EP1924303A1 - Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication - Google Patents

Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication

Info

Publication number
EP1924303A1
EP1924303A1 EP06708240A EP06708240A EP1924303A1 EP 1924303 A1 EP1924303 A1 EP 1924303A1 EP 06708240 A EP06708240 A EP 06708240A EP 06708240 A EP06708240 A EP 06708240A EP 1924303 A1 EP1924303 A1 EP 1924303A1
Authority
EP
European Patent Office
Prior art keywords
nitric oxide
implant
coating
eluting
polymer
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Withdrawn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
EP06708240A
Other languages
German (de)
English (en)
Inventor
Tor Peters
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.)
Nolabs AB
Original Assignee
Nolabs AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nolabs AB filed Critical Nolabs AB
Priority to EP06708240A priority Critical patent/EP1924303A1/fr
Publication of EP1924303A1 publication Critical patent/EP1924303A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/408—Virucides, spermicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules

Definitions

  • This invention pertains in general to the field of a coating of an implant, said implant being configured for surgical treatment of fractures, deformities, tumour diseases, replacement of tissue, such as bone, and promotion of osteo-integration and wound-healing of the implant, said coating involving the use of nitric oxide
  • the present invention pertains to a kit of such coated implants .
  • the body of the patient, in which the implant has been inserted recognises implants as foreign objects, possibly leading to local and systemic reactions.
  • a problem in prior art is osteo-integration of the implants.
  • Living cells account for about 15% of the weight of compact bone, and these cells are engaged in an unceasing process of remodelling.
  • One class of cells osteoclasts destroys old bone matrix while another (osteoblasts) deposits new bone matrix. This mechanism provides for continuous turnover and replacement of the bone matrix in the interior of the bone through which it can adapt to the load it bears. This is also a prerequisite to successful osteo-integration of implants .
  • nitric oxide provides an alternative to conventional therapies, such as antibiotics.
  • Nitric oxide is a highly reactive molecule that is involved in many cell functions.
  • nitric oxide plays a crucial role in the immune system and is utilized as an effector molecule by macrophages to protect itself against a number of pathogens, such as fungi, viruses, bacteria etc., and general microbial invasion. This improvement of healing is partly caused by NO inhibiting the activation or aggregation of blood platelets, and also by NO causing a reduction of inflammatory processes at the site of an implant.
  • NO is also known to have an anti-pathogenic, especially an anti-viral, effect, and furthermore NO has an anti-cancerous effect, as it is cytotoxic and cytostatic in therapeutic concentrations, i.e. it has among other effects tumoricidal and bacteriocidal effects.
  • NO has for instance cytotoxic effects on human haematological malignant cells from patients with leukaemia or lymphoma, whereby NO may be used as a chemotherapeutic agent for treating such haematological disorders, even when the cells have become resistant to conventional anti-cancer drugs.
  • This anti- pathogenic and anti-tumour effect of NO is taken advantage of by the present invention, without having adverse effects as for instance many anti-cancer drugs .
  • NO is actually toxic in high concentrations and has negative effects when applied in too large amounts to the body. NO is actually also a vasodilator, and too large amounts of NO introduced into the body will cause a complete collapse of the circulatory system.
  • NO has a very- short half-life of fractions of a second up to a few seconds, once it is released. Hence, administration limitations due to short half-life and toxicity of NO have been limiting factors in the use of NO in the field of anti-pathogenic and anti-cancerous treatment so far.
  • polymers with the capability of releasing nitrogen oxide when getting in contact with water.
  • polymers are for example polyalkyleneimines, such as L-PEI (Linear
  • PolyEthylenelmine and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible.
  • NO eluting polymers are given in US-5, 770, 645, wherein polymers derivatized with at least one -NO x group per 1200 atomic mass unit of the polymer are disclosed, X being one or two.
  • One example is an S- nitrosylated polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups .
  • Akron University has developed NO-eluting L-PEI molecule that can be nano-spun onto the surface of permanently implanted medical devices such as implanted grafts, showing significant improvement of the healing process and reduced inflammation when implanting such devices.
  • a coating for medical devices provides nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate .
  • Linear poly (ethylenimine) diazeniumdiolate releases nitric oxide (NO) in a controlled manner to tissues and organs to aid the healing process and to prevent injury to tissues at risk of injury.
