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WO2021242783A1 - Composés anticoagulants et méthodes et dispositifs pour leur utilisation - Google Patents

Composés anticoagulants et méthodes et dispositifs pour leur utilisation Download PDF

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Publication number
WO2021242783A1
WO2021242783A1 PCT/US2021/034108 US2021034108W WO2021242783A1 WO 2021242783 A1 WO2021242783 A1 WO 2021242783A1 US 2021034108 W US2021034108 W US 2021034108W WO 2021242783 A1 WO2021242783 A1 WO 2021242783A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic composition
inhibitor
drug
clause
release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2021/034108
Other languages
English (en)
Inventor
John Yan
Xiaoxia Zheng
Vinayak D. Bhat
Motasim Sirhan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Elixir Medical Corp
Original Assignee
Elixir Medical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Elixir Medical Corp filed Critical Elixir Medical Corp
Priority to KR1020227045078A priority Critical patent/KR20230017251A/ko
Priority to JP2022571792A priority patent/JP2023527328A/ja
Priority to CN202180058952.7A priority patent/CN116157164A/zh
Priority to EP21812802.3A priority patent/EP4157383A4/fr
Priority to US17/402,357 priority patent/US11654036B2/en
Publication of WO2021242783A1 publication Critical patent/WO2021242783A1/fr
Anticipated expiration legal-status Critical
Priority to US18/106,452 priority patent/US20230190499A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
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    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate

