WO2001010344A1 - Dispositifs medicaux liberant de l'oxyde nitrique - Google Patents

Dispositifs medicaux liberant de l'oxyde nitrique Download PDF

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Publication number
WO2001010344A1
WO2001010344A1 PCT/US2000/020566 US0020566W WO0110344A1 WO 2001010344 A1 WO2001010344 A1 WO 2001010344A1 US 0020566 W US0020566 W US 0020566W WO 0110344 A1 WO0110344 A1 WO 0110344A1
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WO
WIPO (PCT)
Prior art keywords
nitric oxide
oxide releasing
releasing compound
tissue
implant
Prior art date
Application number
PCT/US2000/020566
Other languages
English (en)
Inventor
Eugene Tedeschi
John A. Hudson
Chirag B. Shah
Original Assignee
C.R. Bard, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by C.R. Bard, Inc. filed Critical C.R. Bard, Inc.
Priority to JP2001514873A priority Critical patent/JP2003506142A/ja
Priority to EP00948985A priority patent/EP1207811A4/fr
Publication of WO2001010344A1 publication Critical patent/WO2001010344A1/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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2493—Transmyocardial revascularisation [TMR] devices
    • 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
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO
    • 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
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/12—Blood circulatory system
    • A61M2210/125—Heart

Definitions

  • the invention relates to medical devices that release nitric oxide to alter their angiogenic effect when implanted in tissue Specifically, a method for adhering nitric oxide compounds to medical devices is provided so that the nitric oxide may be released gradually while implanted within tissue Additionally, myocardial implants having nitric oxide releasing compounds are provided.
  • Ischemia causes pain in the area of the affected tissue and, in the case of muscle tissue, can interrupt muscular function
  • ischemic tissue can become infarcted and permanently non-functioning Ischemia can be caused by a blockage in the vascular system that prohibits oxygenated blood from reaching the affected tissue area
  • ischemic tissue can be revived to function normally despite the deprivation of oxygenated blood because ischemic tissue can remain in a hibernating state, preserving its viability for some time Restoring blood flow to the ischemic region serves to revive the ischemic tissue
  • ischemia can occur in various regions of the body, often myocardial tissue of the heart is affected by ischemia Frequently, the myocardium is deprived of oxygenated blood flow due to coronary artery disease and occlusion of the coronary artery, which normally provides blood to the myocardium
  • the ischemic tissue causes pain to the individual affected
  • Treatment of myocardial ischemia has been addressed by several techniques designed to restore blood supply to the affected region
  • a conventional approach to treatment of ischemia has been to administer anticoagulants with the objective of increasing blood flow by dissolving thrombus or preventing formation of thrombus in the ischemic region.
  • CABG coronary artery bypass grafting
  • Performing TMR by placing stents in the myocardium also is disclosed in U.S. Patent No. 5,810,836 (Hussein et al.).
  • the Hussein patent discloses several stent embodiments that are delivered through the epicardium of the heart, into the myocardium and positioned to be open to the left ventricle. The stents are intended to maintain an open channel in the myocardium through which blood enters from the ventricle and perfuses into the myocardium.
  • Angiogenesis the growth of new blood vessels in tissue, has been the subject of increased study in recent years. Such blood vessel growth to provide new supplies of oxygenated blood to a region of tissue has the potential to remedy a variety of tissue and muscular ailments, particularly ischemia.
  • angiogenic factors such as human growth factors produced from genetic engineering techniques. It has been reported that injection of such a growth factor into myocardial tissue initiates angiogenesis at that site, which is exhibited by a new dense capillary network within the tissue. Schumacher et al., "Induction of Neo- Angiogenesis in Ischemic Myocardium by Human Growth Factors", Circulation, 1998; 97:645-650. Encouraging the initiation of naturally occurring angiogenic mechanisms within tissue such as the release of growth factors during coagulation and fibrin formation would be a desirable method of treating ischemic tissue. It has been recognized that coagulation proteases and regulatory acting during thrombus formation may initiate vascular proliferative responses.
