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WO2009089632A1 - Dispositifs implantables pour favoriser une ré-endothélialisation et leurs procédés d'utilisation - Google Patents

Dispositifs implantables pour favoriser une ré-endothélialisation et leurs procédés d'utilisation Download PDF

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Publication number
WO2009089632A1
WO2009089632A1 PCT/CA2009/000055 CA2009000055W WO2009089632A1 WO 2009089632 A1 WO2009089632 A1 WO 2009089632A1 CA 2009000055 W CA2009000055 W CA 2009000055W WO 2009089632 A1 WO2009089632 A1 WO 2009089632A1
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WIPO (PCT)
Prior art keywords
implantable device
receptor agonist
estrogen receptor
blood vessel
stent
Prior art date
Application number
PCT/CA2009/000055
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English (en)
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WO2009089632A8 (fr
Inventor
Jean-François Tanguay
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Estracure Inc.
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Publication date
Priority claimed from US12/113,570 external-priority patent/US20090274738A1/en
Application filed by Estracure Inc. filed Critical Estracure Inc.
Priority to CA2711073A priority Critical patent/CA2711073A1/fr
Priority to EP09702997A priority patent/EP2234599A1/fr
Publication of WO2009089632A1 publication Critical patent/WO2009089632A1/fr
Publication of WO2009089632A8 publication Critical patent/WO2009089632A8/fr

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    • 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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/395—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—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
    • 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
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • 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
    • A61L27/54—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
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • 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
    • A61L2300/43—Hormones, e.g. dexamethasone
    • 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
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • 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

Definitions

  • the present invention relates to implantable devices for promoting reendothelialization and methods of use thereof. More specifically, the present invention is concerned with implantable devices for the controlled delivery of an estrogen receptor agonist at an injured site of an injured vessel.
  • 17- ⁇ -Estradiol (E2, CAS 50-28-2, 17 ⁇ -estra-1 , 3,5(10)-triene-3, 17- diol) is known to inhibit proliferation of smooth muscle cells (neointima formation) and promote reendothelialization in vitro and in vivo.
  • Co-pending application 10/088,405 has shown that estradiol inhibits restenosis and promotes reendothelialization in a pig model for restenosis.
  • BiodivYsioTM phosphorylcholine coated stainless steel stents with a dose of 2.52 ⁇ g per mm 2 of stent (i.e., about 250 ⁇ g per stent with 18 mm x 3 mm stents namely about 13.88 ⁇ g per mm of length of stent).
  • Estrogen Vascular Technology, LLC conducted another clinical trial (Ethos I) using a biostable polymer (PEVA/PBMA BravoTM) coated RTM stent (open cell, flexible) loaded with 16 ⁇ g/mm stents (240 ⁇ g on a 15 mm stent coated with 564 ⁇ g of biostable polymer) coated with fast-release and moderate-release formulations.
  • 95 patients were enrolled (32 with the bare metal stent (BM), 31 with the fast release and 32 with the moderate release).
  • the release profile of the moderate release formulations measured in porcine coronary artery was expected to be of 28 days.
  • Estrogen Vascular Technology, LLC reported preclinical trials results which revealed that estradiol enhanced endothelial progenitor cell growth between 10 nM and 100 nM concentration but has a strong negative effect higher than 10 ⁇ M and above and that estradiol enhanced foetal bovine aortic endothelial cell growth between 0.1 nM and 1OnM concentration but that this effect was lost at 10OnM and above. In view of this, Estrogen Vascular Technology, LLC.
  • estradiol is more likely to produce beneficial effects at lower doses.
  • Estrogen Vascular Technology, LLC reported that it expected that its future experiments using a dosage of 75 ⁇ g on a 15 mm stent (i.e. 5 ⁇ g/mm) (Ethos II) coated with 282 ⁇ g biostable polymer would yield better results and using a dosage of 20 ⁇ g on a 15 mm stent (i.e. 1.33 ⁇ g/mm) (Ethos III) coated with 80 ⁇ g of a degradable abluminal polymer would yield even better results. After 6 months, Ethos Il showed no effect when compared to BMS. To the Applicant's knowledge no results were reported for the Ethos III trials.
  • Late stent thrombosis generally refers to thrombosis that occurs at least one month following stent implantation, while very late stent thrombosis generally refers to events that occur more than 12 months following stent placement (Hodgson J. et al. Cardiovascular Interventions 2007;69:327-33). It has been reported that delayed or incomplete reendothelialization is likely a cause of late susceptibility to stent thrombosis. In particular, there is a reported increase of late stent thrombosis with both sirolimus-eluting and paclitaxel- eluting stents between 1 and 4 years of follow-up.
