WO2008067273A2 - Dispositifs implantables avec surfaces de distribution de thérapie et procédés associés - Google Patents

Dispositifs implantables avec surfaces de distribution de thérapie et procédés associés Download PDF

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Publication number
WO2008067273A2
WO2008067273A2 PCT/US2007/085570 US2007085570W WO2008067273A2 WO 2008067273 A2 WO2008067273 A2 WO 2008067273A2 US 2007085570 W US2007085570 W US 2007085570W WO 2008067273 A2 WO2008067273 A2 WO 2008067273A2
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WO
WIPO (PCT)
Prior art keywords
dipyridamole
micrograms
per square
square millimeter
implantable structure
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PCT/US2007/085570
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English (en)
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WO2008067273A3 (fr
Inventor
Jing Tang
S. Eric Ryan
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Cornova, Inc.
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Publication of WO2008067273A2 publication Critical patent/WO2008067273A2/fr
Publication of WO2008067273A3 publication Critical patent/WO2008067273A3/fr

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Classifications

    • 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
    • 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
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body

Definitions

  • This invention generally relates to drug therapy delivery systems in connection with the tissue-to-surface interface of implantable devices.
  • Such systems include polymer-based coatings and drug eluting polymer coatings for intravascular implants having, in particular, anti-thrombotic and anti-stenotic characteristics.
  • a critical aspect of medical implants are their long- and short-term effectiveness and safety.
  • Potential adverse reactions to placement of intravascular implants include inflammation, restenosis (the narrowing of a blood vessel due to the undesired tissue growth about the implant) and thrombosis (the formation of a blood clot within the vessel).
  • Thrombosis in particular, can lead to serious complications and death such as from a resulting heart attack. Therefore, in addition performing their primary function (e.g. prosthesis), implants preferably include surfaces that reduce the risk of the above-identified adverse reactions.
  • a number of surface technologies have been developed for avoiding restenosis and thrombosis, including various biocompatible metallic surfaces and polymer-based drug eluting surfaces.
  • metal surfaces include corrosion-resistant noble types such as gold, platinum, silver, and alloys thereof. Restenosis rates resulting from bare-metal surfaces over a period of about 36 months have been observed to occur in about 20% to 25% of stent applications and thrombosis rates have been observed to be between about .5% and 1%.
  • surfaces have been developed that elute drugs specifically targeting, for example, restenosis and/or thrombosis. These surfaces typically include porous polymer-based coatings prepared and mixed in a manner to time-release an amount of a selected drug upon insertion into a vessel.
  • Various drug eluting technologies have shown promise by significantly reducing stenosis (e.g. down to rates of about 6.4%), however, some current studies have suggested that many of these drug eluting technologies increase the rate of the more damaging thrombosis events, particularly later- term (3-7 days and longer) thrombosis, to about 1.5%.
  • the desired effects of such drugs typically include an anti-proliferative effect to prevent the growth of cells along the vessel walls (e.g., to prevent restenosis) such as through the use of, for example, sirolimus, paclitaxel and their structurally-related derivatives.
  • Other desired effects include anti-coagulant/anti-platelet activation properties (e.g., to prevent thrombosis) through the use of, for example, heparin.
  • endothelial cells about the stent and vessel are re-formed in order to provide a smooth vessel lumen surface through which blood passes.
  • Cell cycle inhibitors including those previously disclosed, can potentially interfere with this process, leaving a roughened lumen surface.
  • the absence of proper healing and lack of further anti-thrombotic effects to the vessel walls may finally result in drastic coagulation/platelet-activation in the area and result in thrombosis and serious consequences therefrom (e.g., heart attacks).
  • many doctors will prescribe a long-term or life-long dosage of anti-coagulant drugs (e.g. Clopidogrel).
  • An aspect the invention provides a therapeutic surface coating system for implantable devices.
  • the coating system can include one or more polymer-based layers over the surface of an implantable structure.
  • a surface layer is provided which elutes a therapeutically effective dosage of dipyridamole that, in comparison to a bare metallic surface, can significantly reduce the likelihood of thrombosis and/or restenosis along the implantable structure upon deployment.
  • the implantable structure can be, for example, a stent with an underlying metallic flexible substrate.
  • a surface coating system for implantable devices is provided including an implantable structure having a surface thereon and one or more coatings layered upon the surface.
