WO2009064861A2 - Polymères de diazéniumdiolate libérant du monoxyde d'azote, compositions, dispositifs médicaux et utilisations de ceux-ci - Google Patents

Polymères de diazéniumdiolate libérant du monoxyde d'azote, compositions, dispositifs médicaux et utilisations de ceux-ci Download PDF

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WO2009064861A2
WO2009064861A2 PCT/US2008/083375 US2008083375W WO2009064861A2 WO 2009064861 A2 WO2009064861 A2 WO 2009064861A2 US 2008083375 W US2008083375 W US 2008083375W WO 2009064861 A2 WO2009064861 A2 WO 2009064861A2
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Prior art keywords
optionally substituted
polyol
polyisocyanate
nitric oxide
group
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PCT/US2008/083375
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WO2009064861A3 (fr
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Joseph A. Hrabie
Larry K. Keefer
Aisa Sendijarevic
Craig D. Friedman
Arindam Datta
Arthur Tinkelenberg
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Biomerix
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Publication of WO2009064861A2 publication Critical patent/WO2009064861A2/fr
Publication of WO2009064861A3 publication Critical patent/WO2009064861A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • 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
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/005—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters containing a biologically active substance, e.g. a medicament or a biocide
    • 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
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/04—Non-resorbable 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/44—Polycarbonates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
    • C08G18/758—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing two or more cycloaliphatic rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
    • C08L75/04—Polyurethanes
    • 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

  • Wound healing is a multi-stage process involving many different cell types such as platelets, fibroblasts, and epithelial cells.
  • the wound healing response initially involves an inflammatory phase as the wound is populated by platelets and erythrocytes, followed by an influx of polymorphonuclear cells, macrophages, and lymphocytes. Proliferation, differentiation, and apoptosis of several cell types occur, including keratinocytes, fibroblasts, and endothelial cells.
  • Angiogenesis the growth of new blood vessels, is another key component of wound repair. Collagen synthesis, deposition, and remodeling complete the wound healing process. Included among the many agents produced by the various cells involved in wound healing is nitric oxide (NO).
  • NO nitric oxide
  • Nitric oxide is believed to play a particularly key role in the initial inflammatory phase of wound healing. Many of the effects of NO, such as vasodilation, antimicrobial activity, antiplatelet effects, and induction of vascular permeability, are especially important in the inflammatory phase. NO is believed to achieve its effect by modulating inflammation- associated cytokines, such as IL-8, IL-I, IL-6, TGF-pl, and TNF-a. NO also affects the process of cellular proliferation during wound healing. NO has been shown to modulate the differentiation, proliferation, and apoptosis of keratinocytes (Yamaoka et al., Free Radio.
  • NO has been shown to increase angiogenesis (Murohara et al., J Clin. Invest, 101(11): 2567-2568 (1998)). Conversely, NO inhibitors impair angiogenesis in gastric ulcer healing (Brzozowski et al., Digestion, 56(6): 463-471 (1995)). Finally, the role of NO in the last phases of collagen synthesis, deposition, and remodeling has been well-described in in vitro and in vivo studies.
  • Wound dressings have long been used to minimize tissue loss in chronic wounds by preventing the loss of body fluids and proteins from the body, reducing bacterial infection rates, and improving the healing process by providing a supportive network for proliferating cells.
  • a wide range of synthetic polymers have been used for wound dressings.
  • Polyurethane foams in particular offer a number of advantages including absorptive capacity, mechanical strength, and mass transport and flow-through, and the ability to incorporate bioactive agents.
  • Polyurethane foam dressing products are commercially available, including Hydrasorb (Kendall), Allevyn (Smith & Nephew), Lyofoam (BMS Convatec), and Polymem (Ferris).
  • Diazeniumdiolated compounds have been incorporated into the backbone or pendant side-branches of polyurethanes via reaction with specific moieties of the pre-formed polymer (see, e.g., U.S. Patent 5,405,919).
  • the incorporation of an NO- releasing group into a polymer was carried out by grafting into the main backbone, attaching to the main backbone as a pendant group, or onto a side chain of the substrate polymer by reaction of nitric oxide gas and an active hydrogen (e.g., N-H).
  • the invention provides novel nitric oxide-releasing polymers, such as those based on polyurethane, polyurea, and a combination thereof.
  • the polymers of the invention comprise at least two polyurethane or polyurea repeat units and contain at least one nitrogen- bound diazeniumdiolate.
  • the invention also provides compositions and medical devices, such as wound dressings, comprising such diazeniumdiolated polymers and methods of preparing and using such polymers.
  • Figure 1 is a graph of time (minutes) versus moles of nitric oxide released from a diazeniumdiolated polyurethane film in accordance with an embodiment of the invention.
  • novel polyurethane-based polymers comprise at least two polyurethane or polyurea repeat units and have at least one and polyurethane-urea polymers of the invention are stable, that is they do not release nitric oxide until used, but when used, are capable of releasing nitric oxide.
  • the incorporation of the diazeniumdiolated moiety occurs during the polymerization of the polyurethane, the polyurea, or the copolymer.
  • the polyurethane or polyurea is prepared with prepolymers that have terminal isocyanate groups.
  • the terminal isocyanate groups can react with at least one diazeniumdiolated polyamine and create one or more linkages that typically constitute at least part of the hard segments of polyurethane/polyurea compositions or are incorporated as a part of the hard segments of polyurethane/polyurea compositions.
  • the diazeniumdiolated functional group (-N 2 O 2 " ) remains unreacted during the polymerization step(s), thereby allowing the resulting polyurethane/polyurea to retain the NO-donating ability of the parent polyamine.
  • the incorporation of the diazeniumdiolated functional group as a part of the hard segments of a polyurethane/polyurea composition provides the ability to control the rate of release of nitric oxide over an extended period of time as the chemical composition or structure of both the hard and soft segments can be engineered in various ways.
  • being able to incorporate a diazeniumdiolate functional group into the hard segments of a polyurethane/polyurea composition provides increased flexibility or options in the structural positioning and controlling the amount of diazeniumdiolate functional group that can be incorporated into the polymer backbone. As a result, additional control of the rate of nitric oxide release becomes possible.
  • the present invention provides a nitric oxide-releasing polyurethane prepared from a composition comprising
  • At least one polyol selected from the group consisting of an alkyl polyol, a cycloalkyl polyol, an aryl polyol, a polyether polyol, a polyester polyol, a polycarbonate polyol, a polycaprolactone polyol, a polyester polycarbonate polyol, silicone polyol, acrylic polyol, and a combination thereof;
  • At least one polyisocyanate selected from the group consisting of an optionally substituted aromatic di- or polyisocyanate, an aralkyl di- or polyisocyanate, an aliphatic di- or polyisocyanate, and an alicyclic di- or polyisocyanate;
  • the N 2 O 2 " group is attached to the hard segment of the polyurethane backbone.
  • the N 2 O 2 " group is attached to and is an integral part of the hard segment of the polyurethane backbone or is incorporated into the hard segment of the polyurethane backbone.