  • Electrospun nano-fibers of linear poly (ethylenimine) diazeniumdiolate deliver therapeutic levels of NO to the tissues surrounding a medical device while minimizing the alteration of the properties of the device.
  • a nanofiber coating because of the small size and large surface area per unit mass of the nanofibers, provides a much larger surface area per unit mass while minimizing changes in other properties of the device.
  • US 2004/0131753 discloses a coating for medical devices, which coating provides NO delivery by using nanofibers of L-PEI. The technical effect of US
  • 2004/0131753 is that the released NO will help prevent platelet aggregation and smooth muscle cell proliferation. It is unclear how the elution of NO is initiated in this application. The elution of nitric oxide from the coating according to US 2004/0131753 is not regulated in any way. Furthermore, US 2004/0131753 is totally silent about improved osteointegration.
  • US 6,270,779 describes biocompatible metallic medical devices with silanized surfaces coupled to nucleophilic residues that release therapeutic amounts of nitric oxide to specific sites within a mammalian body.
  • the medical devices according to this patent are all metallic, and the method of manufacturing them are in need of a silanization step.
  • the elution of nitric oxide from the metallic surface according to US 6,270,779 is not regulated in any way.
  • US 6,270,779 is totally silent about improved osteointegration.
  • WO 03/026717 describes a method for preparing a nitric oxide-releasing substrate, such as medical devices, similar to those mentioned in US 6,270 ,779.
  • the elution of nitric oxide from the substrate according to WO 03/026717 is not regulated in any way.
  • WO 03/026717 is totally silent about improved osteointegration .
  • US 2003/083739 discloses a system for treating vascular in-stent restenosis, with silanized medical devices. The elution of nitric oxide from the silanized device according to US 2003/083739 is not regulated in any ⁇ way. Furthermore, US 2003/083739 is totally silent about improved osteointegration.
  • US 5,770,645 discloses medical devices coated with nitric oxide eluting polymers for reducing platelet deposition and restenosis. The elution of nitric oxide from the device according to US 5,770,645 is not regulated in any way. Furthermore, US 5,770,645 is totally silent about improved osteointegration.
  • Pulfer, S. K., et al . "Incorporation of nitric oxide-releasing crosslinked polyethyleneimine microspheres into vascular grafts", Journal of Biomedical Materials Research, Wiley, New York, NY, US, vol. 37, no. 2, November 1997, discloses site-specific delivery of nitric oxide by entrapping nitric oxide releasing polyethyleneimine microspheres in the pores of a vascular graft.
  • the effects obtained with these grafts are inhibition of platelet aggregation, smooth-muscle cell proliferation, and elimination of need for systemic anticoagulants .
  • the elution of nitric oxide from the polymer according to this article is not regulated in any way.
  • Bohl Masters, K. S., et al . "Effects of nitric oxide releasing poly (vinyl alcohol) hydrogel dressings on dermal wound healing in diabetic mice” Wound Repair and Regeneration, Mosby-Year Book, St. Louis, MO, US, vol. 10, no. 5, 2002, describes in vitro and in vivo responses to a novel hydrogel, manufactured by ultraviolet light-initiated polymerization from poly (vinyl alcohol) with a NO donor covalently coupled to the polymer backbone, that produces therapeutic levels of NO. This is a dermally applied polymer, hence nothing is indicated about osteointegration. Furthermore, the elution of nitric oxide from the hydrogel according to this article is not regulated in any way.
  • the disclosure is both silent concerning an improvement of present technology in respect of a coating of an NO eluting polymer on implants to provide an antibacterial, anti-fungi, and anti-viral effect, by elution of nitric oxide NO, to thereby also obtain an improved osteointegration. Furthermore, the disclosure is silent concerning regulating and/or controlling the elution of nitric oxide from such coatings .
  • the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves among others at least the problems mentioned above, at least partly by providing a coating, an implant, and a kit of implants, according to the appended patent claims .
  • a coating which coating allows for anti-viral, anti- fungal, and anti-bacterial effect, and promotion of osteo- integration of the implant, bone healing, bone growth, and wound healing, on an implant.
  • Said coating comprises a nitric oxide (NO) eluting polymer, such that a therapeutic dose of nitric oxide is eluted from said nitric oxide eluting polymer, allowing for anti-viral, anti-fungal, and anti-bacterial effect, and promotion of osteo-integration of the implant, bone healing, bone growth, and wound healing.
  • NO nitric oxide
  • an implant is provided, which implant has at least partly said coating.
  • a kit of said implants is provided.
  • the present invention has at least the advantage over the prior art that it provides target exposure of a tissue or organ in the vicinity of an implant to NO, whereby an increased circulation in the tissue or organ area, antiviral, anti-fungal, and anti-bacterial effect, and promotion of osteo-integration of the implant, bone healing, bone growth, and wound healing, while not developing resistance against the active pharmaceutical substance, pain etc, simultaneously are obtained.