  • the coatings include a surface layer manufactured to elute, upon deployment of said implantable structure within a human, a therapeutically effective dosage of dipyridamole sufficient to significantly reduce the likelihood of at least one of thrombosis or restenosis along said implantable structure.
  • the implantable structure is a stent.
  • the effective dosage of dipyridamole includes maintaining about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surface that directly encompasses the implantable structure.
  • the surface layer elutes the effective dosage at a rate of at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period.
  • the surface layer elutes the effective dosage at a rate of between about .002 and .008 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of a target therapy period.
  • the target therapy period includes at least the initial 7 days after deployment of the implantable structure.
  • the surface layer elutes the effective dosage at a rate of between at least about .01 to .08 micrograms of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval of at least a portion of the target therapy period.
  • the portion of the target therapy period includes at least the first 3 days after deployment of the implantable structure.
  • the target therapy period includes at least the initial 7 days after deployment of the implantable structure during which period a rate of at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area is eluted during each 10 hour interval.
  • the surface of the implantable structure does not significantly elute any other therapeutically active agent other than the therapeutically effective dosage of dipyridamole.
  • a method of delivering an implantable device includes providing an implantable structure having a surface thereon, placing the implantable structure into a living subject, eluting from the surface of the implantable structure a therapeutically effective dosage of dipyridamole, the dosage being sufficient to significantly reduce the likelihood of at least one of thrombosis or restenosis along the implant structure.
  • the implantable structure is a stent.
  • eluting the therapeutically effective dosage of dipyridamole maintains about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surface directly encompassing the implantable structure.
  • eluting a therapeutically effective dosage includes eluting at least about .0022 to .008 micrograms of dipyridamole per square millimeter of the tissue surface area during each 10 hour interval for a target therapy period.
  • eluting a therapeutically effective dosage includes eluting between about .0022 to .008 micrograms of dipyridamole per square millimeter of the tissue surface area during each 10 hour interval for a target therapy period.
  • the target therapy period includes at least the initial 7 consecutive days after deployment of the implantable structure.
  • eluting a therapeutically effective dosage includes eluting between about .01 to .08 micrograms or more of dipyridamole per square millimeter of said tissue surface area during each 10 hour interval for at least a portion of said target therapy period.
  • the at least a portion of the target therapy period includes the initial 3 consecutive days after deployment of said implantable structure.
  • the target therapy period includes at least the initial 7 days after deployment of the implantable structure during which at least about .0022 to .008 micrograms of dipyridamole per square millimeter of said tissue surface area is eluted during each 10 hour interval.
  • the implantable structure does not significantly elute any other therapeutically active agent other than the therapeutically effective dosage of dipyridamole.
  • a method of stenting a vessel includes the steps of providing a stent having a surface thereon, placing the stent into the vessel, eluting dipyridamole from the surface of the stent at a rate of least about .0022 to .008 micrograms of dipyridamole per square millimeter of inner vessel surface area surrounding the stent during each 10 hour interval for a target therapy period.
  • the target therapy period includes the initial 7 days after deployment.
  • dipyridamole is eluted at a rate of about .01 to .08 micrograms of dipyridamole per square millimeter of inner vessel surface area surrounding the stent during each 10 hour interval for a period of at least 3 days.
  • an implantable device in an aspect of the invention, includes a substrate and a polymer-based layer coating the substrate.
  • the polymer-based layer has a dipyridamole-to-polymer ratio of at least about 20% by weight. In an embodiment of the invention, the polymer-based layer has a dipyridamole-to-polymer ratio of between about 20% and 30% by weight.
  • a method for eluting a locally effective dosage of dipyridamole or its derivatives from a vessel implant includes determining the approximate minimum concentration of dipyridamole in blood from an established systemic dosage for a targeted region (e.g., the cardiovascular region), translating the concentration of diyridamole in blood into an amount of dipyridamole per unit area of targeted vessel tissue (wherein substantially all of the dipyridamole in blood at an instant of time and encompassed by the tissue walls is assumed to be absorbed), and adapting a polymer-based drug-eluting coating for an implant such that it elutes a sufficient amount of dipyridamole to maintain the previously calculated dipyridamole per unit area concentration for a prescribed period of time.