Definitions

  • 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.
  • At least one of the first drug formulation and the second drug formulation may comprise either or both a direct factor Ila inhibitor and a direct factor Xa inhibitor.
  • the first (rapid release) drug formulation may release drug from the first therapeutic composition over a first time period is in a range from 3 hours to 28 days after implantation, usually from 3 hours to 7 days after implantation, preferably from 3 hours to 3 days after implantation, where the at least one drug of the first drug formulation is typically at a mean rate in the range from 1 pg/hour to lOpg/hour, usually from 1 pg/hour to 5pg/hour, preferably from 2 pg/hour to 4 pg/hour over a 24 hour period following exposure to the vascular environment, where the mean rate may be determined based on the amount (weight) of drug released over the total duration of the release.
  • the methods may further comprise releasing an anti-proliferative agent from at least one of the first therapeutic composition and the second therapeutic composition on the scaffold to the location of injury.
  • anti-proliferative agents include (1) 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, preferably comprising sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof and (2) paclitaxel, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.
  • the extended release of the drug formulation acts to accelerate dissolution of one or more of inflammation, cell proliferation, internal elastic lamina (TEL) injury, thrombin, fibrin formation, platelet aggregation, platelet activation, and clot or thrombus formation; and/or inhibit one or more of inflammation, cell proliferation, internal elastic lamina (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.
  • TEL internal elastic lamina
  • IEL internal elastic lamina
  • 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.
  • 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.
  • 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.
  • the coating thickness may be uniform between surfaces or vary between surfaces of the structure.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the therapeutic composition is formulated to release a dose of the direct factor Xa inhibitor sufficient to generate a plasma drug level area under the curve (AUC (0-24) or AUC (0- ⁇ )) in ng.h/ml which is less than a median (AUC (0-24) or AUC (0- ⁇ )) in ng.h/ml of the direct factor Xa inhibitor generated by systemic delivery of the direct factor Xa inhibitor when taking one or more oral dose of said factor Xa inhibitor.
  • the systemic delivery comprises a single oral dose, a daily oral dose, or a smallest oral dose of the direct factor Xa inhibitor.
  • the structure causes an injury at the injury site and the therapeutic composition is formulated to release the one or more active substances before the injury occurs.
  • the structure forms at least a portion of an implantable device. In some examples, the structure forms at least a portion of a surgical tool.
  • 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.
  • 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), poly(styrene-b-isobutylene-b-styrene), phosphorylcholine polymer, poly(ethylene-co-vinyl acetate), poly(n-butyl methacrylate), blend of thermoplastic Silicone-Polycarbonate-urethane with poly n-butyl methacrylate, poly(vinylidene-co-hexafluoropropylene), Blend of polyvinylpyrrolidone, poly(hexylmethacrylate)-co- polyvinylpyrrolidone -co-poly vinyl acetate, and poly(n-butyl methacrylate) -co- poly(viny
  • the structure forms at least a portion 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.
  • 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
  • the coating comprises the three drugs and a carrier.
  • the stent is formed from a tube, bend wire, rolled flat sheet, or printed.
  • the stent is substantially tubular, tapered, or is configured to have various shapes and configurations along the length of the stent.
  • the therapeutic composition is positioned on or in the device to release the two or more active substances to the injury site to increase activated clotting time and/or extend the time it takes for blood to clot.
  • the composition further comprises an anti-platelet agent.
  • the composition comprises two or more compositions to control one or more of release rate, one or more drug release, release duration of the one or more drugs, or other.
  • At least a rapid release portion of the therapeutic composition is formulated to locally release the two or 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, typically within about 3 hours to about 7 days or to about 28 days after the surface of the structure is positioned adjacent the injury site.
  • IEL internal elastic lamina
  • At least an extended release portion of the therapeutic composition is formulated to locally release the two, three or more active substances to the injury site at a rate or a concentration sufficient 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; and/or to extend time before clot formation, 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.
  • IEL internal elastic lamina
  • 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 Ila inhibitor.
  • release of the of the direct factor Ila 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.
  • the therapeutic composition may include a base layer formed over a surface of the structure and an top layer formed over the base layer.
  • the base layer and top layer may differ in at least some properties.
  • the base layer and top layer differ in at least one of drug dose, drug release rate, and drug release duration.
  • the scaffold has an outer surface, an inner surface, and one or more edge surfaces therebetween.
  • the therapeutic composition is disposed on at least a portion of the outer surface, wherein the therapeutic composition comprises three or more active substances including an anti-proliferative agent, a direct factor Ila inhibitor, and a direct factor
  • the direct factor Xa inhibitor comprises at least one of apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l-methylpiperidin-4- yljpiperazin- 1 -yl)-2-oxo- 1 -phenylethyl)- 1 h-indole-6-carboxamide(L Y -517717), daraxaban (YM- 150), 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l-ethanimidoylpiperidin-4- yl)oxyphenyl]sulfamoyl]acetic acid (YM-466 or YM-60828), or eribaxaban (PD 0348292), carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-
  • 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.
  • 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.
  • 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.
  • each of the base and top layers comprises the at least three active substances are mixed in a biodegradable polymeric matrix.
  • fast release composition and/or a fast release rate and an extended release rate composition of factor Xa inhibitor resulted in prolonged anti-coagulant effects (e.g., one or more of inhibition of fibrin, inhibition of thrombin formation, enhanced fibrin dissolution, enhancing thrombin inhibition, inhibition of clot formation, and/or extending time before clotting) compared to control and/or a slower release composition profile.
  • the combination of a direct factor Xa inhibitor and a direct Ila inhibitor composition was also surprisingly found to improve one or more of inhibition of fibrin, inhibition of clot formation, and extend time before clotting, compared to either agent alone.
  • Rivaroxaban two formulations of Rivaroxaban were tested in a local delivery in- vivo animal model, wherein one formulation comprised a faster release dose release within 7 days versus control within 7 days. It was unexpected result that the composition comprising faster release dose released within 7 days was more effective than control, within 7 days. The composition comprising faster dose formulation inhibited fibrin more effectively through 28 days compared to the 7 days slower release dose.
  • Clause 18 The device of clause 17, wherein 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.
  • Clause 27 The device of clause 26, wherein 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.