  • neointima is not a negative parameter so long as the artery lumen is not reduced below a certain threshold (Finn A et al. Circ 2007;115 :2435-41 , Kotani et al. J. Am Coll Cardiol 2006;47 :2108-11 ).
  • the present invention is concerned with the surprising finding that administration of a dosage of estrogen receptor agonist of at least 16.7 ⁇ g/mm of implantable device at the injured site of a vessel accelerates and optimizes vessel repair.
  • a mean detected concentration of 13,6 ⁇ g estradiol/g of coronary tissue with a maximum of 50 ⁇ g estradiol/g of coronary tissue could be detected in the tissue post implantation using the method GC/MS.
  • 0.51 % of 10 mg i.e. 51 ⁇ g in the tissue overall
  • the mean detected concentration during the first 48 hours was up to 12 ⁇ g estradiol/g of coronary tissue and during the first week (168 hours) of up to 10,6 ⁇ g estradiol/g of coronary tissue. Reaching as fast as possible an effective dose for reendothelialization in the tissue is desirable since early reendothelialization reduces the risk of restenosis.
  • an implantable device for the controlled delivery of an estrogen receptor agonist to an injured site in the lumen of a mammalian blood vessel, wherein the estrogen receptor agonist is present in an amount of at least about 16.7 ⁇ g/mm implantable device length.
  • the blood vessel is procedurally traumatized.
  • the estrogen receptor agonist is present in an amount of at least about 21.7 ⁇ g/mm of device length.
  • the device is adapted for the controlled delivery of an estrogen receptor agonist.
  • the estrogen receptor agonist is present in an amount of at least about 27.8 ⁇ g/mm of device length. In another specific embodiment of the implantable device of the present invention, the estrogen receptor agonist is present in an amount of at least about 30.8 ⁇ g/mm of device length. In another specific embodiment of the implantable device of the present invention, the estrogen receptor agonist is present in an amount of at least about 49.5 ⁇ g/mm of device length. In another specific embodiment of the implantable device of the present invention, the controlled delivery enables a mean concentration of estrogen receptor agonist in coronary tissue of at least about 9.1 ⁇ g/g of coronary tissue over at least about 2 weeks.
  • the controlled delivery enables a mean concentration of estrogen receptor agonist in coronary tissue of at least about 10.6 ⁇ g/g of coronary tissue over at least about 1 week. In another specific embodiment of the implantable device of the present invention, the controlled delivery enables a mean concentration of estrogen receptor agonist in coronary tissue of at least about 12.0 ⁇ g/g of coronary tissue over at least about 48 hours. In another specific embodiment of the implantable device of the present invention, the controlled delivery enables a mean concentration of estrogen receptor agonist in coronary tissue of at least about 13.6 ⁇ g/g of coronary tissue over at least about 24 hours.
  • the controlled delivery enables a mean concentration of estrogen receptor agonist in coronary tissue of at least about 50 ⁇ g/g of coronary tissue over at least about 24 hours.
  • the implantable device of the present invention is a stent.
  • the implantable device of the present invention is a shunt.
  • the implantable device of the present invention is a mesh.
  • the implantable device of the present invention is an artificial graft.
  • the estrogen receptor agonist is E2 (CAS 50-28-2, 17 ⁇ - estra-1 ,3,5(10)-triene-3,17-diol).
  • the estrogen receptor agonist is releasably embedded in, coated on, or embedded in and coated on, the device.
  • the device further comprises a controlled release polymer coating.
  • the polymer coating is biodegradable.
  • the E2 amount is sufficient to allow complete reendothelialization of the injured site.
  • the implantable device of the present invention further comprises an agent selected from the group consisting of an antioxidant, an anti-proliferative/cytostatic agent, an anti- inflammatory/immunomodulator agent; an anti-migration agent, a pro-healing agent, and combinations thereof.
  • the cytostatic agent is paclitaxel or an analog thereof. In another specific embodiment, the cytostatic agent is rapamycin or an analog thereof. In another specific embodiment, the cytostatic agent is sirolimus or an analog thereof. In another specific embodiment, the anti-migration agent inhibits migration of vascular smooth muscle cells. In another specific embodiment, the inhibitor of migration of vascular smooth muscle cells is cytochalasin.
  • the mammalian blood vessel is a human blood vessel.
  • a method for promoting reendothelialization of an injured blood vessel of a subject comprising implanting the implantable device of the present invention at an injured site of the blood vessel of the subject, whereby reendothelialization is promoted.
  • the subject is human.
  • the device is implanted before, during or after vascular injury.
  • the injured mammalian blood vessel is a procedurally traumatized blood vessel.