  • Nitric oxide (NO) may prove to be a useful compound in promoting angiogenesis in tissue.
  • nitric oxide compounds can be difficult to deliver nitric oxide effectively to tissue because it is highly volatile and its concentration diminishes too quickly to be therapeutically effective.
  • U.S. patent no. 5,676,963 discloses retaining a nitric oxide releasing compound in a polymer matrix that has been applied to an implantable medical device.
  • angiogenic implant devices for the myocardium that can reliably and controllably release nitric oxide compounds while implanted in myocardial tissue to promote angiogenic activity in that tissue. It also would be desirable to provide a mechanism for joining nitric oxide releasing compounds to a device that does not require use of a polymer matrix on the device.
  • the present invention provides methods for joining nitric oxide (NO) releasing compounds to implantable medical devices.
  • NO nitric oxide
  • the NO is believed to have an effect on angiogenic activity in tissue.
  • NO may be useful in prohibiting angiogenesis, which is useful in preventing the growth of tumors.
  • NO may hold potential in increasing angiogenic activity in tissue.
  • Tissue that would benefit from angiogenic activity may include ischemic regions of the myocardium of the heart. Therefore, angiogenic implants configured to promote angiogenesis in the myocardium of the heart could be more effective if treated to release NO in a controlled fashion while implanted.
  • the angiogenic implant devices may comprise a flexible helically spring body measuring on the order of approximately 1 to 1 ⁇ ⁇ millimeters in diameter and having a length slightly shorter than the thickness of the myocardial wall into which they are to be placed (on the order of 7-9 millimeters).
  • the devices may be made from any material, but preferably materials include: surgical grade stainless steel, nickel- titanium alloys, MP35N, or polymers either permanent or biodegradable.
  • the device may be implanted either percutaneously through a delivery catheter that has been navigated into the left ventricle of the heart and as configured to penetrate the endocardium to deliver to insert the implant.
  • the device may be delivered surgically through the epicardium over a piercing delivery device, or may be delivered transthoracically.
  • the device is not only configured to promote angiogenesis by triggering an injury response to the tissue at the implant site but also serve as a depot for carrying the nitric oxide releasing compounds and maintaining them in proximity the tissue to be treated.
  • the devices may carry other angiogenic agents such as growth factors, or may carry cellular compositions useful in regenerating ischemic tissue.
  • NO releasing compound can be reacted with organosilane to bond the NO releasing compound to the structure of the implantable device.
  • the formula for organosilane shows two classes of functionality (R n X (4 ⁇ 1) ).
  • the X group will be involved in the reaction with the substrate of the chosen medical device.
  • R is a non-hydrolyzable organic radical that possess s functionality, which will enable the coupling agent to bond with the NO releasing compounds.
  • NO releasing compound may be associated with a metal medical device material by the following steps. Applying coating of primer onto the metal surface having excess isocyanate groups. Thereafter, exposing the surface to NO releasing compounds to produce a coating that is capable of releasing NO upon activation.
  • nitric oxide is associated with a medical device surface by first, applying silane onto the surface. Next, a graft polymer is created around the surface having excess functional groups such as isocyanate. Next, the surface is exposed to NO releasing compounds, which will be capable of performing as a medical device coating capable of releasing nitric oxide upon activation.
  • NO releasing compounds are held in a hydrophilic polyurethane matrix.
  • the matrix may comprise the hydrophilic polyurethane material.
  • the polyurethane matrix may be applied to the device and permitted to cure, then submersed in an aqueous solution of the NO to permeate the matrix with the NO releasing compounds.
