WO2010059561A2 - Systèmes et méthodes pour traiter des anévrismes au moyen de chélateur(s) de zinc - Google Patents

Systèmes et méthodes pour traiter des anévrismes au moyen de chélateur(s) de zinc Download PDF

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Publication number
WO2010059561A2
WO2010059561A2 PCT/US2009/064567 US2009064567W WO2010059561A2 WO 2010059561 A2 WO2010059561 A2 WO 2010059561A2 US 2009064567 W US2009064567 W US 2009064567W WO 2010059561 A2 WO2010059561 A2 WO 2010059561A2
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WO
WIPO (PCT)
Prior art keywords
stent graft
zinc chelator
coating
aneurysm
zinc
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Application number
PCT/US2009/064567
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English (en)
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WO2010059561A3 (fr
Inventor
Susan Rea Peterson
Original Assignee
Medtronic Vascular, Inc.
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Application filed by Medtronic Vascular, Inc. filed Critical Medtronic Vascular, Inc.
Priority to EP09828077A priority Critical patent/EP2365837A2/fr
Publication of WO2010059561A2 publication Critical patent/WO2010059561A2/fr
Publication of WO2010059561A3 publication Critical patent/WO2010059561A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
    • A61M25/0026—Multi-lumen catheters with stationary elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
    • A61B17/12113—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm
    • A61B17/12118—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm for positioning in conjunction with a stent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
    • A61B17/12186—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices liquid materials adapted to be injected
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/07—Stent-grafts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
    • A61M25/0068—Static characteristics of the catheter tip, e.g. shape, atraumatic tip, curved tip or tip structure
    • A61M25/007—Side holes, e.g. their profiles or arrangements; Provisions to keep side holes unblocked
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2002/065—Y-shaped blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/07—Stent-grafts
    • A61F2002/075—Stent-grafts the stent being loosely attached to the graft material, e.g. by stitching
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/07—Stent-grafts
    • A61F2002/077—Stent-grafts having means to fill the space between stent-graft and aneurysm wall, e.g. a sleeve
    • 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
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
    • A61M25/06—Body-piercing guide needles or the like
    • A61M25/0662—Guide tubes
    • A61M2025/0681—Systems with catheter and outer tubing, e.g. sheath, sleeve or guide tube

Definitions

  • the present invention relates to the treatment of aneurysms through the local administration of zinc chelator(s).
  • the zinc chelator(s) can be locally administered by placing them directly onto a stent graft, incorporating them into a coating found on a stent graft, including them in a delivery device that is associated with a stent graft and/or injecting them through delivery and/or injection catheters at or near the time of stent graft deployment.
  • An aneurysm is a localized dilation of a blood vessel usually caused by degeneration of the vessel wall. These weakened sections of vessel walls can burst, causing an estimated 32,000 deaths in the United States each year. Additionally, aneurysm deaths are suspected of being underreported because sudden unexplained deaths, about 450,000 in the United States alone, are often simply misdiagnosed as heart attacks or strokes while many of them may be due to aneurysms. [0003] United States surgeons treat approximately 50,000 abdominal aortic aneurysms each year, typically by replacing the abnormal section of vessel with a polymer graft in an open surgical procedure.
  • a less-invasive procedure that has more recently been used is the placement of a stent graft at the aneurysm site.
  • Stent grafts are tubular devices that span the aneurysm site to provide support without replacing a section of the vessel.
  • the stent graft when placed within a vessel at an aneurysm site, acts as a barrier between blood flow and the weakened wall of a vessel, thereby decreasing pressure on the damaged portion of the vessel.
  • Patients whose multiple medical comorbidities make them very high risk for conventional aneurysm repair can be candidates for stent grafting.
  • Embodiments according to the present invention provide methods and stent grafts that can be used to treat aneurysms following stent graft deployment.
  • One embodiment is a method of treating an aneurysm comprising: delivering a stent graft to the site of the aneurysm; deploying the stent graft to span the aneurysm; and locally administering zinc chelator(s) to the site of the aneurysm.
  • methods described are methods of local administration comprising: applying the zinc chelator(s) to the outer surface of the stent graft and/or incorporating the zinc chelator(s) into a coating on the stent graft.
  • methods described are methods of local administration comprising: incorporating the zinc chelator(s) into a coating and placing the coating on the outer surface of the stent graft.