  • Figs. 1 A-IB show an elution profile of dipyridamole from a polymer-coated stent in accordance with an embodiment of the invention.
  • Fig. 2 A is an illustrative side view of a stent in accordance with an embodiment of the invention.
  • Fig. 2B is an illustrative transverse cross-sectional view of a strut of the stent of Fig. 2 A, taken along section lines I-F of Fig. 2 A.
  • Fig. 3 A is a cross-sectional view of a vessel segment from a study in which a bare stainless steel stent was placed in a rat aorta.
  • Fig. 3B is a cross-sectional view of a vessel segment from a study in which a stent coated with a dipyridamole-eluting polymer was placed in a rat aorta.
  • Fig. 3C is a cross-sectional view of a vessel segment from a study in which a stent coated with a non-drug-eluting polymer was placed in a rat aorta.
  • Fig. 4 is a chart from a study including comparative measurements of neo-intimal growth associated with stents of various surface types placed in rat aortas.
  • a drug delivery system that elutes effective dosages of dipyridamole is provided so as to further improve the biostability of an implant surface.
  • Dipyridamole in various dosages, can provide anti-thrombotic benefits (CW. Kopp, et al., "Parameters of the tissue factor pathway with coumadin/dipyridamole versus ticlopidine as adjunct antithrombotic-drug regimen in coronary artery stenting," Blood Coagul Fibrinolysis, Vol. 14(4):379-86 (2003), the entire contents of which is herein incorporated by reference).
  • Dipyridamole has also been shown to have effective anti-stenotic benefits (J.P. Singh, "Dipyridamole directly inhibits vascular smooth muscle cell proliferation in vitro and in- vivo: implications in the treatment of restenosis after angioplasty", J Am Coll Cardiol., Vol. 23(3):665-71 (March 1994), the entire contents of which is herein incorporated by reference). In certain studies, dipyridamole has shown to have even a greater anti-proliferative effect than paclitaxel (SJ Kim et al., "Arterial and venous smooth-muscle cells differ in their responses to antiproliferative drugs," J Lab Clin Med. Vol. 144(3): 156-62 (2004)).
  • dipyridamole has been delivered systemically to reduce postoperative thromboembolism, particularly in patients with artificial heart components and has been used as a vasodilator in diagnostic assays.
  • a controlled dosage of dipyridamole is eluted from an implant surface so as to work at least in an anti-coagulant/anti-platelet-activation capacity, thus providing effective anti-thrombotic benefits.
  • Dipyridamole is known to provide anticoagulant/anti-platelet activation benefits in systemic dosages of, for example, between about .5 and 1.9 micrograms per milliliter volume of blood (e.g., see http://www.rxlist.com/cgi/generic3/aggrenox_cp.htm for the clinical pharmacology of the dipyridamole-based anti-thrombotic drug Aggrenox).
  • Dipyridamole has the formula 2,2',2",2'"-(4,8-dipiperidinopyrimido[5,4-d]pyrimidine-2,6-diyldinitrilo)tetraethanol or, using alternative nomenclature, 2,6-bis(diethanolamino)-4, 8-dipiperidinopyrimido- [5,4d]pyrimidine.
  • dipyridamole derivates may be appropriate, with accordingly modified dosages, including a photoreactive version consisting of a triply protected dipyridamole and photoreactive 4-azidobenzoyl group ("Synthesis of a New Photoreactive Derivative of Dipyridamole and Its Use in the Manufacture of Artificial Surfaces with Low Thrombogenicity", Bioconjugate Chem., Vol. 8(3):296-303 (1997), the entire contents of which is herein incorporated by reference). Additional appropriate derivatives are described in U.S. Patent No. 5,498,613 by Rodgers et al.,the content of which is herein incorporated by reference in its entirety.
  • Embodiments include a process for providing a target minimum (anti-thrombotic) effective amount of dipyridamole to be directly eluted into the vascular tissue from a drug- eluting implant surface. If an overstated assumption is made that, in order to be effective, all of the dipyridamole from a prescribed systemic dosage is required to be absorbed into a given cardiovascular region, an amount of drug to be absorbed for a given area of tissue can be calculated.
  • the minimal dosage per area ( ⁇ g/mm 2 ) of vessel tissue wall of length L will be about half of this radius (r) multiplied by the prescribed systemic dosage (sd): ⁇ g sd - m 1 - L sd - r mm 2 2 ⁇ r • L 2
  • a systemic dosage of between about .5 and 1.9 micrograms per milliliter of blood is translated into a steady-state tissue administration to actively maintain between about .000275 to .001 micrograms of dipyridamole per square millimeter of tissue surrounding the cylindrical form of the stent.
  • a delivery system such as a dipyridamole-carrying polymer for effecting prescribed dosages for a given area of tissue can then be developed in accordance with an embodiment .
  • the mixture of polymer to drug will depend on the area of tissue affected by the stent, the expanded drug-eluting surface area of the stent, the drug-eluting characteristics of the polymer, the drug-absorbing characteristics of the affected tissue, the targeted time period of application, and the half-life(s) of dipyridamole.