  • the implantable device of the present invention for promoting reendothelialization of an injured blood vessel of a subject.ln an embodiment the implantable device is implanted before, during or after vascular injury.
  • the blood vessel is a procedurally traumatized blood vessel.
  • estradiol receptor agonist refers to estradiol such as E2, 17-alpha estradiol and their hydroxylated metabolites with or without subsequent glucuronidation, sulfation, esterification or O- methylation; an estradiol precursor; an active estradiol metabolite such as estrone and estriol; an active analog such as mycoestrogens and phytoestrogens including coumestans, prenylated flavonoid, isoflavones (e.g.
  • a modulator capable of positively influencing the activity of the estradiol receptor(s) or of enhancing the binding and/or the activity of estradiol towards its receptor such as a selective estrogen receptor modulator (SERM) including tamoxifen and a derivative thereof including clomifene, raloxifene, toremifene, apeledoxifene, lasofoxifene, ormeloxifenem, tibolone and idoxifene; a selective estrogen receptor down-regulator (SERD) including sulvestrant, ethamoxytriphetol and nafoxidine; and a high dose estradiol such as diethylstilbestrol and ethinyloestradiol; testosterone.
  • SERM selective estrogen receptor modulator
  • SELD selective estrogen receptor down-regulator
  • DHEA Dehydroepiandrosterone
  • cytochrome P450 enzymes Cholesterol is converted to pregnenolone by the enzyme P450 sec (side chain cleavage) and then another enzyme CYP17A1 converts pregnenolone to 17 ⁇ - Hydroxypregnenolone and then to DHEA.
  • P450 sec side chain cleavage
  • CYP17A1 converts pregnenolone to 17 ⁇ - Hydroxypregnenolone and then to DHEA.
  • DHEA is the dominant steroid hormone and the precursor of all sex steroids. After side chain cleavage, and either utilizing the delta-5 pathway or the delta-4 pathway, androstenedione is another key intermediary.
  • Androstenedione is either converted to testosterone, which in turn undergoes aromatization to estradiol, or, alternatively, androstenedione is aromatized to estrone which is converted to estradiol.
  • estradiol precursor include androstenedione and estrone.
  • procedurally traumatized mammalian blood vessel refer to a vessel injured by a surgical/mechanical/cryotherapy/laser intervention into mammalian vasculature.
  • procedural traumas include organ transplantation, such as heart, kidney, liver and the like, e.g., involving vessel anastomosis; vascular surgery, e.g., coronary bypass surgery, biopsy, heart valve replacement, atherectomy, thrombectomy, and the like; transcatheter vascular therapies (TVT) including angioplasty, e.g., laser angioplasty and PTCA procedures, employing balloon catheters, and indwelling catheters; vascular grafting using natural or synthetic materials, such as in saphenous vein coronary bypass grafts, dacron and venous grafts used for peripheral arterial reconstruction, etc.; placement of a mechanical shunt, e.g., a PTFE hemodialysis shunt used for
  • delivery system includes without being so limited implantable devices, perivascular gels, microspheres and micelles.
  • the implantable device of the present invention may further comprise at least one further agent selected from the group consisting of an antioxidant such as but not limited to nitric oxide; an anti-proliferative or cytostatic agent such as but not limited to paclitaxel, rapamycin, sirolimus and analogs thereof, everolimus, tacrolimus, zotarolimus, biolimus, statin, mitomycin, actinomycin, C-myc antisens, restenase, PCNA ribozyme, 2- chlorodeoxyadenosine, vincristine, methothrexate, angiopeptin or a PDGF inhibitor; an anti-inflammatory/immunomodulator agent such as but not limited to cyclosporine, Interferon ⁇ -1 b, dexamethasone, leflunomide, sirolimus, tacrolimus, everolimus, mycophenolic acid, mizorbine or tranilast; an anti- migration agent such as but not limited
  • implantable device refers to, without being so limited, stent, shunt, mesh (membrane polymer, intracoronary, endocardiac, epicardiac) and graft made of natural or synthetic materials.
  • injured site when used to refer to an injured site in a vessel refer to the site of injury or upstream of the injury.
  • biodegradable polymer refers to a polymer that is biocompatible with target tissue and the local physiological environment into which the dosage form to be administered and capable of being decomposed into biocompatible products by natural biological processes. Such polymers degrade over a period of time preferably between from about 48 hours to about 180 days, preferably from about 1-3 to about 150 days, or from about 3 to about 180 days, or from about 10 to about 30 days.