  • the -N 2 ⁇ 2 " -containing polyamine residue, after reaction, is incorporated into the hard segment.
  • the present invention also provides nitric oxide-releasing polyurea prepared from
  • At least one polyisocyanate selected from the group consisting of an optionally substituted aromatic di- or polyisocyanate, an aralkyl di- or polyisocyanate, an aliphatic di- or polyisocyanate, and an alicyclic di- or polyisocyanate;
  • the -N 2 O 2 " group is attached to the hard segment of the polyurea backbone.
  • the N 2 O 2 " group is attached to and is an integral part of the hard segment of the polyurethane backbone or is incorporated into the hard segment of the polyurea backbone.
  • the polyol is any suitable polyol used for polyurethane chemistry, such as an alkyl polyol, a cycloalkyl polyol, an aryl polyol, a polyether polyol, a polyester polyol, a polycarbonate polyol, a polycaprolactone polyol, a polyester polycarbonate polyol, silicone polyol, and acrylic polyol.
  • the silicone polyol is selected from a specific structural type of silicone nonionic surfactant polymers, having multiple polyoxyalkylene sidechains, such as dimethicone copolyol.
  • the polyol can be a polyester that is biodegradable (e.g., glycolide, L-lactide, D-L lactate, caprolactone, copolymers of lactide and glycolide, copolymers of D-L lactide and glycolide, copolymers of L-lactide and caprolactone, copolymers of L-lactide and glycolide, poly paradioxanone, or combinations thereof).
  • the polyol can have any desired molecular weight, ranging from several hundred to several thousand Daltons (e.g., about 200-10,000 g/mol, about 500-8,000 g/mol, about 500-5,000 g/mol, about 1,000-5,000 g/mol).
  • Polyether polyols e.g., poly(tetramethylene ether) glycol
  • polyester polyols e.g., polyethylene adipate
  • Suitable polyether polyols usually are manufactured from propylene oxide (PO) and ethylene oxide (EO) and have a relatively low molecular weight (e.g., about 200-8,000 g/mol, about 500-5,000 g/mol, about 500-3,000 g/mol).
  • the functionality of the polyether polyol i.e., the number of active hydroxyl groups per molecule
  • a functionality of 2 typically provides a more elastomeric matrix suitable for elastomers
  • a functionality of 3 provides a base for flexible matrix or a soft segment cross-linked
  • 3 to 6 or more provides a base for rigid matrix.
  • Polyester polyols are typically produced by the condensation reaction of a diol such as ethylene glycol with a dicarboxylic acid.
  • the polyisocyanate is any suitable optionally substituted aromatic di- or polyisocyanate, an aralkyl di- or polyisocyanate, an aliphatic di- or polyisocyanate, or an alicyclic di- or polyisocyanate.
  • the polyisocyanate is selected from the group consisting of methylene-4,4'-diphenyldiisocyanate (MDI), methylene-2,4'- diphenyldiisocyanate, methylene-2,2'-diphenyldiisocyanate, polymeric MDI (PMDI), naphthalene- 1 ,5-diisocyanate (NDI), carbodiimide-modified MDI, tolylene diisocyanate (TDI), paraphenylene diisocyanate (PPDI), 4,4 '-methylene bis(cyclohexyl isocyanate) (H12MDI), isophorone diisocyanate (IPDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,6- hexamethylene diisocyanate (HMDI), isocyanate-terminated biuret adduct of HDI, isocyanate terminated trimerization products based on HD
  • the polymer backbone can be prepared with components that provide a biodegradable backbone.
  • biodegradable NO- releasing polyurethanes polyureas
  • polyurethane/ureas polyurethane/ureas.
  • a biodegradable polyol and/or polyisocyanate can be used.
  • the polyol component can be a polyester that is biodegradable (e.g., glycolide, L-lactide, D-L lactate, caprolactone, copolymers of lactide and glycolide, copolymers of D-L lactide and glycolide, copolymers of L-lactide and caprolactone, copolymers of L-lactide and glycolide, poly paradioxanone, or combinations thereof).
  • the isocyanate component also can be biodegradable (e.g., lysine diisocyanate, 1,6- hexamethylene diisocyanate, 1,4-butane diisocyanate, or combinations thereof).
  • the chain extender can be any suitable hydroxyl- or amine-functionalized chain extender known in polyurethane or polyurea chemistry.
  • the hydroxyl- functionalized chain extender is selected from the group consisting of 1,3 -propanediol, 1,4- butanediol, 1,6-hexanediol, 1,12-dodecanediol, dimethylcyclohexyldiol, 1,4-bis- hydroxydiethyl hydroquinone (HQEE), diethylene glycol, dipropylene glycol, neopentyl glycol, diethanolamine, dipropanolamine, bis(hydroxyethyl)biphenol, and bis(hydroxypropyl)biphenol.
  • HQEE 1,4-bis- hydroxydiethyl hydroquinone
  • the amine-functionalized chain extender is selected from the group consisting of 1,3-propanediamine, 1,4-butanediamine, 1,6-hexanediamine, isophoronediamine, and 1,4-cyclohexanediamine.
  • a cross-linker to react with and cross-link the residual isocyanate groups present on the (pre)polymer used.
  • the cross-linker is preferably multifunctional with two or more groups that are reactive with isocyanate.
  • the cross-linker is preferably multi-functional with at least three groups that are reactive with isocyanate.
  • Cross-linkers with terminal hydroxyl, amine, and carbonyl groups are typically suitable.
  • the cross-linker can be selected from the group consisting of glycerol, trimethylolpropane, pentaerythritol, sorbitol, sucrose, triethanolamine, a low molecular weight poly(oxyalkylene) glycerol adduct, a low molecular weight poly(oxyalkylene) trimethylolpropane adduct, a low molecular weight polycaprolactone triol, and an oxyalkylene derivative of ethylenediamine.
  • silicone polyethylene oxide copolymer with terminal hydroxyl groups e.g., Surfactant 193, Dow Corning
  • an ethylene glycol/propylene glycol copolymer e.g., Pluronic L-64, BASF
  • other alkylene oxide surfactants e.g., Pluronic 17Rl and 25R2, BASF; and BRIJ, ICI Americas.
  • the diazeniumdiolated polyamine is any suitable polyamine, such as those disclosed in, for example, U.S. Patents 5,155,137 and 5,250,550. Thus, there is more than one free amino group in the diazeniumdiolated polyamine.
  • the polyamine preferably has at least three amino groups, at least one of which is bonded to a diazenimdiolate (-N 2 O 2 " ) group. In an embodiment, the polyamine comprises three or four amino groups.
  • the diazeniumdiolated polyamine can have the structure of formula (I)
  • a 1 and A 2 are the same or different and each is hydrogen, an optionally substituted C 1-12 alkyl, optionally substituted C 3-30 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 4 and R 5 are the same or different and each is an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl, optionally substituted C 3-30 cycloalkyl, or optionally substituted aryl, and
  • M is a counterion as described herein.
  • the diazeniumdiolated polyamine may or may not contain peptide bonds or amino acid residues.