  • Clause 31 The device of clause 29, wherein 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 0.3 ng/mg to about 10 ng/mg within about 24 hours.
  • Clause 33 The device of clause 32, wherein the dose of the direct factor Xa inhibitor is about 1.25 to about 5 times larger than a dose of the anti-proliferative agent.
  • Clause 35 The device of clause 34, wherein the systemic delivery comprises a single oral dose, a daily oral dose, or a smallest oral dose of the direct factor Xa inhibitor.
  • therapeutic composition comprises a coating disposed on the external surface of the structure, and wherein the coating consists of a single layer of a polymeric material which releasably contains the direct factor Xa inhibitor and the anti-proliferative agent.
  • Clause 81 The device of clause 76 or 77, wherein 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.
  • Clause 90 The device of clause 1 or 2, wherein the structure causes an injury at the injury site and wherein the therapeutic composition is formulated to release the one or more active substances before the injury occurs.
  • Clause 98 The device of clause 93, wherein the device is a stent.
  • Clause 111 The device of clause 105, wherein the anti-proliferative agent comprises sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.
  • the anti-proliferative agent comprises sirolimus, biolimus, everolimus, myolimus, novolimus, ridaforolimus, temsirolimus, zotarolimus, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.
  • Clause 114 The device of clause 105, wherein the direct factor Ila inhibitor comprises argatroban, the direct factor Xa inhibitor comprises apixaban, and the anti-proliferative agent comprises sirolimus.
  • Clause 115 The device of clause 104 or 105, wherein the therapeutic composition is formulated to reduce cell proliferation compared to either the direct factor Ila inhibitor or the direct factor Xa inhibitor alone.
  • Clause 116 The device of clause 104 or 105, wherein the therapeutic composition is formulated to maintain reduced cell proliferation at the injury site for about 28 days after the external surface of the structure is positioned adjacent the injury site.
  • Clause 131 The device of clause 125, wherein the systemic delivery comprises a single oral dose, a daily oral dose, or a smallest oral dose of the direct factor Ila inhibitor.
  • Clause 145 The device of clause 104 or 105, therapeutic composition is formulated to release the two or more active substances at a dose within a range of about 1 pg/mm 2 device to about 12 pg/mm 2 device within about 12 hours.
  • Clause 148 The device of clause 104 or 105, wherein the therapeutic composition is formulated to release the two or more active substances at a rate sufficient to generate a tissue concentration of about lng/mg at about 14 mm from the external surface of the structure within about 28 days.
  • Clause 154 The device of clause 105, wherein the therapeutic composition is formulated to release the direct factor Xa inhibitor and the direct factor Ila inhibitor faster than the anti proliferative agent.
  • Clause 175. The device of clause 174, wherein the first layer comprises apixaban and argatroban and the second layer comprises sirolimus.
  • Clause 179 The device of clause 177, further comprising a top layer or coat of the same or different material as the first layer, the second layer, or the third.
  • Clause 200 The device of any one of clauses 183-193, wherein 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), poly(styrene-b-isobutylene-b-styrene), phosphorylcholine polymer, poly(ethylene-co-vinyl acetate), poly(n-butyl methacrylate), blend of thermoplastic Silicone-Polycarbonate-urethane with poly n-butyl methacrylate, poly(vinylidene-co-hexafluoropropylene), Blend of polyvinylpyrrolidone, poly(hexylmethacrylate)-co- polyvinylpyrrolidone -co-poly vinyl acetate, and poly(n-butyl methacrylate) -co- poly(vinyl)
  • Clause 207 The device of clause 206, wherein the catheter is a diffusion catheter, infusion catheter, balloon-catheter, or weeping catheter.
  • Clause 309 The device of clause 301 to 303, wherein the therapeutic composition is formulated to commence release of the direct factor Xa inhibitor before commencing release of the direct factor Ila inhibitor [0485] Clause 310.
  • Clause 315 The device of clause 313, wherein the direct factor Xa inhibitor comprises apixaban, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.
  • Clause 327a The device of clause 301 to 327, wherein the therapeutic composition further comprises an adjuvant.
  • each layer comprises an excipient mixed with the therapeutic agent.
  • Clause 336a The device of clause 336, wherein the base layer and top layer differ in at least some properties.
  • Clause 338 The device of clause 337, wherein the active substances are 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.
  • a vascular prosthesis comprising: a scaffold having an outer surface, an inner surface, and one or more edge surfaces therebetween; and a therapeutic composition on at least a portion of the outer surface, wherein the therapeutic composition comprises three or more active substances including an anti-proliferative agent, a direct factor Ila inhibitor, and a direct factor Xa inhibitor; said therapeutic composition including at least a base layer and a top layer, wherein the top layer is formulated to release the at least three active substances in a bolus when exposed to a vascular environment and the base layer is formulated to release the at least three active substances over an extended time period when exposed to the vascular environment.
  • a method for treating tissue injury in a patient comprising: deploying a structure at a target location in the patient’s body lumen, said target location having a tissue injury; and releasing a therapeutic composition from the deployed structure to the location of injury, wherein the therapeutic composition comprises at least a direct factor Ila inhibitor, a direct factor Xa inhibitor, and an anti-proliferative agent.
  • Clause 360 The method of clause 359, wherein the release of the of the direct factor Ila inhibitor commences from 1 minute to 3 days, usually 6 hours to 1 day, after release of the direct factor Xa inhibitor has commenced.
  • Clause 366 The method of clause 351 to 365, wherein the anti-proliferative agent comprises an m-Tor 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 m-Tor 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.
  • Clause 367 The method of clause 366, wherein the anti-proliferative agent comprises sirolimus, or a salt, isomer, solvate, analog, derivative, metabolite, or prodrugs thereof.
  • Clause 368 The method of clause 351 to 365, wherein the anti-proliferative agent comprises paclitaxel, or a salts, isomer, solvate, analog, derivative, metabolite, or prodrug thereof.
  • Clause 392 The method of clause 391, wherein deployment of the structure causes the injury and wherein the therapeutic composition is formulated to release the direct factor Ila inhibitor, the direct factor Xa inhibitor, or the anti -proliferative agent before the injury occurs. [0574] Clause 393.
  • FIG. 1 A shows a side perspective view of a medical device example having a therapeutic coating disposed thereon, in accordance with examples
  • FIG. IB shows a cross-sectional view of a medical device having a therapeutic coating comprising a first layer disposed thereon, in accordance with examples
  • FIG. 1C shows a cross-sectional view of a medical device having a therapeutic coating comprising a first layer and a second disposed thereon, in accordance with examples
  • FIG. 2C shows a cross-sectional view of a medical device having a therapeutic coating comprising a first layer and a second disposed thereon, in accordance with examples
  • FIG. 4 shows a flowchart of a method of treating clotting in patient with a device, in accordance with examples
  • FIG. 6 A shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of apixaban, in accordance with examples;
  • FIG. 6B shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of argatroban, in accordance with examples;
  • FIG. 6C shows a plot of HAoSMC cell proliferation in the presence of rapamycin and varying concentrations of apixaban and argatroban, in accordance with examples
