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    • 专利摘要:
    wound dressing, method for forming a wound dressing, and wound dressing kit are provided, according to some embodiments, wound dressings including a polymeric matrix and polysiloxane macromolecules which release nitric oxide in and / or in the polymeric matrix. wound dressing kits and methods of using and forming such wound dressings are also provided.
    公开号:BR112012003804B1
    申请号:R112012003804-4
    申请日:2010-08-20
    公开日:2019-02-19
    发明作者:Nathan Stasko；Susanne Bauman；Pranav R. Joshi
    申请人:Novan, Inc.；
    IPC主号:
    专利说明:

    “WOUND DRESSING, METHOD FOR FORMING A WOUND DRESSING, AND, WOUND DRESSING KIT”
    CROSS REFERENCE WITH RELATED REQUESTS
    This order claims the priority of Conditional Order U.
    S. Series N ° 61 / 235,927, filed on August 21, 2009 and Conditional Application U. S. Series N ° 61 / 235,948, filed on August 21, 2009 whose disclosures are hereby incorporated by reference here in their entirety.
    GOVERNMENTAL FINANCING DECLARATION
    The Research for this order was partially funded through a Phase I NIH SBIR grant entitled “Nitric Oxide-Releasing Antibacterial Wound Dressing” (grant number 5R43AI074098-02). The government may have certain rights with respect to this request.
    FIELD OF THE INVENTION
    The present invention relates to materials that can be used as wound dressings that can release nitric oxide. The present invention also relates to methods of making and using wound dressings that can release nitric oxide.
    BACKGROUND OF THE INVENTION
    An important aspect of wound care is infection control, which can facilitate the healing process. Wound dressings are one of the most commonly used tools to protect the wound from infection. Antimicrobial agents are often incorporated into the wound dressing to treat and prevent infection. however, there are several disadvantages associated with the use of antimicrobial agents. It has been observed that an increasing number of pathogens have developed resistance to treatment with conventional antibiotics. According to statistics, antibiotic resistance pathogens are the
    Petition 870180057101, of 07/02/2018, p. 11/19 primary reason for a majority of all lethal nosocomial infections. See Robson et al., Surg. Clin. N. Am. 77, 637-650 (1977). In addition, many antiseptic agents not only kill pathogens, but also pose a threat to the proliferation of granulation tissue, fibroblasts and keratinocytes that can help with the wound healing process. In addition, some antimicrobial agents can cause allergic reactions in some patients.
    It is known that nitric oxide has a broad spectrum of antimicrobial activity and can be used as an alternative to conventional antibiotics for drug-resistant bacteria. In addition, some recent studies have shown that nitric oxide can also play an important role in the wound healing process by promoting angiogenesis through the simulation of vascular endothelial development factor (VEGF) and increased fibroblast collagen synthesis. See Schaffer MR, et al., Diabetes-impaired healing and reduced wound nitric oxide synthesis: A possible pathophysiologic correlation. Surgery 1997; 121 (5): 513-9 and Shi HP, et al., The role of iNOS in wound healing. Surgery 2001; 130 (2): 225-9. In this way, nitric oxide has a promising and / or alternative addition to treatment with conventional antibiotic for wound care.
    Nitric oxide is a gas at room temperature and atmospheric pressure and has a short half-life in a physiological environment. Several small molecule nitric oxide donor prodrugs have been developed and have contributed greatly to the understanding of nitric oxide in various disease states. However, due to the results with stability, indiscriminate NO release, monotypic nitric oxide release kinetics and inability of specific target tissue types in clinically viable solutions currently exist for the administration of nitric oxide out of its gaseous form. Reproducible release at the appropriate levels of nitric oxide for a given therapeutic indication is important because the release of large amounts of nitric oxide can be toxic or create undesirable side effects, such as decreased angiogenesis or increased inflammation. Therefore, it was challenging to use nitric oxide in the field of wound care, other than through exogenous application, particularly in topical wound healing applications where nitric oxide has concentration-dependent effects and benefits for release in a controlled manner. and targeted.
    Thus, there is a need for wound treatment and dressings that can release nitric oxide by a controlled release method.
    SUMMARY OF THE INVENTION
    According to some embodiments, wound dressings are provided that include a polymeric matrix, and nitric oxide (NO) release polysiloxane macromolecules within and / or in the polymeric matrix. In some embodiments, such wound dressings are non-toxic and stably store NO. In some embodiments, the NO-release polysiloxane macromolecules include functional groups of N-diazeniodiolate and, in some embodiments, include functional groups of S-nitrosothiol.
    In some embodiments of the invention, the concentration of the polysiloxane macromolecules that release NO is in the range of about 0.1 to about 20 weight percent.
    Wound dressings may include additional additives. For example, wound dressings may include a water-soluble progeny such as sodium chloride, sucrose, glucose, lactose, sorbitol, xylitol, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof. Wound dressings can also include at least one therapeutic agent, such as antimicrobial compounds, anti-inflammatory agents, pain relievers, immunosuppressants, vasodilators, wound healing agents, anti-bio-film agents and mixtures thereof.
    In some embodiments, the wound dressing includes a polymeric matrix that includes a hydrophilic polyurethane, such as, for example, an aliphatic polyurethane polyether that absorbs water in an amount ranging from 10 percent to 60 percent of its dry weight .
    In some embodiments of the invention, the wound dressing includes a flexible open cell polyurethane foam that includes at least one polyisocyanate segment and at least one polyol segment. In some embodiments, macromolecules that release NO are present within and, optionally, cross-linked to the polymeric matrix of the polymeric foam.
    In some embodiments, the storage of nitric oxide in the wound dressing is in the range of 0.1 pmol of NO cm 'to 100 pmol of NO cm' 2 , in some embodiments, in a range of 100 pmol of NO cm 'at 1000 pmol NO cm' and in some embodiments, in a range of 1 nmol NO cm to 10 pmol NO cm '.
    In addition, according to some embodiments, wound dressing kits, methods of treating wounds and methods of forming wound dressings are provided.
    BRIEF DESCRIPTION OF THE DRAWINGS
    The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated and form a part of this application, illustrate certain embodiments of the invention.
    Figure 1 depicts a cross-sectional view of a wound dressing in accordance with an embodiment of the invention.
    Figures 2A and 2B describe cross-sectional views of wound dressings according to the embodiments of the invention.
    Figures 3A and 3B describe cross-sectional views of wound dressings according to the embodiments of the invention.
    Figures 4A and 4B depict cross-sectional views of wound dressings according to the embodiments of the invention.
    Figures 5A and 5B depict cross-sectional views of wound dressings according to the embodiments of the invention.
    Figures 6A and 6B describe cross-sectional views of wound dressings according to the embodiments of the invention.
    Figure 7 shows the water absorption of particular polyurethane polymer matrices over time.
    Figure 8 shows the water absorption for Tecophilic® HP-60D-20 aliphatic thermoplastic polyurethane (“T20”) loaded with increasing weight percentage of 8000 MW poly (ethylene glycol) as a porogen.
    Figure 9 shows the water absorption for TG-2000 solvent of Tecophilic® hydrogel thermoplastic polyurethane included in thin film dressings of polymeric films and soaked in phosphate buffered saline at physiological temperature and pH.
    Figure 10 illustrates the covalent storage of nitric oxide in the N-methylaminopropyltrimethoxysilane aminosilane as a NO diazeniodiolate donor, followed by co-condensation with a main chain alkoxysilane, tetraethoxysilane, to form the composition Nitricil ™ 70.
    Figure 11 describes the chemiluminescent detection of NO release from free Nitricil ™ 70 silica particles in solution, wound dressing J composition and wound dressing D measured in physiological buffer, pH, and temperature.
    Figure 12 The efficacy of various wound dressing NO-release compositions on both levels of planktonic bacteria sprayed from the wound and the levels of scraped bio-film bacteria from the wound are shown compared to controls covered with Tegaderm ™.
    Figures 13A and 13B describe the NO behavior of the finished device soaked in buffer at physiological temperature and pH (37 ° C, 7.4).
    Figure 14 describes the% complete re-epithelialization versus time for wound dressings according to the embodiments of the invention compared to controls covered with Tegaderm ™. DETAILED DESCRIPTION OF WAYS OF CARRYING OUT THE INVENTION
    The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It must be estimated that the invention can be embodied in different forms and should not be construed as limited to the embodiments presented here. Instead, these embodiments are provided so that this disclosure will be complete and complete and will fully address the scope of the invention for those skilled in the art.
