EP2094326A2 - Dispositif médical capable de libérer no - Google Patents

Dispositif médical capable de libérer no

Info

Publication number
EP2094326A2
EP2094326A2 EP07787993A EP07787993A EP2094326A2 EP 2094326 A2 EP2094326 A2 EP 2094326A2 EP 07787993 A EP07787993 A EP 07787993A EP 07787993 A EP07787993 A EP 07787993A EP 2094326 A2 EP2094326 A2 EP 2094326A2
Authority
EP
European Patent Office
Prior art keywords
medical device
rns
adduct
polymer
nitric oxide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07787993A
Other languages
German (de)
English (en)
Inventor
Kent Høier NIELSEN
Frederik Enemark Poulsen
Christian Jensen
Lars Niklas Larsson
Steen Guldager Petersen
Finn Munk Ulrich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arsenal Medical Inc
Original Assignee
Arsenal Medical 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
Priority claimed from PCT/DK2007/000030 external-priority patent/WO2007085254A1/fr
Application filed by Arsenal Medical Inc filed Critical Arsenal Medical Inc
Priority to EP07787993A priority Critical patent/EP2094326A2/fr
Publication of EP2094326A2 publication Critical patent/EP2094326A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • the present invention relates to the introducer sheath used during the Seldinger technique and related surgical techniques.
  • the desired vessel or cavity is punctured with a sharp hollow needle called a trocar, with ultrasound guidance if necessary.
  • a round-tipped guidewire is then advanced through the lumen of the trocar, and the trocar is withdrawn.
  • An introducer sheath is then passed over the guidewire into the cavity or vessel.
  • drainage tubes are passed over the guidewire (as in chest drains or nephrostomies). After passing of the introducer sheath, the guidewire is withdrawn.
  • the introducer sheath can be used to introduce catheters or other devices to perform endoluminal (inside the hollow organ) procedures, such as angioplasty. Fluoroscopy may be used to confirm the position of the catheter and to manoeuvre it to the desired location. Injection of radiocontrast may be used to visualise organs. Interventional procedures, such as thermoablation, angioplasty, embolisation or biopsy, may be performed.
  • a sealing device may be used to close the hole made by the procedure.
  • the Seldinger technique is used for angiography, insertion of chest drains and central venous catheters, insertion of PEG tubes using the push technique, and numerous other interventional medical procedures.
  • Charles Dotter and Andreas Gruentzig developed angioplasty. Higgs ZC, Macafee DA, Braithwaite BD, Maxwell-Armstong CA.
  • the Seldinger technique 50 years on. Lancet 2005;366: 1407-9. PMID 16226619.
  • EP 0 752 866 discloses that polymers to which are bound nitric oxide releasing N 2 O 2 " functional group may be used for the treatment of restenosis and related disorders. It was found that nitric oxide treated polyethylenimine was effective in triggering vaso-relaxation.
  • WO2005037339 which refers to expandable balloon for use in angioplasty procedures, discloses that expandable stents, used in the treatment of restenosis, may be coated with a pharmaceutical agent, such as nitric oxide (NO) and that such nitric oxide releasing matrixes may also relax or prevent arterial spasm once the medical device is in place.
  • a pharmaceutical agent such as nitric oxide (NO)
  • NO nitric oxide
  • WO2005039664 refers to a medical device, such as a guide wire, an embolization device, or a guide shaft for a microcatheter, which comprises an outer surface layer formed by electrospun nanofibers of polymeric linear poly(ethylenimine) diazeniumdiolate. It is also disclosed that nitric oxide releasing matrixes may relax or prevent arterial spasm once the medical device is in place.
  • a guide shaft for a microcatheter is a tube that covers the controlling wire along the length of the catheter from distil (site of entry) to proximal end of the microcatheter.
  • a guide shaft is not an introducer sheath.
  • the artery selected for vascular access is usually the femoral artery as it is easy to puncture and has an adequate size to insert an introducer sheath with a large diameter.
  • the procedure requires a long procedural time, such as between 6-8 hours along with bed rest in hospital and post-operative compression for the point of entry to prevent excessive bleeding. Due to the large diameter of the femoral artery, the incidence of vasospasm induced by the introduction of an introducer sheath may, in some cases be tolerated, as the medical devices can still be inserted and removed without excessive mechanical damage to the endothelial lining of the femoral artery.
  • VerapamilTM does not up-regulate endothelial nitric oxide synthase expression.
  • vasospasm can result in collapse of the blood vessel, restricting blood flow. This in turn may result in loss of function and or the body parts affected by loss of blood flow. For example, when a radial artery collapses, it may require amputation of fingers as there is insufficient blood flow to maintain all the digits on the hand.
  • the invention provides improved introducer sheaths, suitable for use in the Seldinger technique which overcomes the problems associated with mechanically induced vasospasm of the arteries at the site of insertion.
  • an introducer sheath which is either manufactured from or coated with at least one compound or composition which is capable of releasing a reactive nitrogen species, such as nitric oxide, under physiological conditions.
  • a reactive nitrogen species such as nitric oxide
  • the invention is particularly useful for use in intravascular surgery which comprises the use of the introducer sheath via access other than the femoral artery, such as via transradial access.
  • the invention provides for a medical device, suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introducer sheath, a dilator, an introducer sheath guide wire, and a trocar needle, wherein said medical device comprises a reactive nitrogen species adduct, such as nitric oxide adduct capable of releasing a reactive nitrogen species, under physiological conditions.
  • a reactive nitrogen species adduct such as nitric oxide adduct capable of releasing a reactive nitrogen species
  • the invention further provides for a kit of parts for performing vascular or neurovascular surgery which comprises at least one medical device suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introducer sheath, a dilator, an introducer sheath guide wire, and a trocar needle, wherein said medical device comprises a reactive nitrogen species adduct, such as nitric oxide adduct, capable of releasing the reactive nitrogen species, under physiological conditions, and at least one other (further) medical device used in vascular or neurovascular surgery.
  • a reactive nitrogen species adduct such as nitric oxide adduct
  • the invention further provides for a method for the manufacture of a sterilised medical device or kit of parts, suitable for use in the introduction of further medical devices into the vascular system of a living being such as by the Seldinger technique, said method comprising the following sequential steps, i) preparing a medical device, or a kit of parts which comprises at least such a medical device, which is suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introducer sheath, a dilator, an introducer sheath guide wire, and a trocar needle, wherein said medical device comprises a reactive nitrogen species adduct, such as nitric oxide adduct capable of releasing the reactive nitrogen species, under physiological conditions; ii) sterilising said medical device or kit of parts prior to use.
  • a reactive nitrogen species adduct such as nitric oxide adduct capable of releasing the reactive nitrogen species
  • the invention also provides for the sterilised medical devices or kits or parts prepared according to the methods of the invention.
  • the invention further provides for a method for the prevention and/or reduction of vasospasm (vasoconstriction) associated with the insertion of a medical device into the vascular or neurovascular system, said method comprising utilising a medical device, or a kit of parts which comprises at least such a medical device, which is suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introducer sheath, a dilator, an introducer sheath guide wire, and a trocar needle, wherein said medical device comprises a reactive nitrogen species adduct, such as nitric oxide adduct, capable of releasing the reactive nitrogen species, under physiological conditions; or a medical device or kit or parts prepared according to the methods of the invention.
  • a medical device or a kit of parts which comprises at least such a medical device, which is suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introduce
  • the invention further provides for a method for performing intravascular surgery comprising utilising a first medical device or kit or parts which comprises at least such a medical device, which is suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introducer sheath, a dilator, an introducer sheath guide wire, and a trocar needle, wherein said medical device comprises reactive nitrogen species adduct, such as nitric oxide adduct, capable of releasing the reactive nitrogen species, under physiological conditions; or a medical device or kit or parts prepared according to the methods of the invention; and secondly a further medical device, such as a further medical device selected from: Neuro medical devices, neuro guiding catheter, neuro microcatheter, neuro microwire, neurostent delivery system, neuron ballon; Coronary medical devices, coronary wires, coronary guiding catheter, PTCA angioplasty balloon, stent delivery system, coronary wires, coronary guiding catheter, PTA angioplasty balloon
  • the invention further provides for the use of a compound capable of releasing reactive nitrogen species adduct, such as nitric oxide adduct, capable of releasing a reactive nitrogen species, such as nitric oxide under physiological conditions, for the manufacture of a medical device for use in vascular or neurovascular surgery, such as for performing the Seldinger technique, for the prevention or reduction of vasospasm (vasoconstriction) associated with the insertion of an introducer sheath during said surgery, wherein said medical device is selected from an introducer sheath, a dialotor, an introducer sheath guide wire, or a trocar.
  • a compound capable of releasing reactive nitrogen species adduct such as nitric oxide adduct
  • a reactive nitrogen species such as nitric oxide under physiological conditions
  • PCT/DK2006/000714 which is hereby incorporated by reference, provides a method and system for measurement of nitric oxide release from nitric oxide adducts.
  • the method allows for the level of nitrite to be taken into account or even eliminated in order to obtain a precise measurement of NO that has not hitherto been achievable.
  • the Medical Device The Medical Device
  • a preferred reactive nitrogen species (RNS) eluting medical device is comprised of two key components: the introducer sheath including a dilator where the RNS eluting coating applied on at least the distal portion of the sheath.
  • the primary mode of action of this device is identical to that of the traditional introducer sheath : for use for the intravascular introduction of interventional and/or diagnostic devices.
  • the device according to the invention may be particularly suitable for transradial access - and in one embodiment may for a transradial introducer sheath.
  • the ancillary action of the RNS (such as the nitric oxide) elution is to prevent vessel spasm and occlusion during the introduction of interventional and/or diagnostic devices through the introducer sheath. It is envisaged that the use of the introducer sheath of the present invention will also reduce the likelihood of blood clot formation, thrombosis and related disorders.
  • a preferred device is an introducer sheath coated with a RNS (such as a nitric oxide) eluting coating applied on at least the distal 10 cm of the sheath.
  • proximal lcm of the introducer sheath is not coated.
  • the device is intended for radial intravascular introduction of interventional/diagnostic devices.
  • the primary mode of action of this device is identical to that of the traditional introducer sheath (which typically is inserted via the femoral artery).
  • the ancillary action of the device is RNS (such as nitric oxide) elution to enhance the clinical safety during the procedure decreasing vasospasm.
  • RNS such as nitric oxide
  • This is particularly a concern when using an access point other than the femoral artery - the femoral artery is typically much wider and as such the incidence or risk of vasospasm is lower.
  • the technology disclosed herein allows for other access sites to be used, for example the radial artery.
  • an 'introducer sheath' as used herein is a device which is used to introduce medical devices into the human body, such as the vascular or neurovascular system which comprises a hollow tube, typically made of a flexible material through which other medical devices are introduced into the vascular or neurovascular system.
  • Introducer sheaths are often coated with a lubricating surface or made from a lubricating material, such as TeflonTM.
  • TeflonTM TeflonTM.
  • the proximal end of the introducer sheath is exterior to the body, whilst the majority of the length of the introducer sheath is within the lumen of a vessel of the vascular system.
  • the introducer sheath typically has a length of about 10 to about 30 cm in length and a diameter of 5 or 6 french.
  • French are units which correspond to the internal diameter of the introducer sheath, and the external diameter of subsequent medical devices inserted into introducer sheath, such as catheters. 1 French is l/3 rd of a millimetre. Although wall thicknesses of the introducer sheath may vary, it is preferable to have as thin a wall as possible, whilst retaining the structural robustness of the introducer sheath.
  • the insertion of the introducer sheath involves a first act of making an incision into the human body using a hollow needle (a trocar) into an arterial wall (venepuncture). Subsequently a soft tipped guide wire is passed through the needle and the needle removed. An introducer sheath, comprising the dilator within is then passed over the guide wire. The dilator is removed and the medical device, typically comprising a catheter is passed over wire and wire is removed.
  • the medical device is not made from polytetrafluoroethylene (PTFE) (TeflonTM) or Fluorinated polyethylene (FEP).
  • PTFE polytetrafluoroethylene
  • FEP Fluorinated polyethylene
  • medical device such as the introducer sheath (tubing) is manufactured from a material which is capable of being sterilised using radiation based techniques, such as gamma radiation or e-beam.
  • Nylon is a suitable based material.
  • Other suitable materials may be selected from the group consisting of, for example ⁇ polyurethanes, aromatic polyesters, polycarbonates, polyethylenes, polystyrenes, and polysulfones.
  • the dilator may be made, for example, from high density polyethylene.
  • the medical device preferably comprises an introducer sheath.
  • the external surface of the proximal end of the introducer sheath is not coated with said RNS (such as nitric oxide) adduct.
  • RNS such as nitric oxide
  • the region of the external surface of the proximal end of the introducer sheath not coated is sufficient to reduce bleeding from the entry point into the vascular or neurovascular system, as compared to an equivalent proximally coated sheath.
  • the introducer sheath has a length of between 10 and 30cm.
  • the introducer sheath has an inner diameter of between 4 and 12 French.
  • Other sizes may be appropriate depending on the size of the patient (and their arteries), and the size of the medical device to be inserted via the introducer sheath.
  • the diameter may be between 4 and 7 French, such as between 5 - 6 French, may for example be used for radial arteries 4 French introducer sheaths may be suitable for use in small children. 8 or 9 French may be used for larger equipment to be entered via the femoral artery, and even up to 12 to 14 French for devices such as aortic stents. However, typically 5 to 6 French is sufficient for normal cardiac procedures.
  • the introducer sheath is a transradial introducer sheath.
  • the RNS coated transradial introducer sheath is particularly useful in avoiding the vasospasm associated with entry via the radial arteries.
  • the size of the introduce sheath is less than 8 french.
  • Introducer sheaths are typically manufactured as kits of parts, which in addition to the introducer sheath comprises a dilator.
  • the term 'dilator' as used herein, is a device which is inserted into the introducer sheath, which ensures the structural robustness of the introducer sheath upon insertion into the vascular system, and are removed prior to insertion of the medical device to be inserted to the introducer sheath.