  • biodegradable polymers encompassed by the present invention include polylactic acid (PLLA), polyglycolic acid (PGA), polyesthers, polyanhydride, polyiminocarbonate, inorganic calcium phosphate, polycaprolactone (PCL), aliphatic polycarbonates, polyphosphazenes, phosphorylcholine-based, hydroxybutarate valerate, and polyethyleneoxide/polybutylene terepthalate.
  • PLLA polylactic acid
  • PGA polyglycolic acid
  • PCL polycaprolactone
  • aliphatic polycarbonates polyphosphazenes
  • phosphorylcholine-based hydroxybutarate valerate
  • hydroxybutarate valerate hydroxybutarate valerate
  • polyethyleneoxide/polybutylene terepthalate polyethyleneoxide/polybutylene terepthalate.
  • the terms "effective amount of biodegradable polymer” refers to an amount of polymer that enables the loading of as much estrogen receptor agonist as possible in accordance with the present invention.
  • the precise amount of polymer thus depends on its nature and on the nature of the estrogen receptor agonist.
  • Polymers such as PEA from Medivas enables the loading of therapeutic agent in an amount about equal to its own weight (e.g. for 500 ⁇ g of polymer, up to 500 ⁇ g of estrogen receptor agonist can be loaded).
  • a top coat of polymer can also be applied in addition to this amount to decrease release speed.
  • the present invention also encompasses the chemical coupling of the estradiol receptor agonist to the polymer to slow down its release from this polymer.
  • controlled release is meant to refer to gradual release as opposed to immediate release. This type of release can be achieved with or without a polymer coating. Without being so limited, a controlled release without a polymer can be achieved with a TransluminaTM stent.
  • controlled release polymer coating refers to a polymer coating that dispenses the therapeutic agent that it contains in the body gradually. It includes delayed release, fast and slow release.
  • biological system refers to a cell or cells, a tissue or a subject.
  • the term "subject” is meant to refer to any mammal including human, mice, rat, dog, cat, pig, cow, monkey, horse, etc. In a particular embodiment, it refers to a human.
  • coronary tissue is meant to refer to coronary arteries.
  • the terms "prior to" or “before” in the context of contacting cells (or administration of) with at least two therapeutic agents refers to a release of a first agent at a time prior to (or overlapping with) the release of the second agent so that the release of the first agent starts before the release of the second agent.
  • the release of the at least two agents can be achieved either in the same delivery system or in different delivery systems.
  • the stent could have multiple coatings for controlled release enabling the release of the first agent prior to the second agent.
  • cytostatic drug refers to, without being so limited, to paclitaxel, rapamycine, sirolimus or analogs thereof, zotarolimus, everolimus, tacrolimus, and biolimus.
  • One embodiment of the invention provides a method for biologically stenting a procedurally traumatized mammalian blood vessel.
  • the method comprises administering to the blood vessel an amount of an estrogen receptor agonist in a vehicle effective to biologically stent the vessel.
  • biological stenting means the fixation of the vascular lumen in a dilated state near its maximal systolic diameter, e.g., the diameter achieved following balloon dilation and maintained by systolic pressure.
  • the method comprises the administration of an effective amount of an estrogen receptor agonist to the blood vessel.
  • the estrogen receptor agonist is dispersed in a pharmaceutically acceptable liquid carrier.
  • a portion of the amount administered penetrates to at least about 6 to 9 cell layers of the inner tunica media of the vessel (or much deeper than that in the case of where E2 is used as estrogen receptor agonist) and is thus effective to biologically stent the vessel.
  • the present invention encompasses using in the method of the invention an estrogen receptor agonist alone or in combination with an agent able to reduce expression of an estrogen receptor beta.
  • the agent is an antisense such as those described in US 7,235,534 to Tanguay et al.
  • the agent is a small interference (siRNA) or a small hairpin RNA (shRNA).
  • siRNAs and shRNAs have been successfully be used to suppress the expression of various genes in the cardiovascular field (see Dev KK. IDrugs. 2006;; 9(4):279-82; Sugano M. et al, Atherosclerosis. 2007; 191 (1 ):33-9.; Takahashi et al.
  • the present invention comprises using more than one estrogen receptor agonist.
  • the method uses E2 and an agent that blocks estrogen receptor beta.
  • the implantable device of the present invention possesses at least one of the following advantageous properties: accelerates reendothelialization, reduces macrophage infiltration, reduces leukocyte and/or platelet adhesion and reduces type I collagen levels. This last effect allows estradiol's deep penetration and its consequent reduction of migration of smooth muscle cells from the media to the injured region exposed to blood circulation as detected in the adventitia and peri-coronary muscular and white fat tissues (Figure 10).
  • the adventitia includes the vasa vasorum, small vessels which provide nutriment to the vascular wall but which are also an entry door for inflammatory cells.