    The terminology used in describing the invention here is for the purpose of describing the particular embodiments only and is not intended to be limiting of the invention. As used in describing the embodiments of the invention and the appended claims, the singular forms "one", "one", "o" and "a" are also intended to include plural forms, unless the context clearly dictates other way. Also, as used here, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. In addition, the term "about", as used here when referring to a measurable value such as an amount of a compound, dose, time, temperature and the like, is understood to cover variations of 20%, 10%, 5% , 1%, 0.5% or 0.1% of the specified quantity. It will also be understood that the terms "understands" and / or "that understands", when used in this specification, specifies the presence of established characteristics, integers, steps, operations, elements and / or components, but does not prevent the presence or addition of one or more other characteristics, integers, steps, operations, elements, components and / or groups of these. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by a person of ordinary skill in the technique to which this invention belongs.
    All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In the event of conflicting terminology, this specification is controlling.
    The embodiments described in one aspect of the present invention are not limited to the aspects described. The embodiments can also be applied to a different aspect of the invention as long as the embodiments do not avoid these aspects of the operating invention for its intended purpose.
    Chemical Definitions
    As used herein, the term "alkyl" refers to Ci_ 2 o inclusive, linear (i.e., "straight chain"), branched or cyclic saturated or at least partially and, in some cases, totally unsaturated hydrocarbon chains (ie is, alkenyl and alkynyl), including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl groups , butynyl, pentinyl, hexynyl, heptinyl and alenyl. "Branched" refers to an alkyl group, in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. Exemplary branched alkyl groups include, but are not limited to, isopropyl, isobutyl, tert-butyl. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a Cl-8 alkyl), for example, 1, 2, 3,
    4, 5, 6, 7 or 8 carbon atoms. "Upper alkyl" refers to an alkyl group having about 10 to about 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms . In certain embodiments, "alkyl" refers, in particular, to straight chain Cl-
    5. In other embodiments, "alkyl" refers, in particular, to Cl-5 branched chain alkyls.
    The alkyl groups can optionally be substituted (a "substituted alkyl") by one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxy, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkyl. One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms can be optionally inserted together with the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to here as "alkylaminoalkyl") or aryl.
    Thus, as used herein, the term "substituted alkyl" includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate and mercapto.
    The term "aryl" is used here to refer to an aromatic substituent which may be an aromatic ring or multiple aromatic rings that are fused together, covalently bonded or linked to a common group, such as but not limited to, a portion of methylene or ethylene. The common bonding group can also be a carbonyl, as in benzophenone or oxygen, as in diphenyl ether or nitrogen, as in diphenylamine. The term "aryl" specifically encompasses aromatic heterocyclic compounds. Aromatic rings can comprise phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine and benzophenone, among others. In particular embodiments, the term "aryl" means a cyclic aromatic comprising about 5 to about 10 carbon atoms, for example, 5, 6, 7, 8, 9 or 10 carbon atoms and including aromatic rings of 5- and 6-membered hydrocarbon and heterocyclic.
    The aryl group can be optionally substituted (a "substituted aryl") with one or more aryl group substituents, which may be the same or different, where the "aryl group substituent" includes alkyl, substituted alkyl, aryl, substituted aryl , aralkyl, hydroxyl, alkoxy, aryloxy, aralkyloxy, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamyl, dialkylcarbyl, aryl, aryl, aryl, aryl, aryl, aryl, aryl 1 and R ”can independently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and aralkyl.
    Thus, as used herein, the term "substituted aryl" includes aryl groups, as defined herein, in which one or more atoms or functional groups in the aryl group are replaced by another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate and mercapto. Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole and others.
    "Cyclic" and "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system of about 3 to about 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The cycloalkyl group can optionally be partially unsaturated. The cycloalkyl group can also be optionally substituted by an alkyl group substituent as defined herein, oxo, and / or alkylene. These can optionally be inserted along the cyclic alkyl chain one or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms, where the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl and cycloheptyl. Multicyclic cycloalkyl rings include adamantila, octahydronafitila, decaline, camphor, camphan and noradamantila.
    "Alkoxyl" refers to an alkyl-O- group where alkyl is as previously described. The term "alkoxy" as used herein, can refer to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy and pentoxyl. The term "oxyalkyl" can be used interchangeably with "alkoxy". In some embodiments, the alkoxy has 1, 2, 3, 4 or 5 carbons.
    "Aralkyl" refers to an arylalkyl group in which aryl and alkyl are previously described and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl and naflylmethyl.
    “Alkylene” refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group can also be optionally unsaturated and / or substituted by one or more "alkyl group substituents." These can optionally be inserted along the alkylene group one or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms (also referred to herein as "alkylaminoalkyl"), where the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH 2 -); ethylene (-CH2-CH2-); propylene (- (CH2) 3-); cyclohexylene (C 6 H 10 -); -CH = CH-CH = CH-; -Cl UCU-CI1 2 -; where each of q and q is independently an integer from 0 to about 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19 or 20 and R is hydrogen or lower alkyl; methylenedioxy (-O-CH 2 -O-) and ethylenedioxy (-O- (CH 2 ) 2 -O-). An alkylene group can have about 2 to about 3 carbon atoms and can still have 6 to 20 carbons.
    "Arylene" refers to a divalent aryl group. An exemplary arylene is phenylene, which may have ring carbon atoms available for bonding in ortho, meta positions or with respect to each other, that is, respectively. The arylene group can also be naptilene. The arylene group can be optionally substituted (a "substituted arylene") with one or more "aryl group substituents" as defined here, which can be the same or different.
    "Aralkylene" refers to a divalent group that contains both alkyl and aryl groups. For example, aralkylene groups can have two alkyl groups and an aryl group (i.e., -alkyl-aryl-alkyl-), an alkyl group and an aryl group (i.e., -alkyl-aryl-) or two aryl groups and an alkyl group (i.e., -aryl-alkyl-aryl-).
    The term "amino" and "amine" refer to nitrogen-containing groups, such as NR 3 , NH 3 , NHR 2 and NH 2 R, where R can be alkyl, branched alkyl, cycloalkyl, aryl, alkylene, arylene, aralkylene. In this way, "amino" as used here, can refer to a primary amine, a secondary amine or a tertiary amine. In some embodiments, an R of an amino group may be a stabilized diazeniodiolate cation (ie, NONO'X + ) ·
    The terms "cationic amine" and "quaternary amine" refer to an amino group having an additional group (i.e., a quarter), for example, a hydrogen or a nitrogen-bonded alkyl group. In this way, cationic and quaternary amines carry a positive charge.
    The term "alkylamine" refers to the group -alkyl-NH 2 .
    The term "carbonyl" refers to the group - (C = O) -.
    The term "carboxyl" refers to the group -COOH- and the term "carboxylate" refers to an anion formed from a carboxyl group, that is, -COO
    The terms "halo", "halide" or "halogen" as used here, refer to groups of fluorine, chlorine, bromine and iodine.
    The term "hydroxyl" and "hydroxy" refer to the -OH group.
    The term "hydroxyalkyl" refers to an alkyl group substituted by an -OH group.
    The term "mercapto" or "uncle" refers to the group -SH. The term "silyl" refers to groups that comprise silicon (Si) atoms.
    As used herein, the term "alkoxysilane" refers to a compound that comprises one, two, three or four alkoxy groups attached to a silicon atom. For example, tetraalkoxysilane refers to Si (OR) 4, where R is alkyl. Each alkyl group can be the same or different. An "alkylsilane" refers to an alkoxysilane in which one or more of the alkoxy groups has been replaced by an alkyl group. In this way, an alkylsilane comprises at least one alkyl-Si bond. The term "fluorinated silane" refers to an alkylsilane in which one of the alkyl groups is replaced by one or more fluorine atoms. The term "cationic or anionic silane" refers to an alkylsilane in which one of the alkyl groups is still replaced by an alkyl substituent that has a positive (ie, cationic) charge or a negative (ie, anionic) charge or it can be taken charged (that is, it is ionizable) in a particular environment (that is, in vivo).
    The term "silanol" refers to a Si-OH group.
    According to some embodiments, wound dressings are provided that include a polymeric matrix and nitric oxide (NO) release polysiloxane macromolecules within and / or in the polymeric matrix. The appropriate combination of polymeric matrix and polysiloxane macromolecules that release NO may allow for a wound dressing that stably stores NO and may provide controlled release of NO to the wound.