  • Fig. 1 is an illustration of one example of an implant according to an embodiment of the present invention .
  • the patient according to the embodiments may be a human or animal, such as mammals selected from the group consisting of cat, dog, horse, cattle etc.
  • nitric oxide nitrogen monoxide, NO
  • NO nitric oxide synthase
  • cNOS constitutive enzyme
  • iNOS inducible enzyme
  • NO reacts with active oxygen to attack exogenous microorganisms and cancer cells, but also to cause inflammation and tissue injury.
  • cGMP cyclic GMP
  • vasodilator action improvement of the blood circulation, antiplatelet- aggregating action, antibacterial action, anticancer action, acceleration of the absorption at the digestive tract, renal function regulation, neurotransmitting action, erection (reproduction), learning, appetite, and the like.
  • inhibitors of the enzymatic activity of NOS have been examined for the purpose of preventing inflammation and tissue injury, which are considered to be attributable to NO generated in a large amount in a living body.
  • the promotion of the enzymatic activity (or expressed amount) of NOS has not been examined for the purpose of exhibiting various protective actions for a living body by promoting the enzymatic activity of NOS and producing NO appropriately.
  • NO is an important local mediator of bone cell activity. Changes in the mechanical forces acting on bone lead to adaptive remodelling of the bone. NO is an important signalling molecule on mature bone tissue, triggering the adaptive response.
  • Osteoblasts and osteclasts both produce and respond to NO; low doses of NO support and higher doses inhibit osteoclast and osteoblast function. All three types of NOS are involved in the development and homeostasis of bone tissue. Basal low-level NO synthesis by eNOS and nNOS stimulates osteoblasts and osteoclasts, respectively, and is essential for their function. Lack of eNOS results in reduced bone formation and bone volume. ENOS-deficient osteoblasts also show weaker response to the growth factor TGF-beta that is necessary for the requirement of osteoblasts to remodelling sites. nNOS-deficiency, on the other hand, show defective bone turn-over. Exogenous NO in still higher concentrations inhibits bone resorption by suppressing the formation and activity of osteoclasts .
  • the present invention takes advantage of these facts and therefore presents an unexpected effect in respect of osteo-integration of implants by using the NO eluting coating on implants .
  • polymers with the capability of releasing nitrogen oxide when getting in contact with water.
  • polymers are for example polyalkyleneimines, such as L-PEI (Linear
  • PolyEthylenelmine and B-PEI Branched PolyEthylenelmine
  • the polymers employed in embodiments of the present invention may be manufactured by electro spinning, air spinning, gas spinning, wet spinning, dry spinning, melt spinning, and gel spinning.
  • Electro spinning is a process by which a suspended polymer is charged. At a characteristic voltage a fine jet of polymer releases from the surface in response to the tensile forces generated by interaction by an applied electric field with the electrical charge carried by the jet. This process produces a bundle of polymer fibres, such as nano-fibres. This jet of polymer fibres may be directed to a surface to be treated.
  • US 6,382,526, US 6,520,425, and US 6,695,992 disclose processes and apparatuses for the production of such polymeric fibres . These techniques are generally based on gas stream spinning, also known within the fiber forming industry as air spinning, of liquids and/or solutions capable of forming fibers . Gas stream spinning is suited for producing devices according to certain embodiments of the invention.
  • an NO eluting polymer is electro spun onto an implant.
  • the implant may, according to different embodiments, for example be a temporary, a permanent, or biodegradable implant.
  • Temporary implants are implants that are removed after a certain time period of implantation.
  • a per se known device 1 comprising screws and/or plates, as shown in Fig. 1, is fixed to a fractured bone across the fracture site thereof.
  • the device is however provided with a coating eluting NO during a certain time after implantation of the device 1.
  • osteo-integration is promoted and the fracture bone heals faster than in the case where device 1 does not have such an advantageous coating. After healing is at least partly achieved, e.g.
  • biodegradable implants have the ability to break down, safely and relatively quickly, by biological means, into the raw materials of nature and disappear from the body where they were implanted in.
  • the coating eluting NO during a certain time after implantation is also biodegradable or at least biocompatible.