  • a hydrophilic polymer is applied to the surface of the device and permitted to cure after which it is exposed to the aqueous solution of NO containing adduct. The aqueous medium may then be removed by evaporation. It is an object of the present invention to provide a angiogenic myocardial implant device having associated with it nitric oxide releasing compounds.
  • FIG. 1 is a side view of an embodiment of the tissue implant device
  • FIG. 2 is a partial sectional view of the tissue implant device shown in FIG. 1
  • FIG. 3 is a partial sectional view of a variation of the tissue implant device shown in FIG. 2
  • FIG. 4A. is a side view of a tissue implant device delivery system
  • FIG. 4B is a detailed side view of the distal end of the tissue implant device delivery system
  • FIG. 4C is a detailed side view of the distal end of the tissue implant device delivery system carrying an implant.
  • FIGS. 5A-5D are diagramatic illustrations of an implant device being delivered to the myocardium by a percutaneously inserted delivery catheter;
  • FIG. 6A is a side view of a delivery device carrying an implant device to a tissue location.
  • FIG. 6B is a side view of a delivery device after releasing an implant device to a tissue location. Description of the Illustrative Embodiments
  • the present invention provides for a wide range of myocardial implants having associated with them nitric oxide (NO) releasing compounds to aid in initiating angeogenic activity in the myocardial tissue into which the device is implanted.
  • Angiogenic implants and methods for implanting them are disclosed in pending U.S. Patent Application Serial Numbers 09/073,119 09/164,163, 09/164,884, 09/164,173, 09/521 ,332, 09/299,795, 60/134,331 and 60/134,106, the entirety of which is incorporated by reference herein.
  • FIG. 1 shows an embodiment of a tubular implant device.
  • the canted coil device 40 is formed from a filament 42 of rectangular cross-section such as a strand of flat wire. As shown in FIG. 2, the coil is formed so that the major cross-sectional axis 47 of the rectangular wire is oriented at an acute angle to the longitudinal axis 50 of the coil 40 The orientation gives each turn 46 of the coil a projecting edge 44, which tends to claw into tissue to serve as an anchoring mechanism for the device.
  • FIG. 3 shows a segment of a wrapped ribbon implant embodiment.
  • the implant 60 is formed by a filament of a rectangular cross-sectional filament around a ribbed mandrel.
  • the major axis 47 of the rectangular cross-section ribbon is oriented substantially perpendicular to the longitudinal axis 50 of the implant, as is shown in FIG. 3.
  • the major axis 47 of the coils 42 of the rectangular ribbon do not extend radially from the longitudinal axis 50 of the implant 40 at an acute angle.
  • the implant is preferably formed from 316 stainless steel rectangular cross-section forming wire. Preferred dimensions for the rectangular cross-section filament are on the order of .003 inches to .005 inches for the minor axis width and .015 to .018 inches for the major axis.
  • FIGS. 4A - 4C show an example of a surgical delivery device that may be used to deliver the implants into tissue such as that of the myocardium of the heart
  • the delivery device shown in FIG 4A, comprises an obturator 80 that includes a main shaft 82, by which it can be gripped and manipulated
  • the distal end 81 of the shaft 82 is shown in detail in FIG 4B and includes a reduced diameter device support section 84 having a sharp distal tip 86 adapted to pierce tissue
  • the diameter of the shaft segment 84 is such as to fit closely within the interior of the devices
  • the proximal end of the segment 84 terminates in a shoulder 88 formed at the junction of a proximally adjacent, slightly enlarged diameter portion 90 of the shaft
  • the distal end of the device support segment 84 may include a radially projecting pin 92 dimensioned to project and fit between adjacent turns of the coils of a device The pin 92 engages the coils in a
  • the intended tissue location is first accessed surgically, such as by a cut-down method
  • the obturator with an implant device loaded on to segment 84, then may be advanced into the tissue to deliver the implant
  • the sharp tip pierces the tissue permitting the obturator and implant to be pushed inward into the tissue