    The polymeric matrix
    As used herein, the term "polymeric matrix" is understood to encompass any natural or synthetic polymeric material that can retain at least some of the polysiloxane macromolecules that release NO here or in these. As such, the polymeric matrix can be a homopolymer, heteropolymer, random copolymer, block copolymer, graft copolymer, mixture or combination of any suitable polymers and it can be in any suitable physical form, such as a foam, film, woven material or non-woven, hydrogel, gel matrix, mixtures and combinations of these and others. As described in further details below, the choice of the polymeric matrix and its physicochemical properties for a particular wound dressing may depend on factors, such as the polysiloxane macromolecules that release NO within and / or in the polymeric matrix and the type of action desired therapy.
    In some embodiments of the invention, the polymeric matrix includes at least one of hydrophilic polyurethanes, hydrophilic polyacrylates, co-polymers of carboxymethylcellulose and acrylic acid, Nvinylpyrrolidone, poly (hydroxy acids), polyanhydrides, polyesters, polyamides, polycarbonates, polyalkylates (polyalkylates) polyethylene and polypropylene), polyalkylene glycols (eg poly (ethylene glycol)), alkylene polyoxides (eg ethylene polyoxide), polyalkylene terephthalates (eg polyethylene terephthalate), polyvinyl alcohol, polyvinyl ethers, polyvinyl esters , polyvinyl halides (eg poly (vinyl chloride)), polyvinylpyrrolidone, polysiloxanes, poly (vinyl acetates), polystyrenes, polyurethane copolymers, cellulose, derivatized celluloses, alginates, poly (acrylic acid), poly (acidic) derivatives acrylic), acrylic acid copolymers, methacrylic acid, methacrylic acid derivatives o, copolymers of methacrylic acid, poly (butyric acid), poly (valeric acid), poly (lactide-co-caprolactone), copolymers thereof and combinations thereof.
    In some embodiments of the invention, the polymeric matrix can include a superabsorbent polymer (SAP). A polymer is considered super-absorbent, as defined by IUPAC, as a polymer that can absorb and retain large amounts of water in relation to its own mass. SAPs can absorb water more than 500 times my own weight and still expand more than 1000 times its original volume. Exemplary SAPs include sodium polyacrylate, Tecophilic® TG-T2000 polyurethane, polyacrylamide copolymer, anhydrous maleic ethylene copolymer, cross-linked carboxymethylcellulose, polyvinyl alcohol copolymers and crosslinked polyethylene oxide.
    In some embodiments of the invention, polymers that are relatively hydrophobic, as defined by a water absorption value of less than 10% by weight, can be used. Any suitable hydrophobic polymer can be used. However, exemplary polymers that are relatively hydrophobic include aromatic polyurethanes, silicone rubber, polycaprolactone, polycarbonate, polyvinyl chloride, polyethylene, poly-l-lactide, poly-DL-glycolide, polyether etherketone (PEEK), polyamide, polyimide and acetate polyvinyl.
    In addition, in some embodiments of the invention, the polymeric matrix is modified to reduce the swelling of the polymer and therefore prevents leaching of the macromolecule (for example, migration of the polysiloxane molecule that releases NO from a polymeric matrix to the layer of the injury). Such modifications can include crosslinking of polymer chains. The polymeric matrix can also be modified by reacting the polymer with additional reagents. For example, the polymer can be modified to add hydrophilic groups, such as anionic, cationic and / or zwiterionic moieties or to add hydrophobic groups, such as silicone moieties, to the polymer chain.
    In some embodiments, the polymeric matrix includes polymeric foam. The term "polymeric foam" is understood to encompass any natural or synthetic polymer that is present as a foam and that can retain at least some polysiloxane macromolecules that release NO here or in these. In some embodiments, the polymeric foam has an average cell size in the range of 50 gm and 600 gm. In addition, in some embodiments, the foam may be an open cell foam. In some embodiments, the open cell walls of the foam may include pores of average size less than 100 gm, with individual pore sizes between 10 and 80 gm. As used herein, the term "open cell foam" refers to a foam that has cells that are substantially interconnected, such as foams in which at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the cells are connected and at least one other cell. In some embodiments, the foam can be flexible. As used here, the term "flexible" refers to foam that has a flexural strength of at least 40 MPa.
    In some embodiments of the invention, the polymeric foam is polyurethane foam. Any suitable polyurethane foam can be used. However, in some embodiments, the polyurethane foam may include at least one polyisocyanate segment and at least one polyol segment. Polyurethanes can be formed from the reaction of polyisocyanates and polyols. The polyisocyanate segment refers to a portion of the polyurethane formed from at least one polyisocyanate.
    In some embodiments of the invention, the at least one polyisocyanate segment is formed from at least one of tolylene diisocyanate, methylphenylene diisocyanate, modified diisocyanates (e.g., uretdiones, isocyanurates, allophanates, biurets, prepolymers isocyanates and carbodi-modified isocyanates) and / or mixtures thereof. The exemplary diisocyanate includes toluene diisocyanate; 1,4-tetramethylene diisocyanate; 1,4-hexamethylene diisocyanate; 1,6-hexamethylene diisocyanate; 1.12-of the diisociating dean; cyclobutane-1,3-diisocyanate; cyclohexane-1,3 diisocyanate; cyclohexane-1,4-diisocyanate; l-isocyanate-3,3,5-trimethyl-5isocyanatomethylcyclohexane; 2,4-hexahydrotolylene diisocyanate; 2,6hexahydrotolylene diisocyanate; 2,6-hexahydro-1,3-phenylene diisocyanate; 2,6hexahydro-1,4-phenylene diisocyanate; perhydro-2,4'-diphenyl methane diisocyanate; per-hydro-4,4'-diphenyl methane diisocyanate; 1,3-phenylene diisocyanate; 1,4 phenylene diisocyanate; 2,4-tolylene diisocyanate, 2,6-toluene diisocyanates; diphenyl methane-2,4'-diisocyanate; diphenyl methane-4,4'-diisocyanate; naphthalene-
    1,5-diisocyanate; 1,3-xylylene diisocyanate; 1,4-xylylene diisocyanate; 4,4'methylene-bis (cyclohexyl isocyanate); 4,4'-isopropyl-bis- (cyclohexyl isocyanate); 1,4-cyclohexyl diisocyanate; 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (IPDI); 1-methoxy-2,4-phenylene diisocyanate; 1-chlorophenyl-2,4-diisocyanate; p (1-isocyanatoethyl) -phenyl isocyanate; m- (3-isocyanatobutyl) -phenyl isocyanate; 4- (2isocyanato-cyclohexyl-methyl) -phenyl isocyanate and mixtures thereof.
    The polyol segment refers to a portion of a polyurethane foam formed from at least one polyol. Polyols can include polyether polyols and / or polyester polyols. Polyether polyols can have a significant amount of ether bonds in their structure, whereas polyester polyols can have ester bonds within their structure. Any suitable polyol can be used. However, in some embodiments of the invention, the at least one polyol segment is formed from a diol having from 2 to 18 carbon atoms, and in some embodiments, the diol having from 2 to 10 carbon atoms. Exemplary diols include 1,2-ethanediol, 1,3propanediol, 1,4-butanediol, 1,6-hexanediol, 1,5-pentanediol, 1,10decanediol, 2-methyl-1,3-propanediol, 2-methyl- 2-butyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2,2-dimethyl-1,4-butane diol, 2-ethyl-2-butyl-1,3-propanediol, neopentyl glycol hydroxypivalate, diethylene glycol and triethylene glycol. Higher functionality triols and polyols can also be used and include compounds having 3 to 25, and in some embodiments, 3 to 18 and, in the particular embodiments, 3 to 6 carbon atoms. Examples of triols that can be used are glycerol or trimethylolpropane. As polyols of higher functionality, it is possible, for example, to use erythritol, pentaerythritol and sorbitol. In some embodiments, low molecular weight reaction products of the polyols can be used, for example, those of trimethylolpropane with alkylene oxides, such as ethylene oxide and / or propylene oxide. These low molecular weight polyols can be used individually or as mixtures.
    Examples of polyether polyols include the commercially available polyols PETOL28-3B, PETOL36-3BR and PETOL563MB, Multranol®, Arcol® and Acclaim® (Bayer Material Science) and the Caradol® family of polyols (Shell Chemical Corporation).
    Examples of polyester polyols that can be suitably used in the current invention include diethylene glycol adipate diol, Dipraphate Diol and in general, esters of dicarboxylic and hydroxy acids with glycol and polyester oligomers functionalized with glycol, polylactate, polycaprylate, PET and formulations such as Desmophen® C polycarbonate diols and Desmophen® polyacrylate diols (Bayer).