  • the dilator has an outer diameter allowing a close fit with the introducer sheath, whilst not impeding its removal.
  • the dilator also has an inner diameter, through which the guide wire passes upon insertion into the patient.
  • Dilators are also made from a flexible material, and when fully inserted into the introducer sheath they typically extends beyond the distal tip of the introducer sheath, and typically comprises a tapered end which facilitates insertion of the introducer sheath/dilator into the vessel.
  • the dilator also may comprise a distal region of radio opaque material which, using X ray images, is used to locate the end of the introducer sheath assembly to ensure correct insertion.
  • the term 'guide wire for an introducer sheath' is specific term describing the guide wire which is used for guiding the insertion of the introducer sheath into the blood vessel.
  • the guide wire ranges from 0.018-0.038" (0.4572-0.9652mm) in diameter and 35-80cm in length.
  • the guide wire for an introducer sheath does not reach the site of intervention, indeed, in one embodiment it is not necessary for the guide wire to extend beyond the distal tip of the introducer sheath or dilator.
  • An introducer sheath assembly refers to a kit of parts which comprises an introducer sheath and at least one other medical device which is used during the insertion of the introducer sheath into the vascular system, for example by the Seldinger technique.
  • the Introducer sheath assembly may also comprise, in its proximal end, which is not inserted into the body, a valve to facilitate the introduction of further medical devices, such as catheters.
  • the introducer sheath may also comprise a valve to allow insertion of fluid administration such as therapeutic agents.
  • a suture ring on the valve housing may provide secure anchoring of the sheath.
  • Suitable introducer sheath assembly suitable for coating with the compound capable of releasing the RNS (such as nitric oxide) under physiological conditions is disclosed in US 5,409,463.
  • Suitable introducer sheaths for coating using the method of the invention are available from Thomas Medical Products Inc., Malvern, Pennsylvania, and may be prepared by e.g. spray coating, such as coating with the coating system and/or coating with nanofibres, such as by electrospinning (US 6,382,526, US 6,520,425).
  • the kit of parts comprises a dilator according to the invention wherein said dilator is capable of being inserted into an introducer sheath, such as the introducer sheath according to the invention, or an introducer sheath that is not coated with an RNS (such as nitric oxide) adduct.
  • the dilator may also, preferably, be capable of being inserted over an introducer sheath guide wire, such as the introducer sheath guide wire according to the invention.
  • the dilator when fully inserted into said introducer sheath, it extends beyond the distal tip of said introducer sheath, and the region of the dilator which extends beyond the distal tip of said introducer sheath comprises a tapered end which is coated with said compound capable or releasing the RNS, such as nitric oxide, under physiological conditions.
  • said compound capable or releasing the RNS such as nitric oxide
  • the region of said dilator which does not extend beyond the distal end of the introducer sheath when fully inserted is not coated with said compound capable or releasing the RNS, such as nitric oxide, under physiological conditions.
  • the kit of parts may also comprise an introducer sheath guide wire which is optionally coated in a RNS, such as nitric oxide adduct, which is capable of releasing RNS, such as nitric oxide, under physiological conditions, such as the RNS/nit ⁇ c oxide adducts and/or coating systems as referred to herein.
  • a RNS such as nitric oxide adduct
  • RNS such as nitric oxide
  • physiological conditions such as the RNS/nit ⁇ c oxide adducts and/or coating systems as referred to herein.
  • the trocar needle used for making the initial insertion may also be coated with a RNS adduct such as a nitric oxide adduct.
  • the trocar is hollow to allow passage of the guide wire through into the lumen of the vessel. Whilst it is considered beneficial that the distal portion of the trocar is coated in the RNS, such as nitric oxide adduct and/or coating systems as referred to herein, in one embodiment, the proximal end of the trocar, i.e. the portion which after insertion into the patient, is in contact with the wound site, is not coated with the RNS adduct, such as nitric oxide adduct or coating system as referred to herein.
  • the medical device according to the invention may be made from or comprise a base material which comprises the RNS adduct.
  • the medical device is pre-manufactured, and the subsequently coated with the RNS adduct.
  • the RNS donor (adduct) may be incorporated into a polymeric matrix.
  • the coating comprises of 3 layers: (i) an optional primer layer, which ensures and optimizes coating adherence to the device, (ii)
  • the RNS (e.g. nitric oxide) donating layer (first domain) which may for example be a mixture of polyurethanes or other polymers referred to herein (see under coating system) and L-PEI-NONO (LPN)(which, may for example be suitably dissolved in an alkali organic solvent, such as pyridine or pH adjusted methanol (prepared for example by addition of a suitable alkali, such as NaOH) for spray application onto the medical device).
  • the recipe for the nitric oxide (e.g. LPN) donating layer may include a pH adjusted solvent (e.g.
  • an alkali organic solvent such as an alcohol such as methanol, or pyridine
  • the alkali agent is preferably retained in the first domain to ensure that the pH of the first domain remains above 7(Ni) an optional topcoat (Outer layer/coat), which serves to ensure coating integrity, appropriate rate of water absorption and appropriate rate of RNS (e.g. NO)diffusion (and prevents systemic release of LPEI-NONO).
  • 'homogeneous' refers to a single phasic system which is uniform in structure and/or composition throughout.
  • Coats (i) and (iii) may be optional, but are preferred.
  • the method for preparing a coated medical device according to the invention consists of a first optional step of applying the priming layer (i), an second step of applying the nitric oxide adduct layer (ii), and a third optional step of applying the top coat (iii). Further coatings, as referred to herein, may be applied either before during or subsequent to the application of the nitric oxide adduct layer.
  • a topcoat When a topcoat is applied, the release of the RNS (such as nitric oxide) typically deviates significantly from a l'order release. This is due to the barrier properties of the topcoat: limiting the water absorption and the diffusion of RNS through the coating leading to a more constant release over time.
  • a priming layer Prior to application of the RNS (such as NO) adduct coating, a priming layer, as herein described, may be applied prior to application of the RNS (such as NO) adduct coating.
  • the priming layer may be applied by any suitable means, such as dipping, spaying, or extrusion.
  • the layers may e.g. be formed by dip-coating, spraying, painting, printing, vapor deposition, extrusion or a combination thereof.
  • the layers are not formed by electro spinning techniques. Spray coating has been found to be a highly convenient way of applying the domains and layers to medical devices.
  • the inner layer(s) may be textured e.g. by sanding prior to application of the outer layer, so as to obtain a textured or roughened outer surface of the inner layer providing improved bonding of the outer layer.
  • the RNS adduct (such as NO adduct) is applied either directly to the base material of the medical device, or to the primer layer or a further layer, such as the second or third domains.
  • the RNS adduct (first domain) itself may be applied, for example, in one embodiment LPEI- NONO nanofibres may be applied. Alternatively a coating system as herein described may be employed.
  • the coating system may comprise a polymer mixture applied to said external surface of the medical device, wherein said polymer mixture comprises at said at least one RNS adduct, and a hydrophilic (supporting) polymer or polymer blend, and wherein the RNS adduct and the (supporting) polymer or polymer blend form a homogeneous phase.
  • hydrophilic polymer or polymer blend typically provides support within the polymer matrix allowing transport of water and ions to the RNS adduct and transport of the RNS to the external (physiological) environment.
  • the hydrophilic polymer or polymer blend may therefore be referred to as a hydrophilic supporting polymer or polymer blend herein.
  • the pH modifying layer may include a pH modifying agent, which in a broad embodiment may include any atom, molecule or ion, including H + and OH " , capable of affecting pH by shifting the local balance between H + and OH " ions.
  • a change in pH may arise due to direct increase or decrease of H + or OH " ions by means of ingress of acid or base, or due to ingress of molecules or ions that trigger chemical reactions that confer a change of pH.
  • the NO release from NO adducts is typically sensitive to pH, with release of NO being favoured in acidic conditions, whereas HNO release is favoured in alkaline conditions. Therefore the use of a further layer which is capable of shifting the local balance between H + and OH " ions upon wetting (e.g. in physiological media) allows the release rate of the RNS, such as NO from the RNS (such as nitric oxide) adduct to be controlled.
  • the further layer of material may comprise, for example an acid, such as an acid selected from ascorbic acid, polyacrylic acid, oxylic acid, acetic acid and lactic acid. The acid may be incorporated into a polyurethane polymer for application.
  • an outer coating as herein described is also applied.
  • the outer coating may be applied directly to the coating system layer, or to one or more further layers applied to the coating system layer.
  • the donor-compound containing coating is preferably applied under conditions that are unfavourable for release, e.g. conditions of low temperature, low pressure, lower water content or low humidity.
  • premature release of the therapeutic agent is achieved by deposition of the donor- compound, i.e. therapeutic agent, under pH conditions which inhibit release of the therapeutic agent - suitably under alkaline conditions of pH greater than 7 (particularly when NO is the RNS).
  • pH conditions which inhibit release of the therapeutic agent - suitably under alkaline conditions of pH greater than 7 (particularly when NO is the RNS).
  • HNO is the RNS acidic conditions (less than pH 7 may be preferred.
  • Neutral pH may be useful for RNS adducts where both HNO and NO are desirable RNSs.
  • the method of manufacture according to the fifth aspect of the invention preferably takes place at a relative humidity of at most 40%, such as at most 30%, such as at most 25%, such as at most 20%, such as at most 15% or 10%.
  • a relative humidity of at most 40% may be maintained in the package, such as at most 30%, such as at most 25%, such as at most 20%, such as at most 15% or 10%.
  • the medical device may be manufactured and stored at a pH inhibiting such release, e.g. at a pH of at least 7, such as at least 8, 9, 10, 11, 12, 13 or 14, or, in the alternative, at a pH of at most 6, such as at most 5, 4, 3, 2 or 1. Combinations of humidity and pH and optionally other parameters may be applied to further inhibit premature release of the therapeutic agent.
  • the medical device is then packaged, and sterilised.
  • the packaging is performed in a confined environment where the relative humidity does not exceed about 40%, such as does not exceed about 30%, such as does not exceed about 20% or about about 10%.
  • the relative humidity is less than about 1%, or substantially free of water (i.e. less than 0.1% water).
  • the medical device or kit of parts is packaged in a sealed pouch, such as an aluminium sealed pouch with N 2 atmosphere.
  • the O 2 (g) is less than about 0.1%, or substantially free of O 2 (g) (i.e. less than 0.1% O 2 ).
  • the packaging should preferably prevent moisture, oxygen and light from entering the package.
  • a water absorber into the inside of the packaging material to ensure low water environment within the packaging - this not only extends the shelf life of the sealed products, but also protects the top coat during sterilisation.
  • levels of gaseous water as low as 0.01% within the packaging can be obtained (www.mgc- a. com).
  • the sterilisation is performed using radiation sterilisation, such as e- beam of gamma radiation.
  • the method of manufacture involves coating the entire external surface of the medical device. However, as described herein, in one embodiment it is advantageous to coat only part of the medical device.
  • RMS Reactive nitrogen species
  • reactive nitrogen species refers to a free radical which comprises a nitrogen atom.
  • the reactive nitrogen species has a molecular weight of less that 250, such as less than 100, such as less than 50, such as less than 40, such as less than 35.
  • the reactive nitrogen species is gas at 20°C under normal atmospheric pressure.
  • Particularly preferred reactive nitrogen species are nitric oxide (NO), and nitroxy (HNO).
  • the RNS is nitric oxide (NO).
  • the RNS adduct may therefore be an NO adduct.
  • the RNS may also be referred to as the therapeutic agent herein.
  • the RNS is (HNO).
  • the RNS adduct may therefore be an HNO adduct.
  • HNO is also considered as a highly effective vasodiolator, and as such is a suitable RNS for use in intravascular medical devices.
  • HNO can be indirectly detected N 2 O by using the propensity of HNO to undergo dimerization according to the following reaction:
  • N 2 O can then be detected by eg. gas chromatography.
  • the RNS comprises both nitric oxide (NO) and (HNO) - the RNS adduct may therefore be capable of releasing both HNO and NO under physiological conditions.
  • the RNS is applied to the medical device in the form of an RNS adduct.
  • RNS adducts Reactive nitrogen species adducts
  • the RNS is typically administered indirect as a substance which gives off the RNS as a result of a chemical reaction when wetted or exposed to enzymes or other chemicals, generally these are called RNSs adducts.
  • the RNS adducts may be monomers of polymers, and may be selected from compounds which, for example, comprise nitrosyl, nitrite, nitrate, nitroso, nitrosothio, nitro, metal-NO complex, nitrosamine, nitrosimine, diazetine dioxide, furoxan, benzofuroxan or NONOate (- N 2 O 2 " ) groups.
  • the RNS adducts may be selected from the group consisting of nitroglycerin, sodium nitroprusside, S-nitroso-proteins, S-nitrosothiols, long carbon-chain lipophilic S-nitrosothiols, nitrosocarbonyls, S-nitroso-dithiols, iron-nitrosyl compounds, thionitrates, thionitrites, sydnonimines, furoxans, organic nitrates, and nitrosated amino acids, nitroso-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, and S-nitrosopenicillamine, S-nitrosothiols, S-nitrosylated polysaccharides such as S-nitrosylated cyclodexrins, hydroxy
  • RNS adduct When referring to RNS adduct herein, it should be understood that the term refers to NO adducts, HNO adducts, and HNO/NO adducts.
  • the compound capable of releasing the RNS under physiological conditions preferably comprises a RNS-nucleophile complexes (such as NO-nucleophile complexes).
  • RNS-adduct may be monomer or a polymer.
  • RNS adducts which are monomeric molecules may be soluble or insoluble in physiological media. Suitable monomeric RNS adducts are, for example, disclosed in US 4,954,526.
  • the RNS adduct such as the NO-adduct is in the form of a polymer, such as a linear polymer, a branched polymer, and/or a cross linked polymer, to which is bound a RNS releasing functional group, such as a RNS-nucleophile complexes.