  • Figure 1 presents a morphometric analysis of the stented coronary arteries 1 month post-implantation. The number of sections (n) analysed in each group is indicated between brackets;
  • Figure 2 presents an immunohistology analysis of MAC-2 expression of the stented coronary arteries 1 month post-implantation, n values indicated in brackets represent number of sections analysed by group. ( * p ⁇ 0.05 vs CypherTM, BM and PEA groups; ** p ⁇ 0.05 vs 300 ⁇ g E2 group);
  • Figure 3 presents the percentage of reendothelialization analysed by immunohistology of CD31 positive cells on the stented coronary artery 2 weeks post-implantation, n values indicated in brackets represent number of sections analysed by group. ( * p ⁇ 0.05 vs 300 ug E2); [0054] Figure 4 schematically shows two overlapping stents used in
  • Diagram demonstrates two overlapping stents in a coronary artery. The lengths of each stent and of the overlapping region are indicated in millimetre (mm);
  • Figure 5 presents the scanning electronic microscope pictures at
  • Figure 6 presents the scanning electronic microscope pictures at
  • the dashed white box indicates the enlarged region
  • Figure 7 presents the adhesion of platelets and leukocytes on the endothelium surface of stented swine coronary segments at 1 month post- implantation. Scoring was performed as described in Example 7; excluding areas of exposed struts. For those results, three (TaxusTM, CypherTM) and five (500 ug E2) stented arteries were analysed;
  • Figure 8 presents scanning electronic microscope pictures at
  • Figure 9 presents E2 concentration in stented coronary segments at different time points after stent implantation; three arteries were stented in two animals for each time point.
  • RCA right coronary artery
  • LAD left anterior descending artery
  • LCX circumflex.
  • the green dashed line represents the baseline endogenous concentration of estradiol measured in coronary arteries of an untreated age-matched control animal;
  • Figure 10 presents the quantification of estradiol in tissues in close proximity but not in direct contact with the 500ug E2 releasing stents. Quantification by GC/MS of estradiol concentration reached in the adventitia of the right coronary artery, in peri-coronary muscle, in peri-coronary white fat tissues and in the apex of the heart was performed. Tissues were isolated from two animals for each time point. Values are expressed as a mean ⁇ SEM;
  • Figure 11 presents in percentage of the initial total load, the cumulative release of E2 from stents at different time points after implantation in vivo.
  • the percentage of E2 was determined using 500 ⁇ g as the reference value. Each value is the mean ⁇ SEM of measures obtained with 3 to 6 stents.
  • Figure 12 presents the kinetic of the reduction in E2 concentration in stented coronary segments during a two-week period.
  • Stents and hormone used for the procedures were prepared by MicroPort (MicroPort Medical Co 1 Ltd. Shanghai). Stainless steel bare metal stents were of 18 mm and 23 mm length and were spray coated by MicroPort with 300 ⁇ g or 500 ⁇ g of E2 matrixed with MediVasTM poly (ester-amide) (MVPEA.I.(Ac)) tempo polymer. In addition to the polymer- steroid matrixed base coat, a 200ug MVPEA.I.(Ac).tempo protective topcoat was applied to the stents to decrease drug elution speed.
  • PEA polymer poly (ester-amide)
  • E2 stents used in Examples presented herein were prepared by MicroPort (MicroPort Medical Co 1 Ltd. Shanghai). Stainless steel bare metal stents were of 18 mm and 23 mm length and were spray coated by MicroPort with 300 ⁇ g or 500 ⁇ g of E2 matrixed with MediVasTM poly (ester-amide) (MVPEA.I.
  • the stents were sterilized by ethylene oxide at the Microport Medical Co facilities under the recommendation of Medivas.
  • the sizes of CypherTM stents were; 3 x 18 mm, 3.5 x 18 mm, 3 x 23 mm, 3.5 x 23 mm (Johnson & Johnson).
  • the sizes of TaxusTM stents were 2.25 x 12 mm, 3 x 16 mm, 3.5 x 16 mm, 3 x 24 mm, 3.5 x 24 mm (Boston Scientific).
  • the estradiol (USP) used to load the polymer poly (ester-amide) (PEA)/E2 stents was bought from Xenex labs (Coquitlam, Canada) and send to Microport.
  • the estradiol used for local delivery by catheter was the water soluble form coupled with hydroxypropyl-heta- cyclodextrin (HPCD).
  • IM Telazol [tiletamine and zolazepam] (6mg/kg) mixed with Atropine (0.05 mg/kg) before transfer to the angioplasty room.