    In some embodiments, certain polyols or mixtures thereof specifically formulated for the manufacture of high resilience polyurethane foams can be used. Examples of polyols include a polyol having an ethylene oxide content in a range of 50% to 80%, a primary hydroxyl content of at least 40% and a molecular weight in the range of 2500 and 6000; a polyol polymer prepared by the in situ polymerization of a high functionality poly (oxyethylene) -poly (oxypropylene) oligomer, with a second poly (oxyethylene) polyol oligomer with a molecular weight ranging from 450 to 30,000 and a poly content (oxyethylene) greater than 70% and biofounded polyols derived from soybean oil, castor oil, palm oil, linseed oil and canola oil.
    Polyisocyanates and polyols can be used, including polyols and polyisocyanates having other functional groups in this. As such, in some embodiments, polyisocyanates and polyols may include other functional groups, such as ether, ester, urea, acrylate, pyrrolidone, vinyl, phenyl and amino bonds, as long as the resulting polyurethane is suitable for the formation of a foam.
    In some embodiments of the invention, the polymeric foam includes a superabsorbent polymer (SAP). Super-absorbency can be introduced into the foam structure by including polymeric segments that have superabsorbency in the polyol or the 'soft' segment of the foam. Examples of polymer segments having superabsorbency may include polyacrylamide copolymer, anhydrous ethylene maleic polymer, crosslinked carboxymethylcellulose, polyvinyl alcohol copolymers and crosslinked polyethylene oxide.
    In some embodiments of the invention, polymeric foams that are relatively hydrophobic can be used. Any suitable hydrophobic polymer can be used. Hydrophobicity can be introduced by selecting the polyisocyanate or the 'soft' segment of a polyurethane foam. The choice of highly hydrophobic polyisocyanates can result in a rigid foam, which needs adequate hydrophobicity can prevent the formation of the foam structure.
    The polyisocyanates commonly used for hydrophobic foams include diphenylmethane diisocyanate and its isomers, toluene diisocyanate, hexamethylene diisocyanate and mixtures thereof. In some embodiments, polyisocyanates can also include copolymers of the diisocyanates previously mentioned. In some embodiments, isocyanate groups can also be introduced at the terminals of polymer segments of relatively hydrophobic polymers to provide better foam control. Other polymers that are relatively hydrophobic include silicone rubber, polycaprolactone, polycarbonate, polyvinyl chloride, polyethylene, poly-l-lactide, poly-DLglycolide, polyetheretherketone (PEEK), polyamide, polyimide and polyvinyl acetate.
    The polymer to be foamed can also be modified by reacting the polymer with additional reagents. For example, the polymer can be modified to add hydrophilic groups, such as anionic, cationic and / or zwitterionic moieties or to add hydrophobic groups, such as silicone groups, to the polymer chain.
    The polymeric foam can be prepared by reacting between the isocyanate portions of the 'hard' polyisocyanate segments and the nucleophilic end groups of the polyols or 'soft' segments. Nucleophilic groups can include hydroxyl, amine and / or carboxylic groups.
    In some embodiments, the foam may also contain chain extender segments in addition to the polyol and polyisocyanate building blocks. Polyamine co-reagents, due to their reactivity with isocyanates, are the chain extenders most commonly used to increase the chain length and flexibility of the foam. The polyamines most commonly used polyamines are polyaspartic esters, polyaldimines, butylenes diamines and other short chain alkyl diamines.
    Nitric Oxide Release Polysiloxane Macromolecules
    The term "NO-releasing polysiloxane macromolecules" refers to a synthesized structure of monomeric silane constituents that result in a larger molecular structure with a molar mass of at least 500 DA and a nominal diameter ranging from 0.1 nm to 100 gm and can comprise the aggregation of one or more macromolecules, since the macromolecular structure is still modified with a NO donor group. For example, in some embodiments, the NO donor group may include nitric diazeniodiolate oxide functional groups. In some embodiments, the NO donor group may include functional groups of S-nitrosothiol.
    In some embodiments of the invention, polysiloxane macromolecules that release NO may be in the form of particles that release NO, such as those described in U.S. Publication No. 2009/0214618, the disclosure of which is incorporated by reference in its entirety. Such particles can be prepared by methods described herein.
    As an example, in some embodiments of the invention, NO-releasing particles include precipitated NO-charged silica ranging from 20 nm to 10 pm in size. The NO-charged precipitated silica can be formed from silane monomers modified by a nitric oxide donor in a co-condensed siloxane network. In some embodiments of the invention, the nitric oxide donor is an N-diazeniodiolate.
    In some embodiments of the invention, the nitric oxide donor can be formed from an aminoalkoxysilane by a preload method and the co-condensed silane network can be synthesized from the condensation of a silane mixture that includes an alkoxysilane and the aminoalkoxysilane to form a cocondensed siloxane network modified by a nitric oxide donor. As used here, the "preload method" means that the aminoalkoxysilane is "pre-treated" or "preloaded" with nitric oxide before co-condensation with alkoxysilane. In some embodiments, preloading nitric oxide can be performed by chemical methods. In another embodiment, the "preload" method can be used to create co-condensed siloxane networks and more densely functionalized materials with NO donors.
    The co-condensed siloxane network can be and uniform silica particles, a collection of silica particles with a variety of sizes, amorphous silica, fumigated silica, nanocrystalline silica, ceramic silica, colloidal silica, a silica coating, a silica film, organically modified silica, mesoporous silica, silica gel, bioactive glass or any suitable form or state of silica.
    The composition of the siloxane network, (for example, quantity or chemical composition of the aminoalkoxysilane) and the nitric oxide loading conditions (for example, the solvent and the base) can be varied to optimize the quantity and duration of the release of nitric oxide. In this way, in some embodiments, the composition of the silica particles can be modified to regulate the average release life of NO from the silica particles.
    In some embodiments, the alkoxysilane is a tetraalkoxysilane having the formula Si (OR) 4 , where R is an alkyl group. The R groups can be the same or different. In some embodiments, tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS) or tetraethyl orthosilicate (TEOS). In some embodiments, the aminoalkoxysilane has the formula: R ”- (NH-R ') n Si (OR) 3 , where
    R is alkyl, R 'is branched alkylene, alkylene or aralkylene, n is 1 or 2 and R ”is selected from the group consisting of alkyl, cycloalkyl, aryl and alkylamine.
    In some embodiments, the aminoalkoxysilane can be selected from N- (6-aminoexyl) aminopropyltrimethoxysilane (AHAP3); N (2-amino ethyl) -3-aminopropyltrimethoxysilane (AEAP3); (3-trimethoxysilylpropyl) diethylenetriamine (DET3); (amino ethylaminomethyl) phenethyltrimethoxysilane (AEMP3); [3 (methylamino) propyl] trimethoxysilane (MAP3); N-butylaminopropyltrimethoxysilane (n-BAP3); t-butylamino-propyltrimethoxysilane (tBAP3); N-ethylaminoisobutyltrimethoxysilane (EAÍB3); N-phenylaminopropyltrimethoxysilane (PAP 3); and N-cyclohexylaminopropyltrimethoxysilane (cHAP3).
    In some embodiments, the aminoalkoxysilane has the formula: NH [R'-Si (OR) 3] 2, where R is alkyl and R 'is alkylene. In some embodiments, the aminoalkoxysilane can be selected from bis (3triethoxysilylpropyl) amine, bis- [3- (trimethoxysilyl) propyl] amine and bis - [(3trimethoxysilyl) propyl] ethylene diamine.
    In some embodiments, as previously described, the aminoalkoxysilane is preloaded for the release of NO and the amino group is replaced by a diazeniodiolate. Therefore, in some embodiments, the aminoalkoxysilane has the formula: R ”-N (NONOX + ) R'-Si (OR) 3, where R is alkyl, R 'is alkylene or aralkylene, R” is alkyl or alkylamine and X + is a cation selected from the group consisting of Na + , K + and Li + .