  • FIG. 6E shows a plot of HAoSMC cell proliferation in the presence of difference concentrations of argatroban, in accordance with examples
  • FIG. 7C 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;
  • FIG. 9 shows low magnification images of a luminal surface of control stents (left) and test stents (middle and right), in accordance with examples
  • FIG. 11 shows a reaction scheme of Argatroban with poly N-(2-Hydroxypropyl) methacrylamide, in accordance with examples.
  • 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.
  • any of the devices described herein may, at least partially, cause an injury to the tissue which may initiate the coagulation cascade.
  • 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.
  • a direct Xa inhibitor and a direct Ila inhibitor formulation resulted in unexpected anti-proliferative effects (e.g., reduced cell proliferation) in combination, while each agent alone had little to no anti-proliferative effect.
  • direct Xa inhibitor and a direct Ila inhibitor combination with an anti-proliferative agent formulation improved or enhanced the anti proliferative effect compared to the anti-proliferative agent formulation alone.
  • Xa inhibition to 100,000 times the IC50 of factor Xa inhibition preferably ranges from 500 times to 10,000 times the IC50 of factor Xa inhibition.
  • the tissue concentration in the adjacent tissue segment (e.g., ⁇ 5 mm) at 28 days after injury and/or release of said agent to the tissue segment ranges from zero times the IC50 of factor Xa inhibition to 100 times the IC50 of factor Xa inhibition, preferably ranges from 10 times to 1,000 times the IC50 of factor Xa inhibition.
  • FIG. ID shows a cross-sectional view of a medical device 100 having a therapeutic coating 120 comprising a first layer 122, a second layer 124, and a third layer 126 disposed thereon.
  • the coating 120 may comprise a therapeutic composition of bioactive agents.
  • the therapeutic composition may comprise one or more bioactive agents distributed within the first layer 122, the second layer 124, and/or third layer 126.
  • the first layer 122 may comprise an anti-proliferative agent
  • the second layer 124 may comprise a direct factor Ila inhibitor
  • the third layer 124 may comprise a direct factor Xa inhibitor.
  • the first layer 122 may comprise an anti proliferative agent
  • the second layer 124 may comprise a direct factor Xa inhibitor
  • the third layer 124 may comprise a direct factor Ila inhibitor.
  • any of the coatings 120 described herein may comprise any number of layers (122, 124, 126, etc.) desired and that the layers may comprise any number and combination of bioactive agents, carrier materials, etc. desired.
  • FIG. 2B shows a cross-sectional view of a medical device 100 having a therapeutic coating 120 comprising a first layer 122 disposed thereon.
  • the device 100 may comprise a drug-coated balloon 130 having a first layer 122 of a coating 120 disposed thereon.
  • the first layer 122 may comprise one or more bioactive agents.
  • the first layer 122 may comprise one bioactive agent, two bioactive agents, three bioactive agents, or more.
  • the first layer may comprise a direct factor Ila inhibitor, a direct factor Xa inhibitor, and/or an anti-proliferative agent, or any other agent described herein or known to one of ordinary skill in the art based on the teachings herein.
  • the first layer 122 may be substantially similar to any of the layers described herein (e.g., substantially similar to the layers described with respect to FIG. IB).
  • FIG. 2C shows a cross-sectional view of a medical device 100 having a therapeutic coating 120 comprising a first layer 122 and a second layer 124 disposed thereon.
  • the coating 120 may comprise a therapeutic composition of bioactive agents.
  • the therapeutic composition may comprise one or more bioactive agents distributed within the first layer 122 and/or second layer 124.
  • the first layer 122 and/or second layer 124 may be substantially similar to any of the layers described herein (e.g., substantially similar to the layers described with respect to FIG.
  • the drug coated balloon is to facilitate rapid and efficient uptake of drug by target tissue during transitory device deployment at a target site.
  • the coated layers may be more than one.
  • the therapeutic agent is rapidly released after the medical device is brought into contact with tissue and is readily absorbed.
  • the therapeutic agent in the coating solution is a factor Xa inhibitor such as rivaroxaban or apixaban.
  • each of the one or more agents that inhibit or enhance dissolution of fibrin formation and/or thrombus formation or promote fibrin dissolution and/or thrombus dissolution is released from a temporary device such as drug coated balloon, and optionally is administered locally, over a period of at least about 1 sec., 10 sec. 30 sec., 1 min., 2min, or up to 10 minutes continuously or intermittently.
  • each of the one or more active substances is released from a drug coated balloon at a rate sufficient to generate a tissue concentration of each of the agents within a range of about 1 ng/mg tissue to about lOOng/mg tissue at the site of the first substantial injury within about 1-2 minutes of tissue contact.
  • FIG. 3A shows a medical device 100 having a therapeutic coating 120 disposed adjacent an injury site for delivery of a therapeutic agent(s) to the tissue segment 200.
  • FIG. 3 A is not drawn to scale.
  • the device 120 may comprise a stent 110 and a therapeutic coating 120 disposed thereon.
  • the device 100 may comprise a balloon or other device or instrument described herein (e.g., balloon 130 shown in FIG. 2 A).
  • the stent 110 may be configured to be positioned within a vessel adjacent to a vessel wall.
  • the therapeutic coating 120 may locally release the one or more bioactive agents to the device surface, which may be disposed adjacent a tissue segment of interest.
  • the coating 120 may release the one or more bioactive agents to the device surface in sufficient dose/concentrations to inhibit platelet aggregation, thrombus, thrombin, and/or clot formation.
  • the vicinity to the wall or tissue contacting blood should have sufficient drug concentration to inhibit platelet aggregation, fibrin, thrombin, and/or clot formation.
  • the therapeutic coating 120 may locally release the one or more bioactive agents into the blood adjacent the tissue segment.
  • the therapeutic coating 120 may be configured to release one or more of the agents at a dose substantially below a systemic therapeutic dose of each agent to minimize off-target effects.
  • the dose is at least about 5 times or more lower than the systemic dose or more preferably about 10 times or more lower than the systemic dose.
  • a tissue segment is composed of the tissue segment coupled to the device releasing agent.
  • the tissue segment is 20 mm in length.
  • the agent is released beyond the tissue segment.
  • the tissue adjacent to the tissue segment is called the adjacent tissue segment.
  • the adjacent tissue segment ranges from 1 mm to 10 mm, preferably within a range from 1 mm to 5 mm, more preferably about 5 mm proximal and/or distal to the tissue segment, and most preferably is about 5 mm proximal and distal to the tissue segment.
  • FIG. 3B shows a medical device 100 disposed adjacent an injury site for delivery of a therapeutic agent(s) to the tissue segment 200.
  • the device 120 may comprise a stent 110.
  • the stent 110 may be substantially similar to any of the stents described herein except that it may not comprise a coating. Instead, the stent may be impregnated with the therapeutic composition and/or the stent may be coupled to a reservoir containing the therapeutic composition.
  • the device 100 may comprise a balloon with a reservoir, an infusion catheter, or other device or instrument described herein
  • the therapeutic composition may be formulated to locally release the one or more active substances such that a tissue segment proximal to (e.g., adjacent tissue segment 210 within about
  • the device 100 achieves a therapeutic concentration of the one or more bioactive agents within about 30 minutes to about 4 hours of implantation.