  • the swine were intubated and ventilation started using a mixture of 70% of pure oxygen and 30% of room air. Animals were then maintained at 0.5-2% lsoflurane and supplemented with oxygen. Venous access was obtained with a 20-gauge angiocatheter in the ear vein. Maintenance intravenous hydration was provided with 0.9% sodium chloride solution at a rate of 10 ml/kg/hr, including estimated blood loss.
  • Examples presented herein 24 h, 14 days, 1 month and 3 months postprocedure, animals were re-anaesthetized and an arterial stick was inserted in the right or left femoral artery.
  • a 7 or 8 French guiding catheter was placed into the sheath and advanced via a 0.035" guide wire under fluoroscopic guidance into the treated vessels. After placement of the guiding catheter into the artery, angiographic images of the vessels were taken to evaluate the treatment site by QCA measurements.
  • Animals used in Examples 1 and 2 were euthanized and stented segments were perfusion-fixed ex vivo with 10% buffered formalin at 100 mmHg. The stented vessels were harvested and transferred to the Histology Laboratory for complete histological analysis.
  • Quantitative coronary angiography was performed pre and post stent deployment, and before sacrifice at each target vessel including proximal and distal reference segments. Each angiography was performed after intra-coronary administration of 100-200 ⁇ g nitroglycerin. Angiographic patency and the physiological responses of the vessels to all implanted stents were evaluated at 24 hours, 14 days, 1 and 3 months by QCA analysis. A balloon to artery ratio (B/A ratio) of 1.1 to 1.2:1 was achieved in all groups. No significant difference was observed in vessel diameter of the proximal (Prox) and distal (Dist) reference segments, and of the treated (Tx) coronary segment at baseline, after balloon dilation or immediately post stent implantation. EXAMPLE 2
  • vascular healing was evaluated in six animals (swine) for each type of stent (bare metal stent (BM), polymer poly (ester-amide) (PEA) only, PEA with 300 ⁇ g E2, PEA with 500 ⁇ g E2, at 24 hours, 14 days, 1 and 3 months after the stent implantation and 2 animals for CypherTM and TaxusTM at 1 month post-implantation.
  • BM bare metal stent
  • PEA polymer poly (ester-amide)
  • Stents Three stents were implanted in each animal. All animal groups were successfully completed and survived until the pre-determined time point.
  • Measurements of the neointima area (Neointima), the lumen area (Lumen), media area (Media) (i.e. thickness of intima and adventitia together), and the percentage of stenosis are summarized for control bare metal stent (BM), PEA polymer only (PEA), coated with PEA + 300 ⁇ g of E2 (300 ⁇ g E2) or PEA + 500 ⁇ g of E2 (500 ⁇ g E2) treatments) in 1 month groups in Table 1.
  • Histogram compilation of the neointima, inflammation and lumen area for stent coated with PEA, PEA + 300 ⁇ g of E2 (300 ⁇ g E2) or PEA + 500 ⁇ g of E2 (500 ⁇ g E2) of 1 month group is presented in Figure 1.
  • All the stents were patent (i.e. not occluded).
  • the 300 ⁇ g E2 and 500 ⁇ g E2 groups presented no significant difference in the degree of Ni formation with the BM, PEA, TaxusTM and CypherTM groups ( Figure 1 and Table 1 below).
  • the 300 ⁇ g E2 group had a more pronounced reduction in lumen area compared to the other groups and an increased percentage of stenosis.
  • Tx treatment T. total artery, INJ injury, Ni neoi ⁇ tima, L lumen, M media, Inf. inflammation, mm. millimeter. * p ⁇ 0,05 vs PEA group, f p ⁇ 0,05 vs BM and PEA groups.
  • Tx treatment T' total artery, [NJ injury, Nr neomtima, L 1 lumen, M media, Inf inflammation, mm: millimeter.
  • Macrophage infiltration is used as an inflammation marker and as an indication of risk of thrombosis.
  • Macrophage infiltration was evaluated using an anti-MAC- 2 specific antibody (MAC-2), a cell surface marker for macrophages. Macrophage infiltration was scored for each strut as follow: 0: absence of macrophages, 1 : very rare number of macrophage, 2: limited number macrophages, 3: high number of MAC-2 positive cells, 4: very high number of macrophages around the strut and between the struts.
  • MAC-2 anti-MAC- 2 specific antibody
  • the mean of scores of the struts corresponds to the score for the artery.
  • the 300 ⁇ g E2 group had more macrophages (mean grade of 2) than three other groups but it is comparable to infiltration levels observed with the TaxusTM stents.
  • the 500 ug E2 group had an infiltration level not statistically different to the CypherTM stents (see Figure 2).