    In some embodiments of the invention, the co-condensed siloxane network includes at least one cross-linkable functional portion of the formula (Ri) x (R 2 ) ySiR 3j where Ri and R 2 are each independently C 1-5 alkyl or C 1-5 alkoxy, X and Y are each independently 0, 1, 2 or 3 and X + Y equal to 3 and R 3 is a crosslinkable functional group. In another embodiment, R is alkoxyl CI_ 3 and R 2 is methyl. In another embodiment, R 3 is selected from the group consisting of acrylic, alkoxy, epoxy, hydroxy, mercapto, amino, isocyan, carboxy, vinyl and urea. R 3 communicates an individual functionality to the silica that results in a multifunctional device. In yet another embodiment, the crosslinkable functional portion is selected from the group consisting of methacryloxymethyltrimethoxysilane, methacryloxypropyltrimethoxysilane, methacryloxypropyltriethoxysilane, 3-acryloxypropyl) trimethoxysilane, N- (3-methyl-6-hydroxy-3-hydroxy-3-hydroxy-3-hydroxy-3-hydroxy-3-hydroxy 2- (3,4-epoxicicloexil) ethyltrimethoxysilane, 3glicidoxipropil) trimethoxysilane, 3-aminopropyltrimethoxysilane, 3aminopropiltrietoxissilano, 3-isocianatopropiltrietoxissilano, 3mercaptopropiltrimetoxissilano, mercaptopropyltriethoxysilane, 11mercaptoundeciltrimetoxissilano, 2-cianoetiltrietoxissilano, ureidopropiltrietoxissilano, ureidopropyl trimethoxysilane, vinilmetildietoxissilano, vinilmetildimetoxissilano, vinyltriethoxysilane, vinyltrimethoxysilane, viniltriisopropoxissilano and vinyltris (2methoxyethoxy) silane. In some embodiments, R 3 can be used to crosslink the No donor modified silica with or within the polymeric matrices.
    The polysiloxane macromolecules that release NO can be present within and / or in the polymeric matrix in any suitable concentration, but in some embodiments, the polysiloxane macromolecules that release NO are present within a polymeric matrix in a concentration sufficient to increase the wound healing rate, decrease inflammation and / or exert an antimicrobial effect. In the particular embodiments, the concentration of the polysiloxane macromolecules that release NO can be in the range of about 0.1 to about 20 weight percent.
    In some embodiments, the polysiloxane macromolecules that release NO may be evenly distributed within a polymeric matrix. Thus, in such embodiments, the concentration of polysiloxane macromolecules that release NO is substantially constant throughout the polymeric matrix.
    Interaction between a polymeric matrix and polysiloxane macromolecules that release NO
    Wound healing occurs in several different stages and can happen in 0-12 months (or more). The wound healing phases include:
    (1) Coagulation (2) Cell proliferation (3) Granulation Tissue Formation (4) Epithelialization (5) Neovascularization or angiogenesis (6) Injury contraction (7) Matrix deposition including collagen synthesis (8) Tissue remodeling, including scar formation and remodeling
    The wound healing phase plays a role in the selection of polysiloxane macromolecules that release NO and a choice of the polymeric matrix. Nitric oxide can play a role in wound healing by a number of different mechanisms. First, extended exposure to low concentrations of nitric oxide can promote wound healing so nitric oxide acts as a signaling molecule in a number of wound healing cascades. Additionally, nitric oxide can also play a role in mitigating inflammation following damage. The modulation of inflammatory cytokines and the cells of the inflammatory response through nitric oxide can significantly alter the wound healing phases described above. In addition, injury and pain complications can be significantly reduced with topical administration of nitric oxide as an anti-inflammatory agent. In addition, nitric oxide can act as a broad-spectrum antimicrobial agent, particularly at relatively high concentrations. The antimicrobial effects of nitric oxide are wide ranging and different types of injuries can be colonized with different injury pathogens (for example, gram negative bacteria, gram positive bacteria, fungi, etc.). In addition, different pathogens may be more sensitive to nitric oxide than other pathogens. In some embodiments, nitric oxide can act as an antimicrobial agent to directly kill planktonic bacteria and other organisms; directly kill bacteria included in the bio-film and other organisms; indirectly kill microorganisms through nitrosative / oxidative stress; increases cross-drug permeability to microbial membranes; and / or avoiding the recurrence of infection or the formation of a bio-film.
    Therefore, in some embodiments, nitric oxide released from a particular wound dressing can provide a particular therapeutic action, such as acting as a signaling molecule in a wound healing cascade, acting as an anti-inflammatory agent. and / or act as an antimicrobial agent. The desired therapeutic action may determine that the polysiloxane macromolecules that release NO and the polymeric matrix are used in a dressing for a particular wound. For example, two classes of particular nitric oxide donors are diazeniodiolates and nitrosothiols. Both of these nitric oxide donors have at least one mechanism for the release of nitric oxide. Diazeniodiolate can be triggered to release nitric oxide by exposure to water or another proton source and a diazeniodiolate protected by O 2 can be triggered to release nitric oxide by exposure to light, enzymatic action and / or pH adjustment. Nitrosothiols can be fired to release nitric oxide through radioactive and thermal processes, and / or through copper and other thiols (for example, glutathione). Therefore, the mechanism of release of nitric oxide from the polysiloxane macromolecules that release NO can affect which polymeric matrix is chosen.
    Especially, because of the different polysiloxane macromolecules that release NO can release nitric oxide by different mechanisms, a chosen polymeric matrix must complement the macromolecule that releases the particular NO used. Several properties of a polymeric matrix can be cut based on the polysiloxane macromolecules that release NO used and the desired therapeutic action of the wound dressing. Such properties include:
    (i) Moisture absorption / retention
    The mixture absorption rate can be adjustable to meet the requirements of the kinetics that release NO from the macromolecule in order to achieve the desired therapeutic action of the wound dressing. The equilibrium moisture retention can vary from 5 percent for certain aliphatic polymers to 2000 percent for hydrogels and superabsorbent polymers. In this way, in some embodiments, the polymer matrix has a slow equilibrium moisture retention in a range of 0 to 10 percent. In some embodiments, the polymeric matrix has a moderate equilibrium moisture retention in a range of 10 to 100 percent. In addition, in some embodiments, the polymer matrix has a high equilibrium moisture retention of 100 percent or more.
    Moisture vapor transfer rate (MVTR)
    The MVTR can be adjusted on breathable polymer films to match the requirements of a polysiloxane reactive water macromolecule that release NO in a thin film yet still maintain the MVTR suitable for the desired injury or damage area. Wound dressings that keep a wound layer moist are termed occlusive. A great MVTR maintains a moist wound environment that activates debridement enzymes and development factors that promote wound healing. Occlusive dressings also act as a barrier towards exogenous microbes, thus preventing infection. Occlusive dressings are characterized by an MVTR of less than 35 g water / m / h.
    Expansion capacity
    The ability of the wound dressing to expand without dissolving on contact with moisture from the wound is beneficial in high breathing wounds. The wound dressing serves to inhibit excess moisture which may otherwise cause the wound to macerate and noxious odor.
    Surface energy
    Hydrophobic wound dressings are characterized by low surface energy whereas loaded and / or hydrophilic wound dressings have a high surface energy. Low surface energy is desired to allow easy dressing removal without damage to the wound layer.
    Oxygen permeability
    The adequate oxygen level facilitates neovascularization, helps in the synthesis of collagen and can prevent or minimize microbial infection of the wound. Due to the damaged vasculature in the wounds, there is a low oxygen tension in the wound layer, leaching to hypoxia and anaerobic metabolism that can delay the healing process. Wound dressings can be oxygen permeable so that the wound receives adequate topical oxygen for healing.
    Nitric oxide permeability
    The polymeric matrix of the wound dressing may have adequate permeability towards nitric oxide such that the nitric oxide generated by the polysiloxane macromolecules that release NO is available to the wound layer at a desired therapeutic rate. Hydrophilic materials typically have a lower NO permeability towards nitric oxide as compared to hydrophobic materials. The NO permeability of the dressing can be matched to the release kinetics of the polysiloxane macromolecules that release NO and a water absorption rate by the polymer, in order to provide for the optimal release of NO from the dressing.
    Biodegradability / Bioabsorbability
    Biodegradability refers to the property of the wound dressing breaking down into lower molecular weight components under physiological conditions. Bioresorbability refers to the property by which the wound dressing can break in the seeds of lower molecular weight and the segments are completely removed from the body without any biological reaction. This property is desired if the dressing is used in a long term for the cavity type wound.
    Tensile strength
    Tensile strength is the ability of the wound dressing to resist breaking in stretching in any direction. The wound dressing material needs to have adequate tensile strength in order to withstand the stresses that occur as a result of normal patient use. Biocompatibility
    The polymeric matrix of the wound dressing can be biocompatible, non-toxic and non-irritable.
    Ionic character
    The ionic character of the dressing can affect surface energy and biocompatibility. The ionic character of the dressing can be quantified by measuring the zeta potential of the wound dressing material under physiological conditions. In some embodiments, the zeta potential of the surfaces can be between -30 mV and +20 mV, and in some embodiments, between -10 mV and +10 mV, and in some embodiments, approximately zero. Surfaces with highly negative (<-30 mV) or highly positive (> + 20 mV) zeta potential may be undesirable as these can be an anti- or procoagulant effect on the wound and can increase the dressing's surface energy.