  • the implant according to an embodiment of the invention is an orthopaedic implant, such as (i) a hip joint, (ii) screws, cannulated screws, nails, intramedullary nails, and plates intended to join or attach bone fragments, pieces, or parts with each other, (iii) external fixators, (iv) implants intended for treatment of degenerative instabilities, fractures, tumours, and deformities in respect of the spine, (v) cranio- maxillofacial implants intended for treatment of fractures, reconstruction, and correction of deformities, of mandible, mid-face, or skull.
  • the implant may be chosen from the group : 1) dental implants and sealing caps, that are temporarily put over e.g.
  • a titanium screw before an artificial tooth is mounted on the titanium screw 2) internal and external wound closure, 3) cosmetic surgery, 4) reconstructive surgery, 5) wire leads, 6) heart surgery, such as heart valve surgery, 7) aneurysm clips, 8) ear implants, such as drainage tubes through the eardrum during infection, 9) infusion systems, such as cytostatic infusion systems, 10) stomia systems, such as colostomy, tracheotomy- tubes and systems, and 11) tear channel implants.
  • the implant may be mounted, placed, or applied on the area in need of implantation.
  • the coated implant is in place and gets in contact with the inevitable moisture or water in the body, in which the implant has been implanted, the NO eluting polymer in the coating of the implant starts to elute NO.
  • the implant is partially covered with NO eluting polymer.
  • This embodiment may for example be used when only a part of the implant that is inside the subject body, such as in respect of fixation means for holding a head, vertebra, or knee in a position, which position, for some reason, needs regulation during the healing process. It is of course also within the scope of the present invention to cover the entire implant in these cases with the NO eluting coating, but it would be more economically to only cover the part in contact with the subject body, i.e. a target area.
  • the elution of NO brings about an anti-viral, anti-fungal, and anti-bacterial effect, and promotion of osteo-integration of the implant, bone healing, bone growth, and wound healing on the target area.
  • Three important factors in controlling and regulating the elution of nitric oxide from a nitric oxide eluting polymer are how quickly a proton donor comes in contact with the nitric oxide releasing polymer, such as a diazoliumdiolate group, the acidity of the environment surrounding the nitric oxide eluting polymer, and the temperature of the environment surrounding the nitric oxide releasing polymer (higher temperature promotes elution of nitric oxide) .
  • the NO eluting polymer is co-spun together with a carrier material, such as another polymer, or other polymers, onto the implant.
  • a carrier material such as another polymer, or other polymers
  • Co-spun in the present context is intended to be interpreted as spun, as a polymer mixture, together with the NO eluting polymer, either by air-spinning, electro spinning, wet spinning, dry spinning, air spinning, melt spinning, or gel spinning.
  • This/these other polymer/polymers may for example be chosen from the group: polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
  • CMC Carboxy Methyl Cellulose
  • a nitric oxide eluting polymer such as L-PEI-NO
  • a carrier polymer such as L-PEI-NO
  • the nitric oxide eluting polymer may be mixed with more than one carrier polymer, whereby be elution or release may be tailor made to fit specific needs.
  • Such a need may for example be a low elution during a first period of time, when the environment of the nitric oxide eluting polymer is hydrophobic, and a faster elution during a second period of time, when the environment of the nitric oxide eluting polymer has been altered to be more hydrophilic.
  • hydrophilic polymer acts the opposite way.
  • an hydrophilic polymer is polyethylene oxide
  • one example of an hydrophobic polymer is polystyrene.
  • Fig. 4 illustrates two elution profiles (NO concentration vs. time) for two different polymer mixtures; a nitric oxide eluting polymer mixed with a hydrophilic carrier polymer in an acidic environment (A) , and a nitric oxide eluting polymer mixed with a hydrophobic carrier polymer in a neutral environment (B) .
  • this carrier polymer is substituted by another material with hydrophobic or hydrophilic properties. Therefore, the term "carrier material" in the present context should be interpreted to include carrier polymers and other materials with hydrophilic or hydrophobic properties .
  • the elution of nitric oxide from a nitric oxide eluting polymer, such as L-PEI-NO is influenced by the presence of protons. This means that a more acidic environment provides a quicker elution of nitric oxide.
  • nitric oxide eluting polymer or mixture of nitric oxide eluting polymer and carrier material
  • an acidic fluid such as an ascorbic acid solution
  • the carrier polymers and carrier materials mentioned above may affect other characteristics than the regulation of nitric oxide elution. Examples of such characteristic is mechanical strength.
  • the NO-eluting polymer may be integrated in, spun together with, or spun on top of, any of these materials in all of the embodiments of the present invention.
  • This spinning includes electro spinning, air spinning, dry spinning, wet spinning, melt spinning, and gel spinning.