  • the RNS adduct such as the nitric oxide adduct is selected from the group consisting of: nitroglycerin, sodium nitroprusside, S-nitroso-proteins, S-nitrosothiols, long carbon-chain lipophilic S-nitrosothiols, S-nitroso-dithiols, iron-nitrosyl compounds, thionitrates, thionitrites, sydnonimines, furoxans, organic nitrates, and nitrosated amino acids.
  • nitroso-Nacetylcysteine S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso- cysteine, S-nitroso-glutathione, and S-nitrosopenicillamine, S-nitrosothiols, S-nitrosylated polysaccharides such as S-nitrosylated cyclodexrins, NONOate compounds (i.e. compounds which comprise the anionic NONOate functional group (N 2 O 2 " )), NONOate polymers.
  • NONOate compounds i.e. compounds which comprise the anionic NONOate functional group (N 2 O 2 " )
  • NONOate polymers i.e. compounds which comprise the anionic NONOate functional group (N 2 O 2 " )
  • the RNS adduct such as the nitric oxide adduct is selected from the group consisting of: nitroglycerin, sodium nitroprusside, S-nitroso-proteins, S-nitrosothiols, long carbon-chain lipophilic S-nitrosothiols, nitrosocarbonyls, S-nitroso-dithiols, iron-nitrosyl compounds, thionitrates, thionitrites, sydnonimines, furoxans, organic nitrates, and nitrosated amino acids, nitroso-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, and S-nitrosopenicillamine, S-nitrosothiols, S- nitrosylated polysaccharides such as S-nitrosyl
  • RNS adducts/NO adducts are water inducible, also refered to as proton inducible, i.e. they accept protons from ionic water, which results in the release of the RNS, such as nitric oxide, (e.g. NONOates). It is preferable that such water inducible RNS adducts are used.
  • RNS adducts such as NO adducts
  • NO adducts may also be employed.
  • enzymatic release of NO may also be utilised by incorporation of suitable enzymes into the nitric oxide adduct layer, the enzymes then become activated when the come into contact with water, causing the release of nitric oxide.
  • the RNS adduct is a NONOate, such as a polymeric NONOate selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchlo ⁇ de, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, biopolymers such as peptides, proteins, oligonucleotides, antibodies and nucleic acids, starburst dend ⁇ mers.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchlo ⁇ de, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyure
  • Polyimines represent a diverse group of polymer which may have diazeniumdiolate moieties covalently bound thereto.
  • Polyimines include poly(alkylen ⁇ m ⁇ nes) such as poly(ethylen ⁇ m ⁇ nes).
  • the polymer may be a linear poly(ethylen ⁇ m ⁇ ne) diazeniumdiolate (L-PEI-NONO) as disclosed in US 6,737,447 which is hereby incorporated by reference.
  • L-PEI-NONO linear poly(ethylen ⁇ m ⁇ ne) diazeniumdiolate
  • the loading of the nitric oxide donor onto the linear poly(ethylen ⁇ m ⁇ ne) (PEI) can be varied so that 5-80%, e.g.
  • the (L)-PEI-NONO can liberate various fractions of the total amount of releasable RNS, such as nitric oxide.
  • Polyimines with diazeniumdiolate moieties may e.g. be used as polymers for an electrospinning process because such polymers typically have a suitable hydrophilicity and because the load of diazeniumdiolate moieties (and thereby the load of latent RNS, such as NO molecules) can be varied over a broad range, cf. the above example for PEI-NONO.
  • the RNS adduct is a poly(alkylen ⁇ m ⁇ nes) diazeniumdiolate, such as PEI- NONO.
  • PEI-NONO also exists as a branched polymer, which may also be used, or a linear polymer LPEI-NONO (linear), the linear form is particularly preferred.
  • a most preferred RNS adduct polymer is polyethylenimine diazeniumdiolate, such as linear polyethylenimine diazeniumdiolate (LPEI-NONO).
  • LPEI-NONO linear polyethylenimine diazeniumdiolate
  • US 6,855,366 provides methods for the preparation to LPEI-NONO.
  • the loading of the RNS donor, such as nitric oxide onto the linear poly(ethylenimine) (PEI) can be varied so that 5-80%, e.g. 10-50%, such as about 20 to about 40%, such as about 30% of the amine groups of the PEI carry a diazeniumdiolate moiety.
  • the L-PEI-NONONO can liberate various fractions of the total amount of releasable RNS, such as nitric oxide.
  • the RNS adduct e.g. NO adduct
  • the RNS adduct such as (L)PEI-NONO is kept in an alkaline environment during the formulation and processing of the (L)PEI-NONO and the application of such (alkali) (L)PEI-NONO formulations to medical devices.
  • the invention provides for alkali stabilised formulations of polyethylenimine diazeniumdiolate, such as linear polyethylenimine diazeniumdiolate, and medical devices which comprise, such as are coated with such alkali stabilised formulations, such as medical devices which comprise at least said first domain as described herein.
  • the MW of the RNS adduct polymer such as NO adduct polymer, will, in one embodiment, such as when the RNS adduct is LPEI-NONO, depend upon the size of the starting materials used to prepare the RNS adduct, and in some cases the degree of branching of the polymer. Typically, larger polymers sizes are preferable in terms of reducing in vivo solubility, however, large polymers may also interfere with the ability to solubilise and coat the medical device.
  • LPEI-NONO the use of branched precursors results in cleavage of the molecular structure at branch points, reducing the average molecular weight of the polymer molecules present in the final NO polymer adduct Hence MW is used to define whether the LPEI-NONO is linear:
  • the RNS adduct such as the LPEI-NONO polymer has an average molecular weight of between about 5kDa and about 20OkDa, such as between about 1OkDa and about 10OkDa, such as more preferably between about 3OkDa and about 7OkDa, such as about 55kDa with a preferred polydispersity between about 1 and 3 and more preferably about 2.
  • the RNA adduct has a MW of about 3OkDa.
  • the average molecular weight is determined by size exclusion chromatography (SEC) of the polymer backbone, linear polyethyleneimine (L-PEI) using various polyethylene glycols (PEG) with known molecular weights as standards.
  • the total amount of NO in the NO loaded polymer can be determined my elemental analysis (EA).
  • EA elemental analysis
  • the average molecular weight of the RNS, such as NO, loaded polymer can be calculated based on the results from the size exclusion chromatography (SEC) and the elemental analysis (EA).
  • the RNS adduct which may form a coating (i.e. an RNS, such as NO, eluting coating), is based on with pendant NONO groups.
  • This group is stabilized by the formation of a Zwitter-ion complex with an adjacent -NH 2 + - amine group in the L-PEI backbone.
  • Nitric oxide loaded linear polyethyleneimine releases the nitric oxide when it is exposed to a proton donating (H + ) environment like ionized water or blood.
  • the device is stored in a sealed aluminum pouch with N 2 atmosphere.
  • the product is thereby protected against moisture, light and oxygen during storage.
  • the RNS such as nitric oxide
  • dose delivered to the vessel wall is determined by the release rate and the time in contact with the artery wall.
  • the dose delivered to the target i.e. the smooth muscle cell (SMC) depends furthermore on the thickness of the vessel wall, potential plaque, presence of blood/hemoglobin, the presence of oxygen and the diffusion constant D.
  • polymeric NONOates such as those which contain diazeniumdiolate groups can generate undesirable small molecule side products such as nitrosamines (see US 6,875,840).
  • the present invention overcomes the potential generation of undesirable small molecule side products, whilst allowing controlled release of the RNS, such as nitric oxide, under physiological conditions by the incorporation of polymeric NONOates, such as polyethyleminine diazeniumdiolate, in a hydrophilic (support) polymer or polymer blend.
  • LPEI-NONO solubility of LPEI-NONO in physiological fluids presents a previously unrecognized problem relating to its use to coat medical devices, such as intravascular medical devices in that the release of LPEI-NONO from the medical device into the blood stream will result in the systemic release of LPEI-NONO and undesirable release of nitric oxide at sites remote to the site of therapy.
  • an outer-coat layer external to the LPEI-NONO layer which effectively reduces the release of LPEI-NONO to an insignificant concentration upon insertion into body fluid, such as blood.
  • the outer-coat can have a beneficial controlling effect upon the release kinetics of the RNS, such as nitric oxide from polyethylenimine diazeniumdiolate coated medical devices
  • the RNS such as NO
  • the properties of the outer-layer, and in some respects the first, second and third domains, as referred to herein, particularly the nature of the hydrophilic support polymer/polymer blend used in said domains, are important in determining (i.e. controlling) the nature of this initial period.
  • Diazeniumdiolates as an example of an RNS adduct, can act both as NO and/or as HNO donors depending on whether the are attached to a primary (HNO donor) or an secondary (NO donor) amine.
  • the NO -release from NONO'ates is pH-dependant and follows first order kinetics. Hence the only requirements for NO release are an aqueous environment and sufficient amounts of protons (Dutton et al, 2004).
  • the overall reaction with H + results in 2 NO and a secondary amine group on the Nitric Oxide donor.
  • HNO release is known to occur from e.g. diazeniumdiolates linked to a primary amine by a pH dependent release mechanism expected to occur as illustrated below, (e.g. Miranda et al., 2005)
  • LPEI-PEI-NONO linear Polyethylenimine diazeniumdiolate
  • L-PEI-NONO covalently bound NONO-groups
  • other polymers such as biocompatible polymers. This results in NO being released from a LPEI- NONO coated product (no small molecule by-products).
  • NO-donors such as sodium nitroprusside, molsidomine, and the nitrate esters requires redox activation in order to release the NO and the more recently introduced agents of the S- nitrosothiol family which can release NO through hemolytic cleavage, forming reactive thiyls as a by-product, or through trace transition metal (concentration dependant) catalytic breakdown, forming disulfide in the process (Singh et al., 1996). They are also prone to produce larger amounts of by-products, such as nitrite and nitrate and the small molecule donors are generally more toxic than the polymeric donors.
  • density (i.e. concentration) of application of the RNS adduct, such as polyethylenimine diazeniumdiolate onto the surface of the medical device is between about 0.05 and about lOOmg/cm 2 , such as between about 0.1 and about 10 mg/cm 2 , such as preferably between about 0.2 and about 3 mg/cm 2 .
  • density (i.e. concentration) of application of the RNS adduct, such as polyethylenimine diazeniumdiolate onto the surface of the medical device is between about 0.05 and about 200 ⁇ mol NO/cm 2 , such as between about O.land about 20 ⁇ mol NO/cm 2 , such as preferably between about 0.5 and about 3 ⁇ mol NO/cm 2 .
  • alkali stabilised formulations of polyethylenimine diazeniumdiolate such as linear polyethylenimine diazeniumdiolate
  • medical devices which comprise, such as are coated with such alkali stabilised formulations, such as medical devices which comprise at least said first domain as described herein.
  • a key aspect in controlling this premature release of nitric oxide from polyethylenimine diazeniumdiolate is therefore to increase the pH of the polyethylenimine diazeniumdiolate (local environment - e.g. first domain) to above 7, such as between pH 8 and 13.
  • Alkaline formulations of polyethylenimine diazeniumdiolate are typically made by dissolving the polyethylenimine diazeniumdiolate in alkalinized organic solvents, such as alcohols, such as ethanol and methanol, tetrahydrofurane, pyridine, and the like.
  • alkalinized organic solvents such as alcohols, such as ethanol and methanol, tetrahydrofurane, pyridine, and the like.
  • the alkalinized solvents are typically prepared by dissolving suitable alkali compounds (bases) prior to the addition of the (L)PEI-NONO polymer.
  • the OH " added should be between about 1 mM to about 100 mM OH- such as between 10 mM to about 75 mM OH- such as about between 20 mM and about 50 mM,
  • the pH of the solvent is modulated by adjusting the amount of alkali added.
  • PEI-NONO polyalkylenimine diazenumdiolates
  • suitable alkali agents such as inorganic alkali, such as NaOH, KOH, Ca(OH) 2 , and LiOH, or organic alkali, such as lithium diisopropylamide and methylamine.
  • the alkali may be an alkoxide such as methoxide or ethoxide.
  • the alkali may be a organiic or inorganic alkali buffer such as phosphate, ethanolamine, ADA, carbonate, ACES, PIPES , MOPSO, imidazole, BIS-TRIS propane, BES, MOPS, HEPES, TES, MOBS, DIPSO , TAPSO, triethanolamine (TEA), pyrophosphate, HEPPSO, POPSO, tricine, hydrazine, glycylglycine , Trizma (tris), EPPS, HEPPS, BICINE, HEPBS, TAPS, 2-amino-2-methyl-l,3-propanediol (AMPD), TABS, AMPSO, taurine (AES), borate, CHES, 2-amino-2-methyl-l-propanol (AMP), glycine , ammonium hydroxide, CAPSO, carbonate, methylamine , piperazine, CAPS, CABS, and pipidine.
  • the pH of the first domain is such that the OH ' concentration is between about 0.02 mM to about 2 mM OH " such as between 0.05 to about 1 mM OH " such as about 0.1 mM.
  • alkali methanol such as NaOH dissolved in methanol (typically at a concentration of between 0.1 and 10 ⁇ g/ml, such as between 1 and 2 ⁇ g/ml, such as about 1.67 ⁇ g/ml).
  • the RNS adduct such as nitric oxide adduct
  • the RNS adduct is in the form of a coating applied to at least part of the external surface of the medical device according to the invention. This may be referred to as an RNS coating herein.
  • the medical device according to the invention comprises a RNS adduct, such as nitric oxide adduct, in the form of a coating system comprising a polymer mixture, wherein said polymer mixture comprises said RNS adduct, and a hydrophilic polymer or polymer blend, and wherein the said RNS adduct, and the supporting polymer or polymer blend form a homogeneous phase.
  • a RNS adduct such as nitric oxide adduct
  • the hydrophilic polymer or polymer blend is a hydrophilic supporting polymer or polymer blend.