  • a wide variety of delivery systems including polymers, stents and stent sizes may be selected depending on the particular stenting application.
  • Various delivery systems include polymer-based diffusion-controlled matrix systems widely marketed and sold, swelling-controlled release systems, and bioabsorbable systems. Studies can generally be performed for characterizing and adapting the elution profile of dipyridamole for a given delivery system.
  • dipyridamole Since dipyridamole has highly hydrophobic characteristics, a substantial amount of the eluted drug is predicted to be absorbed by surrounding tissue. Further studies can be performed for determining the precise tissue-absorption behavior of dipyridamole from a drug-eluting stent. Metabolism of the drug delivered intravenously includes three half-lives known to be about 3-4 minutes for a first period, 39 minutes for a second period, and about 15.5 hours for a third half-life period (see http://www.rxlist.com/cgi/generic3/aggrenox_cp.htm for the clinical pharmocology of the dipyridamole-based anti-thrombotic drug Aggrenox).
  • a dosage level of at least about 8 times the targeted steady-state amount is delivered over each 10 hour period until about the end of the target therapy period.
  • One critical period in which to address anti-thrombotic effects is about the first 7 days after deployment, an important period for promoting proper healing around the tissue of the stent, and is also during which period there is the highest potential for thrombosis.
  • a rate of about at least 8 times .000275 to .001 micrograms (or .0022 to .008 micrograms) of dipyridamole is eluted per square millimeter of tissue surrounding the cylindrical form of the stent over about each 10 hour interval during the target period.
  • the target period is the first 7 or more days after deployment.
  • a certain amount of the drug will potentially not be absorbed (washed out) or not be evenly distributed within the targeted surrounding tissue, particularly within certain lesions resistive to diffusion (see “Handbook of Dmg-Eluting Stents,” Serruys, P. W. and Gershlick, A.H., eds., Taylor & Francis, pp. 47-56 (2005), the entire contents of which is herein incorporated by reference). Additionally, a localized dosage moderately increased in relation to the proscribed systemic dosage is not known or expected to cause significant local or systemic adverse reactions, and will generally increase the anti-restenosis effect (e.g., see Figs. 3A-C & 4 and accompanying description of results).
  • an increased elution rate of about 5 to 10 times more than what would be optimally targeted for absorption and even distribution is locally delivered over each 10 hour period until about the end of the target therapy period.
  • the target therapy period for the increased dosage is at least the first 3 days following placement of the stent, a period when adverse tissue growth can be particularly prolific.
  • a rate of at least about 5 to 10 times .0022 to .008 micrograms (or at least about .01 to .08 micrograms) is eluted per square millimeter of tissue surrounding the cylindrical form of the stent over about each 10 hour interval after deployment.
  • a rate of between about .0022 to .008 micrograms per square millimeter or more, or between about .01 to .08 micrograms per square millimeter or more is eluted over about each 10 hour interval for least 7 or more consecutive days.
  • a rate of between .01 to .08 or more micrograms per square millimeter over each 10 hour interval is eluted over the first 3 days after stent deployment and between .0022 to .008 micrograms per square millimeter or more is eluted over each 10 hour interval during the subsequent 4 days.
  • FIG. 3A, 3B, and 3C cross-sectional views of Wistar rat aortas are shown from a pre-clinical study during which were placed a bare stainless steel stent, a stent coated with a dipyridamole-eluting polymer, and a stent coated with the same polymer without dypyridamole.
  • Eighteen (18) stents (six of each type) were placed in the abdominal aortas of the rats for a period of 28 days after which the aortal segments were harvested and histologies performed.
  • Fig. 3A, 3B, and 3C cross-sectional views of Wistar rat aortas are shown from a pre-clinical study during which were placed a bare stainless steel stent, a stent coated with a dipyridamole-eluting polymer, and a stent coated with the same polymer without dypyridamole.
  • FIG. 2A is an illustrative side view of the basic geometry of a stent 50 in accordance with an embodiment and that of the stents used in the study.
  • Fig. 2B is an illustrative transverse cross-sectional view of a strut 60 of the stent of Fig. 2A, taken along section lines I-I' of Fig. 2A. Further details of the stent design used in the study and other designs in accordance with other embodiments are more fully described in U.S. Patent Application No. 1 1/613,443, published as U.S. Patent Publication No. US2007/0173925A1, the contents of which is herein incorporated by reference.
  • the stents used in the study were 9 mm in length and expanded to about 2.5 mm in diameter (from a crimped diameter of about 1 mm) within the aortas.
  • a polymer layer 80 with a dipyridamole matrix is coated over stent 50, and adhered to stent 50 with the aid of a tie-coat 70.