  • methods described are methods of local administration comprising: attaching a delivery device to the stent graft wherein the delivery device holds and releases zinc chelator(s).
  • the delivery device is a pouch.
  • methods described are methods of local administration comprising: providing a stent graft with two layers wherein following deployment the first layer is exposed to blood flow and the second layer faces the blood vessel wall and wherein the second layer is semi-permeable; partially adhering the layers together so that pouches are formed; and loading the pouches with zinc chelator(s).
  • methods described are methods of local administration comprising: associating the zinc chelator(s) with a carrier before loading the pouches with the zinc chelator(s).
  • methods described are methods of local administration comprising: applying zinc chelator(s) directly to the outer surface of the stent graft while the stent graft is compressed within a stent deployment catheter.
  • methods described are methods of local administration comprising: administering the zinc chelator(s) through a delivery catheter and/or an injection catheter.
  • methods described are methods of local administration comprising: the zinc chelator(s) substantially fill the aneurysm sac.
  • methods described are methods of local administration comprising: the injection catheter is selected from the group comprising a single lumen injection catheter and a multilumen injection catheter.
  • methods described are methods of local administration comprising: administering the zinc chelator(s) through at least two injection catheters wherein the first and second injection catheters reach the aneurysm through a different route.
  • One stent graft embodiment includes a stent graft comprising zinc chelator(s) wherein the zinc chelator(s) are one or more of several coatings applied to the outer surface of the stent graft, incorporated within a coating applied to the stent graft or within a delivery device associated with the stent graft.
  • the stent graft comprises zinc chelator(s) incorporated within a coating applied to the stent graft wherein the coating is biodegradable.
  • the stent graft comprises zinc chelator(s) incorporated within a coating applied to the stent graft wherein the coating is temperature-sensitive and/or pH-sensitive.
  • the stent graft comprises zinc chelator(s) incorporated within a coating applied to the stent graft wherein the coating is formulated to be a quick-release coating, a medium-release coating or a slow- release coating.
  • the stent graft comprises zinc chelator(s) within a delivery device associated with the stent graft and wherein the zinc chelator(s) are further associated with a carrier.
  • the carrier is selected from the group consisting of a sheet, a slab, a gel, a capsule, capsules, microparticles, nanoparticles, and combinations thereof.
  • the delivery device is a pouch associated with the stent graft.
  • the pouch is created by providing a stent graft with two layers wherein following deployment the first layer is exposed to blood flow and the second layer faces the blood vessel wall and wherein the second layer is semi-permeable; and partially adhering the layers together so that one or more pouches are formed.
  • FIG. 1 depicts a fully deployed stent graft with an exterior metal scaffolding as used in an abdominal aortic aneurysm
  • FIG. 2 depicts a delivery device associated with a stent graft deployed at an aneurysm site
  • FIG. 3a is a side view of a pouch delivery device
  • FIG. 3b is a cross-sectional view of a stent graft with a pouch delivery device wrapped around its outer surface
  • FIG. 4 illustrates a stent graft delivery catheter adapted to allow coating of the outer wall of a stent graft with zinc chelator(s) within the delivery catheter;
  • FIG. 5 illustrates an alternative stent graft delivery catheter adapted to allow coating of the outer wall of a stent graft with zinc chelator(s) within the delivery catheter;
  • FIGs. 6a-6c illustrates stent graft deployment with the delivery of zinc chelator(s) through an injection catheter at the treatment site;
  • FIGs. 7a-c illustrates stent graft deployment with the delivery of zinc chelator(s) through injection catheters at the treatment site;
  • FIG. 8 illustrates an alternate method of delivering zinc chelator(s) directly into the aneurysm sac after deployment of a stent graft;
  • FIG. 9 illustrates an alternate method of delivering zinc chelator(s) directly into the aneurysm sac after deployment of a stent graft
  • FIG. 10 illustrates yet another alternate method of delivering zinc chelator(s) directly into the aneurysm sac after deployment of a stent graft.
  • An aneurysm is a swelling, or expansion of a blood vessel and is generally associated with a vessel wall defect.
  • Previous methods to treat aneurysms involved highly invasive surgical procedures where the affected vessel region was removed (or opened) and replaced (or supplemented internally) with a synthetic graft that was sutured in place. However, this procedure was highly invasive and not appropriate for all patients. Historically, patients who were not candidates for this procedure remained untreated and thus at continued risk for sudden death due to aneurysm rupture.