    Transparency
    The ability of the wound dressing material to allow visible light to pass through may allow for visual monitoring of the wound healing process. As used here, a wound dressing or polymeric matrix is transparent if it has an optical transparency value of 80 percent or more transmission as measured by solid-state spectrophotometry.
    As the humidity facilitates the release of nitric oxide from the diazeniodiolate functionalized macromolecules, a wound dressing that includes the diazeniodiolate modified polysiloxane macromolecules inside and / or a hydrophilic polymer will allow for the release of nitric oxide to a wound in a wound. higher rate than a hydrophobic polymer would be. In this way, the desired nitric oxide level to be applied to the wound can be cut by increasing or decreasing the hydrophilicity of the polymer. Therefore, by combining a hydrophilic polymer with a diazeniodiolate-modified macromolecule, a concentrated dosage of nitric oxide can be delivered to a wound and by combining a diazeniodiolate-modified macromolecule with a relatively hydrophobic polymer, an “extended release” dosage of nitric oxide can be supplied to the wound. An extended release formulation can allow the release of nitric oxide in a predetermined time, such as 0-7 days. Additionally, As thermal energy and / or light it can facilitate the decomposition of nitrosothiol modified polysiloxane macromolecule, a polymeric matrix and / or additional layers above a polymeric matrix including nitrosothiol modified polysiloxane macromolecules can be transparent so that the light can facilitate the release of nitric oxide from nitrosothiol. Transparency can be modified to control the level of nitric oxide release.
    In this way, the polymeric matrix and the polysiloxane macromolecules that release NO can be selected based on at least one property of a polymeric matrix and at least one property of the polysiloxane macromolecules that release NO such that the interaction of the properties of a polymeric matrix and the polysiloxane macromolecules that release NO provide a predetermined macromolecule to the wound dressing. In some embodiments of the invention, the at least one property of a polymeric matrix may include moisture absorption / retention, wet vapor transfer rate (MVTR), surface energy, oxygen permeability, nitric oxide permeability, biodegradability / pore size bioabsorbability, tensile strength, biocompatibility, ionic character and / or transparency. In some embodiments of the invention, the at least one property of the polysiloxane macromolecules that release NO may include the nitric oxide release mechanism (for example, water, heat, light, enzyme, pH and others), total amount of oxide nitric acid stored in moles NO / mg silica, the hydrophobicity / hydrophilicity of the co-condensed silica and the biodegradability / bioresorbability of the macromolecular structure. The predetermined characteristics may be the ability of nitric oxide in the wound dressing to signal one or more healing of wound cascades, to act as an anti-inflammatory agent and / or to act as an antimicrobial agent.
    As used here, the term "interaction of properties" refers to the ability of particular properties of a polymeric matrix and properties particular to polysiloxane macromolecules that release NO to combine and produce a wound dressing that has a predetermined characteristic, as defined here . For example, the particular hydrophilicity of a polymeric matrix can interact with a particular concentration of polysiloxane-reactive water macromolecules that release NO to produce the desired rate of nitric oxide release from a polymeric matrix.
    An exemplary calculation of the reaction rate of nitric oxide release as a function of the rate of water absorption in the dressing, is shown below. In this calculation, water absorption at all times in the wound dressing is modeled. It is assumed that the release of NO from the polysiloxane macromolecules that release NO starts immediately in contact with the diffused water.
    Referring to FIG. 1, by a thin film 100 (thick
    2a) of a polymeric matrix including uniformly dispersed polysiloxane macromolecules that release NO in percent loading concentration of G (100 xg silica / g polymer that release NO), when the film is subjected to D / 2 and immersion in water, the water diffuses in the 3 film at a rate given by the expression of diffusion of the irregular state:
    4 «
    where D = water diffusion coefficient in a polymeric matrix, C (t) = water concentration at time t and Ceo is the equilibrium water concentration, which is the surrounding concentration (55 M). At a given time, t, the water diffuses only up to a certain thickness in the polymer film, therefore “activating” like the polysiloxane macromolecules that release NO up to that depth, z (t). The water concentration in the film is the water concentration only up to this depth and is equal to the water mass 5 spread to that depth, divided by the volume of penetration, in this way
    Where ε is the porosity of the polymer film, which is considered because of the water it will only penetrate the interconnected pores between the polymer chains. The mass of water in the film at a given time 10 (t) can be calculated by measuring the water absorption rate (U) by the volume of the polymer, which can be experimentally determined and is defined as:
    poly
    Where Mpoii = mass of the polymer film. In this way the substitution of this expression for the water body, in the expression for the depth of penetration as defined above,
    If the intrinsic NO release rate of the polysiloxane macromolecules that release NO is known as a function of time, f (t), the rate of NO release from the silica in the polymer that was "activated" at time t is given by:
    AZO (r) = m M (0x / (0
    Where [NO ( t )] = micromols of NO released at time t, m N0 = mass of silica that releases activated NO at time (t). By defining the loading of the co-condensed release silica in the polymer wound dressing it is expressed as,
    100 xm ^,
    M poly
    Where Mpoii = mass of whole polymer film, of which only M po ii (t) was very wet by water in time (t). Therefore, m (0 = 0.0 IGÀp ^ (0 and since,
    Therefore, the total rate of NO release from the polymer is given by jV <9 (í) = 10 *
    GU (f)
    f (t) e
    Dl **
    4th 2
    In some embodiments of the invention, the storage of nitric oxide in the dressing is in the range of 0.1 pmol NO cm 'to 100 pmol NO cm''In some embodiments, the storage of nitric oxide release in the dressing The dressing is in a range of 10 pmol of NO cm ' 2 to 1 nmol NO cm' 2 . In some embodiments, the storage of nitric oxide in the dressing is in the range of 1 nmol NO cm 'to 10 pmol NO cm' 2 . The total nitric oxide storage (t [NOJ) and the surface flow can be measured in real time through the chemiluminescent detection of nitric oxide summarized by Hetrick et al. (Hetrick et al. Analytical Chemistry of nitric oxide, Annu. Rev. Anal. Chem. 2009, 2, 409-433, which is therefore incorporated by reference in its entirety). The additional kinetic parameters for the release of nitric oxide that can be measured during your technique are the time of release of the maximum NO flow (t m ), amount of NO in the maximum flow ([NO] m ), average release life of nitric oxide (ti / 2 ) and the duration of nitric oxide release (t d ).
    In some embodiments of the invention, the instantaneous flow of nitric oxide release from the surface of the hydrated dressing is in the range of 0.1 pmol NO cm 's' to 100 pmol NO cm 's' and constitutes a slow initial range release. In some embodiments, the instantaneous flow of nitric oxide release from the surface of the hydrated dressing is in the range of 100 pmol NO cm 's' to 1000 pmol NO cm 2 s' 1 and constitutes an intermediate release range. In some embodiments, the instant flow of nitric oxide from the surface of the hydrated dressing is in the range of 1 nmol NO cm 's' to 10 pmol NO cm ' 2 s' 1 and constitutes a rapid rupture or NO release kinetics fast.
    Stability
    According to some embodiments of the invention, wound dressings can stably store NO as long as NO is not released before its intended therapeutic use. In some embodiments, 95 percent or more of the original NO loading is retained after one week at 25 ° C. In addition, in some embodiments, 85 percent of the NO loading is retained for up to 2 years at 25 ° C. .
    In some embodiments of the invention, wound dressings form a stable matrix by which leaching of silica particles is minimized. The thermodynamics of particulate leaching from polymeric matrices was not a challenge previously found in the prior art. The leaching of siloxane based on macromolecules can be determined through the dispersion of static light or elemental analysis by Si in the absorbed solutions. In some embodiments, greater than 98 percent of the polysiloxane macromolecules that release fixed NO is retained following incubation under physiological conditions (pH = 7.4, 37 ° C, phosphate buffered saline) for 48 hours. In other embodiments, greater than 95 percent of the polysiloxane macromolecules that release fixed NO is retained following incubation under physiological conditions (pH = 7.4, 37 ° C, phosphate buffered saline) for more than 30 days.
    Example of forms of achievements
    In some embodiments, the polysiloxane macromolecule that releases NO is Nitricil ™ (Novan, Inc.), which is a precipitated silica modified by diazeniodiolate.
    In some embodiments, the polymer matrix is an aliphatic polyether polyurethane that absorbs water in an amount of about 6 percent to about 100 percent of its dry weight. In some embodiments, the aliphatic polyether polyurethane absorbs water in an amount of about 10 to 60 percent of its dry weight and in some embodiments, 10 to 20 percent of its dry weight.