  • the coating system preferably comprises an antioxidant, such as a sterically hindered phenolic antioxidant (eg. Octadecyl-3-(3,5-di-tert.butyl-4-hydroxyphenyl)-propionate, tradename Irganox 1076, Ciba specialty chemicals), such as between about 0.01 and 1%; such as between about 0. 1% and 0.5% (w/w).
  • an antioxidant such as a sterically hindered phenolic antioxidant (eg. Octadecyl-3-(3,5-di-tert.butyl-4-hydroxyphenyl)-propionate, tradename Irganox 1076, Ciba specialty chemicals), such as between about 0.01 and 1%; such as between about 0. 1% and 0.5% (w/w).
  • the term 'hydrophilic' refers to a substance which has a higher solubility in water than in oil or other hydrophobic solvents. Hydrophilic molecules are capable of forming hydrogen bonds, which makes then soluble not only in
  • the use of such a polymer mixture can control the release of the RNS adduct, such as nitric oxide adduct, from said inner layer into the physiological medium.
  • the embodiment of the RNS releasing adduct will be improved to minimize the release of the RNS releasing adduct into the surrounding environment.
  • This is particularly of relevance for the medical devices, such as transient medical devices, where the release of the RNS adducts may lead to a low level of undesirable systemic effects, and may therefore also require more stringent regulatory approval process.
  • the use of the polymer matrix can prevent the leakage of small molecule by-products from said polymer mixture into the physiological medium.
  • the use of the polymer mixture is also a key determinant in controlling the rate and timing of the release of RNS, such as nitric oxide from said inner layer into the physiological medium. This is controlled by adjusting the polymer or polymer blend to balance the level of support compared to hydrophilic characteristics, thereby creating the desired structure which can provide the controlled diffusion of water from the physiological medium into the inner layer under physiological conditions to release the RNS.
  • Parameters important for the RNS releasing adduct are, as mentioned above, good stability, a fast activation of the RNS release, a continuous release within physiological relevant concentration and ensuring no, or minimal, release of the RNS releasing polymer into the external environment.
  • the polymer mixture should show a good water conductance performance.
  • this parameter can be measured by determining the release rate of RNS from a RNS adduct coated with the polymer and a suitable RNS adduct. This may be achieved by supplying a polymer with high water conductance and a high water conductance/swelling ratio to the RNS releasing polymer layer.
  • the polymer mixture, polymer blend, coating system, and/or hydrophilic polymer should allow water transport into the RNS adduct layer rapidly enough to induce a increase in RNS release of about 0.01 to about 50 nmol cm "2 min "1 per minute such as about 0.25 to about 20 nmol cm “2 min “1 per minute such as preferably between 0.5 to about 10 nmol cm “2 min “1 per minute when measured at the maximum rate of increase of RNS release (see Figure 6).
  • This may be determined by preparing a 30% LPEI-NONO, 70% hydrophilic polymer (or polymer mixture or polymer blend), on an inert base material such as nylon, and measuring the rate of release of RNS (e.g.
  • the RNS (e.g. NO) adduct used to determine the RNS (e.g. NO) release may be the LPEI-NONO as prepared in the example 1.
  • the hydrophilic polymer or polymer blend when used in the homogeneous polymer blend, provides a water (proton) transport rapidly enough to obtain a maximum rate of increase of RNS release with a slope of about 0.01 and about 80 (nmol/min/cm 2 )/min. when inserted into physioloigical conditions, such as when inserted into phosphate buffered saline, pH 7.4 at 37°C.
  • the ratio of polymer mixture to said RNS (e.g. NO) adduct present in the coating system is between about 5/95 to about 95/5, such as between 40/60 and 90/10, preferably between about 50/50 and about 80/20, such as about 70/30, as measured weight/weighty
  • the RNS (e.g. NO) donor itself may be form the hydrophilic or support polymer, or polymer blend, and as such the RNS (e.g. NO) adduct is suitable for use as a coating system per se.
  • the coating system may comprise up to 100% of the RNS (e.g. NO) adduct.
  • the hydrophilic polymer may be selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, silicones.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, silicones.
  • polystyrene resins More specifically they may be selected from the group consisting of: aromatic polyurethanes, ethylene acrylate polyolefins, hydrophilic aliphatic polyurethanes or silicones, all with a high ratio of water conductance towards water absorbance.
  • aromatic polyurethanes ethylene acrylate polyolefins
  • hydrophilic aliphatic polyurethanes or silicones, all with a high ratio of water conductance towards water absorbance.
  • These polymers can be selected from the tecophilic, estane, EMAC and EBAC polyolefins families or high water vapour conducting silicones.
  • the support polymer may be selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes with good adhesion and structural stability, fulfilling the stability criteria stated above.
  • it could preferably be an aliphatic polyether- based polyurethane such as eg. Tecoflex SG 85A.
  • the ratio of support polymer to hydrophilic polymer used in the coating system can be between about 95/5 to about 35/65. by weight depending on the characteristics of the polymers used. In one system, using an aliphatic polyether-based polyurethane together with an aromatic polyurethane, the ratio can vary from about 90/10 to about 50/50 by weight.
  • the ration of support to hydrophilic polymer used in the coating system is about 70/30 by weight.
  • the ratio of support polymer to hydrophilic polymer is a ratio which excludes the NO adduct, which is also present in the coating system.
  • the NO adduct may itself be part of either of the hydrophilic and/or supporting polymer.
  • the NO adduct is not the supporting polymer or hydrophilic polymer referred to in the coating system, although may comprise support and/or hydrophilic properties.
  • Suitable methods for the preparation of hydrophilic and/or supporting polymer nitric oxide adducts are disclosed in US 5,405,919 or other references referring to synthesis of NO polymers, such as those referred to herein.
  • the thickness of the coating system is between about 1 to about 100 ⁇ m, such as between 5 and about 20 ⁇ m in dry state.
  • the coating or coating system comprising the nitric oxide adduct is applied to the exterior surface of said medical device by one or more of the following methods: spray coating, painting, dipping.
  • the RNS (e.g. NO) adduct may be in the form of a first domain in the form of the coating system referred to herein.
  • the first domain is a discrete domain which does not form a homogenous phase with the second domain, if present (See figure 7, for examples).
  • the first domain may be in the form of a uniform layer of approximately uniform thickness ( Figure 7A-E).
  • Figure 7F to I for example.
  • the first domain may comprise the hydrophilic polymer or polymer blend combined with one or more alkali (base) agents or basic side groups.
  • the hydrophilic polymer or polymer blend suitable for use in the first domain is described in EP application No. 06023223 and US provisional 60/864,886, and PCT/DK2007/00030.
  • the first domain may form discrete particles, such as nanoparticles, which are embedded into a further domain, such as the second domain.
  • the second domain may form discrete particles which are embedded in a further domain, e.g. the outer-layer and/or the first domain (see Figure 7, F to I for example).
  • the first domain forms a homogeneous layer.
  • the first domain or coating system is not in the form of, or does not comprise, LPEI-NONO fibres, such as electrospun fibres or nanofibres.
  • the first domain or coating system forms a homogeneous phase.
  • the first domain or coating system is not heterogeneous.
  • the pH of the first domain or coating system may be controlled in numerous ways known in the art.
  • (L)PEI-NONO is typically dissolved in a nonaqueous solvent,
  • the first domain or coating system is an alkaline domain, i.e. when it comes into contact with a suitable solvent, for example water
  • the pH of the local domain is above pH 7, such as above about pH 7.5, such as above about pH 8, such as above about pH 9, such as above about pH 10, such as above about pH 11, such as above about pH 12, such as above about pH 13, such as about pH 14, or such as between above pH 7 and about pH 14.
  • the pH of first domain is between about pH 9 and about pH 12, most preferred between about pH 8 and about pH 11, such as between about pH 9 to about pH 10.
  • high pH e.g. 12 and above, the polymer systems, such as the hydrophilic support polymer/polymer blend, that the high pH can alter the physical properties of the polymer, which in some cases may be detrimental, for example high pH may effect the stability of the coating systems.
  • the first domain when the RNS is NO, therefore typically comprises an alkaline compound which may be organic or inorganic.
  • Suitable inorganic alkali compounds include by way of example NaOH, KOH, Ca(OH) 2 , and LiOH.
  • Suitable alkali organic compound include, by way of example lithium dnsopropylamide and methylamine or methoxide.
  • the alkali compound may be a alkaline buffer, such as a buffer selected form the group consisting of: phosphate (pK2), ethanolamine, ADA, carbonate (pKl), ACES, PIPES , MOPSO, imidazole, BIS-TRIS propane, BES, MOPS, HEPES, TES, MOBS, DIPSO , TAPSO, t ⁇ ethanolamine (TEA), pyrophosphate, HEPPSO, POPSO, t ⁇ cine, hydrazine, glycylglycine (pK2), T ⁇ zma (t ⁇ s), EPPS, HEPPS, BICINE, HEPBS, TAPS, 2-am ⁇ no-2-methyl-l,3-propaned ⁇ ol (AMPD), TABS, AMPSO, taurine (AES), borate, CHES, 2-am ⁇ no-2-methyl-l-propanol (AMP), glycine (pK2) , ammonium hydroxide
  • the alkaline compound may also be an alkaline polymer, such as a polymer containing a inorganic or organic base, such as an alkaline side group.
  • the alkaline compound including alkali polymers, preferably has a pKb of less than 6, more preferable a pKb of less than 5.
  • the alkali compound or group may be selected from the group consisting of a primary amine, a secondary amine and a tertiary amine.
  • the alkali compound or group may be selected from the group consisting of lithium dnsopropylamide, methylamine, and chloroquine.
  • the first domain typically comprises a further polymer, such as a polyurethane, or a hydrophilic polymer or polymer blend as referred to herein (see under coating systems).
  • a further polymer such as a polyurethane, or a hydrophilic polymer or polymer blend as referred to herein (see under coating systems).
  • the first domain may comprise a polymer selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchlo ⁇ de, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, silicones.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchlo ⁇ de, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, silicones.
  • the first domain may comprise a polymer selected from the group consisting of: aromatic polyurethanes, et hylene acrylate polyolefins, hydrophilic aliphatic polyurethanes or silicones, all with a high ratio of water conductance towards water absorbance.
  • aromatic polyurethanes et hylene acrylate polyolefins
  • hydrophilic aliphatic polyurethanes or silicones all with a high ratio of water conductance towards water absorbance.
  • These polymers can be selected from the tecophihc, estane, EMAC and EBAC polyolefins families or high water vapour conducting silicones.
  • the first domain may comprise a polymer selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchlo ⁇ de, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes with good adhesion and structural stability, fulfilling the stability criteria stated above.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchlo ⁇ de, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes with good adhesion and structural stability, fulfilling the stability criteria stated above.
  • it could preferably be an aliphatic polyether-based polyure
  • PCT/DK2007/000030 provides further examples of the different domains, including further domains.
  • the second domain is a discrete domain which does not form a homogenous phase with the first domain (see Figure 7 for example).
  • the second domain may be in the form of a uniform layer of approximately uniform thickness - see Figure 7 A and B for examples.
  • the second domain may be in many other forms.
  • the second domain may comprise the hydrophilic supporting polymer or polymer blend combined with one or more acidic agents or acidic side groups.
  • the hydrophilic supporting polymer or polymer blend suitable for use in the second domain is described in EP application No. 06023223 and US provisional 60/864,886.
  • the second domain may form discrete particles, such as nanoparticles, which are embedded into a further domain, such as the first domain.
  • the second domain may form discrete particles which are embedded in a further domain, e.g. the outer-layer and/or the first domain (see e.g. figure 7).
  • the second domain may also comprise (L)PEI-NONO. However, in one preferred embodiment, the second domain does not comprise (L)PEI-NONO.
  • the second layer is not in the form of, or does not comprise, LPEI-NONO fibres, such as electrospun fibers or nanofibers.
  • the second domain forms a homogeneous phase.
  • the pH of the second domain may be controlled in numerous ways known in the art.
  • the second domain may e.g. comprise ascorbic acid, polyacrylic acid, lactic acid, acetic acid and/or oxylic acid as H + -releasing agents for affecting release of the therapeutic agent from the first domain.
  • the second domain may comprise a polymer which is acidic, or comprises acidic side groups, which are capable of releasing protons upon contact with water.
  • Further acidic agents or side groups, which may be used in the second domain include lactic acid or vitamin C, and/or an acid agent selected from the group consisting of: ascorbic acid, polyacrylic acid, oxylic acid, acetic acid and lactic acid.
  • the acidic agent may have a pKa of less than 6, more preferable any organic acid with a pKa of less than 5.
  • the acidic agent is an inorganic acid, such as hydrochloric acid, sulphuric acid, nitric acid or hydrobromic acid.
  • the acidic agent may be, or comprise an acidic buffer, such as a buffer selected form the group consisting of: maleate, phosphate, glycine, citrate, glycylglycine, malate, formate, , succinate, acetate, propionate, pyridine, piperazine, cacodylate, MES, , maleate, histidine, bis-t ⁇ s, ethanolamine, ADA, and carbonate.
  • an acidic buffer such as a buffer selected form the group consisting of: maleate, phosphate, glycine, citrate, glycylglycine, malate, formate, , succinate, acetate, propionate, pyridine, piperazine, cacodylate, MES, , maleate, histidine, bis-t ⁇ s, ethanolamine, ADA, and carbonate.
  • the acidic compound may be, in one embodiment, a polymer containing an inorganic or organic acid such as a side group.
  • the acidic compound, such as the acidic polymer comprises carboxylic groups.
  • the acidic compound may therefore be a fruit acid, or an equivalent, for example a hydroxy acid, or an acidic derivative thereof.
  • the second domain may be either internal or external to the first domain.