  • Stent grafts can be positioned and deployed using minimally invasive procedures. Essentially, a catheter having a stent graft compressed and fitted into the catheter's distal tip is advanced through an artery to a position spanning the aneurysmal site. The stent graft is then deployed within the vessel lumen juxtaposed to the weakened vessel wall forming an inner liner that insulates the aneurysm from passing blood flow and its resulting hemodynamic forces that can promote stress and rupture. The size and shape of the stent graft is matched to the treatment site's lumen diameter and aneurysm length.
  • Stent grafts generally comprise a metal scaffolding having a biocompatible graft material lining or covering such as Dacron ® , expanded polytetrafluoroethylene, or a fabric-like material woven from a variety of biocompatible polymer fibers.
  • the graft material can be stitched, glued or molded to the scaffold.
  • the scaffolding expands the graft material to fill the lumen and exerts radial force against the lumen wall.
  • Figure 1 depicts an exemplary stent graft placement at the site of an abdominal aortic aneurysm.
  • stent graft 100 is deployed through left iliac artery 114 to aneurysm sac (site) 104.
  • Stent graft 100 has distal end 102 and iliac leg 108 to anchor the stent graft in right iliac artery 116.
  • Stent graft 100 is deployed first in a first deployment catheter and iliac limb (leg) 108 is deployed in a second deployment catheter and the two segments are joined at overlap 106.
  • stent graft 100 contacts the blood vessel wall at least at sites 110, 120 and 122 to prevent leakage of blood into the aneurysm sac at these points.
  • MMPs Matrix metalloproteinases
  • MMPs are a family of structurally related zinc-containing enzymes that mediate the breakdown of connective tissue in normal physiological processes.
  • the MMPs are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity to maintain the appropriate equilibrium with other re-synthesis and repair processes.
  • Over-expression of MMPs or an imbalance between MMPs can lead to excessive tissue breakdown and resulting degenerative disease processes, including but not limited to, aneurysms that are characterized by the excessive breakdown of the extracellular matrix or connective tissues.
  • inhibiting the actions of MMPs could provide an effective strategy to treat defective vessel walls at aneurysm sites.
  • the mammalian MMP family has been reported to include at least 20 enzymes. Some of these enzymes include collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), matrilysin (MMP-7), gelatinase A (MMP-2), gelatinase B (MMP-9), neutrophil collagenase (MMP-8), interstitial fibroblast collagenase (MMP-1 ), type IV collagenase, telopeptidase, and other membrane- associated MMPs.
  • MMP-13 collagenase-3
  • MMP-3 stromelysin-1
  • MMP-11 matrilysin
  • MMP-7 matrilysin
  • MMP-2 gelatinase A
  • MMP-9 gelatinase B
  • neutrophil collagenase MMP-8
  • interstitial fibroblast collagenase MMP-1
  • type IV collagenase type IV collagenase
  • the catalytic zinc molecule of MMPs participates intimately in the chemistry of degrading collagen. That is, the binding of zinc to an ionic site is required for this hydrolytic activity. As a result, if an MMP's catalytic zinc could be blocked or removed, the activity of the MMP could be inhibited.
  • Zinc chelator(s) provide one method to prevent zinc from participating in an MMP's hydrolytic activity.
  • a zinc chelator as described herein is any compound that binds zinc (whether or not the molecule is a true chelator).
  • any molecule that has the ability to ligand or chelate a zinc molecule can be used in conjunction with the apparatus and methods described herein.
  • Particular chelators that can be used include but are not limited to, histidine, spironaphthoxazine, EDTA (ethylenediamine tetraacetic acid), TPEN (tetrakis-(2-pyridylmethyl)ethylenediamine), EGTA (ethyleneglycol tetraacetic acid), DTPA (diethylenetriamine pentaacetic acid), CDTA (1 ,2- cyclohexanediaminetetraacetic acid), HEDTA (N-hydroxyethyl-ethylenediamine- triacetic acid), NTA (nitrilotriacetic acid), diacetic acid, hydroxamic acid, carboxylic acid, sulphydryl, or oxygenated phosphorus (for example, phosphinic acid and phosphonamidate, including
  • one aspect of an embodiment according to the present invention is to administer one or more zinc chelating agents locally to an aneurysm site utilizing stent grafting procedures.