  • a preferred embodiment of the polyamine of formula (I) is a compound of formula (Ia),
  • a 1 and A 2 are the same or different and each is hydrogen, an optionally substituted Ci -12 alkyl, optionally substituted C 3-3O cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
  • a 3 is -N 2 O 2 M, hydrogen, an optionally substituted C 1-12 alkyl, optionally substituted C 3-30 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • x, y, and z are independently 2-12 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12);
  • a is 0 or 1 ;
  • M is a counterion as described herein.
  • a 1 and A 2 are preferably hydrogen.
  • a 3 is preferably or -N 2 O 2 M or an optionally substituted C 1-12 alkyl.
  • R 4 and/or R 5 are
  • a C 2-12 alkylene i.e., -(CH 2 ) 2 . 12 -) or
  • Specific polyamines suitable for the present invention include diazeniumdiolated di ethylene triamine, 3,3'-iminobispropylamine, and triethylenetetraamine.
  • a preferred diazeniumdiolated polyamine is diethylenetriamine NONOate ("DET A/NO").
  • the concentration of the -N 2 O 2 " functional groups bound to the polyurethane/polyurea can be controlled, e.g., by the equivalent weight of the starting components.
  • the polyurethane or polyurea backbone can contain numerous -N 2 O 2 " groups.
  • each -N 2 O 2 " group on the polymer also comprises a suitable counterion to balance the charge.
  • the counterions can be the same or different, but preferably they are the same.
  • the counterion is a pharmaceutically acceptable counterion which could be a metal or non-metal counterion, e.g., alkali metal counterions such as sodium ion, potassium ion, lithium ion, and the like; alkaline earth metal counterions such as magnesium ion, calcium ion, and the like; Group III metal counterions such as aluminum ion; Group IV metal counterions such as tin ion; and transition metals, including iron ion, copper ion, manganese ion, zinc ion, cobalt ion, vanadium ion, molybdenum ion, platinum ion, and the like.
  • Non-metal counterions include quaternary ammonium ions. The only requirement for the pharmaceutical
  • the amine-functionalized flexible segment and chain extenders include amine- terminated polyethers, C 1-10 alkyl, C 2-10 alkenyl, and C 3-12 cycloalkyl mono- and diamines such as methylamine, ethylamine, diethylamide, ethylmethylamine, n-propylamine, allylamine, isopropylamine, «-butylamine, «-butylmethylamine, «-amylamine, «-hexylamine, 2-ethylhexylamine, cyclohexylamine, ethylenediamine, polyethyleneamine, 1 ,4- butanediamine, 1,6-hexanediamine, N-methylcyclohexylamine and alkylene amines such as ethyleneimine.
  • the present invention provides a nitric oxide- releasing polyurethane or polyurea comprising at least one repeat unit of the structure:
  • X is O or NH
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are the same or different and each is an optionally substituted C 1-J2 alkyl, optionally substituted C 3-30 cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkoxyalkyl, optionally substituted polyether, optionally substituted polyester, optionally substituted polycarbonate, optionally substituted polycaprolactone, optionally substituted polyester polycarbonate, or optionally substituted heteroaryl; and
  • M is a counterion as described herein.
  • Any one or more of the C 1-12 alkyl, C 3-30 cycloalkyl, aryl, aralkyl, alkoxyalkyl, polyester, polycarbonate, polycaprolactone, polyester polycarbonate, or heteroaryl described above can be substituted.
  • each of these moieties can have 1 to 10 substituents (e.g., 1 to 8, 1 to 6, 1 to 4, 1 to 3 substituents) that are independently selected from the group consisting of halo, C 1-12 alkyl, C 6-3O aryl, heteroaryl, C 1-12 alkoxy, C 1-I2 aryloxy, acyloxy, acetyl, and carboxyl.
  • a polymer of the invention has at least one repeat unit with the following structure:
  • R is the flexible segment made from, e.g., optionally substituted polyether, optionally substituted polyester, optionally substituted polycarbonate, and optionally substituted polycaprolactone.
  • R 3 is optionally substituted Cj -12 alkyl, optionally substituted C 3-30 cycloalkyl, or optionally substituted aryl.
  • a polymer of the invention has at least one repeat unit with the following structure:
  • R 2 is the flexible segment made from, e.g., optionally substituted polyether, optionally substituted polyester, optionally substituted polycarbonate, and optionally substituted polycaprolactone.
  • R 3 is optionally substituted C 1-12 alkyl, optionally substituted C 3-30 cycloalkyl, or optionally substituted aryl.
  • prepolymer means a reactive relatively low-molecular weight macromolecule or oligomer that has at least one functional group capable of further polymerization.
  • the polyol can be pre-reacted with part or all of the polyisocyanate to form a prepolymer.
  • the reactive terminal isocyanate group on the prepolymer can then be reacted with the at least one diazeniumdiolated polyamine.
  • Suitable polyurethane polymers or prepolymers can be synthetically prepared using standard techniques.
  • a polymer comprising at least two polyurethane or polyurea repeat units can be prepared using condensation polymerization and free radical polymerization.
  • Suitable catalysts in these reactions are amine or organometallic catalysts including di- and tributyltin dilaureate and stannous octoate.
  • the desired form of the polymer or prepolymer and/or the desired molecular weight will dictate the polymerization conditions to be used.
  • Diazeniumdiolated polyamines that contain at least one, preferably two or more, -NH- or NH 2 terminal groups can react directly with isocyanate (or an isocyanate prepolymer) in solution to form a polyurethane solution.
  • the diazeniumdiolated polyamine is covalently bound to the polyurethane by prepolymer-based reactions between an amino group and an isocyanate or a hydroxyl group and an isocyanate.
  • an NO-releasing segmented poly(urethane-urea) is prepared by reacting NCO- prepolymer (or quasi-prepolymer) with amine-containing diazeniumdiolate compounds.
  • NO-releasing segmented polyurethane is prepared by reacting NCO- prepolymers or quasi-prepolymers with hydroxyl-containing diazeniumdiolate compounds.
  • the diazeniumdiolated compound is an integral part of the hard segment of the polyurethane backbone.
  • the synthesis is designed such that incorporation of the diazeniumdiolated polyamines occurs via a mechanism similar to the incorporation of chain extenders or cross-linkers in a typical polyurethane/urea reaction.
  • the polymerization reaction occurs over several hours at room temperature.
  • an inert atmosphere e.g., nitrogen blanket
  • an inert atmosphere e.g., nitrogen blanket
  • the resulting NO-releasing material can be in any suitable form, such as a film (including a biostable film), powder, tube, extruded fiber or an extruded and annealed fiber, an injection molded part, an injection molded device, a matrix or reinforcement components of composites, coating, foam, and reticulated foam.
  • suitable forms include a fiber, a yarn, a fabric, a membrane, a gel, a plastic, or a matrix.
  • the desired form usually is dictated by the desired end use.
  • the polyurethane based device is a composite with a polyurethane substrate comprising open-celled hydrophobic polyurethane foam with a hydrophilic polyurethane foam (microporous) coating.
  • the polyurethane based device is a composite with a polyurethane substrate comprising reticulated hydrophobic polyurethane matrices containing inter-connected and intercommunicating pores with a hydrophilic polyurethane foam (microporous) coating.