  • the second domain is capable of affecting the pH of the first domain by shifting the local balance between H + and OH " ions upon wetting of at least a portion of the medical device, i.e. the second domain is capable of reducing the pH of the first domain upon wetting of at least a portion of the medical device. Therefore release rate of the nitric oxide from the first domain is dependent on the pH of at least one of the first domain and in one embodiment the second domain.
  • the second domain is an acidic domain, i.e. when it comes into contact with a suitable solvent, for example water, the pH of the local domain is below pH 7, such as below about pH 6.5, such as below about pH 6, such as below about pH 5, such as below about pH 4, such as below about pH 3, such as below about pH 2, such as about pH 1, or such as between below pH 7 and about pH 1.
  • the pH of the second domain may, for example be between about pH 2 and about pH 6. or between about pH 3 to about pH 5.
  • the acidity can effect the physical properties of the polymers used in the second coat, and this may effect the stability of the coat detrimentally.
  • the medical device is at least partially coated with both a first and a second domain.
  • the first domain comprises a first coating layer of the device which is applied to, or is immediately adjacent to, either the base material of the medical device or the primer layer.
  • the second domain may therefore comprise a second coating layer of the device which is applied to, or is immediately adjacent to said first coating
  • the release rate of the RNS (e.g. NO) from the first domain is dependent on the pH of at least one of the first domain and/or the second domain.
  • the first and second domains may have any form or shape, however, layered structures are preferred, such that the first domain forms one coating layer and that the second domain forms another coating layer.
  • the medical device may be coated with one material forming the second domain as an initial surface coating, which subsequently is being covered with another material forming the first domain as a further coating layer onto of the initial surface coating.
  • the donor-compound containing layer i.e. first domain
  • the pH modifying layer i.e. second domain
  • the pH modifying layer i.e. second domain
  • the two layers may be applied simultaneously, for example by extrusion of two independent layers, or by coating of a layer which comprises both the first and second domains, e.g. for example when the first and/or second domains are in the form of particles, one domain may form a 'matrix', whist the other domain forms discrete (i.e. non- homogeneous) particles, such as nano-particles within the 'matrix' domain, or both first and second domains may be in the form of discrete particles within a suitable matrix composition, such as the hydrophilic supporting polymer or polymer blend referred to herein.
  • a suitable matrix composition such as the hydrophilic supporting polymer or polymer blend referred to herein.
  • the first domain is capable of releasing one or more therapeutic agents, the release rate being e.g. dependent on the pH of the domain.
  • the second domain is capable of affecting the pH of the first domain by release of H + ions, upon wetting of at least a portion of the medical device, the pH of the first domain decreases upon wetting of a portion of the device, and accordingly the release of the therapeutic agent is triggered or enhanced.
  • the present invention provides for the controlled release of the therapeutic agent (typically nitric oxide or HNO) in dependency of the humidity or water content of a portion of the medical device, such as the water content of the second domain.
  • the second domain is wetted by blood upon entry into the vascular system of a human or animal body.
  • the timing of the release of RNS may be further influenced by the arrangement of the first and second domains, and by the addition of further layers, such as the outer-coat.
  • the second domain is applied prior to, i.e. is interior to, the first domain. This ensures that as the protons diffuse out of the second domain to the external environment they must pass through the first domain, thereby ensuring the maximum RNS (e.g. NO) release.
  • RNS e.g. NO
  • the first domain is also referred to as the bioactive domain
  • the second domain is also referred to as the pH active domain.
  • the first domain is also pH active, but in contrary to the second domain the pH (or potential pH upon wetting) of the first domain is alkaline, where as the pH (or potential pH upon wetting) of the second domain is acidic.
  • the medical device may comprise a third domain.
  • the third domain may be an additional domain which is positioned between the first domain and the second domain.
  • the medical device may comprise a first domain and a third domain.
  • the third domain may be a neutral layer, which controls the rate of influx of water (and protons) from the body fluid (optionally via the second domain) into the first domain.
  • the third domain may, in one embodiment, comprise a buffer, which limits the influx of protons into the first domain, thereby providing for 'long and low' RNS (e.g. NO) release kinetics.
  • the third domain comprises or consists of the hydrophilic supporting polymer or polymer blend as referred to herein, such as that disclosed in EP application No. 06023223 and US provisional application 60/864/886.
  • the third domain consists or comprises a hydrophilic polymer.
  • the third domain consists or comprises a hygroscopic polymer.
  • the third domain may comprise a buffer, such as a buffer of pH around 7, when it comes into contact with water.
  • the third domain can control the rate at which the protons diffuse from the second domain into the first domain by acting as a proton quencher. This is useful when the medical device may come into contact with water or water vapour prior to the time at which the therapeutic release is required or optimal.
  • the third domain can act as a -OH quencher, preventing the undesirable alkalisation of the acidic layer.
  • the thickness of the third domain may, for example be between about O. l ⁇ m and about lO ⁇ m, such as between l ⁇ m and about 5 ⁇ m.
  • the third domain does not comprise a buffer. In one embodiment the pH of the third domain is about 7.
  • composition of the outer-coat and the third layer may, in one embodiment be identical.
  • the coating comprising the RNS adduct, such as the nitric oxide adduct is applied to the exterior surface of said medical device in the form of fibres such as nanofibres, such as electrospun nanofibres (such as the polyethylenimine diazeniumdiolate nanofibres disclosed in US 6,382,526, US 6,520,425).
  • nanofibres such as electrospun nanofibres (such as the polyethylenimine diazeniumdiolate nanofibres disclosed in US 6,382,526, US 6,520,425).
  • fibres/nanofibres may also be encased in the polymer system as described herein.
  • the fibres/nanofibres may be applied directly to the surface of the medical device or a primer layer as described herein.
  • the fibres/nanofibres may be further coated with an outer layer as herein described.
  • the RNS adduct such as the nitric oxide adduct is applied to the area of the medical device to be coated as a uniform layer, such as in the form of a coating system as described herein.
  • a primer is typically a first coating formulated to seal raw surfaces and hold succeeding finish coats.
  • the base material of the medical device i.e. external surface and/or the surface which comes into contact with the physiological media, is coated with an inner priming layer between the base layer of the medical device and said coating system or nitric oxide adduct, or said first or second domains.
  • the inner priming layer may be selected from the group consisting of polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchloride, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluo ⁇ de, polyvinylchloride, de ⁇ vatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes.
  • the inner priming layer has good adhesion and structural stability, withstanding a traction force applied to the surface of the polymer coat of about 4 to 100 Newton cm “2 such as about 8 to 50 newton cm “2 such as preferably between 10 tp 20 Newton cm “2 .
  • a preferred primer polymer is an aliphatic polyether-based polyurethane such as eg. Tecoflex SG 85A.
  • the thickness of the priming layer is between 0.2 and 5 ⁇ m.
  • the priming layer need not be uniform in thickness, over the surface as its role is to secure the coating and/or NO adduct to the medical device. It is therefore required to provide sufficient anchor points to provide a robust platform on which to apply the addition coat ⁇ ng(s).
  • the priming layer has effectively complete coverage over the base material to be coated as this ensures maximum structural integrity of the subsequent layers. Further layers
  • a further layer or layers may be applied over the RNS adduct, such as the nitric oxide adduct, such as the coating system or fibre layers.
  • Such further layers include the second domain and third domains as well as the outer-coating (outer-layer) as herein disclosed.
  • At least one of the first, second, third domains comprises polyurethane, such as both the first and second domains, such as the first and third domains.
  • the medical device according to the invention comprises a RNS adduct, such as the nitric oxide adduct (first domain) capable of releasing the RNS, such as nitric oxide, under physiological conditions as herein described, and at least one further layer (second domain) of a material which is capable of affecting the pH of the RNS adduct, such as the nitric oxide adduct (the first domain), such as the RNS adduct, such as the nitric oxide adduct coating system or fibres, upon insertion into physiological media, (see European application No. 06075159 and PCT/DK2007/000030 which iare hereby incorporated by reference).
  • a RNS adduct such as the nitric oxide adduct (first domain) capable of releasing the RNS, such as nitric oxide, under physiological conditions as herein described
  • second domain of a material which is capable of affecting the pH of the RNS adduct, such as the nitric oxide a
  • the further layers are sufficiently flexible to allow movement and flexing of the medical device without risking the integrity of the further layers.
  • the further layers may be hydroscopic and swell with water when in use.
  • the routine submersion of introducer sheath apparatus in isotonic solution prior to use therefore allows the further layers to absorb sufficient water to ensure sufficient flexibility, and reduced friction upon insertion.
  • Some polymers, for example the tecophillic polymers used for the outer coating may swell to about 60% of their volume when inserted in aqueous media.
  • a further advantage of using further coats of polymers which swell is that the swelling will mask any pin-hole defects or imperfections in the further coats, therefore ensuring the integrity of the coating system when in use.
  • the further layer or layers are applied externally to said RNS (e.g. NO) adduct (i.e. located between the RNS (e.g. NO) adduct and the physiological media when in use), it is also recognised that the further layer may be applied as a layer between the base material of the medical device and the RNS (e.g. NO) adduct.
  • the RNS (e.g. NO) adduct coating such as coating system may be formulated with a coating component that regulates the pH, and therefore NO release from the nitric oxide adduct when it comes into contact with physiological media.
  • an outer coating as herein described is also applied. The outer coating may be applied directly to the coating system layer, or to one or more further layers applied to the coating system layer.
  • the medical device comprises an outer layer situated externally to the RNS (e.g. NO) adduct, and if relevant any further coating layers, and said outer layer comprises a polymer which controls one or more of the following: i) the release of the RNS (e.g. NO) adduct from said inner layer into the physiological medium either by forming a diffusion barrier between the RNS (e.g. NO) releasing adduct and the physiological medium, or by applying a diffusion resistance to the diffusing molecule and thereby significantly slowing down the diffusion process . ii) the release of RNS (e.g. NO) from said inner layer into the physiological medium by presenting a low conductance to the RNS (e.g.
  • the outer layer should be able to restrict the activation, and/or the continuous release, of the nitric oxide release by a factor of about 1 to 20 such as about 1.5 to 10 such as preferably between 2 to 5 compared to the activation of RNS (e.g. NO) release from the RNS (e.g. NO) coating layer itself.
  • the outer layer may also provide structural stability, ensuring the RNS (e.g. NO) adduct and/or coating system remains in place during manufacture, storage, preparation and use of the medical device.
  • RNS e.g. NO
  • the outer coat may consist or comprises of a polymer which has the ability to swell upon insertion into aqueous media.
  • the ability to swell may be determined by a simple experiment where a known volume of polymer, such as in a granular form, is added to an excess of pure water and allowed to reach an equilibrium in term of water absorption. The swollen granules are then removed from the aqueous media, excess water removed, and the change in volume is assessed.
  • polymers suitable for use in the outer coat have an ability to swell of at least 1% volume, such as at least 5%, such as at least 10%, such as at least 20%, such as at least 30%, such as at least 40%, such as at least 50%, such as at least 60%.
  • Such polymers are referred to as hydroscopic polymers. It will however be recognised that the use of hydroscopic polymers should be used carefully so as to not interfere with the functionality of the medical device or removal of the medical device from the patient.
  • the outer layer comprises a hydrophilic polymer, such as a hydroscopic polymer.
  • Polymers which may be used in the outer coating may be selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, silicones, or celluloses. More specifically they can be aromatic polyurethanes, ethylene acrylate polyolefins, hydrophilic aliphatic polyurethanes or silicones, These polymers can be selected from the tecophilic, estanes.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, poly
  • High water vapour conducting polymers such as EMAC and EBAC polyolefins families or high water vapour conducting silicones may also be used.
  • Water vapour conducting polymers can be identified using the ASTM Method E96B - 50%RH, 23°F, preferable water vapour conducting polymers range from moderately breathable, about 350g/m 2 /24hrs MVT to a highly breathable, about 760g/m 2 /24hrs HMVT.
  • Such polymers may, in one embodiment also be useful as hydrophilic polymers for use in the polymer blend/coating systems disclosed herein.
  • the outer layer polymer forms a hydroscopic gel upon insertion into physiological media. It is preferred that the outer coating is selected for its ability to facilitate the insertion and withdrawal of the medical device from the vessel. In this respect hydroscopic or hydrophilic polymers may be preferred in some applications as they form a slippery surface upon insertion into aquatic environments, such as physiological media. It may therefore be preferred that the medical device is contacted with a suitable aqueous solution prior to use, such as isotonic water, for a brief period prior to use, such as for between 1 and 3 minutes.
  • a suitable aqueous solution prior to use such as isotonic water
  • the outer layer polymer comprises a hydrophilic polyurethane.
  • RNS e.g. NO
  • intravascular medical devices such as transient intravascular medical devices (i.e. not implants)
  • the release of the RNS (e.g. NO) adducts may lead to a low level of undesirable systemic effects, and may therefore also require more stringent regulatory approval process.
  • both the coating system (as first domain) as herein disclosed and the outer layer are used, (optionally with the second and/or third or domains) as both these can control the undesirable release of the RNS (e.g. NO) adduct into the physiological media.
  • RNS e.g. NO
  • the outer layer can also be used to control the rate and timing of the release of RNS (e.g. NO) from the RNS (e.g. NO) adduct, such as the coating system as disclosed herein, into the physiological medium.
  • RNS e.g. NO
  • the outer layer may be only partially or unevenly applied, thereby allowing part of the RNS (e.g. NO) adduct to rapidly come into contact with physiological media, giving an initial release of RNS (e.g. NO), whilst the adduct which has an outer coating provides a more sustained release for longer duration.
  • the outer-coat provides a further protection against premature release of RNS (e.g. NO) by preventing the premature hydration of the first and/or second domains.
  • RNS e.g. NO
  • an outer-coat which is, for example, is only partially permeable to water, or only permeable to water vapour, for example an outer-coat made of a hydrophobic polymer - such outer-coats are particularly useful for delayed release, for example in the case of implants such as stents.
  • Suitable hydrophobic polymers are known in the art and include various polymers such as silicones (which may for example be permeable to water vapour but not water) and polyvinyl chloride (PVC) polyurethanes (PU), polyacrylates or other polymers with restricted water conductance or mixtures hereof.