  • the dispersion of the zinc chelator(s) allows the therapeutic reaction to be substantially localized so that overall dosages to the individual can be reduced, and undesirable side effects minimized.
  • Zinc chelator(s) can be delivered to an aneurysm site in three main ways: (1 ) zinc chelator(s) can be placed directly onto a stent graft or incorporated into a coating found on a stent graft; (2) zinc chelator(s) can be provided through a delivery device that is associated with the stent graft, in some embodiments, in association with a carrier and/or (3) zinc chelator(s) can be administered to the aneurysm site through delivery and/or injection catheters at or near the time of stent graft deployment.
  • Zinc chelator(s) can be applied to the surface of a stent graft. Following stent graft deployment, the zinc chelator(s) will diffuse off of the stent graft material to the aneurysm treatment site. When this embodiment is used, zinc chelator(s) can be applied to the surface of the stent graft using methods including, but not limited to, precipitation, coacervation or crystallization. The zinc chelator(s) can also be bound to the stent graft covalently, ionically, or through other intramolecular interactions including, without limitation, hydrogen bonding and van der Waals forces.
  • Zinc chelator(s) can also be incorporated into a coating placed onto the stent graft.
  • a stent graft coating is a material placed onto the fabric of a stent graft that can hold and release zinc chelator(s).
  • Stent graft coatings used in embodiments according to the present invention can be either biodegradable or non-biodegradable.
  • materials that can be used to produce biodegradable coatings include, without limitation, albumin; collagen; gelatin; fibrinogen; hyaluronic acid; starch; cellulose and cellulose derivatives (e.g., methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate); casein; dextran; polysaccharides; poly(lactic acid); poly(D,L-lactide); poly(D,L-lactide-co-glycolide); poly(glycolide); poly(hydroxybutyrate); poly(alkylcarbonate); polyesters; poly(orthoesters); poly(ester amide)s (e.g., based on 1 ,4-butanediol,
  • Non-limiting representative examples of materials that can be used to produce non-biodegradable coatings include poly(ethylene-vinyl acetate) (“EVA”) copolymers; silicone rubbers; acrylic polymers (e.g., polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate, polyalkylcynoacrylate); polyethylene; polypropylene; polyamides (nylon 6,6); polyurethane; poly(ester urethanes); poly(ether urethanes); poly(ester-urea); polyethers (e.g., based on poly(oxyethylene) and poly(oxypropylene) units (Pluronic ® )); poly(ethylene oxide); poly(propylene oxide); other pluronics; poly(tetramethylene glycol)); and vinyl polymers (e.g., polyvinylpyrrolidone, polyvinyl alcohol), polyvinyl acetate phthalate and poly(vinylchloride).
  • EVA ethylene-vinyl
  • polymers such as poly (D,L-lactic acid); poly (L-lactic acid); poly (glycolic acid); poly (caprolactone); poly (valerolactone); copolymers of poly (caprolactone) or poly (lactic acid) with a polyethylene glycol (e.g., MePEG); carboxylic polymers; polyacetates; polyacrylamides; polycarbonates; polyvinylbutyrals; polysilanes; polyureas; polyoxides; polystyrenes; polysulfides; polysulfones; polysulfonides; polyvinylhalides; pyrrolidones; cross-linkable acrylic and methacrylic polymers; vinyl acetate polymers; vinyl acetal polymers; epoxy; melamine; phenolic polymers; water-insoluble cellulose ester polymers (e.g., cellulose acetate propionate, cellulose acetate, cellulose a
  • the selected material used in a particular coating can be obtained from various chemical companies known to those of ordinary skill in the art.
  • polymers are selected as a coating material, because of the potential presence of unreacted monomers, low molecular weight oligomers, catalysts, or other impurities in such commercially available polymers, it can be desirable (or, depending upon the materials used, necessary) to increase the purity of the selected polymer.
  • Such a purification process yields polymers of better-known, purer composition, and therefore increases both the predictability and performance of the mechanical characteristics of the coatings.
  • the exact purification process will depend on the polymer or polymers chosen. Generally, however, in a purification process, the polymer will be dissolved in a suitable solvent.
  • Suitable solvents include (but are not limited to) methylene chloride, ethyl acetate, chloroform, ethanol, and tetrahydrofuran (THF).