  • the coatings on the open-celled hydrophobic polyurethane foam or on the reticulated hydrophobic polyurethane matrices can be a film.
  • the film or foam coating can be at least partially hydrophilic.
  • the resulting composite combines the strength, durability, surface area, and mass transport characteristics of hydrophobic polyurethane, with the biocompatibility, reservoir capacity, and chemical binding properties of hydrophilic coating both in form or foam and film.
  • the polyurethane based composite is hemo-compatible, non- immunogenic, and has a large internal surface area. In one embodiment, A range of pore sizes is available in the device or in the composite including about 20-1,000 ⁇ m (e.g., about 50-800 ⁇ m, 100-600 ⁇ m, and 150-500 ⁇ m).
  • the polyurethane foam composite has the unique ability to incorporate bioactive agents (e.g., enzymes) within the hydrophilic layer of the polymer system.
  • the composite is designed to have elevated enzymatic activity levels per volume due to greater surface area, enhanced flow-through, and reduced deactivation of the enzymes due to thermal degradation during the polymerization step. Both catalase and lipase have been immobilized successfully within the foam composite and demonstrated hydrolytic and synthetic activity levels in in vitro assay systems.
  • the foam composite can be used as an antimicrobial swab that can be impregnated with a broad spectrum of enzymes and/or non-ionic detergents to remove biocontaminants from endoscope biopsy channels.
  • a diazeniumdiolated polyurethane of the present invention typically the following methods can be used: a prepolymer method or one-shot reaction.
  • the prepolymer (or quasi-prepolymer) method involves a two-step process.
  • an NCO-prepolymer is prepared by reacting the polyisocyanate and polyol at an NCO/OH equivalent ratio of about 2/1. If the NCO/OH equivalent ratio is greater than about 2/1, a quasi-prepolymer is formed that contains prepolymer adduct and free monomeric isocyanate.
  • the prepolymer (or quasi- prepolymer) is reacted with at least one -N 2 ⁇ 2 ⁇ -containing polyamine forming a poly(urethane-urea) linkage.
  • prepolymer (or quasi-prepolymer) is reacted with a mixture of at least one -N 2 O 2 " -containing polyamine and chain extender/crosslinker to form a poly(urethane-urea) linkage.
  • a diazeniumdiolated polyurethane is prepared by reacting NCO-prepolymers (or quasi-prepolymers) with hydroxyl group containing diazeniumdiolate compounds and chain extenders/crosslinkers to form polyurethane linkages. Linear poly(urethane-urea) or polyurethane is formed if the functionality of reactive components is two.
  • a linear polymer is formed with di-functional isocyanate and di-functional isocyanate chain-extenders.
  • Crosslinked poly(urethane-urea) or polyurethane is formed if the functionality of reactive components is higher than two.
  • a crosslinked polymer is formed with isocyanate and cross-linkers having functionality greater than 2.
  • hydrogen bonding exists in both linear and cross-linked isocyanate chain-extenders.
  • the prepolymers or quasi-prepolymers can be prepared by bulk or solution polymerization.
  • the chain extension reaction is solution polymerization that minimizes the reaction heat exotherm and thus provides the stability of the NO-releasing poly(urethane-urea).
  • chain extension is carried out by a slow bulk polymerization method as well.
  • At least one polyol selected from the group consisting of an alkyl polyol, a cycloalkyl polyol, an aryl polyol, a polyether polyol, a polyester polyol, a polycarbonate polyol, a polycaprolactone polyol, a polyester polycarbonate polyol, silicone polyol, acrylic polyol, or a combination thereof with
  • At least one polyisocyanate selected from the group consisting of an optionally substituted aromatic di- or polyisocyanate, an aralkyl di- or polyisocyanate, an aliphatic di- or polyisocyanate, or an alicyclic di- or polyisocyanate to form a prepolymer; and
  • N 2 O 2 " -containing polyamine or a hydroxyl group containing diazeniumdiolate to form the nitric oxide-releasing polymer, wherein the N 2 O 2 ' group is attached to the hard segment of the polymer backbone.
  • the mixture of N 2 O 2 " -containing polyamine and at least one polymer modifier selected from the group consisting of a chain extender, a cross-linker, and a mixture thereof can be combined with the prepolymer.
  • the NO-releasing polyurethane/urea polymers can be prepared by combining and reacting all the components (i.e., polyols, polyisocyanates, chain extenders/crosslinkers, and at least one -N 2 O 2 " -containing polyamine) together.
  • the resulting NO-releasing polymer has randomly distributed hard and soft segments.
  • the present invention further provides a method of preparing a nitric oxide-releasing polyurethane comprising combining
  • At least one polyol selected from the group consisting of an alkyl polyol, a cycloalkyl polyol, an aryl polyol, a polyether polyol, a polyester polyol, a polycarbonate polyol, a polycaprolactone polyol, a polyester polycarbonate polyol, silicone polyol, acrylic polyol, or a combination thereof;
  • At least one polyisocyanate selected from the group consisting of an optionally substituted aromatic di- or polyisocyanate, an aralkyl di- or polyisocyanate, an aliphatic di- or polyisocyanate, or an alicyclic di- or polyisocyanate;
  • the present invention includes a method of preparing a nitric oxide-releasing polyurea comprising combining
  • At least one polyisocyanate selected from the group consisting of an optionally substituted aromatic di- or polyisocyanate, an aralkyl di- or polyisocyanate, an aliphatic di- or polyisocyanate, or an alicyclic di- or polyisocyanate;
  • the method can further comprise the addition of an amino-functionalized chain extender.
  • the solvent should not react with any of the starting materials.
  • the solvent preferably is free of reactive amine, hydroxyl, and/or carboxyl groups.
  • Suitable solvents include, but are not limited to, methylene chloride, tetrahydrofuran (THF), dimethylacetamide (DMAC), acetonitrile, chloroform, dichloroethane, dimethyl sulfoxide (DMSO), dichloroethylene, dimethylformamide, N-methylpyrrolidone (NMP), and methylene bromide.
  • the polymers of the invention can have any desired molecular weight based on the choice of starting materials. Typical average molecular weights are up to about 100,000 g/mol but can be as high as about 200,000 g/mol.
  • the polyurethane, polyurea, or copolymer thereof, either before or after incorporation of the -N 2 O 2 " functional group, can be characterized quantitatively using known methods.
  • molecular weight determinations can be made using gel permeation chromatography (also known as size exclusion chromatography and gel filtration chromatography), matrix-assisted laser desorption/ionization mass spectroscopy (MALDI), light scattering (e.g., low angle and multi angle), small angle neutron scattering (SANS), sedimentation velocity, end group analysis, osmometry, cryoscopy/ebulliometry, and viscometry.
  • MALDI matrix-assisted laser desorption/ionization mass spectroscopy
  • SANS small angle neutron scattering
  • further structural characterization of the polymer can be accomplished using, for example, both solution and solid state nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), ultraviolet spectroscopy (UV-vis), differential thermal analysis (DTA), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), and mass spectrometry.