  • fibers of a polymer mixture comprising a nitric oxide eluting polymer and a carrier polymer, or a carrier material, with predefined nitric oxide eluting characteristics. These characteristics may be tailor made for different elution profiles in different applications.
  • NO eluting polymers are given in US-5, 770, 645, wherein polymers derivatized with at least one -NOX group per 1200 atomic mass unit of the polymer are disclosed, X being one or two.
  • One example is an S- nitrosylated polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups .
  • nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate provides nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate .
  • Linear poly (ethylenimine) diazeniumdiolate releases nitric oxide (NO) in a controlled manner.
  • a polymer comprising an O-nitrosylated group is also a possible nitric oxide eluting polymer.
  • the nitric oxide eluting polymer comprises diazeniumdiolate groups, S- nitrosylated and O-nitrosylated groups, or any combinations thereof.
  • said nitric oxide eluting polymer is a poly (alkyleneimine) diazeniumdiolate, such as L-PEI-NO (linear poly (ethyleneimine) diazeniumdiolate) , where said nitric oxide eluting polymer is loaded with nitric oxide through the diazeniumdiolate groups and arranged to release nitric oxide at a treatment site.
  • poly (alkyleneimine) diazeniumdiolate such as L-PEI-NO (linear poly (ethyleneimine) diazeniumdiolate)
  • nitric oxide eluting polymer are selected from the group comprising amino cellulose, amino dextrans, chitosan, aminated chitosan, polyethyleneimine, PEI-cellulose, polypropyleneimine, polybutyleneimine, polyurethane, poly (buthanediol spermate) , poly (iminocarbonate) , polypeptide, Carboxy Methyl Cellulose (CMC) , polystyrene, poly (vinyl chloride), and polydimethylsiloxane, or any combinations of these, and these mentioned polymers grafted to an inert backbone, such as a polysaccharide backbone or cellulosic backbone.
  • an inert backbone such as a polysaccharide backbone or cellulosic backbone.
  • the nitric oxide eluting polymer may be a O-derivatized NONOate . This kind of polymer often needs an enzymatic reaction to release nitric oxide.
  • the nitric oxide eluting polymer may comprise a secondary amine, either in the backbone or as a pendant, as described previously. This will make a good nitric oxide eluting polymer.
  • the secondary amine should have a strong negative charge to be easy to load with nitric oxide. If there is a ligand close to the secondary amine, such as on a neighbour atom, such as a carbon atom, to the nitrogen atom, with higher electronegativity than nitrogen (N) , it is very difficult to load the polymer with nitric oxide.
  • the electronegativity of the amine will increase and thereby increase the possibility to load the nitric oxide elution polymer with nitric oxide.
  • the nitric oxide polymer may be stabilized with a salt.
  • a positive counter ion such as a cation
  • This cation may for example be selected from the group comprising any cation from group 1 or group 2 in the periodic table, such as Na + , K + , Li + , Be 2+ , Ca 2+ , Mg 2+ , Ba 2+ , and/or Sr 2+ .
  • Different salts of the same nitric oxide eluting polymer have different properties.
  • a suitable salt may be selected for different purposes.
  • cationic stabilized polymers are L- PEI-NO-Na, i.e. L-PEI diazeniumdiolate stabilized with sodium, and L-PEI-NO-Ca, i.e. L-PEI diazeniumdiolate stabilized with calcium.
  • Another embodiment of the present invention comprises mixing the nitric oxide eluting polymer, or a mixture of the nitric oxide eluting polymer and a carrier material, with an absorbent agent.
  • This embodiment provides the advantage of an accelerated elution of nitric oxide since the polymer, or polymer mixture, via the absorbent agent, may take up the activating fluid, such as water or body fluid, much faster.
  • absorbent agent is mixed with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material, and in another embodiment 10 to 50 % (w/w) absorbent agent is mixed with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material.
  • the elution of nitric oxide is activated by a proton donor, such as water, it may be an advantage to keep the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material, in contact with said proton donor. If an indication requires an elution of nitric oxide during a prolonged period of time, a system is advantageous, which presents the possibility to keep the proton donor in contact with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material. Therefore, in still another embodiment of the present invention, the elution of nitric oxide may be regulated by adding an absorbent agent.
  • the absorbent agent absorbs the proton donor, such as water, and keeps the proton donor in close contact with the nitric oxide eluting polymer during prolonged periods of time.
  • Said absorbent agent may be selected from the group comprising polyacrylates, polyethylene oxide, carboxymethylcellulose, and microcrystalline cellulose, cotton, and starch.
  • This absorbent agent may also be used as a filling agent. In this case said filling agent may give the nitric oxide eluting polymer, or mixture of said nitric oxide eluting polymer and a carrier material, a desired texture.