  • the epicardial surface of the heart is accessed and penetrated by the obturator to deliver the implant
  • the shoulder 88 prevents proximal movement of the implant along segment 84 during delivery
  • the distal end of the obturator is projected to, and slightly beyond, the endocardium to place the implant device
  • the obturator then may be unscrewed and separated from the implant device If the obturator is configured without the pin 92, the obturator may be withdrawn directly from the device and the tissue Simply applying light closure pressure to the epicardial puncture will cause the puncture hole to clot at the epicardium
  • the implant devices may, alternatively, be
  • a delivery catheter 136 may be navigated to the left ventricle 122 over a guide wire 134 that has been previously navigated to the ventricle and anchored into the tissue by a barbed distal tip 135.
  • a guide catheter (not shown) may be navigated through the patient's vessels to reach the left ventricle 122 of the heart 120.
  • a barbed tip guidewire 134 may then be inserted through the guide catheter and into the ventricle where it pierces the myocardium 124 and becomes anchored within the tissue.
  • the steerable delivery catheter 136 may be advanced over the guidewire to become positioned within the ventricle in close proximity to the endocardium 126 to facilitate delivery of implant devices 40.
  • the guidewire lumen of the delivery catheter 136 may be eccentrically located on the catheter. Therefore, when the catheter is rotated about the guidewire, the center of the catheter will rotate through a circular path as demonstrated in FIGS. 5C and 5D, to encompass a broader delivery area with only a single guidewire placement.
  • the outside diameter of the delivery catheter is preferably less than .100 inch.
  • the delivery catheter may be provided with steering capability by means of a pull wire extending the length of the catheter and attached at its distal end such that pulling on the wire from the proximal end causes the distal tip of the catheter to be deflected.
  • the steering capability provides a broader range of delivery area with a single catheterization. A description of the construction of a delivery catheter for reaching multiple sites within the left ventricle is described in U.S. patent application serial no. 09/073,118 filed May 5, 1998, the entire disclosure of which is herein incorporated by reference.
  • FIGS. 6A and 6B show a side view of a preferred delivery device 140 for the tubular implants 40.
  • the delivery device 140 shown in FIG. 6A may be used with a conventional guide catheter or the steerable catheter 136 discussed above.
  • the delivery device 140 comprises an outer push tube 156 and an independently slidable elongate inner shaft 142 having a sharp obturator head 146 at its distal end.
  • the obturator head 146 is formed at the distal end of the inner shaft 142 by any convenient means and is configured to have a sharp, piercing tip 148.
  • a radiopaque material such as gold or platinum to make the distal area of the device visible under fluoroscopy
  • Heat bonded to the proximal end 150 of the obturator head 146 is a flexible crinkle tube 152, which may be formed from a material such as polyethylene terephthalate (PET)
  • PET polyethylene terephthalate
  • Attached to the proximal end 154 of the crinkle tube 152 by heat bonding is the push tube 156, which may be formed from a closely wound spring having a PET shrink tube formed around its outer surface to fill in the voids created by the coils
  • the crinkle tube 152 collapses under compressive load to form a random pattern of folds 158, which serve to increase the overall diameter of the crinkle tube 152 such that it comes into engagement and f ⁇ ctional contact with the interior surface of a hollow or generally tubular implant device 40 placed over it
  • the crinkle tube When placed in tension as shown in FIG 6B, the crinkle tube elongates and returns to a low diameter configuration without folds
  • the configuration of the crinkle tube is manipulated by relative movement of the inner shaft 142, having its obturator 146 joined to the distal end 155 of the crinkle tube, relative to the push tube 156, which is joined to the proximal end of the crinkle tube 154
  • the inner shaft and push tube are s dable relative to each other and may be made controllable from the proximal end of the device by a suitable handle and core wire extension