    In some embodiments, the polymer matrix is a superabsorbent polymer that absorbs water in an amount of at least 100 percent and varies up to 5000 percent of its dry weight. In some embodiments, the polymer matrix includes Tecophilic® aliphatic thermoplastic polyurethane from Lubrizol, Inc.
    Additions
    In addition to polysiloxane macromolecules that release NO, other additives may be present within and / or in a polymer matrix. Such additives can alter the properties of the polymeric matrix. For example, in some embodiments, the wound dressing may still include water-soluble porogen. Water-soluble porogen is an additive that can facilitate water absorption and diffusion in a polymer matrix. Any suitable porogen can be used, but in some embodiments, the porogen can include sodium chloride, sucrose, glucose, lactose, sorbitol, xylitol, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
    The properties of a polymer matrix and water absorption can also affect the release of nitric oxide and thus additives that affect the properties of a polymer matrix and / or water absorption can, in turn, affect the rate of release of nitric oxide from the polysiloxane macromolecules that release NO.
    Additives can also be included in the polymer foam that directly affect a release of nitric oxide from macromolecules that release NO. For example, in some embodiments, basic or other anionic species can be used to buffer the pH of the polymer foam for the slow decomposition of diazeniodiolate and release of the resulting nitric oxide.
    In other embodiments, chelating agents can be used to decontaminate metal ions similar to Fe 2+ , Cu and Cu to preserve NO nitrosothiol donor stability and prevent rapid nitric oxide release. In some embodiments, additives can be added to enhance the NO donor decomposition by giving the inherently slow NO release kinetics of the polysiloxane macromolecule that releases NO. For example, functionalized additives of carboxylic acid or acid can be added to the foam to create a pH of; internal foam slow in hydration and accelerate the decomposition of N-diazeniodiolate donors. In another embodiment, cysteine or glutathione can be impregnated in the foam matrix to facilitate subsequent thiol-mediated transnitrosation and decomposition of the nitrosothiol-containing macromolecules.
    In addition, other useful additives for foaming and processing may be included. For example, surface active agents can be added to intensify mixing, act as mold release agents and / or to influence the final cell structure of the foam. In addition, blowing agents and their by-products can also be present within the polymer foam. The blowing agents are described in further detail below. Additives that may be useful in forming foams include surface active agents to intensify mixing as well as influence the final foam structure and mold release agents. Exemplary surface active agents can be seen in U.S. Patent No. 6,316,662, the disclosure that is incorporated in this in its entirety.
    The additives can be present in a polymer matrix that can act to provide additional therapeutic effects to the wound dressing, acting synergistically or separately from the polysiloxane macromolecules that release NO. For example, in some embodiments, wound dressings may also include at least one therapeutic agent such as antimicrobial agents, anti-inflammatory agents, analgesic agents, anesthetic agents, antihistamine agents, antiseptic agents, immunosuppressants, antiseptic agents. hemorrhagic agents, vasodilators, wound healing agents, anti-biopellicent agents and mixtures thereof.
    Examples of antimicrobial agents include related penicillins and related drugs, erythromycin, mupirocma, clindamycin, chloramphenicol, macrolide, carbapenems, cephalosporins and aminoglycoside drugs, bacitracin, gramicidin, thiamphenicol, sodium fusidate, lincomycin, thymicine, thymicin, rinaminicin, polybiotin, thymicin, thymicin, thymicin, thymicin, thymicin, thymicin, thymicin, thymicine, thymicin, thymicin, thymicin, thymine. vanomycin, teicoplanin, streptogramins, anti-folate agents including sulfonamides, trimethoprim and combinations thereof, and pyrimethamine, synthetic antibacterials including nitrofurans, methenamine mandelate and methenamine hypurate, nitroimidazole, quinolones, fluoroquinolones, isoniazid, ethanolamine, pyrazinamide, pyrazinamide, pyrazinamide , cycloserine, capreomycin, ethionamide, protionamide, thiacetazone, viomycin, eveminomycin, glycopeptide, glyclyclicine, ketolides, oxazolidinone; imipenene, amikacin, netylmycin, fosfomycin, gentamicin, ceftriaxone, Ziracin, Linezolid, Sinercide, Aztreonam and Metronidazole, Epiroprim, Sanfetrinem sodium, Biapenem, Dinemicine, Cefluprenam, Cefoselis, Sanfetrin, Cefosemilin, Sulopenem, ritipenam acoxil, Ciclothialidina, micacocidina A, carumonam, Cefozopran and Cefetamet pivoxil.
    Examples of antihistamine agents include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate isotypendyl hydrochloride, trypanamineamine hydrochloride, promethazine hydrochloride and others. Examples of local anesthetic agents include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, ethyl ester hydrochloride p-butylaminobenzoic acid 2- (dieethylamino), procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride oxyprocaine, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, diclonin and diclonine hydrochloride.
    Examples of antiseptic agents include alcohols, quartenary ammonium compounds, boric acid, chlorhexidine and chlorhexidine derivatives, iodine, phenols, terpenes, bactericides, disinfectants including thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorinexidine, iodine povidone, cetylpyridinium chloride, eugenol and trimethylammonium bromide.
    Examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents (NSAIDs); propionic acid derivatives such as ibuprofen and naproxen; acetic acid derivatives such as indomethacin; enolic acid derivatives such as meloxicam, acetaminophen; methyl salicylate; monoglycol salicylate; aspirin; mefenamic acid; flufenamic acid; indomethacin; diclofenac; alclofenac; sodium diclofenac; ibuprofen; ketoprofen; naproxen; pranoprofen; fenprofen; sulindac; fenclofenac; clidanac; flurbiprofen; fentiazac; bufexamac; piroxicam; phenylbutazone; oxyphenbutazone; clofezone; pentazocine; mepirizole; thiaramide hydrochloride; steroids such as clobetasol propionate, betamethasone dipropionate, halbetasol propionate, diphlorasone diacetate, fluocinonide, halcinonide, amcinonide, deoxymethasone, acetonide triamcinolone, mometasone furoate, fluticasone propionate, flutonone acetone, propionate, flutamone propionate, betamide , fluocinolonz acetonide, hydrocortisone valerate, prednicarbate, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone and others known in the art, predonisolone, dexamethasone, fluocinolone acetonide, hydrocortisone acetate, predonisone hydrone, betonone acetone, valetone, acetone, hydrochloride, methacrylate, flumetasone, fluorometholone, beclomethasone diproprionate, fluocinonide, topical corticosteroids and can be one of the lower potency corticosteroids such as hydrocortisone, hydrocortisone-21-monoesters (eg hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydr ocortisone-21-propionate, hydrocortisone-21-valerate, etc.), hydrocortisone-17,21-diesters (e.g. hydrocortisone-17,21-diacetate, hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21 -dibutyrate, etc.), alclomethasone, dexamethasone, flumetasone, prednisolone, or methylprednisolone, or they can be a high-potency corticosteroids such as clobetasol propionate, betamethasone benzoate, betamethasone dipropionate, diflorasone diacetate, fluocinonide, fluocinonide, fluocinone acetonide.
    Examples of analgesic agents include alfentanil, benzocaine, buprenorphine, butorfanol, butamben, capsaicin, clonidine, codeine, dibucaine, enkephalin, fentanyl, hydrocodone, hydromorphone, indomethacin, lidocaine, levorfanol, meperidine, methadone, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine, oxyphine. , oxymorphone, pentazocine, pramoxin, proparacaine, propoxyphene, proximetacaine, sufentanil, tetracaine and tramadol.
    Examples of anesthetic agents include alcohols such as phenol; benzyl benzoate; calamine; chloroxylenol; diclonin; ketamine; menthol; pramoxin; resorcinol; troclosan; procaine medications such as benzocaine, bupivacaine, chloroprocaine; cincocaine; cocaine; dexivacaine; diamocaine; dibucaine; ethidocaine; hexylcaine; levobupivacaine; -lidocaine; mepivacaine; oxetazaine; prilocaine; procaine; proparacaine; propoxicaine; pyrrocaine; risocaine; rhodocaine; ropivacaine; tetracaine; and derivatives, such as pharmaceutically acceptable salts and esters including bupivacaine HC1, chloroprocaine HC1, diamocaine cyclamate, dibucaine HC1, diclonine HC1, etidocaine EICl, levobupivacaine HC1, lidocaine EIC1, mepivacaine HC1, procaminocaine E1, procamine , propoxycain HC1, ropivacaine HC1 and tetracaine HCI.
    Examples of anti-hemorrhagic agents include thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranoxamic acid, carbazochrome, sodium carbaxochrome sulfanate, rutin and hesperidin.