  • the NO eluting polymer is ground or milled into nano-particles or micro-spheres. These nano-particles or micro-spheres are then applied on the implant by any convenient method, which method is known by the skilled artisan, such as gluing with a glue that not is dissolvable in the body environment of the implant.
  • fibres, nano-particles, or micro-spheres of NO eluting polymer with other polymers, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
  • other polymers such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamide
  • the term "encapsulating” is intended to be interpreted as fixating the nitric oxide eluting polymer in a three dimensional matrix such as a foam, a film, a nonwoven mat of nano- fibers, fibers, other materials with the capability to fixate the NO eluting polymer, or enclosing the nitric oxide eluting polymer in any suitable material .
  • the nitric oxide eluting polymer such as powder, nano-particles or micro-spheres, can be incorporated in foam.
  • the foam may have an open cell structure, which facilitates the transport of the proton donor to the nitric oxide eluting polymer.
  • the foam can be of any suitable polymer such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, polyolefins, and latex, or any combinations of these, or latex. This foam is then applied on the device, to obtain improved osteointegration.
  • a suitable polymer such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbon
  • the NO eluting polymer is integrated in a film of another suitable polymer (polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC), protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these) film, which film then is glued on the implant under the restrictions mentioned above.
  • another suitable polymer polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers,
  • the nano-particles, or microspheres according to above may be integrated in a soluble film that disintegrates on the implantation area, in order to elute NO at the area of interest when the soluble film gets in contact with the moisture or water in the implantation area.
  • the device elutes nitric oxide (NO) from said eluting polymer in a therapeutic dose, such as between 0.001 to 5000 ppm, such as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 91, 92, 93, 94, 95, 96,
  • the concentration may vary widely depending on where the concentration is measured. If the concentration is measured close to the actual NO eluting polymer the concentration may be as high as thousands of ppm, while the concentration inside the tissue in this case often is considerably lower, such as between 1 to 1000 ppm.
  • the NO-eluting polymers in the coating may be combined with silver, such as hydroactivated silver.
  • silver such as hydroactivated silver.
  • the integration of silver in the devices gives the antimicrobial and anti-viral effect an extra boost.
  • the silver is releasable from the devices in the form of silver ions.
  • the integration of silver in the device may present several advantages .
  • One example of such an advantage is that the silver may keep the device in itself free from bacteria or viruses, while the nitric oxide eluting polymer elutes the therapeutic dosage of nitric oxide to the target site.
  • the NO-eluting coating is acting as a booster for drug eluting implants, e.g. pharmaceuticals, vitamins, nicotin, nitroglycerin, etambutol, Non-Steroidal Anti-Inflammatory Drugs (NSAID) , such as diclofenac, ibuprofen, aspirin, naproxen, COX-2 inhibitors, choline magnesium trisalicylate, diflunisal, salsalate, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, indomethacin, sulindac, tolmetin, meloxicam, piroxicam, meclofenamate, mefenamic acid, nabumetone, etodalac, ketorolac, celecoxib, valdecoxib, and rofecoxib; steroids, such as cortisone, prednisone, methylpredn
  • NSAID Non-
  • the device may be manufactured by, for example electro spinning of for example L-PEI.
  • L-PEI is then charged at a characteristic voltage, and a fine jet of L- PEI releases as a bundle of L-PEI polymer fibres.
  • This jet of polymer fibres may be directed to a surface to be treated.
  • the surface to be treated may for example be any suitable material.
  • the electro spun fibres of L-PEI then attach on said material and form a coating/layer of L-PEI on the device according to the invention.
  • the NO-eluting polymers employed in the coating are electro spun in such way that pure NO- eluting polymer fibres may be obtained.
  • Gas stream spinning, air-spinning, wet spinning, dry spinning, melt spinning, and gel spinning, of said NO- eluting polymers onto the implant is also within the scope of the present invention.
  • the manufacturing process presents the advantages of large contact surface of the NO-eluting polymer fibres or micro particles with the area to be covered with the coating, effective use of NO-eluting polymer, and a cost effective way of coating the implant.
  • the invention may be implemented in any suitable form.
  • the elements and components of the embodiments according to the invention may be physically, functionally, and logically implemented in any suitable way. Indeed, the functionality may be implemented in a single unit, in a plurality of units, or as part of other functional units.