  • the therapeutic composition may be formulated to release one or more of the agents at a dose substantially below a systemic therapeutic dose of each agent to minimize off-target effects.
  • the dose is at least about 5 times lower than the systemic dose or more preferably about 10 times lower than the systemic dose.
  • one or more active substances may optionally be released from the structure prior to the injury being caused.
  • one or more active substances may be released from the structure before, during placement at, and/or after placement at the target location.
  • the one or more active substances may be released from the structure prior to deployment of the structure (which subsequently may cause the injury) at the target location.
  • the one or more active substances may be released from the structure during deployment of the structure at the target location.
  • the structure may be deployed at a target location in a patient’s body.
  • deployment of the structure may comprise expanding the structure against the target location and/or injury site. Deployment of the structure may cause an injury at the target location.
  • the injury is caused before deployment of the structure (e.g., with another device as described in optional Step 401). In some examples, deployment of the structure does not cause an injury to the target location.
  • one or more active substances may be released from the structure to the injury site.
  • one or more active substances may be released from the structure before, during placement at, and/or after placement at the injury site.
  • a therapeutic composition may comprise the one or more active substances.
  • the one or more active substances may comprise a direct factor Xa inhibitor, a direct factor Ila inhibitor, and/or an anti proliferative agent as described herein.
  • the one or more active substances may comprise apixaban, argatroban, and/or sirolimus as described herein.
  • the direct factor Xa inhibitor and/or the direct factor Ila inhibitor may be released faster than the anti proliferative agent.
  • Step 405 may occur be Step 404 such that the structure releases one or more of the active substances before being positioned adjacent the injury site.
  • anti-thrombin thrombin inhibiter, and thrombin formation inhibitor are used interchangeably herein.
  • anti-fibrin, fibrin inhibitor, and fibrin formation inhibitor are used interchangeably herein.
  • a direct factor Xa inhibitor refers to a direct, selective inhibitor of factor Xa that acts directly on factor Xa without using antithrombin as a mediator.
  • the term “direct factor Xa inhibitor” is used herein interchangeably with the term “factor Xa inhibitor” or “anti factor Xa”.
  • Direct factor Xa inhibitors inhibit thrombin formation and/or fibrin formation, thereby inhibiting clot formation.
  • Direct factor Xa inhibitors include, but are not limited to, apixaban, betrixaban, edoxaban, otamixaban, razaxaban, rivaroxaban, (r)-n-(2-(4-(l- methylpiperidin-4-yl)piperazin-l-yl)-2-oxo-l-phenylethyl)-lh-indole-6-carboxamide(LY- 517717), daraxaban (YM-150), or 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(l- ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid ( YM-466 or YM-60828), or eribaxaban (PD 0348292), or 2-(5-carbamimidoyl-2-hydroxy-phenyl) 4-[5-(2,6-d
  • a direct factor Ila inhibitor refers to a direct, selective inhibitor of factor Ila (also referred to herein as thrombin) which acts directly on factor Ila/thrombin.
  • the term “direct factor Ila inhibitor” is used herein interchangeably with the term “factor Ila inhibitor” or “anti-factor Ila”.
  • Direct factor Ila inhibitors inhibit thrombin formation and/or fibrin formation, thereby inhibiting clot formation.
  • Direct thrombin/factor Ila inhibitors include, but are not limited to, argatroban, dabigatran, ximelagatran, melagatran, efegatran, inogatran, atecegatran metoxil (AZD-0837), hirudin, hirudin analogs, bivalirudin, desirudin, and lepirudin.
  • Preferred direct factor Ila inhibitors include argatroban.
  • an anti-proliferative agent refers to anti-proliferative agents, anti-mitotic agents, cytostatic agents and anti-migratory agents which suppress cell growth, proliferation, and/or metabolism.
  • anti-proliferative agents include without limitation inhibitors of mammalian target of rapamycin (mTOR), rapamycin (also called sirolimus), deuterated rapamycin, rapamycin prodrug TAFA93, 40-O-alkyl-rapamycin derivatives, 40-O-hydroxyalkyl- rapamycin derivatives, everolimus ⁇ 40-O-(2-hydroxyethyl)-rapamycin ⁇ , 40-O-(3- hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-alkoxyalkyl- rapamycin derivatives, biolimus ⁇ 40-O-(2-ethoxyethyl)-rapamycin ⁇ ,
  • Preferred anti proliferative agents include mTOR inhibitors and/or taxanes, or salts, isomers, solvates, analogs, derivatives, metabolites, or prodrugs thereof.
  • bioactive agents may be used in combination with one or more additional bioactive agents.
  • agents optionally include anti-mitotic agents, cytostatic agents, anti-migratory agents, immunomodulators, immunosuppressants, anti-inflammatory agents, anti-ischemia agents, anti hypertensive agents, vasodilators, anti-hyperlipidemia agents, anti-diabetic agents, anti-cancer agents, anti-tumor agents, anti-angiogenic agents, angiogenic agents, anti-chemokine agents, healing-promoting agents, anti -bacterial agents, anti-fungal agents, and combinations thereof. It is understood that a bioactive agent may exert more than one biological effect.
  • anti-coagulants or fibrin/thrombus formation-inhibiting agent(s) have surprisingly been found to also enhance or aid in inhibiting cell proliferation, smooth muscle cell proliferation, hyperplasia or restenosis (e.g., smooth muscle cell proliferation or hyperplasia), when two agents factor Xa inhibitor and factor Ila inhibitor (apixaban and argatroban) were tested in combination or additionally in combination with a third antiproliferative agent.
  • two agents factor Xa inhibitor and factor Ila inhibitor apixaban and argatroban
  • a device releasing one or more factor Xa inhibitors, and/or one or more factor Ila inhibitors, and/or one or more antiproliferative agents, wherein said one or more agents inhibit thrombin formation and/or fibrin formation thereby inhibiting clot formation and smooth muscle cell proliferation.
  • the injury to a tissue, surface, vessel/lumen wall, or other body part is the first substantial injury resulting from a surgery or intervention.
  • the surgery or intervention is selected from the group consisting of vascular surgeries and interventions, cardiovascular surgeries and interventions, peripheral vascular surgeries and interventions, vascular grafting, vascular replacement, vascular angioplasty, thrombectomy, vascular stent placement, vascular laser therapy, coronary by-pass surgery, coronary angiography, coronary stent placement, carotid artery procedures, peripheral stent placement, organ transplants, artificial heart transplant, and plastic and cosmetic surgeries and interventions.
  • the injury is the first substantial injury caused by the device delivering the one or more active substances, and optionally one or more other kinds of bioactive agents
  • a substantial injury to a tissue, surface, vessel/lumen wall or other body part results from contact of a device with the tissue, surface, vessel/lumen wall or other body part in a surgery or intervention (e.g., contact of the device causing damage to the endothelium lining a blood vessel, a surgical cutting instrument cutting a tissue, a deployed stent embedding into the wall of a blood vessel, etc.).
  • a substantial injury to a tissue, surface, vessel/lumen wall or other body part has a potential to elicit fibrin/thrombus formation, cell migration, cell proliferation or inflammation, or a combination thereof, at the site of injury or at an area adjacent thereto.
  • the therapeutic composition is formulated to release the one or more active substances at a rate of 1 pg/second/mm device to about 50pg/day/mm device, preferably at a rate of 1 pg/min/mm device to about 30pg/day/mm device, more preferably at a rate of 1 pg/hour/mm device to about 30pg/day/mm device.
  • 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 10 ng/mg tissue to about 100 ng/mg tissue.