  • the polymer solution usually is then mixed with a second material that is miscible with the solvent, but in which the polymer is not soluble, so that the polymer (but not appreciable quantities of impurities or unreacted monomer) precipitates out of solution.
  • a methylene chloride solution of the polymer can be mixed with heptane, causing the polymer to fall out of solution.
  • the solvent mixture then is removed from the copolymer precipitate using conventional techniques.
  • the coatings used in embodiments according to the present invention can be fashioned in a variety of forms with desired release characteristics and/or with other specific desired properties.
  • the coatings can be fashioned to release the zinc chelator(s) upon exposure to a specific triggering event such as increased or decreased pH.
  • pH-sensitive coating materials include poly(acrylic acid) and its derivatives (e.g., homopolymers such as poly(aminocarboxylic acid); poly(acrylic acid); poly(methyl acrylic acid); copolymers of such homopolymers; and copolymers of poly(acrylic acid) and other acrylmonomers.
  • pH sensitive polymers include polysaccharides such as cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate trimellilate; and chitosan.
  • pH sensitive polymers include any mixture of a pH sensitive polymer and a water-soluble polymer.
  • Temperature-sensitive polymeric coatings wherein the release of the active agent is dependent on the temperature of the polymer can also be used.
  • temperature-sensitive materials and their gelatin temperature include homopolymers such as poly(N-methyl-N-n-propylacrylamide) (19.8°C); poly(N-n-propylacrylamide) (21.5°C); poly(N-methyl-N-isopropylacrylamide) (22.3°C); poly(N-n-propylmethacrylamide (28.0 0 C); poly(N-isopropylacrylamide) (30.9 0 C); poly(N,n-diethylacrylamide) (32.0°C); poly(N-isopropylmethacrylamide) (44.O 0 C); poly(N-cyclopropylacrylamide) (45.5°C); poly(N-ethylmethyacrylamide) (50.0°C); poly(N-methyl-N-ethylacrylamide) (56.0 0 C); poly(N--cyclopropylacrylamide
  • Cellulose ether derivatives such as hydroxypropyl cellulose (41 0 C); methyl cellulose (55 0 C); hydroxypropylmethyl cellulose (66°C); and ethyl hydroxyethyl cellulose as well as pluronics such as F-127 (10-15 0 C); L-122 (19°C); L-92 (26°C); L-81 (20°C); and L- 61 (24°C) can also be used.
  • temperature-sensitive materials can be made by preparing copolymers between (among) monomers of the above, or by combining such homopolymers with other water-soluble polymers such as acrylmonomers (e.g., acrylic acid and derivatives thereof such as methylacrylic acid, acrylate and derivatives thereof such as butyl methacrylate, acrylamide, and N-n-butyl acrylamide).
  • acrylmonomers e.g., acrylic acid and derivatives thereof such as methylacrylic acid, acrylate and derivatives thereof such as butyl methacrylate, acrylamide, and N-n-butyl acrylamide.
  • Coatings used in embodiments can also be prepared in a variety of paste or gel forms.
  • coatings are provided which are liquid at one temperature (e.g., a temperature greater than about 37°C, such as about 40°C, about 45°C, about 50°C, about 55°C or about 6O 0 C), and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than about 37°C).
  • a temperature greater than about 37°C such as about 40°C, about 45°C, about 50°C, about 55°C or about 6O 0 C
  • solid or semi-solid at another temperature e.g., ambient body temperature, or any temperature lower than about 37°C.
  • pastes or gels can be made utilizing a variety of techniques.
  • Other pastes or gels can be applied as a liquid, which can solidify in vivo due to dissolution of a water-soluble component of the paste and precipitation of encapsulated drug into the aqueous body environment.
  • Coatings can be fashioned in any appropriate thickness.
  • coatings can be less than about 2 mm thick, less than about 1 mm thick, less than about 0.75 mm thick, less than about 0.5 mm thick, less than about 0.25 mm thick, less than about 0.10 mm thick, less than about 50 ⁇ m thick, less than about 25 ⁇ m thick or less than about 10 ⁇ m thick.
  • coatings will be flexible with a good tensile strength (e.g., greater than about 50, greater than about 100, or greater than about 150 or 200 N/cm 2 ), have good adhesive properties (i.e., adhere to moist or wet surfaces), and have controlled permeability.