  • silicones which may for example be permeable to water vapour but not water
  • PVC polyvinyl chloride
  • PU polyurethanes
  • polyacrylates polymers with restricted water conductance or mixtures hereof.
  • the outer layer does not comprise an acidic agent.
  • Such an outer-layer may be used in the coatings of medical devices where a further layer or layers are applied which comprise an agent which modulates the pH as herein referred to (i.e. a pH modifying layer).
  • the pH of the outer-layer may suitably be about physiological pH, such as between about pH 7 and about pH 8, such as about pH 7.4.
  • the outer layer may comprise a buffer which maintains such a pH, such as a phosphate buffer. By maintaining a pH of about physiological pH the outer-layer can protect the cells which come into contact with the medical device from the pH of the first and/or second domains.
  • nitric oxide One of the dominant processes in the blood vessel is the scavenging of nitric oxide by haemoglobin. Most nitric oxide combines with oxyhaemoglobin in a 60-100% oxygen saturated environment to form methaemoglobin and subsequently nitrate. In low oxygen saturated environment, nitric oxide combines with deoxyhaemoglobin to form nitrosylhaemoglobin, which in the presence of oxygen forms nitrogen oxides and methaemoglobin. The end products of nitric oxide that enter the systemic circulation are methaemoglobin and subsequently nitrate. The nitrate is then transferred to the serum, and the greater part of the nitrate is excreted into the urine through the kidney.
  • the typical half life of nitric oxide in blood is milliseconds.
  • the half-life of nitric oxide is several hundred times longer in tissue than in blood.
  • the biological half-life of haemoglobin- bound nitric oxide is about 15 mm.
  • the concentration in the smooth muscle cells resulting in relaxation is, based on the literature findings, expected to be larger than 200 nM but significantly below 1 mM.
  • the lower limit (200 nM) is determined by the concentration required to activate soluble guanylyl cyclase, which acts as the enzyme that generates the second messenger cyclic GMP resulting in smooth muscles relaxation.
  • the upper limit (1 mM) is determined by the concentration leading to significant oxidative stress and mutations.
  • nitric oxide concentration in tissue ranges form 100 to 500 nM.
  • physiological concentration in healthy endothelial cell is about 100 ⁇ M.
  • nmol/min/cm 2 is one of the highest reported release rates from the natural endothelium. In order to obtain the desired biological response values higher may therefore required. For example, considering the short contact with the vessel wall and the thickness of tissue that the nitric oxide needs to pass before reaching the media of the vessel the desired release rate should preferably be higher to obtain the optimal vasorelaxing response.
  • the effective device release rate has according to the preclinical studies and literature findings a broad range.
  • the upper limit is preferably set to 40 nmol/min/cm 2 .
  • the lower limit is preferably set to 0.5 nmol/min/cm 2 .
  • Lower release rates than 0.5 nmol/min/cm 2 probably also induce relaxation, however they may be less effective.
  • the (maximum) rate of NO release from the medical device according to the invention may be greater than about 0.1 nmol/min/cm 2 , such as greater than 0.25 nmol/min/cm 2 , preferably greater than about 0.32 nmol/min/ cm 2 , such as greater than 0.5 nmol/min/cm 2 , such as greater than lnmol/min/ cm 2 .
  • the maximum rate of NO release from the medical device according to the invention is no more than about 40 nmol/min/cm 2 , such as no greater than about 60 nmol/min/cm 2 , such as no greater than about 80 nmol/min/cm 2 .
  • (maximum) release rate from the medical device according to the invention is between about 0.5 and up to about 3 nmol/min/cm 2 .
  • nitric oxide When a topcoat (outer layer/coating) is applied the release of nitric oxide deviates significantly from a l'order release. This is due to the barrier properties of the topcoat: limiting the water absorption and the diffusion of nitric oxide through the coating.
  • the peak release of nitric oxide, and/or the release after 5 minutes after insertion into an isotonic solution, from the outer surface of the medical device is (e.g. between about 0.5 and about 40 nmol/min/cm 2 ) measured by using a dynamic headspace chamber connected to a chemoluminescence NO detector:
  • the object coated with the described nitric oxide releasing coating system is placed in a head space chamber containing pbs buffer (pH7.4) with 0.00004% Tween 20, kept at 37°C.
  • the solution is continuously flushed with 250 ml_ N 2 gas ensuring oxygen free conditions.
  • the nitric oxide released from the coat into the oxygen free environment is stripped off from the solution and carried to the chemoluminescence NO detector by the NO gas.
  • the examples provide a NO assay which is used to determine the release rate of nitric oxide.
  • the peak release rate is obtained within the first 15 minutes after wetting or inserting the device, such as within the first ten minutes, such as within the first five minutes, such as within the first three minutes after wetting or inserting the device.
  • the assay as described above may be used.
  • the release of nitric oxide from the outer surface of the medical device has a half life in physiological media of at least 30 minutes, such as at least 60 minutes, such as at least 90 minutes or at least 2 hours such as at least 4 hours, at least 6 hours or at least 12 hours.
  • the maximum rate of decrease of NO release after the point of maximum rate of NO release has been obtained is less than about -0.015 nmol/min/cm 2 /min, such as less than about -0.03nmol/min/cm 2 /min, such as less than about -0.06 nmol/min/cm 2 /min.
  • the medical device may be capable of releasing one or more further therapeutic agents.
  • These further therapeutic agents may be provided in the first, second and/or third domains, and or the outer-coating.
  • the therapeutic device may provide other means for delivery of the further therapeutic agents.
  • the release of the further therapeutic agents may also be pH dependant, and as such the acidification of the first domain may cause the release of the therapeutic agent, or the alkalinisation of the second or third domain or outer-layer from the alkali first domain, may trigger the release of the further therapeutic agents.
  • the medical device may be coated in one or more further therapeutic agents, such as a human growth factor, an anti coagulant, such as heparin, an antibiotic agent, such as an antibiotic, a chemotherapeutical agent, a further smooth muscle cell proliferation reducing agents, such as nitric oxide (NO) or a nitric oxide donor, and/or a vasodilation agents, such as NO or an NO donor.
  • a further therapeutic agents such as a human growth factor, an anti coagulant, such as heparin, an antibiotic agent, such as an antibiotic, a chemotherapeutical agent, a further smooth muscle cell proliferation reducing agents, such as nitric oxide (NO) or a nitric oxide donor, and/or a vasodilation agents, such as NO or an NO donor.
  • Ascorbic acid (vitamin C) may be provided as an antioxidant or as a catalyst for release of nitric oxide (i.e. within the second domain).
  • the therapeutic agent in case the release rate of the further therapeutic agent is not per se dependent on pH, the therapeutic agent may be bonded to or encapsulated in a carrier compound, which is characterised by a pH-dependent release rate or a pH-dependent degradation rate of a carrier material encapsulating the therapeutic agent.
  • the further therapeutic agent may be immobilised in a hydrogel, e.g. a hydrogel.
  • a hydrogel e.g. a hydrogel.
  • Certain hydrogels swell under acidic conditions.
  • One possible way to produce such a hydrogel which swells in blood but not in pure water is to co-deposit the therapeutic agent with glucoseoxidase (GOD).
  • GOD glucoseoxidase
  • the further therapeutic agent may e.g. comprise at least one of: heparin or another thrombin inhibitor, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone or another antithrombogenic agent, or mixtures thereof; streptokinase, urokinase, a tissue plasminogen activator, or another thrombolytic agent, or mixtures thereof; paclitaxel; estrogen or estrogen derivatives; a fibrinolytic agent; a vasospasm inhibitor; a calcium channel blocker, a nitrate, nitrite, nitric oxide, a nitric oxide promoter, such as ascorbic acid, or another vasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopdine or another antiplatelet agent; colchicine or another antimitotic, or another microtubule inhibitor; cytochalasin or another actin inhibitor
  • one or more of the therapeutic agents listed above may in one embodiment, be used either in the absence of (L)PEI-NONO, or in addition to (L)PEI-NONO. They may be present in the first domain, second domain, third domain or outer coat and/or further layers as referred to herein.
  • the medical devices/kits of parts according to the invention may be used for performing the Seldinger technique, to prevent or reduction vasospasm (vasoconstriction) associated with the insertion of a medical device into the vascular system.
  • This then allows the insertion of further medical devices into the vascular system, such as a further medical device selected from: Neuro medical devices, neuro guiding catheter, neuro microcatheter, neuro microwire, neurostent delivery system, neuron ballon; Coronary medical devices, coronary wires, coronary guiding catheter, PTCA angioplasty balloon, stent delivery system, coronary wires, coronary guiding catheter, PTA angioplasty balloon, stent delivery system.
  • the site of entry of the medical device may, in one embodiment, be selected form the group consisting of: the femoral artery, the radial artery, the carotid artery, the brachial artery, the auxiliary artery.
  • the site of entry of the medical device is selected form the group consisting of: the radial artery, the brachial artery & the auxiliary artery.
  • the invention provides for a method of controlling, such as reducing or preventing, vasospasm associated with the use of an introducer sheath, said method comprising the step of inserting the medical device according to the invention into a vascular (including neurovascular) system of a subject (typically a patient).
  • a vascular system of a subject
  • the site of entry into the vascular system may be selected form the group consisting of radial artery, the brachial artery & the auxiliary artery, femoral artery, preferably the radial artery, the brachial artery & the auxiliary artery, most preferably a radial artery.
  • the invention provides for a method for performing intravascular or neurovascular surgery said method comprising introducing the medical device according to the invention into the vascular or neurovascular system of a subject (patient).
  • the invention provides for a method of preventing or reducing vasospasm associated with the introduction of a medical device into the vascular or neurovascular system of a subject, said method comprising introducing the medical device according to the invention into the vascular or neurovascular system of a subject (patient).
  • the invention provides for the use of a coating system according to the invention in the manufacture of a medical device for the prevention or reduction of vasospasm associated with the introduction of the medical device into the vascular system of a subject.
  • a medical device suitable for use in the introduction of further medical devices into the vascular or intravascular system of a living being, selected from the group consisting of an introducer sheath, a dilator, the group consisting of an introducer sheath, a dilator, an introducer sheath guide wire and a trocar needle, wherein said medical device comprises a nitric oxide adduct, such as a water inducible nitric oxide adduct, capable of releasing nitric oxide under physiological conditions.
  • a nitric oxide adduct such as a water inducible nitric oxide adduct
  • nitric oxide adduct is selected from the group consisting of nitroglycerin, sodium nitroprusside, S- nitroso-proteins, S-nitrosothiols, long carbon-chain lipophilic S-nitrosothiols, S-nitroso- dithiols, iron-nitrosyl compounds, thionitrates, thionitrites, sydnonimines, furoxans, organic nitrates, and nitrosated amino acids.
  • nitroso-Nacetylcysteine S-nitroso-captopril, S-nitroso- homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, and S-nitrosopenicillamine, S- nitrosothiols, S-nitrosylated polysaccharides such as S-nitrosylated cyclodexrins, NONOate compounds (i.e. compounds which comprise the anionic NONOate functional group (N2O2-)), NONOate polymers.
  • NONOate compounds i.e. compounds which comprise the anionic NONOate functional group (N2O2-)
  • the nitric oxide adduct is a NONOate, such as a polymeric NONOate selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, biopolymers such as peptides, proteins, oligonucleotides, antibodies and nucleic acids, starburst dendrimers.
  • NONOate such as a polymeric NONOate selected from the group consisting of: polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine,
  • nitric oxide adduct is polyethylenimine diazeniumdiolate, such as linear polyethylenimine diazeniumdiolate.
  • the nitric oxide adduct has a molecule weight of between about 5kDa and about 20OkDa, such as between about 1OkDa and about 10OkDa, such as more preferably between about 2OkDa and about 6OkDa, such as about 55kDa.
  • nitric oxide adduct is a polymer, such as a linear polymer, a branched polymer, and/or a cross linked polymer.
  • nitric oxide adduct is in the form of a coating system comprising a polymer mixture, wherein said polymer mixture comprises said nitric oxide adduct and a hydrophilic supporting polymer or polymer blend, and wherein the said nitric oxide adduct and the supporting polymer or polymer blend form a homogeneous phase.
  • the ratio of polymer mixture to said nitric oxide adduct present in the coating system is between about 5% to about 80%, such as between 10% and 50%, preferably between about 20% and about 50%, such as about 30%.
  • hydrophilic polymer or polymer blend when used in the homogeneous polymer blend, provides a release rate of about 0.5 and about 80 nmol/min/cm 2 as measured by using a dynamic headspace chamber connected to a chemoluminescence NO detector at the point of maximum rate of increase of release of nitric oxide when inserted into phosphate buffered saline solution, pH 7.4 at 37°C.
  • the thickness of the coating system is about 1 to about 100 ⁇ m, such as between 5 and about 20 ⁇ m in dry state.
  • the medical device according to any one of the preceding embodiments which comprises a further layer which may be either internal or external to the nitric oxide adduct, wherein said further layer is capable of affecting the pH of the nitric oxide adduct or coating system by shifting the local balance between H + and OH " ions upon wetting of at least a portion of the medical device.
  • the medical device which comprises an outer layer situated externally to the nitric oxide adduct, and said outer layer comprises a polymer which controls one or more of the following : i) the release of polyethylenimine diazeniumdiolate from said inner layer into the physiological medium and ii) the release of nitric oxide from said inner layer into the physiological medium and iii) the diffusion of water from the physiological medium into the inner layer under physiological conditions and iv) the leakage of small molecule by products from said polymer mixture into the physiological medium.
  • the medical device according to any one of the preceding embodiments wherein the density of application of polyethylenimine diazeniumdiolate onto the surface of the medical device is between about 0.05 and about 100mg/cm2, such as between about 0.1 and about 10 mg/cm2, such as preferably between about 0.2 and about 5 mg/cm2.