  • Overlaps were performed with 23 mm long stents (for a dosage of E2 on the single portion of about 21.7 ⁇ g/mm) and 18 mm long stents (for a dosage of E2 on the overlap of about 27.8 ⁇ g/mm) overlapped over a 9 mm segment (for a dosage of E2 on the overlap of about 49.5 ⁇ g/mm) (Figure 4).
  • Single stents were 18 mm long (for a dosage of E2 on the overlap of about 27.8 ⁇ g/mm).
  • One CypherTM stent did not deploy properly and was therefore removed from one animal. In this animal, two single non-overlapped stents were implanted in the RCA.
  • the stented segments and the proximal and distal regions of the arteries were dissected from the formalin-fixed hearts and open longitudinally. A total of 20 stents were recovered.
  • 2 singles stented arteries and 1 arteries stented with overlapped stents were processed for SEM analysis.
  • 2 single stented arteries and 1 overlap were analyzed in SEM.
  • the other stented segments were processed for morphometry analysis.
  • the presence of platelets is an indication of activated endothelium (i.e. an endothelium that expresses certain markers following an injury) while the presence of leucocytes is an inflammation marker.
  • a qualitative evaluation of the number of platelets/leukocytes adhered to the lumen side of the artery was graded as follow; 0: absence of adhered cells, 1 : cells are usually dispersed and rare, 2: significant amount of cells (more than 40 cells in the 500X magnified region), 3: high number of cells on most of the surface (evaluated with the 100X magnified field) with presence of multiple grouped platelets, 4: very high number of cells with large aggregates (thrombus). Results are summarized in Figure 7.
  • PEA 500ug E2 and the CypherTM stents show very comparable number of adhered platelets/leukocytes with maximum number located in the center region. Also of interest is the fact that the overlap region of PEA 500ug E2 in Figure 7 is as good or better than the single stent regions. Indeed the double layer of metal usually presents an increased risk for Ni and thrombosis and this Figure shows that the PEA 500ug E2 was able to prevent this risk.
  • Stents were MicroPortTM stents
  • MVPEA. I. (Ac) MediVas poly(esteramide)
  • tempo protective topcoat was applied to the stent to prevent rapid drug elution.
  • the stents were sterilized by ethylene oxide at the Microport Medical Co facilities under the recommendation of Medivas.
  • Tissue samples and stents were analyzed for each animal for estrogen content.
  • the right coronary artery (RCA) and the left anterior descending artery (LAD) were opened longitudinally and cut into 6 pieces; 2 in the proximal region, 2 in the medial region and 2 in the distal region of the stented segment. One piece in each region was analyzed and the other one was kept as a backup.
  • the left circumflex artery (LCX) was dissected to separate the adventitia from the rest of the artery and the two fractions were analyzed individually. A total of 42 stents were recovered from 14 swine (3 stents/animal). After centrifugation, sera were collected for extraction and analysis by GC/MS.
  • Samples were reconstituted in iso-octane, final volume was adjusted to 50 ⁇ l_ and samples were injected in bench-top standard GC-MS equipment (Agilent Technologies) gas chromatograph coupled to a 5973 Mass Selective DetectorTM.
  • the injections performed by a Model 7683 Series Injector, were of 2 ⁇ l_ in the pulsed-splitless mode.
  • the carrier gas was high-purity helium.
  • An Agilent TechnologiesTM type DB-17ht capillary column was used. Ions 460 and 465, which corresponds to the [M-H] + ions of E2 and of internal standard [ 2 H 5 ]E2 respectively, were monitored with a dwell time of 50 ms per ion.
  • Estrogen quantification data was performed by Gas Chromatography/Mass Spectroscopy (GC/MS) as described above. Diffusion of E2 from the stent was determined in tissue in direct contact with the stent (coronary tissues proximal, medial, distal (see Figure 9)), in close proximity (reference proximal, reference distal, adventitia, peri-coronary muscle, peri-coronary white fat (see Figure 10)) or at distal sites potentially exposed to E2 released from the stent into the blood (carotid artery, femoral artery, apex, auricle, lung, kidney and liver).
  • GC/MS Gas Chromatography/Mass Spectroscopy
  • E2 content measured by GC/MS in the proximal, medial and distal portions of each stented coronary segment were added together. Because the arteries were subdivided in two longitudinal cuts, the value obtained was multiplied by two to extrapolate the concentration in the complete artery segment. The E2 content of the total adventitia dissected from each RCA was also determined.
  • Figure 9 shows that the mean concentration of E2 maintained in the coronary tissues was of about 10.6 ⁇ g/g of tissue during the first week after administration, and of 12.0 ⁇ g/g of tissue after 48 hours of administration.