Abstract

L’invention concerne un revêtement placé sur un implant, ledit implant étant destiné à une implantation dans/sur une zone d’implantation. Le revêtement comprend de l’oxyde nitrique (NO) permettant d’obtenir un effet antiviral, antifongique et antibactérien, et d’améliorer l’ostéo-intégration de l’implant, la guérison de l’os, la croissance de l'os, et la guérison de la blessure au niveau de ladite zone d'implantation. Un polymère éluant de l’oxyde nitrique (NO) est intégré dans une matière porteuse, de manière à ce que ladite matière porteuse, à l’usage, régule et contrôle l'élution d’une posologie thérapeutique d’oxyde nitrique (NO). L’invention concerne également un implant et un kit d’implants comprenant ledit revêtement. L’invention concerne également un procédé de fabrication de l’implant.
EP06708240A 2005-09-09 2006-02-13 Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication Withdrawn EP1924303A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06708240A EP1924303A1 (fr) 2005-09-09 2006-02-13 Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP05019717A EP1764119A1 (fr) 2005-09-09 2005-09-09 Implants ayant une ostéointégration ameliorée
US71619205P 2005-09-12 2005-09-12
EP06708240A EP1924303A1 (fr) 2005-09-09 2006-02-13 Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication
PCT/EP2006/050903 WO2007028657A1 (fr) 2005-09-09 2006-02-13 Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication

Publications (1)

Publication Number Publication Date
EP1924303A1 true EP1924303A1 (fr) 2008-05-28

Family

ID=35462269

Family Applications (2)

Application Number Title Priority Date Filing Date
EP05019717A Withdrawn EP1764119A1 (fr) 2005-09-09 2005-09-09 Implants ayant une ostéointégration ameliorée
EP06708240A Withdrawn EP1924303A1 (fr) 2005-09-09 2006-02-13 Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP05019717A Withdrawn EP1764119A1 (fr) 2005-09-09 2005-09-09 Implants ayant une ostéointégration ameliorée

Country Status (5)

Country Link
EP (2) EP1764119A1 (fr)
JP (1) JP2009507539A (fr)
CN (1) CN101287505A (fr)
CA (1) CA2617549A1 (fr)
WO (1) WO2007028657A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5274248B2 (ja) 2005-05-27 2013-08-28 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 酸化窒素治療及び医生物的応用のための酸化窒素放出粒子
CN101835502A (zh) 2007-09-21 2010-09-15 伊诺克斯生物制药公司 释放抗微生物气体的耳引流管
WO2009111307A2 (fr) * 2008-02-29 2009-09-11 Smith & Nephew, Inc. Revêtement et procédé de revêtement
ES2603961T3 (es) 2008-02-29 2017-03-02 Smith & Nephew, Inc. Recubrimiento de gradiente para aplicaciones biomédicas
GB0821345D0 (en) 2008-11-21 2008-12-31 P Q Silicas Uk Ltd Composition and dressing with nitric oxide
BR112012003804B1 (pt) * 2009-08-21 2019-02-19 Novan, Inc. Curativo para ferimentos, método para formar um curativo para ferimentos, e, kit de curativo para ferimento
EP2467127B1 (fr) 2009-08-21 2023-08-02 Novan, Inc. Gels topiques
EP2488591A1 (fr) * 2009-10-13 2012-08-22 Novan, Inc. Revêtements libérant de l'oxyde nitrique
KR101255337B1 (ko) 2010-10-04 2013-04-16 한국과학기술연구원 온도 감응성 합성 고분자를 이용한 일산화질소 전달체
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
WO2012118819A2 (fr) 2011-02-28 2012-09-07 Novan, Inc. Particules de silice modifiées par des groupements s-nitrosothiols libérant de l'oxyde nitrique et procédés de fabrication associés
CN104225690B (zh) * 2014-09-02 2017-01-11 山东润泽制药有限公司 一种可吸收骨折内固定材料及其制备方法和应用
CN105832434B (zh) * 2015-01-14 2018-08-17 山西医科大学 一种用于种植牙手术中孔距定位及平行的导向装置
CN104667345B (zh) * 2015-01-30 2017-02-22 深圳迈普再生医学科技有限公司 一种具有生物活性的颅骨修复假体及其制备方法
JP7141062B2 (ja) 2016-04-25 2022-09-22 医療法人Natural Smile 歯科用補綴物及びその部品
WO2018189185A1 (fr) * 2017-04-11 2018-10-18 Straumann Holding Ag Implant dentaire
CN109985274A (zh) * 2019-03-28 2019-07-09 北京航空航天大学 具有再生功能的组织工程经导管瓣膜裙体及其制备方法
CN111910441B (zh) * 2020-08-06 2021-11-02 南京诺令生物科技有限公司 一种抗菌芯片及其制备方法和应用