  • the therapeutic composition may be formulated to locally release the one or more active substances to the injury site at a rate sufficient to generate a tissue concentration of the one or more active substances at the injury site within about 3 hours after placement adjacent the injury site within a range bounded by any two of the following values: 2 ng/mg tissue, 5 ng/mg tissue, 10 ng/mg tissue, 20 ng/mg tissue, 30 ng/mg tissue, 40 ng/mg tissue, 50 ng/mg tissue, 60 ng/mg tissue, 70 ng/mg tissue, 80 ng/mg tissue, 90 ng/mg tissue, 100 ng/mg tissue, 110 ng/mg tissue, 120 ng/mg tissue, 130 ng/mg tissue,
  • 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.
  • 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 (e.g., an adjacent tissue segment), within a range of about 0.5 ng/mg to about 500 ng/mg within about 3 hours.
  • 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 0.3 ng/mg to about 10 ng/mg within about 24 hours.
  • the systemic delivery comprises a single oral dose, a daily oral dose, or a smallest oral dose of the direct factor Xa inhibitor.
  • the blood concentration is larger than a median minimum serum concentration (Cmin) of the direct factor Xa inhibitor generated by systemic delivery.
  • the blood concentration is smaller than a median minimum serum concentration (Cmin) of the direct factor Xa inhibitor generated by systemic delivery.
  • the C max is measured using one of plasma blood, serum blood, or whole blood.
  • the median Cmax is 80ng/ml, or 123ng/ml, or 171ng/ml, or 321ng/ml, or 480ng/ml of blood.
  • the therapeutic composition is formulated to release a dose of the direct factor Xa inhibitor sufficient to generate a plasma drug level area under the curve (AUC (0-24) or AUC (0- ⁇ )) in ng.h/ml which is smaller than a median (AUC (0-24) or AUC (0- ⁇ )) in ng.h/ml of the direct factor Xa inhibitor generated by systemic delivery of the direct factor Xa inhibitor when taking one or more oral dose of said factor Xa inhibitor.
  • the systemic delivery comprises a single oral dose, a daily oral dose, or a smallest oral dose of the direct factor Xa inhibitor.
  • the median (AUC (0-24) or AUC (0- ⁇ )) is 724 ng.h/ml, orl437 ng.h/ml, or 2000 ng.h/ml, or 4000 ng.h/ml.
  • the concentration of each of the fibrin/thrombus formation-inhibiting or fibrin/thrombus dissolution- promoting agent(s) released from a temporary or non-temporary device, and optionally administered systemically in addition to locally, in blood or tissue at the site of injury or at an area adjacent thereto, and/or in blood or tissue adjacent to the device independently is about 0.01 or 0.1 nM to about 1000 mM, or about 0.1 or 1 nM to about 500 pM, or about 1 or 10 nM to about 100 pM, or about 50 nM to about 50 pM, or about 10 or 100 nM to about 10 pM, or about
  • the concentration of each of the one or more active substances released from a temporary or non-temporary device is at least about 0.01, 0.1, 1, 10, 50, 100 or 500 ng/gm tissue, or at least about 1, 10, 50 or 100 pg/gm tissue, within about 1 day, 12 hr, 6 hr, 3 hr, 2 hr, 1 hr, 30 min., 15 min., 5 min. or 1 min.
  • the amount of each of the one or more optional other kinds of bioactive agents e.g., anti-proliferative agents, anti-inflammatory agents, etc.
  • the amount of each such agent released from the device independently is at least about 1, 10, 50, 100 or 500 pg, or at least about 1, 5, 10 or 20 mg.
  • the concentration of each of the optional other kind(s) of bioactive agent(s) released from a temporary or non-temporary device, and optionally administered systemically in addition to locally, in tissue at the site of injury or at an area adjacent thereto, and/or in tissue adjacent to the device independently is about 0.01 or 0.1 ng/gm tissue to about 1000 pg/gm tissue, or about 0.1 or 1 ng/gm tissue to about 500 pg/gm tissue, or about 1 or 10 ng/gm tissue to about 100 pg/gm tissue, or about 50 ng/gm tissue to about 50 pg/gm tissue, or about 10 or 100 ng/gm tissue to about 10 pg/gm tissue, or about 100 ng/gm tissue to about 1 pg/gm tissue, or about 1 pg/gm tissue to about 10 pg/gm tissue.
  • the patient has a condition or is susceptible to a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, and diabetes. In certain examples, the patient is diabetic.
  • measurements of blood or tissue described herein comprise one or more of mammalian blood or tissue, porcine blood or tissue, human blood or tissue, rabbit blood or tissue, rat blood or tissue, mouse blood or tissue, or the like.
  • One or more bioactive substances or agents can be delivered from any suitable medical device as described herein.
  • the device can be a temporary device (e.g., a balloon, a catheter, a needle, a surgical knife or other surgical tool, a patch, etc.) or a non-temporary device (e.g., an implant, such as a stent, a graft, etc.).
  • Non-limiting examples of surgical instruments and tools include surgical knives and mechanical cutters (e.g., scalpels, lancets, drill bits, rasps, scissors); other cutting instruments (e.g., microtomes, dermatomes, cryotomes, cutting laser guides) and ultrasound tissue disruptors; graspers (e.g., forceps); clamps, occluders and compressors (e.g., hemostats) for organs and tubular structures (e.g., blood vessels and other lumens); sealing devices (e.g., surgical staplers, LigaSureTM tissue-fusion devices); dilators and specula; retractors (e.g., those used to spread open skin, ribs and other tissues and body parts) and tyndallers (e.g., those used to wedge open brain tissue and other tissues); needles, tips and tubes (e.g., trocars) for introducing or removing material (e.g., fluids); scopes and probes (e.g.,
  • a temporary or non-temporary device contains one or more anti-coagulant, and optionally one or more other kinds of bioactive agents (e.g., anti-proliferative agents, anti-inflammatory agents, etc.) in openings in and/or on the body (including at the surface) of the device, and/or in one or more coatings disposed over the body of the device.
  • bioactive agents e.g., anti-proliferative agents, anti-inflammatory agents, etc.
  • the thickness (e.g., average thickness) of each of the coating(s) independently is no more than about 20, 15, 10, 5, 3 or 1 micron.
  • Rivaroxaban composition comprising fast released from stents at a dose of about 10.7 pg/mm of stent length within 7 days from implant (or from vessel injury) was more effective at inhibiting fibrin formation.
  • Table 1 shows Rivaroxaban composition released from a stent at a dose of about 100 pg, or at a dose comprising of about 1.2 pg/mm 2 , and/or at a dose of about 7.14 pg/mm of stent length, at a release rate comprising of about 70.9% within 7 days when combined with Argatroban composition released from a stent at a dose comprising of about 100 pg, and/or at a dose of about 1.2 pg/mm 2 , and/or at a dose of about 7.14 pg/mm of stent length, at a release rate comprising of about 96.5% within 7 days from implant (or from time of injury) was more effective at inhibiting fibrin formation.
  • Rivaroxaban and poly (n-butyl methacrylate) matrix Poly(n-butyl methacrylate) polymer was dissolved in dichloromethane at room temperature and vortex until the polymer had uniformly dissolved/dispersed. Rivaroxaban was dissolved into dichloromethane at room temperature and vortex until the drug was uniformly dissolved/dispersed. Each polymer solution and each drug solutions were mixed together as a matrix (rivaroxaban to poly(n-butyl methacrylate) by weight ratio was 6: 1 for the rivaroxaban fast formulation without m-TOR).
  • Rivaroxaban composition comprising fast released formulation from a stent was more effective at inhibiting fibrin formation compared to control at 7 days and/or at 28 days when it was released at a faster rate formulation.
  • Rivaroxaban formulation released from a stent was more effective at inhibiting fibrin formation compared to control at 7 days and/or at 28 days when it was released at a rate comprising of about 92.5% within 28 days and/or when a dose of about 92.5 pg, and/or a dose of about 1.1 pg/mm 2 , or a dose of about6.6 pg/mm of stent length, was released at or within 28 days from vessel injury (or from implantation).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