  • the device To deliver an implant device 40 to a tissue location, the device first must be loaded over the crinkle tube The push tube is moved in a distal direction and the core wire is moved in the proximal direction to compress the crinkle tube 152 effectively increasing the diameter of the crinkle tube
  • the increased diameter crinkle tube engages the interior chamber 6 of an implant device 40, holding it in place for delivery into tissue as shown in FIG 6A
  • the distal end of delivery device is then advanced distally out of the guide catheter so that the sharp tip 148 penetrates into the tissue 124 and the device 40 becomes implanted
  • the crinkle tube may be placed in tension, to withdraw the plurality of folds that engage the interior chamber of the implant 40
  • the implant device 40 After reducing the profile of the crinkle tube 152 the implant device 40 easily slides off the crinkle tube over the obturator 146 and remains in place in the tissue 124 The delivery device is then withdrawn from the tissue.
  • an NO releasing compound is adhered to a device surface directly, without requiring a polymer matrix coating first be applied to the device to hold the compounds.
  • the NO releasing compound is reacted with organosilane in a solution.
  • the reaction product is silane-NO releasing compound adduct.
  • the adduct can then be coated on a medical device such as a myocardial implant by subjecting the X group to hydrolysis. After hydrolysis, a reactive silanol group is formed that reacts with the surface of the device to form a covalent bond.
  • the organosilane first may be applied onto the device surface followed by a reaction with NO releasing compound.
  • a film-forming material may be added to the formulation for coating
  • Example 1 The following example illustrates the method.
  • a nitric oxide for nucleophile complex i.e., ((CH 3 ) 2 CHNH[N(0)NO]Na).((CH 3 ) 2 CHNH as in nucleophile residue of a primary amine that can react with silane containing isocyanate functionality (e.g., example 3-isocyanatopropyltriethoxysilane).
  • silane containing isocyanate functionality e.g., example 3-isocyanatopropyltriethoxysilane.
  • the method provides a primer for medical device materials that may not have enough free OH (oxidation) on their surface to bond the molecules.
  • the resulting addict(?) still contains NO releasing functional group (N 2 O 2 ) with added ability to bind to substrate of a medical device the surface of a medical device.
  • the surface could be metal or ceramic or plastic.
  • NO releasing compounds are retained in a hydrophilic polyurethane matrix associated with the device.
  • the matrix can be formed from an isocyanate terminal adduct reacted with a polyol, amine or other moiety that can react with an isocyanate, and adding a polyethylene oxide in the presence of a carrier organic solvent.
  • the NO releasing adduct will be soluble in the carrier organic solvent and is added to the coating mix.
  • a primer may be employed to insure a surface is present with which the polyurethane matrix may react in bond.
  • a polyurethane matrix is formed from an isocyanate terminal adduct (pre-polymer) reacted with a polyol, amine or other moiety that can react with an isocyanate and a polyethylene oxide in the presence of a media.
  • the hydrophilic polyurethane is cured onto the device surface, the device is put into an aqueous solution of the NO releasing adduct.
  • the hydrophilic substance will absorb the aqueous solution of the NO containing adduct.
  • the aqueous media is the then removed by evaporation which can be assisted by a vacuum.
  • a primer may be employed to insure a surface is present for the polyurethane matrix to become bonded.
  • a hydrophilic polymer or a hydrogel could be attached to the surface.
  • NO releasing adduct being soluble in the carrier organic solvent, it is added to the coating mix.
  • NO releasing adduct being soluble in an aqueous media
  • the hydrophilic substrate will absorb the aqueous solution of the NO containing adduct.
  • the aqueous media is then removed by evaporation which can be assisted by vacuum.
  • a primer may be employed to insure a surface to which the polyurethane matrix may react and bond is present.
  • the invention provides particularly effective angiogenic implants, useful in tissue such as ischemic myocardial tissue, that combines an device and NO releasing compounds joined to the device.