  • the drug-eluting polymer used in the study was of an aliphatic polycarbonate polyeurethane type combined with a tie-coat system for better adhering the drug-eluting polymer to the stainless steel substrate (embodiments of which are more fully described in U.S. Patent No. 5,254,662 and U.S. Patent Application No. 60/889,655 filed February 13, 2006, the contents of each which of which are herein incorporated by reference in their entirety).
  • the dipyridamole (Sigma® brand animal-grade Dipyridamole, 98% TLC) was mixed in the polymer solution to about a 23% ratio of drug-to- polymer by weight.
  • the polymer coating was applied to a thickness of about 10 microns while the stent was at a diameter of about 2 millimeters.
  • an elution profile is shown for dipyridamole with the same polymer system having a 30% drug-to-polymer ratio by weight, coated to a thickness of about 10 micrometers over three stents 18 millimeters (mm) in length (of a similar geometry to that placed in the rats), each roughly having a surface area of about 53 square millimeters.
  • the stents were coated while at a diameter of about 2 millimeters, and expanded to a diameter of about 4 millimeters and placed in a 37° C saline solution for 28 days. Measurements of eluted drug were taken after about .5, 1, 3, 7, 14, and 28 days via spectroscopy.
  • the elution profile indicates that the drug eluted (in reference to a surface, if present, directly surrounding the stent) would be at a rate of about .073 micrograms per square millimeter per 10 hour interval over the first 12 hours, about .061 micrograms per square millimeter per 10 hour interval over the next 12 hours, .016 micrograms per square millimeter per 10 hour period over the subsequent 2 days, .007 micrograms per square millimeter per 10 hour interval over the subsequent 4 days, and .004 micrograms per square millimeter per 10 hour interval over the subsequent 7 days.
  • a reduction in neo-intimal growth was observed for the polymer-only stent (Fig. 3C) and an even further reduction was observed for the dipyridamole-eluting polymer (Fig. 3B) in comparison to the bare metal stent (Fig. 3A).
  • the neo-intimal growth around the 18 stents placed in the rats (6 of a bare metal surface, 6 ofa polymer-only surface, and 6 of a 23% dipyridamole-to-polymer coated surface) were measured and compared.
  • dipyridamole-eluting stents were reduced by about an average amount of 23% in comparison to the bare metal stents.
  • the polymer by itself was observed to provide a reduction of neo-intimal growth of by an average amount of about 16% in comparison to the bare-metal stent.
  • improvements in biocompatibility of presently marketed metal surfaces e.g., stainless steel, cobalt-chromium
  • dipyridamole-eluting delivery systems in accordance with embodiments of the invention can provide significant anti-stenotic benefits.
  • dipyridamole In addition to providing anti-thrombotic and anti-stenotic benefits, dipyridamole is also known to have much less toxicity than drugs used with well-known eluting systems (e.g., paclitaxel-eluting and sirolimus-eluting coatings). Dipyridamole does not act substantially as a cell-cycle inhibitor or anti-cancer agent such as, for example, paclitaxel and sirolimus.
  • drugs used with well-known eluting systems e.g., paclitaxel-eluting and sirolimus-eluting coatings.
  • Dipyridamole does not act substantially as a cell-cycle inhibitor or anti-cancer agent such as, for example, paclitaxel and sirolimus.
  • dipyridamole-eluting stents in accordance with embodiments of the invention can provide anti-stenotic and anti-thrombotic benefits in a single drug while not substantially interfering with the proper-healing of vessel wall tissue and, thus, can also reduce the likelihood of late-term thrombosis subsequent to stenting.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un dispositif implantable possédant une surface de distribution de thérapie. Lors de son déploiement, la surface élue une dose thérapeutiquement efficace de dipyridamole suffisante pour réduire la probabilité de thrombose et/ou de resténose. Une dose régulière de dipyridamole est distribuée de façon à maintenir la présence du médicament entre environ o,ooo275 microgramme et 0,001 microgramme par millimètre carré le tissu entourant directement le dispositif pendant une période de thérapie cible. Ce dispositif peut être un stent cardio-vasculaire dans lequel la thérapie est appliquée pendant au moins les sept premiers jours après son déploiement.
PCT/US2007/085570 2006-11-28 2007-11-27 Dispositifs implantables avec surfaces de distribution de thérapie et procédés associés WO2008067273A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US86743806P 2006-11-28 2006-11-28
US60/867,438 2006-11-28
US88965507P 2007-02-13 2007-02-13
US60/889,655 2007-02-13

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WO2008067273A3 WO2008067273A3 (fr) 2008-12-11

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Citations (1)

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US6844044B2 (en) * 2001-06-11 2005-01-18 Sony Corporation Optical recording medium

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* Cited by examiner, † Cited by third party
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US6844044B2 (en) * 2001-06-11 2005-01-18 Sony Corporation Optical recording medium

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