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US673744A (en) * 1900-08-06 1901-05-07 Pearl M Westerfield Vending-box.
US5405919A (en) * 1992-08-24 1995-04-11 The United States Of America As Represented By The Secretary Of Health And Human Services Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions and methods of treating biological disorders
US5770645A (en) 1996-08-02 1998-06-23 Duke University Medical Center Polymers for delivering nitric oxide in vivo
US6299980B1 (en) * 1998-09-29 2001-10-09 Medtronic Ave, Inc. One step lubricious coating
WO2000022207A2 (fr) 1998-10-01 2000-04-20 The University Of Akron Procede et appareil permettant de produire des nanofibres
US6737447B1 (en) 1999-10-08 2004-05-18 The University Of Akron Nitric oxide-modified linear poly(ethylenimine) fibers and uses thereof
US6270779B1 (en) * 2000-05-10 2001-08-07 United States Of America Nitric oxide-releasing metallic medical devices
US6706274B2 (en) * 2001-01-18 2004-03-16 Scimed Life Systems, Inc. Differential delivery of nitric oxide
US6520425B1 (en) 2001-08-21 2003-02-18 The University Of Akron Process and apparatus for the production of nanofibers
JP2005504813A (ja) * 2001-09-24 2005-02-17 メドトロニック・エイヴイイー・インコーポレーテッド 合理的薬剤療法デバイス及び方法
EP1436018A1 (fr) * 2001-09-26 2004-07-14 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Dispositifs medicaux revetus a liberation d'oxyde nitrique et leur procede de preparation
US6695992B2 (en) 2002-01-22 2004-02-24 The University Of Akron Process and apparatus for the production of nanofibers
US20040254238A1 (en) * 2003-04-07 2004-12-16 Osteoscreen Bone growth stimulation with NO/statin and other NO modulating combinations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007028657A1 *

Also Published As

Publication number Publication date
WO2007028657A1 (fr) 2007-03-15
CN101287505A (zh) 2008-10-15
CA2617549A1 (fr) 2007-03-15
JP2009507539A (ja) 2009-02-26
EP1764119A1 (fr) 2007-03-21

Similar Documents

Publication Publication Date Title
US20090010989A1 (en) Coating For Implants and Implants With Improved Osteointegration, and Manufacturing Method
WO2007028657A1 (fr) Revetement pour implants et implants presentant une osteo-integration amelioree, et procede de fabrication
US20080069863A1 (en) Device for treatment of disorders in the oral cavity with nitric oxide, and manufacturing process for the same
EP1846058B1 (fr) Dispositif, procede et utilisation destines a traiter une neuropathie impliquant l'oxyde nitrique
EP1917005B1 (fr) Appareil, systeme, et methode comprenant un donneur de proton micro-encapsule pour liberer de l'oxyde nitrique d'un polymere
EP1861130B1 (fr) Dispositif et technique de traitement de mycose dermatologique et en particulier d'onychomycose
EP1704877A1 (fr) Dispositif de traitement des plaies comprenant un polymère à élution de monoxyde d'azote
WO2006100155A1 (fr) Dispositif pour le soin des plaies, et procede de fabrication associe, impliquant l'utilisation de monoxyde d'azote
US20100016790A1 (en) Treatment And Pre-Treatment Device, And Manufacturing Method Therefor, Involving Nitric Oxide
WO2006084911A2 (fr) Dispositif d'application de medicaments ameliore, procede de fabrication de celui-ci et procede de traitement
US20090098187A1 (en) Composition And Its Use For The Manufacture Of A Medicament For Treating, Prophylactically Treating, Preventing Cancer And/Or Infections In The Urinary Tract
EP1690558A1 (fr) Dispositif de traitment de troubles d'origine diabetique
WO2006084913A2 (fr) Dispositif pour traiter des troubles rectaux, et procede de fabrication associe comportant de l'oxyde nitrique
EP1731176A1 (fr) Dispositif de prétraitement comprenant de l'oxyde nitrique
WO2006084914A2 (fr) Dispositif de traitement gastrique, procede de fabrication associe et utilisation d'oxyde nitrique
EP1690532A1 (fr) Dispositif pour traitement gastrique et son procédé de fabrication
CZ36922U1 (cs) Substrát s funkční vrstvou s antioxidačním účinkem

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080331

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RTI1 Title (correction)

Free format text: DEVICE FOR PERFORMING A TREATMENT WITH NITRIC OXIDE AND MANUFACTURING METHOD THEREFOR

17Q First examination report despatched

Effective date: 20081112

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOLABS AB

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090901