  • NMR nuclear magnetic resonance spectroscopy
  • IR infrared spectroscopy
  • UV-vis ultraviolet spectroscopy
  • DTA differential thermal analysis
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • mass spectrometry mass spectrometry
  • the diazeniumdiolated polymers of the invention can be assessed for free isocyanate content to evaluate the efficiency in consuming or decreasing free isocyanate groups.
  • IR can be used to assess a diazeniumdiolated polyurethane or polyurea for polyurea-NONOate linkages.
  • Nitric oxide detection can be determined using known techniques such as those described in U.S. Patent Nos. 6,511,991 and 6,379,660; Keefer, et al., "NONOates(l- Substituted Diazen-l-ium-1, 2 diolates) as Nitric Oxide Donors: Convenient Nitric Oxide Dosage Forms," Methods in Enzymology, 28: 281-293 (1996); Horstmann et al., “Release of nitric oxide from novel diazeniumdiolates monitored by laser magnetic resonance spectroscopy," Nitric Oxide, 6(2): 135-41 (2002); and Kitamura et al., "In vivo nitric oxide measurements using a microcoaxial electrode,” Methods MoI.
  • the amount of NO produced can be detected by chemiluminescence, electrochemically, or by absorbance.
  • nitric oxide assay kits are commercially available.
  • the diazeniumdiolated polyurethane/polyurea is capable of releasing nitric oxide over an extended period of time.
  • the release of nitric oxide can be either in vivo or ex vivo, depending on the ultimate use of the polymer. It is possible that carriers, solvents, and/or excipients (e.g., water, glycerol) can impact the rate of NO release.
  • the polymer releases nitric oxide at its intended site for treatment of a biological disorder (e.g., to enhance wound healing and/or promote angiogenesis). Accordingly, the present invention provides a method of releasing nitric oxide from a nitric oxide-releasing polyurethane/polyurea of the invention.
  • the release of NO is under physiological conditions.
  • the release of NO can occur in vivo or ex vivo at about 37 °C and pH about 7.
  • a polymer of the present invention releases NO over a period of at least one day (i.e., at least about 24 hours), at least three days (i.e., at least about 72 hours), at least 5 days (i.e., at least about 120 hours), at least 7 days (i.e., at least about 168 hours), at least 10 days (i.e., at least about 240 hours), and at least 14 days (i.e., at least about 336 hours).
  • the incorporation of the diazeniumdiolated functional group as a part of the hard segments of a polyurethane/polyurea composition provides the ability to control the rate of release of nitric oxide.
  • the rate of release of nitric oxide over an extended period of time from diazeniumdiolated polyurethane/polyurea or polyurethane can be controlled in several ways.
  • the release of NO can be controlled through alterations in chemistry, structure or morphology, or the molecular weights of both the hard and soft segments.
  • the type of polyols, molecular weight of the polyols, the crystallinity of the polyols, or a combination of polyols can be altered to control the rate and amount of nitric oxide release.
  • Other methods of controlling the rate and amount of NO release include: varying the amount of the hard segment, varying the amount of urea-based hard segments, varying the amount of chain extenders, varying the amount of cross-linking in the hard segment, varying the amount of cross-linking in the soft segment, varying the amount of hydrogen bonding between components, and combinations thereof. Properties such as flexibility, hydrophilicity, and polarity also can be varied to control the rate and amount of nitric oxide release.
  • the invention provides a pharmaceutical composition comprising at least one diazeniumdiolated polyurethane of the invention.
  • Any suitable pharmaceutically acceptable carrier can be used within the context of the invention, and such carriers are well known in the art.
  • the carrier comprises aqueous and nonaqueous solutions, a liquid that contains a buffer and a salt, sterile powders, granules, and tablets, a semipermeable matrix, a parenteral vehicle, or an intravenous vehicle.
  • the choice of carrier will be determined, in part, by the particular site to which the pharmaceutical composition is to be administered and the particular method used to administer the pharmaceutical composition.
  • compositions comprising at least one diazeniumdiolated polyurethane of the invention to a mammal, e.g., a mammal such as a human
  • a mammal e.g., a mammal such as a human
  • Formulations suitable for topical, oral, or parenteral administration preferably comprise at least one diazeniumdiolated polyurethane/polyurea.
  • Suitable carriers and their formulations are further described in A.R. Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995).
  • a diazeniumdiolated polyurethane/polyurea of the invention can be bound to a substrate.
  • the diazeniumdiolated polyurethane can be contacted with a substrate, in which, preferably, the substrate has moieties that allow for chemical bonding of the diazeniumdiolated polyurethane.
  • the diazeniumdiolated polyurethane/polyurea can be recovered from solution and coated onto a substrate.
  • the coating can have any degree of hydrophobicity or hydrophilicity. See, for example, U.S. Patents 6,703,046, 6,528,107, and 6,270,779, which are incorporated herein in their entirety.
  • the composition used to prepare the diazeniumdiolated polyurethane/polyurea of the invention does not comprise an isocyanatosilane.
  • the substrate can be of any suitable biocompatible material, such as metal, glass, ceramic, plastic, or rubber. Preferably, the substrate is metal.
  • the substrate used in the preparation of the medical device can be derived from any suitable form of a biocompatible material, such as, for example, a sheet, a fiber, a tube, a fabric, an amorphous solid, an aggregate, dust, or the like.
  • Metal substrates suitable for use in the invention include, for example, stainless steel, nickel, titanium, tantalum, aluminum, copper, gold, silver, platinum, zinc, Nitinol, inconel, iridium, tungsten, silicon, magnesium, tin, alloys, coatings containing any of the above, and combinations of any of the above. Also included are such metal substrates as galvanized steel, hot dipped galvanized steel, electrogalvanized steel, annealed hot dipped galvanized steel, and the like.
  • the metal substrate is stainless steel.
  • Glass substrates suitable for use in the invention include, for example, soda lime glass, strontium glass, borosilicate glass, barium glass, glass-ceramics containing lanthanum as well as combinations thereof.
  • Ceramic substrates suitable for use in the invention include, for example, boron nitrides, silicon nitrides, aluminas, silicas, combinations thereof, and the like.
  • Plastic substrates suitable for use in the invention include, for example, acrylic, acrylonitrile-butadiene-styrene, acetals, polyphenylene oxides, polyimides, polystyrene, polypropylene, polyethylene, polytetrafluoroethylene, polyvinylidene, polyethylenimine, polyesters, polyethers, polyamide, polyorthoester, polyanhydride, polyether sulfone, polycaprolactone, polyhydroxy-butyrate valerate, polylactones, polyurethanes, polycarbonates, polyethylene terephthalate, as well as copolymers and combinations thereof.
  • Typical rubber substrates suitable for use in the invention include, for example, silicone, fluorosilicone, nitrile rubbers, silicone rubbers, fluorosilicone rubbers, polyisoprenes, sulfur- cured rubbers, butadiene-acrylonitrile rubbers, isoprene-acrylonitrile rubbers, and the like.
  • the substrate could also be a protein, an extracellular matrix component, collagen, fibrin or another biologic agent or a mixture thereof.