L'invention concerne des dispositifs, des systèmes et des méthodes comprenant une structure ayant une ou plusieurs surfaces conçues pour une utilisation interne dans le corps d'un patient et une ou plusieurs compositions thérapeutiques comprenant une ou plusieurs substances actives comprenant un inhibiteur de facteur Xa direct et un inhibiteur de facteur IIa direct disposé dans ou sur la structure. La structure est conçue pour être positionnée adjacente à un site de lésion dans le corps du patient. La ou les substances actives comprennent éventuellement un agent anti-prolifératif. La composition thérapeutique est formulée pour libérer la ou les substances actives vers le site de lésion pour fournir un ou plusieurs effets parmi inhiber la formation de caillot, favoriser la dissolution des caillots, inhiber ou désagréger l'inflammation, inhiber les lésions vasculaires, augmenter le temps avant la coagulation et/ou inhiber la prolifération cellulaire.
PCT/US2021/034108 2020-05-26 2021-05-25 Composés anticoagulants et méthodes et dispositifs pour leur utilisation Ceased WO2021242783A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
KR1020227045078A KR20230017251A (ko) 2020-05-26 2021-05-25 항응고제 화합물 및 그의 사용을 위한 방법 및 장치
JP2022571792A JP2023527328A (ja) 2020-05-26 2021-05-25 抗凝固化合物ならびにその使用のための方法およびデバイス
CN202180058952.7A CN116157164A (zh) 2020-05-26 2021-05-25 抗凝剂化合物及其使用方法和装置
EP21812802.3A EP4157383A4 (fr) 2020-05-26 2021-05-25 Composés anticoagulants et méthodes et dispositifs pour leur utilisation
US17/402,357 US11654036B2 (en) 2020-05-26 2021-08-13 Anticoagulant compounds and methods and devices for their use
US18/106,452 US20230190499A1 (en) 2020-05-26 2023-02-06 Anticoagulant compounds and methods and devices for their use

