may be performed in any suitable sequence and are not necessarily limited to any particular disclosed sequence. Various operations may be described as multiple discrete operations in turn, in a manner that may be helpful in understanding certain examples, however, the order of description should not be construed to imply that these operations are order dependent. Additionally, the structures, systems, and/or devices described herein may be embodied as integrated components or as separate components.

For purposes of comparing various examples, certain aspects and advantages of these examples are described. Not necessarily all such aspects or advantages are achieved by any particular example or embodiment. Thus, for example, various examples may be carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other aspects or advantages as may also be taught or suggested herein.

Every example of the present invention may optionally be combined with any one or more of the other examples described herein. Every patent literature, and every non-patent literature, cited herein is incorporated herein by reference in its entirety.

The present invention disclosure is described in relation to drug-coated stents, drug-coated balloons, balloon reservoirs, heart implants, hip implants, knee implants, shoulder implants, and the like. However, one of skill in the art will appreciate that this is not intended to be limiting and the devices and methods disclosed herein may be used in other anatomical areas and in other surgical procedures or in other devices whether used as temporary devices or permanent devices.

As used herein, the term coagulation comprises one or more of thrombin formation, fibrin formation, platelet activation, platelet aggregation, and/or thrombus/clot formation. Coagulation typically arises in response to a body part injury and/or to a foreign body such as a device. This may lead to one or more of inflammation, injury, blockage of a lumen or vessel partially or fully, degradation of the device function, formation of clot, and/or adverse clinical events. In some examples, any of the devices described herein may, at least partially, cause an injury to the tissue which may initiate the coagulation cascade.

As used herein, the term anti-coagulant refers to an agent that inhibits one or more of thrombin formation, fibrin formation, platelet activation (typically indirectly), platelet aggregation (typically indirectly), thrombus (clot) formation, thrombin dissolution, fibrin dissolution, or thrombus dissolution, thereby inhibiting one or more of blockage of a lumen or vessel partially or fully, degradation of the device function, formation of clot, and/or adverse clinical events.

Inhibiting one or more of thrombin formation, fibrin formation, platelet activation, and/or platelet aggregation enables the inhibition of one or more of blockage of a lumen or vessel partially or fully, degradation of the device function, formation of thrombus (clot) formation, inflammation, and/or adverse clinical events.

Described herein are devices and methods for locally delivering a therapeutic composition to a patient. The therapeutic composition includes one or more agents which inhibit one or more of thrombin, fibrin, and/or thrombus formation or promote one or more of thrombin, fibrin, and/or thrombus dissolution. In preferred examples, the therapeutic composition includes one or more of a calcium chelating agent, a direct Xa inhibitor and a direct IIa inhibitor. In another preferred example, an anti-proliferative agent may be added to the therapeutic composition of the direct Xa inhibitor and/or the direct IIa inhibitor.

In some examples, the device or the implant comprising: a body structure having a surface configured to be implanted in a patient's body; and a therapeutic composition present on a surface of the body structure, therapeutic composition comprising at least one drug selected from the group consisting of a chelating agent, a direct factor IIa inhibitor, an 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 environment.

In some examples, the implantable scaffold with the therapeutic composition is formulated for a rapid release into the environment surrounding the body structure a preselected time period after implantation of the body structure into environment.

In some examples, the implantable scaffold with the body structure comprises an expandable scaffold, an orthopedic implant or 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. Orthopedic implants include artificial joints, spinal implants, medullary screws, and the like.

In some examples, the implantable scaffold with the therapeutic composition is present at least partly on the surface of the body structure.

In some examples, the implantable scaffold with the therapeutic composition is present at least partly within a cavity or reservoir within the body structure.

In some examples, the implantable scaffold with the therapeutic composition is formulated to inhibit release of the at least one drug into the environment surrounding the body structure for a time period in a range from 5 minutes to 240 minutes, preferably from 5 minutes to 180 minutes, and more preferably from 5 minutes to 60) minutes.

In some examples, the implantable scaffold with the therapeutic composition is 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, more preferably within 6 hours of implantation, and even more preferably within 4 hour of implantation.

In some examples, the implantable scaffold with the therapeutic composition is 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.

In some examples, the implantable scaffold with the drug comprises 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 environment.

In some examples, the implantable scaffold with the chelating agent is 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA), the surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

In some examples, the implantable scaffold with the cationic anti-coagulation enhancer is 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 poly betaaminoester (PBAE), Histone, ethylenediamine, methylenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof.

In some examples, the implantable scaffold with the chelating agent consists essentially of ethylenediaminetetraacetic acid (EDTA).

In some examples, the implantable scaffold with the cationic anti-coagulation enhancer consists essentially of benzyldimethyltetradecylammonium chloride.

In some examples, the implantable scaffold with the cationic anti-coagulation enhancer consists essentially of linear polyethyleneimine (PEI).

In some examples, the implantable scaffold with the at least one drug comprises a direct factor IIa inhibitor 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 examples, the implantable scaffold with the at least one direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with the at least one drug comprises 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)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-yl)-penty: 1]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

In some examples, the implantable scaffold of claim 64, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold of claim 64, wherein the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with therapeutic composition further comprises 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.

In some examples, the implantable scaffold of claim 14, wherein the mTOR inhibitor comprises sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with therapeutic composition further comprises paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

In some examples, the implantable scaffold with the therapeutic composition further comprises an antiplatelet drug.