  • Silicone, fluorosilicone, polyurethanes, polycarbonates, polylactones, and mixtures or copolymers thereof are preferred plastic or rubber substrates because of their proven bio- and hemocompatability when in direct contact with tissue, blood, blood components, or bodily fluids.
  • Polyurethanes and polyureas can be tailored to produce a range of products from soft and flexible to hard and rigid. They can be, for example, extruded, injection molded, compression molded, and solution spun. Thus, polyurethanes and polyureas, are important biomedical polymers, and are used in medical devices, including implantable devices. Thus, the invention provides medical devices which are capable of releasing nitric oxide when in use, but which are otherwise inert to nitric oxide release.
  • the inventive NO- releasing polyurethane/polyurea is coated on a substrate, which is subsequently used as medical device.
  • the diazeniumdiolated polyurethane/polyurea can form the medical device itself.
  • a “medical device” includes any device having surfaces that contact tissue (e.g., skin), blood, or other bodily fluids in the course of their use or operation, which are found on or are subsequently used within a mammal.
  • Medical devices include, for example, extracorporeal devices for use in surgery, such as blood oxygenators, blood pumps, blood storage bags, blood collection tubes, blood filters including filtration media, dialysis membranes, tubing used to carry blood and the like which contact blood which is then returned to the patient or mammal.
  • Medical devices also include endoprostheses implanted in a mammal (e.g., a human), such as vascular grafts (e.g., a vascular occlusion device), stents, a spinal fixation device, a pacemaker, a pacemaker lead, a surgical prosthetic conduit, a heart valve, and the like, that are implanted in blood vessels or the heart.
  • vascular grafts e.g., a vascular occlusion device
  • stents e.g., a spinal fixation device
  • pacemaker e.g., a pacemaker lead
  • surgical prosthetic conduit e.g., a heart valve, and the like
  • Medical devices also include devices for temporary intravascular use such as a catheter (e.g., a central venous catheter), a guidewire, an amniocentesis and/or biopsy needle, a cannula, a drainage tube, a shunt, a sensing device, a transducer, a probe and the like which are placed into the blood vessels, the heart, organs or tissues for purposes of monitoring or repair or treatment.
  • Medical devices also include prostheses such as artificial joints such as hips or knees as well as artificial hearts.
  • medical devices include penile implants, condoms, tampons, sanitary napkins, ocular lenses, sling materials, sutures, hemostats used in surgery, antimicrobial materials, surgical mesh, tissue patches, transdermal patches, and wound dressings/bandages.
  • the medical device is a vascular graft, which can be used to embolize a blood vessel with the intent to block blood flow. It is often desirable to block blood flow in a section of vasculature for purposes such as controlling internal bleeding, stopping a blood supply to a tumor and/or fibroid, and relieving vessel-wall pressure in a region of a vessel aneurysm.
  • a vascular graft can be useful to treat an abdominal aortic aneurysm, aortopulmonary collateral vessels, hemorrhage, renal arteriovenous fistula or carcinoma, coronary artery fistula, or intracranial aneurysm occlusion.
  • the medical device is a wound dressing.
  • the wound dressings can include various combinations of other ingredients without departing from the scope of the present invention, including, for example, medicaments, soaps, disinfecting and sterilizing agents, odor management agents, hemostatic agents, proteins, enzymes, and nucleic acids.
  • these agents can also be incorporated directly and dispersed throughout the prepolymerization mixture and are thereby incorporated into the resulting product (e.g., foam matrix).
  • these other ingredients can be incorporated into the dressing by absorbing them into the formed product (e.g., foam cover layer) following the polymerization reaction by affixing to the formed wound dressing, by any suitable means, an additional layer incorporating such other ingredients, as will be understood by those skilled in the art.
  • the formed product e.g., foam cover layer
  • Suitable medicaments, soaps, disinfecting and sterilizing agents, proteins, and enzymes are commercially available and include those which aid recovery of wounds.
  • the medicaments include antifungal agents, antibacterial agents, and angiogenesis promoting agents. More preferred medicaments include antifungal agents such as metronidazole and antibacterial agents such as chlorhexidine. Any suitable soap, disinfecting and sterilizing agent can be used (e.g., hydrogen peroxide).
  • Suitable proteins and enzymes include those which aid in wound recovery such as fibrin sealants and angiotensins, as described in U.S. Patents 5,962,420 and 5,955,430, hereby incorporated by reference herein.
  • the wound dressings of the present invention can be formed to have any desired thickness or shape.
  • an NO-releasing polyurethane foam is provided as a thin layer (e.g., a thickness of about 1 mm to about 10 mm, and preferably about 1 mm to about 6 mm).
  • a particularly advantageous presentation for the dressing of the invention is as an NO-releasing polyurethane foam layer on a backing layer, wherein at least the marginal portions of the backing layer are coated with adhesive.
  • Any medically acceptable, skin friendly adhesive is suitable, including acrylic-, hydrocolloid-, polyurethane- and silicone- based adhesives.
  • the adhesive can be applied either continuously or discontinuously over the marginal portions of the backing layer.
  • the adhesive is applied continuously over the whole of the backing layer if the backing layer is not itself impermeable to bacteria, so as to ensure that the backing layer/adhesive combination is impermeable to bacteria.
  • Nitric oxide-releasing polymers of the invention are useful for the treatment of many biological disorders, and accordingly, the present invention provides methods of using a nitric oxide-releasing polyurethane/polyurea.
  • a method of treating a mammal e.g., a human
  • the method comprises applying to the wound an effective amount of a diazeniumdiolated polyurethane/polyurea of the invention, a composition thereof, or a medical device thereof in an amount sufficient to treat the wound.
  • the method for treating a wound comprises administering to a specific location on or within the mammal a medical device comprising a nitric oxide-releasing polyurethane/polyurea.
  • the treatment can be prophylactic or therapeutic.
  • prophylactic is meant any degree in inhibition of the onset of the biological disorder, including complete inhibition.
  • therapeutic is meant any degree in inhibition of the progression of the biological disorder in the mammal (e.g., human).
  • a wound can be any wound, as long as the wound is treatable with nitric oxide.
  • Suitable wounds can be of any type, including a surgical wound, a pressure sore, a diabetic ulcer, and a venous ulcer, or can result from any condition, such as an infection, including a viral or parasitic infection, a bacterial infection, or a fungal infection.
  • mammal used herein includes humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • a validated three-dimensional organotypic human skin model can be used to assess the ability of a diazeniumdiolated polyurethane/polyurea of the invention to enhance wound healing.
  • a diazeniumdiolated polyurethane/polyurea of the invention to enhance wound healing.
  • By growing human keratinocytes at an air-liquid interface on a de- epidermalized dermis placed on a contracted collagen gel it is possible to generate a fully differentiated stratified epithelium with normal tissue architecture.
  • These organotypic cultures mimic the essential features of the in vivo tissue and demonstrate normalized growth, differentiation, and basement membrane assembly. In particular, these models respond to wounding in a way that mimics the re-epithelialization seen in vivo.