  • zinc chelator(s) can be, without limitation, linked by occlusion in the matrices of a coating, bound by covalent linkages, to the coating or medical device itself or encapsulated in microcapsules within the coating.
  • the zinc chelator(s) can be provided in noncapsular formulations such as, without limitation, microspheres (ranging from nanometers to micrometers in size), pastes, threads of various size, films or sprays.
  • Coatings used in embodiments can be formulated to deliver the zinc chelator(s) over a period of about several minutes, several hours, several days, several months or several years.
  • "quick release” or “burst” coatings can release greater than about 10%; greater than about 20%, or greater than about 25% (w/v) of the zinc chelator(s) over a period of about 7 to about 10 days.
  • “Slow release” coatings can release less than about 1 % (w/v) of the zinc chelator(s) over a period of about 7 to about 10 days.
  • “Medium-release” coatings can have release profiles between the quick-release and slow-release profiles.
  • coatings used can be coated with a physical barrier to protect the coating during packaging, storage and deployment procedures
  • Physical barriers can also be used to affect the release profile of zinc chelator(s) from the coating once the stent graft is deployed.
  • Such barriers can include, without limitation, inert biodegradable materials such as gelatin, poly(lactic-co-glycolic acid)/methoxypolyethyleneglycol film, polylactic acid, or polyethylene glycol.
  • the coating can also be covered with an inactive form of a zinc chelator(s), which can later be activated.
  • a zinc chelator(s) which can later be activated.
  • the coating could be coated with an enzyme, which causes either the release of the zinc chelator(s) or activates the zinc chelator(s). Activation can also be achieved by injecting another material into the aneurysm sac after the stent graft is deployed.
  • an anticoagulant e.g., heparin
  • heparin a suitable physical barrier over the coating.
  • an anticoagulant e.g., heparin
  • the presence of an anti-coagulant can delay coagulation. As the anticoagulant dissolves away, the anticoagulant activity stops, and the newly exposed zinc chelator(s) coating can initiate its intended action.
  • alternating layers of the zinc chelator(s) coating with a protective coating can enhance the time-release properties of the coating overall.
  • Coatings can be applied according to any technique known to those of ordinary skill in the art of medical device manufacturing.
  • coatings can be applied to the stent grafts used as a "spray", which solidifies into a coating.
  • Such sprays can be prepared from microspheres of a wide array of sizes, including for example and without limitation, from about 0.1 ⁇ m to about 3 ⁇ m, from about 10 ⁇ m to about 30 ⁇ m or from about 30 ⁇ m to about 100 ⁇ m.
  • coatings can be applied by, without limitation, impregnation, spraying, brushing, dipping and/or rolling.
  • a polymer-zinc chelator(s) blend can be used to fabricate fibers or strands that are embedded within the fabric of the stent graft. After a coating is applied, it can be dried. Drying techniques include, but are not limited to, heated forced air, cooled forced air, vacuum drying or static evaporation.
  • zinc chelator(s) can also be administered to an aneurysm site following stent graft deployment with the use of a delivery device associated with the stent graft.
  • the stent graft isolates the aneurysm site from blood flow and provides a structure to which the delivery device can be attached.
  • zinc chelator(s) can be delivered directly to the aneurysm site and not to surrounding healthy tissue. The zinc chelator(s) are released into this relatively sealed environment such that they are largely limited to this region.
  • Delivery devices can include, without limitation, a pouch that is attached to the stent graft or made from stent graft layers wherein the zinc chelator(s) (and associated carriers when used) are placed inside the pouch.
  • FIG. 2 depicts a zinc chelator(s) delivery device in the form of pouch 50.
  • pouch 50 is connected to ring 48 on the outer surface of stent graft 22.
  • Delivery device (50) is positioned such that upon placement at an aneurysm site (in the depicted example, aneurysmal sac 18 of aorta 10), delivery device (50) is located between stent graft 22 and aneurysmal wall 16 of aorta 10.
  • FIG. 3a depicts pouch 50. Pouch 50 can be wrapped around the outer wall of the stent graft and attached, in one embodiment, at end 58 of pouch 50.
  • Pouch 50 can be prepared, for example, by folding a sheet of the pouch material in half, and attaching together the opposed sides projecting from the crease occurring at the fold which forms end 56, such as by sewing, laser welding, adhesives or the like to leave an open end.