Applications Claiming Priority (4)

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US202063030203P 2020-05-26 2020-05-26
US63/030,203 2020-05-26
US202163174496P 2021-04-13 2021-04-13
US63/174,496 2021-04-13

Related Child Applications (2)

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US17/195,478 Continuation US11191656B2 (en) 2016-05-16 2021-03-08 Methods and devices for heart valve repair
US17/402,357 Continuation US11654036B2 (en) 2020-05-26 2021-08-13 Anticoagulant compounds and methods and devices for their use

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WO2021242783A1 true WO2021242783A1 (fr) 2021-12-02

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JP (1) JP2023527328A (fr)
KR (1) KR20230017251A (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114948875A (zh) * 2021-12-28 2022-08-30 河南省儿童医院郑州儿童医院 一种阿加曲班脂质体注射剂及其制备方法
WO2024215886A1 (fr) * 2023-04-12 2024-10-17 Boston Scientific Scimed, Inc. Dispositifs médicaux comprenant des enrobages thérapeutiques pour l'administration locale d'un anticoagulant direct

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080241215A1 (en) * 2007-03-28 2008-10-02 Robert Falotico Local vascular delivery of probucol alone or in combination with sirolimus to treat restenosis, vulnerable plaque, aaa and stroke
US20130115363A1 (en) * 2007-09-04 2013-05-09 Hiroo Iwata Method of making a stent
US20160199205A1 (en) * 2006-10-20 2016-07-14 Orbusneich Medical, Inc. Bioabsorbable medical device with coating
US20160213499A1 (en) * 2007-01-19 2016-07-28 Elixir Medical Corporation Biodegradable endoprostheses and methods for their fabrication
US20200138852A1 (en) * 2013-10-22 2020-05-07 Medtronic Minimed, Inc. Methods and systems for inhibiting foreign-body responses in diabetic patients

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10152460A1 (de) * 2001-10-24 2003-05-08 Bayer Ag Stents
TWI484952B (zh) * 2005-10-14 2015-05-21 Abbott Lab 使用醫療裝置投予雷帕黴素類似物與太平洋紫杉醇之組合物及方法
EP2726015B1 (fr) * 2011-06-30 2019-06-19 Elixir Medical Corporation Endoprothèses biodégradables et leurs procédés de fabrication
ES2726802T3 (es) * 2012-01-25 2019-10-09 Univ Catholique Louvain Composiciones y métodos para el trasplante celular

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160199205A1 (en) * 2006-10-20 2016-07-14 Orbusneich Medical, Inc. Bioabsorbable medical device with coating
US20160213499A1 (en) * 2007-01-19 2016-07-28 Elixir Medical Corporation Biodegradable endoprostheses and methods for their fabrication
US20080241215A1 (en) * 2007-03-28 2008-10-02 Robert Falotico Local vascular delivery of probucol alone or in combination with sirolimus to treat restenosis, vulnerable plaque, aaa and stroke
US20130115363A1 (en) * 2007-09-04 2013-05-09 Hiroo Iwata Method of making a stent
US20200138852A1 (en) * 2013-10-22 2020-05-07 Medtronic Minimed, Inc. Methods and systems for inhibiting foreign-body responses in diabetic patients

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4157383A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114948875A (zh) * 2021-12-28 2022-08-30 河南省儿童医院郑州儿童医院 一种阿加曲班脂质体注射剂及其制备方法
CN114948875B (zh) * 2021-12-28 2023-11-28 河南省儿童医院郑州儿童医院 一种阿加曲班脂质体注射剂及其制备方法
WO2024215886A1 (fr) * 2023-04-12 2024-10-17 Boston Scientific Scimed, Inc. Dispositifs médicaux comprenant des enrobages thérapeutiques pour l'administration locale d'un anticoagulant direct

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JP2023527328A (ja) 2023-06-28
EP4157383A1 (fr) 2023-04-05
EP4157383A4 (fr) 2024-07-03
CN116157164A (zh) 2023-05-23
KR20230017251A (ko) 2023-02-03

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