Abstract

Cette invention porte sur des dispositifs médicaux auxquels est associé un composé libérant de l'oxyde nitrique en vue de modifier l'activité angiogénique des tissus entourant l'implant. L'invention porte notamment sur des implants angiogéniques configurés pour être implantés dans le myocarde. Les composés libérant l'oxyde nitrique peuvent être assemblés au dispositif sous forme d'un revêtement de matrice polymère ou peuvent être assemblés directement à la surface du dispositif après la réaction avec l'organosilane.
PCT/US2000/020566 1999-08-04 2000-07-28 Dispositifs medicaux liberant de l'oxyde nitrique WO2001010344A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2001514873A JP2003506142A (ja) 1999-08-04 2000-07-28 一酸化窒素を放出する医療用装置
EP00948985A EP1207811A4 (fr) 1999-08-04 2000-07-28 Dispositifs medicaux liberant de l'oxyde nitrique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36811999A 1999-08-04 1999-08-04
US09/368,119 1999-08-04

Publications (1)

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WO2001010344A1 true WO2001010344A1 (fr) 2001-02-15

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PCT/US2000/020566 WO2001010344A1 (fr) 1999-08-04 2000-07-28 Dispositifs medicaux liberant de l'oxyde nitrique

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EP (1) EP1207811A4 (fr)
JP (1) JP2003506142A (fr)
WO (1) WO2001010344A1 (fr)

Cited By (21)

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WO2001085227A2 (fr) * 2000-05-10 2001-11-15 Medtronic Ave Dispositifs medicaux metalliques a liberation d'oxyde nitrique
WO2002043786A2 (fr) * 2000-11-30 2002-06-06 Medtronic Ave Inc. Utilisations de dispositifs medicaux presentant une couche de liberation d'oxyde nitrique lubrifiee
WO2003026717A1 (fr) * 2001-09-26 2003-04-03 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Dispositifs medicaux revetus a liberation d'oxyde nitrique et leur procede de preparation
US6656966B2 (en) 2000-06-22 2003-12-02 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
WO2007005910A2 (fr) 2005-06-30 2007-01-11 Mc3, Inc. Revetements d'oxyde nitrique pour dispositifs medicaux
WO2007024501A3 (fr) * 2005-08-25 2007-04-26 Medtronic Vascular Inc Polymeres biodegradables liberant de l'oxyde nitrique utiles comme dispositifs medicaux et revetements associes
WO2007126344A1 (fr) * 2006-04-27 2007-11-08 St. Jude Medical Ab Dispositif médical implantable à composition de libération
US7811600B2 (en) 2007-03-08 2010-10-12 Medtronic Vascular, Inc. Nitric oxide donating medical devices and methods of making same
US7846400B2 (en) 2007-10-30 2010-12-07 The Invention Science Fund I, Llc Substrates for nitric oxide releasing devices
US7862598B2 (en) 2007-10-30 2011-01-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US7897399B2 (en) 2007-10-30 2011-03-01 The Invention Science Fund I, Llc Nitric oxide sensors and systems
US7975699B2 (en) 2007-10-30 2011-07-12 The Invention Science Fund I, Llc Condoms configured to facilitate release of nitric oxide
US8158187B2 (en) 2008-12-19 2012-04-17 Medtronic Vascular, Inc. Dry diazeniumdiolation methods for producing nitric oxide releasing medical devices
US8221690B2 (en) 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
US8241619B2 (en) 2006-05-15 2012-08-14 Medtronic Vascular, Inc. Hindered amine nitric oxide donating polymers for coating medical devices
US8273828B2 (en) 2007-07-24 2012-09-25 Medtronic Vascular, Inc. Methods for introducing reactive secondary amines pendant to polymers backbones that are useful for diazeniumdiolation
US8642093B2 (en) 2007-10-30 2014-02-04 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US8709465B2 (en) 2009-04-13 2014-04-29 Medtronic Vascular, Inc. Diazeniumdiolated phosphorylcholine polymers for nitric oxide release
US8877508B2 (en) 2007-10-30 2014-11-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8980332B2 (en) 2007-10-30 2015-03-17 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US10080823B2 (en) 2007-10-30 2018-09-25 Gearbox Llc Substrates for nitric oxide releasing devices