  • the zinc chelator(s) (with or without carriers) are then loaded into the interior of the pouch 50.
  • Open end 58 can then be sealed.
  • FIG. 3b shows a top cross-sectional view of pouch 50 attached to ring 48 of stent graft 22.
  • multiple pouches can be used, with each pouch being attached to the stent graft.
  • the pouches are arranged so that the spacing between adjacent pouches extending about the circumference of the stent graft is relatively equal. In one embodiment, at least four such delivery devices are equally spaced about the circumference of the stent graft. Alternatively, multiple delivery devices can be located both about the circumference of the stent graft, as well as longitudinally along the stent graft. In another embodiment, appropriately placed pouches can be created by adopting a stent graft that includes two fabric layers. The fabric layers can be adhered together at various places to create any desired number or configuration of pouches.
  • zinc chelator carriers can be, without limitation, a sheet, a slab, a gel, a capsule or capsules, microparticles, nanoparticles and/or combinations of these.
  • a carrier could comprise a polymeric sheet loaded with zinc chelator(s).
  • Such a sheet can be formed by dissolving or dispersing both the polymer and zinc chelator(s) in a suitable solvent, pouring this solution into a suitable mold and removing the solvent by evaporation. The formed sheet can then be cut to fit the delivery device.
  • a gel can be used as a carrier for zinc chelator(s).
  • a gel can be prepared by dissolving a polymer in an organic solvent in which the zinc chelator(s) are either dissolved or dispersed. The gel can be placed into the delivery device, and when the stent graft is implanted, release zinc chelator(s) into the aneurysmal sac, where the delivery device provides a convenient mechanism to maintain the gel adjacent the aneurysmal sac.
  • the delivery device and/or carrier can be biodegradable or non-biodegradable and fashioned with any of the materials described above. As such, the same desired release characteristics and properties can be achieved including those described above relating to pH or temperature sensitivity, quick, medium or slow release profiles, physical barriers, etc.
  • Zinc chelator(s) can also be delivered to the site of an aneurysm using delivery and/or injection catheters at or near the time of stent graft deployment.
  • a stent graft is pre-loaded into a delivery catheter such as that depicted in FIG. 4.
  • Stent graft 100 is radially compressed to fill stent graft chamber 218 in the distal end of delivery catheter 200.
  • Stent graft 100 is covered with retractable sheath 220.
  • delivery catheter 200 has first injection port 208 and second injection port 210 for applying zinc chelator(s) onto the outer wall of the stent graft prior to deployment.
  • Stent graft 100 is then deployed to the treatment site as depicted in FIG. 1.
  • FIG. 5 Another embodiment for coating the outer wall of stent graft 100 within delivery catheter 200 is depicted in FIG. 5.
  • Retractable sheath 220 contains plurality of holes 250 through which zinc chelator(s) can be applied to the outer wall of stent graft 100 compressed within stent graft chamber 218 prior to deployment. Stent graft 100 is then deployed to the treatment site as depicted in FIG. 1.
  • zinc chelator(s) are injected between the stent graft and the vessel wall during or after stent graft placement. As depicted in FIG.
  • stent graft 100 is radially compressed to fill stent graft chamber 218 of stent delivery catheter 300 which is then deployed to the treatment site via left iliac artery 114.
  • Multilumen injection catheter 302 is also deployed to the treatment site through right iliac artery 116.
  • Multilumen injection catheter 302 can be a coaxial catheter with two injection lumens or a dual lumen catheter or alternatively a three lumen catheter if a guide wire lumen is required.
  • Injection catheter 302 has first injection port 304 and second injection port 306 through which a zinc chelator(s) can be delivered to a treatment site.
  • stent delivery catheter 300 and injection catheter 302 are deployed independently to the treatment site.
  • FIG. 6b shows stent graft 100 deployed.
  • delivery catheter 300 has been removed and iliac limb 108 has been deployed.
  • Iliac limb segment 108 of stent graft 100 seals the aneurysm sac at proximal end 122.
  • Injection catheter 302 has also been retracted so that first injection port 304 and second injection port 306 are within aneurysmal sac 104.
  • Zinc chelator(s) 308 can then be injected between the vessel lumen wall and the stent graft within aneurysm sac 104 (FIG. 6c). Injection catheter 302 is then retrieved.