  • Wound dressings prepared with at least one diazeniumdiolated polyurethane/polyurea of the invention are designed to decrease the time course of re- epithelialization in both the ex vivo and transplanted wound models.
  • diazeniumdiolated polymers of the present invention can be used to promote the growth of new blood vessels and capillaries in a process known as angiogenesis.
  • the NO-releasing polyurethanes/polyureas of the present invention can also be used to reduce inflammation and enhance healing when used as a coating or substrate for medical devices.
  • the present invention provides a method for promoting angiogenesis in a tissue of a mammal in need thereof. The method comprises either applying or administering to the mammal a medical device comprising a diazeniumdiolated polyurethane/polyurea of the invention to a specific location on or within the mammal in an amount effective to promote angiogenesis in the tissue.
  • Bio disorders that can be treated in accordance with a method for promoting angiogenesis are characterized by insufficient vascularization (or predisposition thereto) of the affected tissue, i.e., conditions in which neovascularization is needed to achieve sufficient vascularization in the affected tissue.
  • Such biological disorders include, for example, pressure sores, diabetic ulcers, venous ulcer, gangrene, surgical or other wounds requiring neovascularization to facilitate healing, Buerger's syndrome, hypertension, ischemic diseases (e.g., cerebrovascular ischemia, renal ischemia, pulmonary ischemia, limb ischemia, ischemic cardiomyopathy, and myocardial ischemia), ischemia of tissues (e.g., muscle, brain, kidney and lung), and other conditions characterized by a reduction in microvasculature.
  • ischemic diseases e.g., cerebrovascular ischemia, renal ischemia, pulmonary ischemia, limb ischemia, ischemic cardiomyopathy, and myocardial ischemia
  • ischemia of tissues e.g., muscle, brain, kidney and lung
  • Exemplary tissues in which angiogenesis can be promoted include: ulcers (e.g., diabetic ulcers), surgical wounds, and ischemic tissue (i.e.,
  • an "effective amount” means an amount sufficient to show a meaningful benefit in an individual, e.g., enhancing wound healing or promoting angiogenesis. Effective amounts can vary depending upon the biological effect desired in the individual, the condition to be treated, and/or the specific characteristics of the diazeniumdiolated polyurethane of the invention (taking into consideration, at least, the rate of NO evolution, the extent of NO evolution, and the bioactivity of any decomposition products derived from the diazeniumdiolates), the condition of the mammal (e.g., human), and the body weight of the mammal (e.g., human) to be treated.
  • any suitable dose of the diazeniumdiolated polyurethane/polyurea of the invention can be administered to the mammal, according to the type of wound or tissue to be treated.
  • the dose of the diazeniumdiolated polyurethane/polyurea of the invention desirably comprises about 0.1 mg per kilogram (kg) of the body weight of the mammal (mg/kg) to about 400 mg/kg (e.g., about 0.75 mg/kg, about 5 mg/kg, about 30 mg/kg, about 75 mg/kg, about 100 mg/kg, about 200 mg/kg, or about 300 mg/kg).
  • the dose of the diazeniumdiolated polyurethane/polyurea comprises about 0.5 mg/kg to about 300 mg/kg (e.g., about 0.75 mg/kg, about 5 mg/kg, about 50 mg/kg, about 100 mg/kg, or about 200 mg/kg), about 10 mg/kg to about 200 mg/kg (e.g., about 25 mg/kg, about 75 mg/kg, or about 150 mg/kg), or about 50 mg/kg to about 100 mg/kg (e.g., about 60 mg/kg, about 70 mg/kg, or about 90 mg/kg).
  • a suitable concentration in pharmaceutical compositions for topical administration is 0.05 to 15% (by weight).
  • a preferred concentration is from 0.02 to 5%.
  • a more preferred concentration is from 0.1 to 3%.
  • an NO-releasing polyurethane-containing matrix can be used to augment torn or weakened muscle tissue (e.g., neck, back, leg, arm, rotator cuff).
  • the matrix is porous with an open structure that is characterized by interconnected and intercommunicating pores.
  • the matrix is elastomeric and can demonstrate resilient recovery after being deformed under compression and/or tension.
  • the matrix is sized and shaped appropriately from a block of polyurethane-based foam and can be sterilized by any suitable method (e.g., alpha-, beta-, or gamma-radiation, electron radiation).
  • a matrix patch used for tissue extension will integrate, at least to some degree, with the surrounding area (e.g., tendon, bone, etc.).
  • the preparation and deployment of an NO-releasing polyurethane-containing matrix can follow techniques known in the art, e.g., Cole et al., Knee Surgery, Sports Traumatology, Arthroscopy, 15(5): 632-637 (published online September 9, 2006).
  • the present invention is directed to a method of augmenting muscle tissue in a mammal in need thereof.
  • the method comprises either applying or administering to the mammal a matrix (e.g., a t issue patch) comprising a diazeniumdiolated polyurethane (including a copolymer of polyurethane) of the invention to a specific location on or within the mammal in an amount effective to augment the tissue.
  • a matrix e.g., a t issue patch
  • a diazeniumdiolated polyurethane including a copolymer of polyurethane
  • the term "augmenting" means any degree of reinforcing or reducing subsequent tearing or deterioration of the muscle tissue.
  • the matrix will preferably, but not necessarily, integrate with surrounding tissue (e.g., tendon and/or bone).
  • alkyl implies a straight-chain or branched alkyl substituent containing from, for example, about 1 to about 12 carbon atoms, preferably from about 1 to about 8 carbon atoms, more preferably from about 1 to about 6 carbon atoms.
  • substituents include methyl, ethyl, propyl, isopropyl, r ⁇ -butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.
  • alkenyl means a linear alkenyl substituent containing from, for example, about 2 to about 10 carbon atoms (branched alkenyls are about 3 to about 10 carbons atoms), preferably from about 2 to about 8 carbon atoms (branched alkenyls are preferably from about 3 to about 8 carbon atoms), more preferably from about 3 to about 6 carbon atoms.
  • substituents examples include propenyl, isopropenyl, ⁇ -butenyl, sec- butenyl, isobutenyl, tert-butenyl, pentenyl, isopentenyl, hexenyl, octenyl, dodecenyl, and the like.
  • cycloalkyl means a cyclic alkyl substituent containing from, for example, about 3 to about 30 carbon atoms, preferably about 3 to about 8 carbon atoms, preferably from about 5 to about 8 carbon atoms, more preferably from about 5 to about 6 carbon atoms.
  • substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl and the like.
  • the aryl substituent can be optionally substituted as described herein (e.g., tolyl, anisolyl).
  • An aryl substituent generally contains from, for example, about 3 to about 30 carbon atoms, preferably from about 6 to about 18 carbon atoms, more preferably from about 6 to about 14 carbon atoms and most preferably from about 6 to about 10 carbon atoms. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 ⁇ electrons, according to Huckel's Rule.
  • heteroaryl refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized.
  • Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
  • the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
  • heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isothiazolyl, thiazolyl, furyl, phienyl, isoxazolyl, oxadiazolyl, and oxazolyl.