  • estradiol could achieve deep penetration. This is advantageous because some inflammatory cells penetrate the arterial wall via the vasa vasorum of the adventitia, namely in the periphery of the vessel. This resulted in a reduction of migration of smooth muscle cells from the media to the injured region exposed to blood circulation as detected in the adventitia and peri-coronary muscular and white fat tissues (Figure 10).
  • E2 concentration in tissues at distal location from stent are in all cases, at baseline level (endogenous E2), a value determined from the same tissues isolated from swine not treated with E2.
  • E2 released from the stent in the blood stream was not sufficient to affect E2 concentration at distal sites.
  • Enhancement of E2 concentration in sera over the baseline level was detected in 5 of the 14 animals. Elevated E2 levels in the blood were still detected 24h and even 1 week after stent implantation. This could be an indication of variations of E2 content among stents or of the kinetic in E2 release or a combination of both.
  • E2 concentration remaining on the stent at different time points after implantation was also determined.
  • Stents were dissected from LAD, LCX and RCA arteries and E2 extracted for quantification by GC/MS. Results are presented in cumulative percentage of E2 released from stents at the different time points ( Figure 11 ).
  • the percentage of E2 was determined using 500 ⁇ g as the reference value. However, the real amount of E2 on each stent was known to be variable as measured in 3 intact un-deployed E2 500 ⁇ g-stents. The mean ⁇ SEM E2 concentration/stent measured was 554 ⁇ 28 ⁇ g (namely about 30.8 ⁇ g/mm of length of stent). In conclusion, 90% of E2 was eluted from the stent after 1 week, with 50% released in the first 48 hours ( Figure 11 ). It is expected that increasing the top coat thickness will alleviate this problem.
  • the obstructed artery is usually dilated using an angioplasty balloon. Then a stent of the appropriate size is guided to the targeted site. The balloon is inflated to deploy the stent with complete apposition to the arterial wall. The angioplasty balloon is deflated and removed.
  • Ghrelin has novel vascular actions that mimic Pl 3- kinase-dependent actions of insulin to stimulate production of NO from endothelial cells Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E756-64.
  • Platt MO et al. Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis Am J Physiol Heart Circ Physiol. 2007 Mar;292(3):H1479-86. 12. Cashman SM et al., Inhibition of choroidal neovascularization by adenovirus-mediated delivery of short hairpin RNAs targeting VEGF as a potential therapy for AMD. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3496- 504.

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Abstract

L'invention porte sur un dispositif implantable pour l'administration contrôlée d'un agoniste du récepteur de l'œstrogène à un site endommagé dans la lumière d'un vaisseau sanguin de mammifère, l'agoniste du récepteur de l'œstrogène étant présent dans une quantité d'au moins environ 16,7 µg/mm de longueur de dispositif implantable. L'invention porte également sur des procédés d'utilisation de ce dispositif.
PCT/CA2009/000055 2008-01-16 2009-01-16 Dispositifs implantables pour favoriser une ré-endothélialisation et leurs procédés d'utilisation WO2009089632A1 (fr)

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WO2022144810A1 (fr) * 2020-12-29 2022-07-07 Sino Medical Sciences Technology Inc. Endoprothèse à élution de médicament

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CA2381031A1 (fr) * 1999-09-21 2001-03-29 Institut De Cardiologie De Montreal Administration locale de 17-beta estradiol pour la prevention de l'hyperplasie intimale vasculaire et le renforcement des fonctions de l'endothelium vasculaire apres une lesion vasculaire
US6471979B2 (en) * 1999-12-29 2002-10-29 Estrogen Vascular Technology, Llc Apparatus and method for delivering compounds to a living organism
US6617027B2 (en) * 2000-03-31 2003-09-09 Korea Institute Of Science And Technology Biocompatible metallic materials grafted with biologically active compounds and preparation thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2381031A1 (fr) * 1999-09-21 2001-03-29 Institut De Cardiologie De Montreal Administration locale de 17-beta estradiol pour la prevention de l'hyperplasie intimale vasculaire et le renforcement des fonctions de l'endothelium vasculaire apres une lesion vasculaire
US6471979B2 (en) * 1999-12-29 2002-10-29 Estrogen Vascular Technology, Llc Apparatus and method for delivering compounds to a living organism
US6617027B2 (en) * 2000-03-31 2003-09-09 Korea Institute Of Science And Technology Biocompatible metallic materials grafted with biologically active compounds and preparation thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022144810A1 (fr) * 2020-12-29 2022-07-07 Sino Medical Sciences Technology Inc. Endoprothèse à élution de médicament

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