  • a single lumen injection catheter can be used in the place of a multilumen injection catheter. After the guide wire is retrieved from the lumen, zinc chelator(s) can be delivered to the treatment site through the same lumen of the single lumen injection catheter. In an alternate embodiment, more than one single lumen injection catheter can be deployed in each iliac artery with the distal ends of the catheters meeting in the aneurysm sac.
  • more than one injection catheter can be used to deliver zinc chelator(s) to the aneurysm sac (FIG. 7a).
  • stent graft 100 is deployed to the treatment site via left iliac artery 114 (FIG. 7a).
  • Multiple single lumen or multilumen injection catheters 302 and 500 are also deployed to aneurysm sac 104 through right iliac artery 116 and left iliac artery 114 (FIG. 10a).
  • Injection catheters 302 and 500 have injection ports through which zinc chelator(s) can be deposited.
  • Delivery catheter 300 is removed with both stent graft limbs deployed as in FIG.
  • Zinc chelator(s) 308 are then administered to aneurysm sac 104 (FIG. 7c) and injection catheters 302 and 500 can then be retrieved.
  • zinc chelator(s) can be delivered to aneurysm sac 104 by injecting the components through the wall of stent graft 100 (FIG. 8).
  • Injection catheter 900 is advanced to the site of an already deployed stent graft 100 and needle 902 penetrates stent graft 100 to deliver zinc chelator(s) 308 to aneurysm sac 104.
  • Injection catheter 900 can be a multi-lumen or single lumen catheter.
  • zinc chelator(s) are delivered to aneurysm sac 104 by translumbar injection (FIG. 9).
  • Injection device 920 such as but not limited to a syringe, is directed, under radiographic or echographic guidance, to the aneurysm sac where stent graft 100 and iliac leg 108 have already been deployed.
  • Injection device 920 delivers which zinc chelator(s) 308 to aneurysm sac 104.
  • Injection device 920 can have a single lumen or multiple lumens.
  • a collateral artery can be used to access the aneurysm sac (FIG. 10).
  • stent graft 100 can be deployed such that distal end 102 is in abdominal aorta 154 near, but below the renal artery. After deployment of stent graft 100, the deployment catheter is removed and injection catheter 302 is advanced up the aorta past aneurysm sac 104 to superior mesenteric artery 150.
  • Injection catheter 302 is then advanced through superior mesenteric artery 150 and down into the inferior mesenteric artery where it originates at the aorta within aneurysm sac 104.
  • Zinc chelator(s) 308 can then be injected into aneurysm sac 104 through first injection port 304 and second injection port 306.
  • one or more additional bioactive agent can also be locally administered in an embodiment according to the present invention. The choice of bioactive agent to incorporate, or how much to incorporate, can have a great deal to do with, in one embodiment, a polymer selected to coat the stent graft.
  • Non-limiting examples of particular bioactive agents or types of bioactive agents that may be particularly beneficial within the context of the embodiments described herein include anti-proliferatives including, but not limited to, macrolide antibiotics including FKBP-12 binding compounds, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPAR ⁇ ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides, matrix metalloproteinase inhibitors and transforming nucleic acids.
  • macrolide antibiotics including FKBP-12 binding compounds, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma
  • Bioactive agents can also include anti-proliferative compounds, cytostatic compounds, toxic compounds, anti-inflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, growth factors and delivery vectors including recombinant micro-organisms, liposomes, and the like.
  • Exemplary FKBP-12 binding agents include sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican or RAD-001 ), temsirolimus (CCI-779 or amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid as disclosed in U.S. Patent Application No.

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Abstract

L'invention concerne des méthodes et des configurations d'endoprothèses associées au traitement d'anévrismes par administration locale de chélateur(s) de zinc. Le ou les chélateurs de zinc peuvent être administrés localement par mise en place directe de ceux-ci sur une endoprothèse, par incorporation de ceux-ci dans un revêtement présent sur une endoprothèse, par intégration de ceux-ci dans un dispositif d'administration qui est associé à une endoprothèse, et/ou par injection de ceux-ci au moyen de cathéters d'administration et/ou d'injection avant, pendant ou après le déploiement d'une endoprothèse.
PCT/US2009/064567 2008-11-24 2009-11-16 Systèmes et méthodes pour traiter des anévrismes au moyen de chélateur(s) de zinc WO2010059561A2 (fr)

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