  • aralkyl as utilized herein means alkyl as defined herein, wherein at least one hydrogen atom is replaced with an aryl substituent as defined herein.
  • Aralkyls include, for example, benzyl, phenethyl, and substituents of the formula:
  • This example illustrates the preparation of an NO-releasing polyurethane-urea by using a DETA/NO chain extender in accordance with an embodiment of the invention.
  • An NCO-urethane prepolymer was prepared by reacting isocyanate Hl 2MDI (Bayer AG) and polycarbonate diol PC 1122 (Stahl Chemical) at an NCO/OH equivalent ratio 2.05/1, by using the following procedure: H12MDI (54.12 g) was placed in a 0.5 L glass reaction kettle, which was equipped with a mechanical stirrer, thermometer, heating mantle, and a gas inlet outlet for continuous flow of nitrogen.
  • the polycarbonate polyol 200 g was added in several portions to the reactor under constant mixing.
  • the reaction temperature was maintained at 70-80 °C, and samples were periodically withdrawn to determine the isocyanate content.
  • the percentage of isocyanate (NCO%) reached 4.36%, the reaction was stopped by cooling to room temperature, and the prepolymer (P-I) was stored in a sealed glass bottle under nitrogen.
  • 30 g (0.028 equivalents) of the prepolymer P-I and 70 ml of N-methylpyrrolidone (NMP) at room temperature were mixed to homogenize.
  • This example illustrates the preparation of a polyurethane-urea film in accordance with an embodiment of the invention.
  • NO-donor containing polyurethane-urea (2 g) prepared in Example 1 was placed in solution and put in a metal tray approximately 5.5 cm in diameter.
  • the film was placed in a vacuum oven and degassed at room temperature to remove air bubbles and remaining solvent.
  • Isopropyl alcohol (IPA) was poured over the resin, and a film was formed by replacing NMP with IPA (phase inversion process).
  • the film was washed several times by immersing it (together with the metal tray) into IPA. Afterwards, the film was dried in a vacuum oven at room temperature for at least 24 hours. Dried films were stored in a freezer in the closed container filled with zeolites.
  • This example illustrates the release of NO from the diazeniumdiolated polyurethane-urea film prepared in Example 2.
  • a film sample weighing 85 mg as immersed in 0.1 M phosphate buffer (pH 7.4, 37 C). The NO release was measured by a Thermal Energy Analyzer following an inert gas sweep. NO release was biphasic, with half lives of 1.84 h and 12.93 h. See Figure 1. There was detectable NO release for 10 days. A total of 9.6 nmol of NO was released per mg of the polymer film. NO-release from these compounds was measured under in vitro conditions (0.1 M phosphate buffer pH 7.4 at 37°C) and the NO-release monitored by a Thermal Energy Analyzer. The films demonstrated controlled NO release, which appeared to be biphasic, and detectable NO-release occurred for three days (Fig. 1).
  • This example illustrates the preparation of implantable devices carrying nitric oxide releasing polyurethane utilizing -N 2 ⁇ 2 " -containing polyamine-containing polyurethane solution/dispersion.
  • a piece of porous foam (e.g., polycarbonate PU foam) of selected size and shape can be first dipped in the -N 2 O 2 " -containing polyamine-containing polyurethane solution and then immersed into IPA several times to create a fine coating on the foam surface.
  • the foam can be vacuum dried at room temperature.
  • a nitric oxide-releasing flexible tube can be created as well by dipping a wire into -N 2 O 2 " -containing polyamine-containing polyurethane solution/dispersion and then immersed in IPA to precipitate polyurethane around the wire.
  • the NO-containing polyurethane tube can be recovered upon drying.

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Abstract

L'invention concerne de nouveaux polyuréthannes et polyurées ainsi que des copolymères de ceux-ci libérant du monoxyde d'azote. Les polymères de l'invention comprennent au moins deux motifs de répétition de polyuréthanne/polyurée et contiennent au moins un diazéniumdiolate lié à l'azote. Ces polymères à base de polyuréthanne/polyurée et diazéniumdiolate peuvent être utilisés dans des dispositifs médicaux tels que des pansements. L'invention concerne aussi des compositions et des dispositifs médicaux comprenant de tels polymères de diazéniumdiolate et des procédés de préparation et d'utilisation de ces composés.
PCT/US2008/083375 2007-11-13 2008-11-13 Polymères de diazéniumdiolate libérant du monoxyde d'azote, compositions, dispositifs médicaux et utilisations de ceux-ci WO2009064861A2 (fr)

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Cited By (8)

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US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
WO2014014978A1 (fr) * 2012-07-17 2014-01-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Polymères à base de polyvinylpyrrolidone diazéniumdiolés et libérant de l'oxyde nitrique, compositions, dispositifs médicaux et applications associées
US20140271523A1 (en) * 2013-03-13 2014-09-18 Maple Ridge Group, LLC Nitric Oxide Releasing Multifunctional Polymers
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US11129920B2 (en) * 2016-03-31 2021-09-28 Polygames IP B.V. Tissue-adhesive biomedical materials

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WO1995024908A1 (fr) * 1994-03-17 1995-09-21 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation de polymeres liberant de l'acide nitrique dans le but de traiter la restenose et des maladies apparentees
WO1996015781A1 (fr) * 1994-11-22 1996-05-30 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation d'agents liberant de l'oxyde nitrique pour reduire les risques de metastase

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Publication number Priority date Publication date Assignee Title
WO1995024908A1 (fr) * 1994-03-17 1995-09-21 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation de polymeres liberant de l'acide nitrique dans le but de traiter la restenose et des maladies apparentees
WO1996015781A1 (fr) * 1994-11-22 1996-05-30 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation d'agents liberant de l'oxyde nitrique pour reduire les risques de metastase

Cited By (20)

* Cited by examiner, † Cited by third party
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US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11691995B2 (en) 2005-05-27 2023-07-04 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US11583608B2 (en) 2009-08-21 2023-02-21 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US10376538B2 (en) 2009-08-21 2019-08-13 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
AU2013292695B2 (en) * 2012-07-17 2017-04-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Nitric oxide-releasing diazeniumdiolated polyvinylpyrrolidone-based polymers, and compositions, medical devices, and uses thereof
US9540471B2 (en) 2012-07-17 2017-01-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Nitric oxide-releasing diazeniumdiolated polyvinylpyrrolidone-based polymers, and compositions, medical devices, and uses thereof
WO2014014978A1 (fr) * 2012-07-17 2014-01-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Polymères à base de polyvinylpyrrolidone diazéniumdiolés et libérant de l'oxyde nitrique, compositions, dispositifs médicaux et applications associées
US9095734B2 (en) * 2013-03-13 2015-08-04 Maple Ridge Group, LLC Nitric oxide releasing multifunctional polymers
US20140271523A1 (en) * 2013-03-13 2014-09-18 Maple Ridge Group, LLC Nitric Oxide Releasing Multifunctional Polymers
US11129920B2 (en) * 2016-03-31 2021-09-28 Polygames IP B.V. Tissue-adhesive biomedical materials

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