In some examples, the implantable scaffold with the therapeutic composition further comprises an antiproliferative agent selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, azathioprine.

In some examples, the implantable scaffold with the implantable scaffold has at least an outer surface, an inner surface, and one or more edge surfaces between the outer and inner surfaces.

In some examples, the implantable scaffold with at least a portion of the outer surface is coated with the therapeutic compositions.

In some examples, the implantable scaffold with at least a portion of the inner surface is coated with the therapeutic compositions.

In some examples, the implantable scaffold with a portion of the edge surfaces is coated with the therapeutic compositions.

In some examples, the implantable scaffold at least some of the surfaces have receptacles formed therein and at least some of receptacles have therapeutic agent therein.

In some examples, the implantable scaffold with the receptacles comprise one or more of wells, channels, holes, and surface texture.

In some examples, a therapeutic composition present on a surface of the scaffold. The therapeutic composition comprising at least one chelating agent. In some examples, the implantable scaffold the therapeutic composition is present at least partly on the surface of scaffold structure. In some examples, the implantable scaffold the therapeutic composition is present at least partly within a cavity or reservoir within the scaffold structure.

In some examples, the implantable scaffold with the chelating agent in the therapeutic composition is formulated to deplete calcium in the environment surrounding the scaffold upon implantation of the scaffold structure in environment.

In some examples, the implantable scaffold with the therapeutic composition is 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 hours of implantation.

In some examples, the implantable scaffold with the therapeutic composition is 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.

In some examples, the implantable scaffold with the therapeutic composition consists essentially of chelating agent.

In some examples, the implantable scaffold with the chelating agent is 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA). 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA), the surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt. EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

In some examples, the implantable scaffold with the cationic anti-coagulation enhancers is 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 some examples, the implantable scaffold with the chelating agent consists essentially of ethylenediaminetetraacetic acid (EDTA).

In some examples, the implantable scaffold with the cationic anti-coagulation enhancer consists essentially of benzyldimethyltetradecylammonium chloride.

In some examples, the implantable scaffold with the cationic anti-coagulation enhancer consists essentially of linear polyethyleneimine (PEI).

In some examples, the implantable scaffold with the chelating agent is present in the therapeutic composition at a weight percent from 10% to 100%.

In some examples, the implantable scaffold with therapeutic composition comprises additional active and/or inactive substances.

In some examples, the implantable scaffold with the additional active and/or inactive substances are present in the therapeutic composition at a weight percent from 20% to 90%.

In some examples, the implantable scaffold with the therapeutic composition further comprises at least one anti-coagulant.

In some examples, the implantable scaffold with the therapeutic composition is formulated to release at least one anti-coagulant at a rate equal to that of the chelating agent

In some examples, the implantable scaffold with the therapeutic composition is formulated to release at least one anti-coagulant at a rate slower than that of the chelating agent.

In some examples, the implantable scaffold with the therapeutic composition is formulated to release at least one anti-coagulant at a rate faster than that of the chelating agent.

In some examples, the implantable scaffold with the at least one anti-coagulant is selected from the group consisting of a direct factor IIa inhibitor and a direct factor Xa inhibitor.

In some examples, the implantable scaffold with the at least one anti-coagulant comprises a direct factor IIa inhibitor 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 examples, the implantable scaffold with the at least one direct factor IIa inhibitor comprises argatroban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with any one of the at least one anti-coagulant comprises adirect 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)-1h-indole-6-carboxamide (LY-517717), daraxaban (YM-150). 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-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-1-yl)-penty: 1]-3-oxo-3, 4-dihydro-quinoxaline-6-carboxylic acid (PD0313052).

In some examples, the implantable scaffold with the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with the direct factor Xa inhibitor comprises rivaroxaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with the therapeutic composition further comprises 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.

In some examples, the implantable scaffold with the mTOR inhibitor comprises sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.

In some examples, the implantable scaffold with therapeutic composition further comprises paclitaxel, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.

In some examples, the implantable scaffold with therapeutic composition further comprises an antiplatelet drug.

In some examples, the implantable scaffold with therapeutic composition further comprises an antiproliferative agent selected from the group consisting of mycophenolate mofetil, mycophenolate sodium, azathioprine.

In some examples, the implantable scaffold with at least a portion of the outer surface is coated with the therapeutic compositions.

In some examples, the implantable scaffold with at least a portion of the inner surface is coated with the therapeutic compositions.

In some examples, the implantable scaffold with a portion of the edge surfaces is coated with the therapeutic compositions.

In some examples, the implantable scaffold with at least some of the surfaces have receptacles formed therein and at least some of receptacles have therapeutic agent therein.

In some examples, the implantable scaffold with the receptacles comprises one or more of wells, channels, holes, and surface texture.

In some examples, 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 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.

In some examples, the method with 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.

In some examples, the implantable scaffold with the therapeutic composition consists essentially of chelating agent.

In some examples, the implantable scaffold with the chelating agent is 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, tridodecy lmethylammonium 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 (DTPA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diaminocyclohexanetetraacetic acid (CDTA), 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA), the surfactant-EDTA complex, quaternary ammonium EDTA salt, benzalkonium EDTA salt, EDTA complex, salts, analogue, solvate, hydrate and derivatives thereof.

In some examples, the implantable scaffold with the cationic anti-coagulation enhancer is 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 poly betaaminoester (PBAE), Histone, ethylenediamine, methy lenediamine, ammonium chloride, melamine, histamine, histidine, analogue, solvate, hydrate and derivatives thereof.