  • said medical device is not made from polytetrafluoroethylene (PTFE) (TeflonTM) or Fluorinated polyethylene (FEP).
  • kits of parts for performing vascular or neurovascular surgery which comprises at least one medical device according to any of the preceding embodiment and at least one other medical device used in vascular or neurovascular surgery.
  • kit of parts according to embodiment 39 which comprises a dilator according to any one of embodiment 1 to 33, wherein said dilator is capable of being inserted into an introducer sheath, such as the introducer sheath according to any one of embodiment 34 to 38.
  • kit of parts according to embodiment 40 wherein said dilator, when fully inserted into said introducer sheath, extends beyond the distal tip of said introducer sheath, and the region of the dilator which extends beyond the distal tip of said introducer sheath comprises a tapered end which is coated with said compound capable or releasing nitric oxide under physiological conditions.
  • kit of parts according to embodiment 41 wherein the region of said dilator which does not extend beyond the distal end of the introducer sheath when fully inserted is not coated with said compound capable or releasing nitric oxide under physiological conditions.
  • kit of parts according to any one of embodiments 39 to 42, wherein said kit of parts also comprises a guide wire which is optionally coated in a nitric oxide adduct which is capable of releasing nitric oxide under physiological conditions, such as the nitric oxide adducts and/or coating systems according to any one of the preceding embodiment.
  • a coating system comprising a polymer mixture is applied to said external surface of the medical device, wherein said polymer mixture comprises at said at least one nitric oxide adduct which is capable of releasing nitric oxide and a hydrophilic supporting polymer or polymer blend, and wherein the nitric oxide adduct and the supporting polymer or polymer blend form a homogeneous phase.
  • the coating system is as according to any one of embodiments 1-38.
  • a method for the prevention and/or reduction of vasospasm (vasoconstriction) associated with the insertion of a medical device into the vascular or neurovascular system comprising utilising a medical device according to any one of embodiments 1 to 38 or a kit of parts according to any one of embodiments 39 to 43, or a medical device prepared according to the methods of any one of embodiments 44 to 55.
  • a method for performing intravascular surgery comprising utilising a first medical device or kit or parts according to any one of embodiments 1 to 38 or kit of parts according to any one of embodiments 39 to 43, or a medical device prepared according to the methods of any one of embodiments 44 to 55, and secondly a further medical device, such as a further medical device selected from : Neuro medical devices, neuro guiding catheter, neuro microcatheter, neuro microwire, neurostent delivery system, neuron ballon; Coronary medical devices, coronary wires, coronary guiding catheter, PTCA angioplasty balloon, stent delivery system, coronary wires, coronary guiding catheter, PTA angioplasty balloon, stent delivery system, wherein the further medical device is used either simultaneously or sequentially to said first medical device or kit or parts.
  • the site of entry into the vascular system is selected from : the femoral artery, the radial artery, the carotid artery, the brachial artery, and the auxiliary artery.
  • a compound capable of releasing nitric oxide when inserted into physiological medium for the manufacture of a medical device for use in vascular or neurovascular surgery, such as for performing the Seldinger technique, for the prevention or reduction of vasospasm (vasoconstriction) associated with the insertion of an introducer sheath during said surgery, wherein said medical device is selected from an introducer sheath, a dialotor, an introducer sheath guide wire, or a trocar.
  • FIGURE 1 Schematic presentation for the synthesis of L-PEI and further processing to LPEI- NONO'ate.
  • the poly(2-ethyl-2-oxazoline) used was produced by Polymer Chemistry Innovations Inc. (AQUAZOL ® 500) and has an average molecular weight of 500.000 g/mol.
  • FIGURE 2 Diagram of the introducer sheath purchased from Thomas Medical Products, US.
  • FIGURE 3 Principal of the spray pattern analyzer.
  • the spray plume is illuminated by a laser sheet and captured by a high speed camera.
  • FIGURE 4 Simple illustration of the concept: The release of nitric oxide is impacted by the water absorption, the pH and the diffusion rate of nitric oxide through the coating layers.
  • FIGURE 5 Diazeniumdiolates and their suggested the mechanism of release.
  • FIGURE 6 Nitric oxide release dymanics using the primer/ (alkali) NO adduct coating system/outer layer.
  • FIGURE 7 illustrates various coated medical devices according to the invention as described herein.
  • OL refers to outer layer
  • 1 st refers to the first domain
  • 2 nd refers to the second domain
  • 3 rd refers to the third domain
  • BM refers to the base material of the medical device - typically the external surface prior to coating. All embodiments show may also comprise a primer layer on top of the base material.
  • the pH of the 1 st domain is preferably alkaline in embodiments A, B, C, D, F, G, H, and I, and may also be alkaline in E.
  • the pH of the second domain is acidic in all embodiments where it is shown.
  • the pH of the 3 rd domain is typically about neutral.
  • the pH of the outer-coat is typically around physiological pH..
  • Diagrams F, G, H and I represent particles of the first and/or second domains, optionally coated with the third domain, which are embedded in either the first, second or third domains as illustrated.
  • FIGURE 8 A balloon coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 embedded in polyurethane and provided with a top coat of pure polyurethane was immersed in the head space chamber. Nitric oxide release started essentially immediately upon immersion of the inflated balloon in the head space chamber and increased asymptotically to a level of approximately 1.5 nmol/min/cm 2 in approximately 50 minutes. Due to the high load of NO in the LPEI-NONO, the release of NO maintained essentially constant for the remaining measurement period (approximately 140 minutes).
  • LPEI-NONO linear poly(ethylenimine) diazeniumdiolate
  • FIGURE 9 A balloon coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 embedded in polyurethane and supported by a coating layer of 90% polyacrylic acid and 10% polyurethane was immersed in the headspace chamber.
  • Nitric oxide release started essentially immediately upon immersion of the inflated balloon in the head space chamber at a level above the threshould measurement maximum of the nitric oxide analysis apparatus (10 nmol/min/cm 2 ). An asymptotic decrease to a level of approximately 1.2 nmol/min/cm 2 was observed until the measurement was interrupted after approximately 82 minutes.
  • LPEI-NONO linear poly(ethylenimine) diazeniumdiolate
  • FIGURE 10 A balloon coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI- NONO) as disclosed in US 6,737,447 embedded in polyurethane and supported by a coating layer of 80% polyacrylic acid and 20% polyurethane, and further comprising a top coat of polyurethane was immersed in the headspace chamber.
  • Nitric oxide release started essentially immediately upon immersion of the inflated balloon in the head space chamber at a level above the threshold measurement maximum of the nitric oxide analysis apparatus (10 nmol/min/cm 2 ). An asymptotic decrease to a level of approximately 0.4 nmol/min/cm 2 was observed until the measurement was interrupted after approximately 105 minutes.
  • LPEI- NONO linear poly(ethylenimine) diazeniumdiolate
  • FIGURE 11 A and B represent balloons coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 and embedded in polyurethane without top coat. Formulation and processing is equal for both (A) and (B) except from the pH of the methanol used for dissolving the LPEI-NONO.
  • the two balloons were dissolved in respectively alkaline methanol (A) and neutral methanol (B).
  • the Balloons were immersed in the head space chamber. The peaks at approximately 15-17 minutes and at the end of the measurement, represent nitrite measurements (samples are indexed for comparison).
  • 2005 1102 SGP E1-B2 #710 pH adjusted, 20051102 SGP El-Bl #719 not pH adjusted.
  • FIGURE 12 A and B represent nitric oxide release from a modified nylon (pebaxTM) tube coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 and embedded in polyurethane.
  • LPEI-NONO linear poly(ethylenimine) diazeniumdiolate
  • Formulation and processing is equal for both (A) and (B) except for the presence of a top coat in A and the absence of top coat in B.
  • the arrows illustrate where the coated tube has been removed and re-entered the measuring chamber.
  • the nitric oxide signal between the arrow is equal to the nitric oxide release from the LPEI-NONO leaked out of the coat (samples are indexed for comparison).
  • FIGURE 13 Graphical summary of the visual angiographic analysis.
  • the nitric oxide eluting coating applied to the medical device is based on linear polyethyleneimine (L-PEI) with pendant NONO groups.
  • L-PEI linear polyethyleneimine
  • This group is stabilized by the formation of a Zwitter-ion complex with an adjacent -NH 2 + - amine group in the L-PEI backbone.
  • Nitric oxide is a colorless and odorless lipophilic gas that with a ai ⁇ water partition coefficient of 20: 1 and a maximum solubility of 1.7xlO "3 M at 1 atm 25 °C, making it easily diffusible across membranes.
  • NO has an unpaired electron and is thus characterized as a free radical, allowing it to react with other species with unpaired electrons such as O 2 " and other radical species. Additionally, NO possesses high capacity to ligate with hemeproteins such as hemoglobin.
  • the NO used in the manufacture of the NO Eluting Introducer Sheath contains at least 99% V/V of NO.
  • the impurities for the NO include the following gasses: carbon dioxide, nitrogen, nitrogen dioxide, nitrous oxide and water.
  • Nitric Oxide was purchased from Linde Gas. The purity is larger than 99% weight. Impurities are specified as non specific NOX ⁇ 0.5% by weight (N 2 O, N 2 O 3 , N 2 O 4 , NO 2 , N 2 O 5 ) and Nitrogen ⁇ 0.5% by weight (N 2 ). Poly(2-ethyl-oxazol ⁇ ne) was boiled for 24 hours in sulphuric acid. Boiling in a sulfuric acid solution was needed to reach the desired > 90% level of hydrolysis of poly(2-ethyl 2- oxazohne).
  • the formed propionic acid was distilled off and the sulfuric acid was neutralized with sodium hydroxide and then recrystallised several times in water to remove salt impurities, i.e. sodium sulphate and propionic acid residuals.
  • the average molecular weight of the L-PEI-NONO'ate was found to be between 25 and 3OkDa, such as about 28kDa, with a relatively narrow distribution.
  • the introducer sheaths to be coated were purchased bulk from Thomas Medical Products, US.
  • the (percutaneous) introducer sheath is used for intravascular introduction of interventional/diagnostic devices (See Figure 2).
  • mixture B 0.3 g LPN and 14.7 g (18.6 ml) pH adjusted methanol were mixed in a vial. The mixture was shaken briefly. The vessel was sealed and protected against light, and incubated at room temperature with stirring for 1 hours. The mixture was filtered through a 0.45 ⁇ m filter into a new vial.
  • Mixtures A and B were mixed in ratio 7:3 (e.g. 7 ml + 3 ml) into a new vial and sealed in a light proof vessel. 7.
  • Mixture C was used for down stream processing. The maximum time from final preparation of mixture C and until termination of the down stream processes was 9 hours. The solution was shaken just prior to down stream processing.
  • the coating was applied in a three step spray coating process.
  • the first step was to apply a USP class VI tested primer onto the sheath.
  • the primer is dissolved in pyridine.
  • the second step is to spray a mixture of polyurethanes and L-PEI-NONO dissolved in methanol and pyridine onto the introducer sheath.
  • the third step is to apply a top coat.
  • the spray coating is performed with conventional air spraying equipment designed for a small fluid flow and low air pressure.
  • the spray coating process is monitored and controlled to ensure that the spray process delivers a smooth uniform layer, and that the layer thicknesses are not subject to deviations.
  • Variations can include particle size variations and variations in spray plume geometry, e.g. that the spray plume will not be concentrated on the center of the rotating sheath during the spray-coating process.
  • Variations in the spray coating process are typically due to spray fluid drying up on the spray nozzle orifice thus altering the airflow.
  • One way to manage this problem is to optimize the design of the spray nozzle and thereby avoid spray residue build-up.
  • formulation of the spray mixture is optimized to prevent drying of the spray solution on the spray nozzle.
  • the spray process may be examined and optimised using advanced laser technique and highspeed camera.
  • the equipment enables measuring the angle and orientation of the spray plume and analyzing variations. Furthermore, the equipment enables analysis of drop sizes and the impact of different parameters such as air flow and distance to the device surface.
  • the working principal of this spray coating analysis equipment is illustrated by FIGURE 3.
  • the described technique is similar to the method required to validate the spray plume geometry for oral and nasal sprays.
  • target release is in the range from 0.5 nmol/min/cm 2 to 40 nmol/min/cm 2
  • the nitric oxide donor was incorporated into a polymeric matrix (FIGURE 4).
  • the coating consists of 3 layers:
  • the nitric oxide donating layer is a mixture of polyurethanes and L-PEI-NONO (LPN) dissolved in pyridine and methanol onto the medical device.
  • the recipe for the nitric oxide donating layer includes pH adjusted solvent (methanol) to ensure that the LPN is stable during processing.
  • the polymeric topcoat serves to ensure coating integrity, a barrier solubilisation of the LPN polymer, appropriate rate of water absorption and appropriate rate of NO diffusion.
  • a topcoat When a topcoat is applied the release of nitric oxide deviates significantly from a l'order release. This is due to the barrier properties of the topcoat: limiting the water absorption and the diffusion of nitric oxide through the coating.
  • the LPN layer When using confocal fluorescence microscopy the LPN layer has a relatively strong autofluorescence (blue/green). The other layers cannot be detected by this method, probably because they have no or very weak autofluorescence and because the top layer and the priming layers are too thin (less than 0.6-0.7 ⁇ m).
  • the thickness of the LPN layer when dry, is determined to be in the magnitude of 4-5 ⁇ m, when applying 44 cycles of LPN (normal spray-coating parameters). When using only 22 cycles of LPN applied on the devices and when proportionality is assumed the LPN coating is in the magnitude of 2 ⁇ m.
  • the total coat is considered to be in the magnitude of 3 ⁇ m when using 22 cycles. However, coats of up to 40 ⁇ m may be appropriate and can be achieved by increasing the number of coating, such as spraying cycles.
  • the coating When merged into an isotonic solution the coating swells as a result of water absorption. We have determined experimentally that the swelling increase the coating thickness by approximately 0.03 mm (30 ⁇ m).