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085227A3 (fr) * 2000-05-10 2002-04-04 Medtronic Ave Dispositifs medicaux metalliques a liberation d'oxyde nitrique
WO2001085227A2 (fr) * 2000-05-10 2001-11-15 Medtronic Ave Dispositifs medicaux metalliques a liberation d'oxyde nitrique
EP1623728A1 (fr) * 2000-05-10 2006-02-08 Medtronic Vascular, Inc. dispositifs médicaux métalliques à libération d'oxyde nitrique
US6887485B2 (en) 2000-05-10 2005-05-03 Medtronic Vascular, Inc. Nitric oxide-releasing metallic medical devices
US6869973B2 (en) 2000-06-22 2005-03-22 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
US6656966B2 (en) 2000-06-22 2003-12-02 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
WO2002043786A3 (fr) * 2000-11-30 2003-01-30 Medtronic Ave Inc Utilisations de dispositifs medicaux presentant une couche de liberation d'oxyde nitrique lubrifiee
WO2002043786A2 (fr) * 2000-11-30 2002-06-06 Medtronic Ave Inc. Utilisations de dispositifs medicaux presentant une couche de liberation d'oxyde nitrique lubrifiee
WO2003026717A1 (fr) * 2001-09-26 2003-04-03 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Dispositifs medicaux revetus a liberation d'oxyde nitrique et leur procede de preparation
WO2007005910A2 (fr) 2005-06-30 2007-01-11 Mc3, Inc. Revetements d'oxyde nitrique pour dispositifs medicaux
WO2007005910A3 (fr) * 2005-06-30 2007-08-23 Mc3 Inc Revetements d'oxyde nitrique pour dispositifs medicaux
US8021679B2 (en) 2005-08-25 2011-09-20 Medtronic Vascular, Inc Nitric oxide-releasing biodegradable polymers useful as medical devices and coatings therefore
WO2007024501A3 (fr) * 2005-08-25 2007-04-26 Medtronic Vascular Inc Polymeres biodegradables liberant de l'oxyde nitrique utiles comme dispositifs medicaux et revetements associes
WO2007126344A1 (fr) * 2006-04-27 2007-11-08 St. Jude Medical Ab Dispositif médical implantable à composition de libération
US8241619B2 (en) 2006-05-15 2012-08-14 Medtronic Vascular, Inc. Hindered amine nitric oxide donating polymers for coating medical devices
US7811600B2 (en) 2007-03-08 2010-10-12 Medtronic Vascular, Inc. Nitric oxide donating medical devices and methods of making same
US8273828B2 (en) 2007-07-24 2012-09-25 Medtronic Vascular, Inc. Methods for introducing reactive secondary amines pendant to polymers backbones that are useful for diazeniumdiolation
US7846400B2 (en) 2007-10-30 2010-12-07 The Invention Science Fund I, Llc Substrates for nitric oxide releasing devices
US7862598B2 (en) 2007-10-30 2011-01-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8221690B2 (en) 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
US7975699B2 (en) 2007-10-30 2011-07-12 The Invention Science Fund I, Llc Condoms configured to facilitate release of nitric oxide
US7897399B2 (en) 2007-10-30 2011-03-01 The Invention Science Fund I, Llc Nitric oxide sensors and systems
US8349262B2 (en) 2007-10-30 2013-01-08 The Invention Science Fund I, Llc Nitric oxide permeable housings
US8642093B2 (en) 2007-10-30 2014-02-04 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US8877508B2 (en) 2007-10-30 2014-11-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8980332B2 (en) 2007-10-30 2015-03-17 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US10080823B2 (en) 2007-10-30 2018-09-25 Gearbox Llc Substrates for nitric oxide releasing devices
US8158187B2 (en) 2008-12-19 2012-04-17 Medtronic Vascular, Inc. Dry diazeniumdiolation methods for producing nitric oxide releasing medical devices
US8709465B2 (en) 2009-04-13 2014-04-29 Medtronic Vascular, Inc. Diazeniumdiolated phosphorylcholine polymers for nitric oxide release

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JP2003506142A (ja) 2003-02-18
EP1207811A1 (fr) 2002-05-29
EP1207811A4 (fr) 2007-03-07

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