  • EXAMPLE 8 Nitric oxide measurement Nitric oxide measurements were carried out by using a chemiluminescence NO analyzer (Sievers NO Analyser NOA 280 ⁇ -2). The NO analyzer detects the total amount of NO(g) that passes the detector after a sample injection. The detection is based on the reaction :
  • the emitted light (hv) is detected in a photomultiplier and is directly correlated to the amount Of NO.
  • the principle is that NO eluting samples are placed in acid wash bottle (named head space chamber) containing PBS buffer (pH 7.4) added 0.0004%o Tween 20 covering the sample, which is continuously flushed with N 2 gas which carries the released NO gas to the NO analyzer. Due to the continuous flow of N 2 , The presence of oxygen is thereby avoided and so is the formation of nitrite (NO 2 " ). This method ensures that all NO and only NO is measured.
  • Products are then packaged and sealed in an aluminum pouch are appropriate for sterilization by electron beam irradiation.
  • Coated medical devices may be sterilized by electron beam sterilization through a certified sub-contractor, such as Ste ⁇ genics, Espergade, DK.
  • a certified sub-contractor such as Ste ⁇ genics, Espergade, DK.
  • the validation and routine sterilization is performed in accordance with the requirements of EN 552 (Sterilization of medical devices - Validation and routine control of sterilization by irradiation) and ISO 11137 (Sterilization of health care products - Radiation) and the products are sterile in accordance with EN 556 (Sterilization of Medical Devices) (SAL 10 "6 ).
  • nitric oxide (NO) from medical devices according to the present invention is illustrated in the below examples with reference to Figs. 8 - 10
  • Coated balloons with various coatings were immersed in a head space chamber containing phosphate-buffered saline
  • the nitric oxide analysis apparatus comprised a so-called high-sensitivity detector for measuring nitric oxide based on a gas-phase chemiluminescent reaction between nitric oxide and ozone:
  • thermoelectrically cooled, red-sensitive photomultiplier tube As emission from electronically excited nitrogen dioxide is in the red and near-infrared region of the spectrum, it could be detected by a thermoelectrically cooled, red-sensitive photomultiplier tube.
  • the analysis apparatus used was a Nitric Oxide Analyzer NOATM 28Oi provided by Sievers ® , Boulder, Colorado, USA.
  • Example 10a f (Fig. 81 A balloon coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 embedded in polyurethane and provided with a top coat of pure polyurethane was immersed in the head space chamber. Nitric oxide release started essentially immediately upon immersion of the inflated balloon in the head space chamber and increased asymptotically to a level of approximately 1.5 nmol/min/cm 2 in approximately 50 minutes. Due to the high load of NO in the LPEI-NONO, the release of NO maintained essentially constant for the remaining measurement period (approximately 140 minutes).
  • LPEI-NONO linear poly(ethylenimine) diazeniumdiolate
  • Example IQb (Fig. 9): A balloon coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 embedded in polyurethane and supported by a coating layer of 90% polyacrylic acid and 10% polyurethane was immersed in the headspace chamber. Nitric oxide release started essentially immediately upon immersion of the inflated balloon in the head space chamber at a level above the threshould measurement maximum of the nitric oxide analysis apparatus (10 nmol/min/cm 2 ). An asymptotic decrease to a level of approximately 1.2 nmol/min/cm 2 was observed until the measurement was interrupted after approximately 82 minutes.
  • LPEI-NONO linear poly(ethylenimine) diazeniumdiolate
  • Example IQc (Fig. 10): A balloon coated with a linear poly(ethylenimine) diazeniumdiolate (LPEI-NONO) as disclosed in US 6,737,447 embedded in polyurethane and supported by a coating layer of 80% polyacrylic acid and 20% polyurethane, and further comprising a top coat of polyurethane was immersed in the headspace chamber.
  • Nitric oxide release started essentially immediately upon immersion of the inflated balloon in the head space chamber at a level above the threshould measurement maximum of the nitric oxide analysis apparatus (10 nmol/min/cm 2 ). An asymptotic decrease to a level of approximately 0.4 nmol/min/cm 2 was observed until the measurement was interrupted after approximately 105 minutes.
  • the control device was a non-coated introducer sheath (without nitric oxide, Terumo, Radiofocus®
  • the primary endpoint of the study was the safety histological analysis that was performed on the femoral arteries of both the acute animals and the 7 day animals, determining potential negative cellular changes and changes in lumen diameter around where the sheath has been placed.
  • Efficacy was evaluated as any vasospasm-related changes in the vessel lumen diameter during placement and use of a NO-eluting sheath compared to a control sheath, through angiographic analysis.
  • the pigs were fasted overnight and sedated with 12 mg/kg ketamin-hydrochlo ⁇ d + 1 mg/kg xylazin and 0.04 mg/kg atropin. After premedication the anaesthesia were deepened with isofluran and oxygen by using a mask. When the pharyngeal reflex was eliminated the pigs were intubated intratracheally and the anaesthesia was maintained with 1.5-2.5 vol% isofluran, 1.6-1.8 vol% oxygen and 0.5 vol% N 2 O. During anaesthesia the following parameters were measured: puls/min, breath/min, SpO 2 , and ECG.
  • Access to the right or left femoral artery was performed through direct puncture of the artery under sterile conditions, and a 6F introducer sheath (either a test device or a control device) was inserted in the artery. Either a test device or a control device (depending on the first sheath inserted) was inserted in the contralateral artery using the same access procedure. Heart rate, arterial blood pressure and temperature were monitored. The procedure was not blinded for the physician since the test device and the control device have obvious differences in packaging and appearance.
  • heparin sodium After administration of 60 IU/kg of heparin sodium, a 6Fguiding catheter was advanced into the ascending aorta. Furthermore, heparin (400 I.U./h) was given as a slow continuous infusion during the procedure.
  • a coronary angiography was performed using regular contrast agent, followed by a sham stenting procedure (balloon dilation of the artery with low pressure and short time not to expose the animals for an unexpected coronary event). After a coronary complication in the pig No 6, which induced the death of the animal, the sham stenting procedure was modified and the balloon was dilated inside the guiding catheter.
  • the sheaths were left in place in order to reach an inserted time of at least Ih in total. Angiography of the femoral artery was repeated.
  • control angiography of the femoral arteries was performed through carotid artery access.
  • a guide wire (0.035") was navigated into the descending aorta.
  • a 6F diagnostic right coronary catheter was pushed to the aorto-iliaca bifurcation.
  • Angiography of the left and right sided arteria iliaca communis, and femoralis communis was performed.
  • the right or left arteria femoralis communis was then selectively cannulated, and a selective arteriography of the arteria femoralis superficialis was also performed. Subsequently, the animals were euthanized with 10 ml saturated potassium chloride.
  • Pen-procedure and follow-up quantitative angiographic parameters were measured by means of a computer-assisted quantitative coronary arteriography edge detection algorithm (ACOMPC, Siemens, Germany). The minimal lumen, reference diameters and percent diameter of potential lumen narrowing were assessed. The measurements were done at least four times during the procedure: before sheath placement (baseline), after sheath placement, after sham stenting, after pull back of the sheath with a length of 50%, and after Ih (final).
  • ACOMPC computer-assisted quantitative coronary arteriography edge detection algorithm
  • Sections of each arterial segment were stained with both hematoxylin-eosin and Verhoeff-van Gieson-elastin to determine the location and extent of injury.
  • intimal or neointima area area of the intimal or neointimal tissue, mm 2 .
  • inflammation description (cell types and locations), haemorrhage and necrosis and vessel wall and luminal thrombosis were described.
  • the Angio-SealTM did not function in all cases. In the cases where it was necessary to close the vessel for the 1-week follow-up, surgical closure of the arteries had to be done (3 control sheaths and 2 NO-sheaths)
  • ECG changes ECG was recorded before, during, and after the procedure and at the follow-up time in order to exclude any effects on the myocardium by NO). No sheath- related ECG-changes were observed 5. Unexpected death during the follow-up period: MIS-6 died as a consequence of the coronary procedure. Autopsy was performed, which confirmed, that the death was not related to the sheath placements
  • Results are summarized by means and standard deviations. Differences between the groups were tested by using two-sided t-test for identification of statistical significance. The same types of statistics were used throughout the report.
  • Consecutive numbering of the histological samples The most distal part of the artery contacted with the sheath (site of the puncture) received the number "1". The most proximal part (at the tip of the previously placed sheath) received the number "11". R means right side, L means left side.
  • Distal or proximal references represent arterial segments 1 cm within distal (distal to the puncture site) or proximal (proximal to the tip of the previously placed sheath) to the previously placed sheath, respectively.
  • the insertion of the NO-eluting sheath proved to be safe and effective to prevent acute vasospasm during catheterization. Insertion of NO-eluting sheaths resulted in a trend towards less vessel wall and luminal thrombosis and significantly less cellular proliferation, initiated by the local vascular wall injury. Additionally, the mechanical properties of the NO- eluting sheath were similarly excellent as compared to that of the conventional sheath. The use of the NO-eluting sheath did not cause any systemic response related to the local NO- release from the sheath, and did not influence the systemic circulation and heart function.
  • the baseline vessel size was similar in the 2 groups. 4. After sheath placement a trend towards a larger vessel diameter at the distal part was observed in NO-sheath group. 5. Angiography after coronary artery procedure revealed a significantly less vessel constriction expressed as %DS and a wider distal vessel diameter after placement of
  • NO-sheaths as compared with the control sheaths. 6. After 50% withdrawal of the sheaths (triggered spasm); NO-sheath placement led to a significantly higher vessel size both proximal and distal to the sheath placement.
  • the amount of neointima and a mildly higher %area stenosis in the control sheath group remains in the acceptable and clinically still not relevant ranges.
  • Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate Comparison with enzymatically formed nitric oxide from L-arginine Pharmacology, Vol. 90, pp. 8103-8107, September 1999

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Abstract

La présente invention concerne des gaines d'introduction utilisées pour la technique Seldinger et des techniques chirurgicales afférentes. Les gaines d'introduction ou des parties de celles-ci comprennent des adduits d'azote réactif qui libèrent des espèces d'azote réactif, telles que l'oxyde nitrique et le nitroxyle, au cours de leur utilisation, pour prévenir les vasospasmes mécaniquement induits. Les gaines d'introduction sont particulièrement utiles pour permettre une entrée via un accès autre que l'artère fémorale, tel que l'accès radial.
EP07787993A 2006-11-08 2007-07-27 Dispositif médical capable de libérer no Withdrawn EP2094326A2 (fr)

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EP07787993A EP2094326A2 (fr) 2006-11-08 2007-07-27 Dispositif médical capable de libérer no

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US86488606P 2006-11-08 2006-11-08
US86489306P 2006-11-08 2006-11-08
US86487906P 2006-11-08 2006-11-08
EP06023222 2006-11-08
EP06023223 2006-11-08
EP06023203 2006-11-08
PCT/DK2007/000030 WO2007085254A1 (fr) 2006-01-24 2007-01-24 Dispositif médical à libération de médicament dépendant du ph
EP07787993A EP2094326A2 (fr) 2006-11-08 2007-07-27 Dispositif médical capable de libérer no
PCT/EP2007/057779 WO2008055718A2 (fr) 2006-11-08 2007-07-27 Dispositif médical

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US8017074B2 (en) 2004-01-07 2011-09-13 Noxilizer, Inc. Sterilization system and device
WO2005067986A1 (fr) 2004-01-07 2005-07-28 Noxilizer, Inc. Systeme et dispositif de sterilisation
US20090157047A1 (en) * 2007-12-13 2009-06-18 Boston Scientific Scimed, Inc. Medical device coatings and methods of forming such coatings
EP2517736B1 (fr) 2009-02-23 2014-03-26 Noxilizer, Inc. Dispositif de stérilisation par gaz
WO2011127181A2 (fr) * 2010-04-06 2011-10-13 Syracuse University Système et procédé pour la libération d'oxyde nitrique à l'aide de supports nanométriques
KR101255337B1 (ko) 2010-10-04 2013-04-16 한국과학기술연구원 온도 감응성 합성 고분자를 이용한 일산화질소 전달체
CN103432630B (zh) * 2013-09-06 2015-03-18 烟台隽秀生物科技有限公司 一种双网交织复合神经导管的制备方法
GB201505347D0 (en) * 2015-03-27 2015-05-13 Salupont Consulting Ltd Sterilisation of s-nitrosothiols
US20180126043A1 (en) * 2016-10-11 2018-05-10 Mladen I. Vidovich Sheath Introducer For Peripheral Artery Catheterization Procedures
US20230355662A1 (en) * 2019-06-19 2023-11-09 Zylo Therapeutics, Inc. Sulfur functionalized monoliths and particles derived from the same as nitric oxide carriers for pharmaceutical and cosmetic applications
KR20230029815A (ko) * 2020-06-23 2023-03-03 엔테그리스, 아이엔씨. 내산성 필터 매체

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WO2005037339A1 (fr) * 2003-10-14 2005-04-28 Cube Medical A/S Ballonnet utilisable en angioplastie
CA2608071A1 (fr) * 2005-03-24 2006-09-28 Nolabs Ab Dispositif d'acces medical intravasculaire, interstitiel ou intra-organes et procede de fabrication faisant appel a du monoxyde d'azote
JP2009523584A (ja) * 2006-01-24 2009-06-25 ミリメッド・アクティーゼルスカブ Ｐｈ依存性薬物放出を有する医療デバイス
WO2007126344A1 (fr) * 2006-04-27 2007-11-08 St. Jude Medical Ab Dispositif médical implantable à composition de libération

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JP2010508925A (ja) 2010-03-25
WO2008055719A3 (fr) 2009-02-26
WO2008055718A3 (fr) 2008-11-27
WO2008055718A2 (fr) 2008-05-15
JP2010508924A (ja) 2010-03-25
EP2107914A2 (fr) 2009-10-14
WO2008055719A2 (fr) 2008-05-15

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