    Wound dressing devices
    Any suitable wound dressing device configuration can be used. Referring to FIG. 2A, in some embodiments, wound dressing 101 is a single layer that includes a polymer matrix 103 and polysiloxane macromolecules that release NO 105 therein and / or thereafter. Referring to FIG. 2B, in some embodiments, the single-layer wound dressing may include a medical grade adhesive 107 on the surface of the wound dressing that contacts the wound layer. Referring to FIGS. 3-5, in some embodiments, the wound dressing may include two or more layers. For example, referring to FIG 3A, in some embodiments, wound dressing 101 has two layers, a first layer 109 that includes a polymer matrix 103 and polysiloxane macromolecules that release NO 105 inside and / or in a polymer matrix 103; and a second layer 111 in the first layer 109. Furthermore, referring to FIG. 3B, in some embodiments, a medical grade adhesive 107 may be on the surface of the first layer 109 which contacts the wound layer. Referring to FIG. 4A, in some embodiments, polymer matrix 103 and polysiloxane macromolecules that release NO 105 into and / or a polymer matrix 103 is included in second layer 111, which can provide an anti-microbial barrier to the dressing for injury 101. Thus, first layer 109 may or may not include polymer matrix 103 and polysiloxane macromolecules that release NO 105 within and / or in a polymer matrix 103. Regardless of whether first layer 109 includes a matrix of polymer 103 and polysiloxane macromolecules that release NO 105 into and / or in a polymer 103 matrix, a medical grade adhesive 107 may be on the surface of the first layer 109 that contacts the wound layer. Additionally, in some embodiments, the first layer 109 or the second layer 111 can be substantially free of the polysiloxane macromolecules that release NO 105.
    Referring to FIGS. 5A and 5B, as another example, in some embodiments, wound dressing 101 has three layers, a first layer 109 that contacts the wound layer, the second layer 111 in the first layer 109 and a third layer 113 in the second layer 111. A medical grade adhesive 107 can be on the surface of the first layer 109 (FIG. 5B). The polymer matrix 103 and polysiloxane macromolecules that release NO 105 inside and / or in a polymer matrix 103 can be present in a first layer 109, the second layer 111 and / or the third layer 113. In some embodiments at least one of the first layer 109, the second layer 111 and the third layer 113 are substantially free of the polysiloxane macromolecules that release NO 105. However, as shown in FIG. 5, in some embodiments, the polymer matrix 103 and the polysiloxane macromolecules that release NO 105 inside and / or in a polymer matrix 103 are present only in the second layer 111. The first layer 109 can act as a layer of wound contact that avoids polysiloxane macromolecules that release NO 105 from leaching into the wound and / or provides a hydrophobic or non-sticky wound contact surface. The third layer 113 can act by containing nitric oxide within the wound dressing 101 and can control MVTR, oxygen diffusion and / or microbial penetration in the wound dressing 101.
    Referring to FIG. 6A, in some embodiments, at least one layer of the wound dressing 101 includes a perforated layer 115. The perforated layer 115 includes at least one hole 117 defined within the polymer matrix 103. In some embodiments, a matrix of polymer 103 includes an orifice arrangement 117 defined therein. Holes 117 in a polymer matrix 103 can be any suitable width 119, but in some embodiments, holes 117 have a width 119 in a range of about 200 to about 5000 microns. The term width 119 refers to the longest cross to the orifice. For a cylindrical orifice 117, width 119 is the diameter. The width 119 of holes 117 can be chosen based on a variety of parameters, such as wound moisture, polymer matrix, layer thickness and / or dressing, whether the adhesive is used and / or whether it is being used with negative pressure injury (NPWT). In some embodiments, the polysiloxane macromolecules that release NO 105 can be present in a polymer matrix 103 of perforated layer 115. Such perforated layers 115 can be used with other perforated layers 115 and / or with unperforated layer, in any suitable combination. In addition, perforated layers 115 cannot include polysiloxane macromolecules that release NO 105 and / or can be used in combination with other layers that include a polymer matrix 103 and a polysiloxane macromolecules that release NO 105 into and / or in a matrix of polymer 103. In addition, as shown in FIG. 6B, a medical grade adhesive 107 may be on the surface of the perforated layer 115 which contacts the wound layer. The use of a perforated layer 115 can allow the wound moisture to interact with silica that releases NO in a layer in the perforated layer 115, can increase the diffusion of the gas (eg nitric oxide) to the wound layer and provides a suitable material for use with NPWT.
    The perforated layer 115 can be formed by any suitable method. However, in some embodiments, the perforated layer 115 is formed by using a mold, or by pressing an object into a polymer matrix 103 to form at least one hole 117, where the ends of the hole can also be formed. melted and mixed depending on the nature of a polymer matrix 103. In addition, in some embodiments, holes 117 of the perforated layers 115 can be formed by curing the polymer matrix 103 in a mold, for example, in a temperature process low and / or anhydrous and then granulated or packaged in individual perforated trays.
    According to some embodiments of the invention, additional therapeutic agents, such as those described herein, can be present in any of the wound dressing layers. As an example, in some embodiments, the layer that is substantially free of the polysiloxane macromolecules that release NO may include at least one therapeutic agent. As a further example, a layer that includes the polysiloxane macromolecules that release NO can also include at least one additional therapeutic agent.
    In some embodiments, the wound dressing may further include a polymer backing layer that contacts the polymer matrix or a polymer layer in a polymer matrix. In some embodiments, the wound dressing is an island-shaped wound dressing and the polymer backing layer and optionally at least a portion of a polymer matrix that contacts the wound layer, may include a grade adhesive. doctor in this. For example, the wound dressing can include the polymer backing layer and a polymer matrix layer including a polymer matrix having polysiloxane macromolecules that release NO in this or thereafter, where a polymer matrix layer is bonded to a portion of the polymer backing layer and at least a portion of the polymer backing layer that is covered but not bonded to a polymer matrix layer is coated with a medical grade adhesive. Such a wound dressing can also include additional layers, such as the wound contact layer, where the wound contact layer is on the face of a polymer matrix layer that is not bonded to the polymer backing layer.
    Each wound dressing layer according to embodiments of the invention can be of any suitable thickness. However, in some embodiments, one or more layers of the wound dressing can have a thickness in the range of about 10 to about 5000 microns. In some embodiments of the invention, at least one layer of the wound dressing may be substantially transparent. Yet, in some embodiments, the wound dressing as a whole can be substantially transparent. The term substantially transparent refers to a material that has a transmission percentage of 80 percent or more, as determined using a solid-state spectrophotometer. Additionally, as described above, in some embodiments, at least one layer of the wound dressing has a medical grade adhesive on it. For example, the wound dressing surface that contacts the wound may have a medical grade adhesive on it.
    Examples of medical grade adhesive that can safely be used on the skin are acrylate based adhesives, such as 2-ethylhexyl acrylate, isooctyl acrylate or n-butyl acrylate copolymerized with polar functional monomers such as acrylic acid, methacrylic acid, acetate vinyl, methyl acrylate, N-vinylcaprolactam, or hydroxyethyl methacrylate. Additional examples include octylcyanoacrylate, AcrySure ™ adhesives (MACtac), silk protein based adhesives, silicone gel based adhesives (Silbione®O by Bluestar Silicones) and polyurethane based adhesive mixes.
    Wound dressing kits
    As described above, wound healing can be accomplished through prolonged low concentrations of nitric oxide administration so nitric oxide acts as a signaling molecule in a number of wound healing shells. In some embodiments, the instantaneous flow of nitric oxide release from the surface of the hydrated dressing needed to promote wound healing can be in the range of 0.5 pmol NO cm 's to 20 pmol NO cm's' in the application to the patient and constitutes a slow release rate. A wound dressing that releases intermediate NO can relieve the inflammatory phase immediately following damage, following debridement of a chronic wound, in simulated or infected wounds. In the inflammatory phase, the flow of release from the hydrated dressing surface is in the range of 20 pmol NO cm ' 2 s' 1 to 1000 pmol NO cm ' 2 s' 1 in the initial application to the patient and constitutes an intermediate release range . High levels of NO released from a third polysiloxane matrix / macromolecule that releases the NO composition may be required to effect antimicrobial activity, using the rapid breakdown of nitric oxide to kill microorganisms through nitrosative / oxidative intermediates. In these embodiments, the flow of nitric oxide release from the surface of the hydrated dressing is in the range of 1 nmol NO cm-2 s ' 1 to 1 pmol NO cm' s in the initial application and may constitute a rapid oxide rupture nitric acid needed to provide one or more reduction against a wide range of microorganisms.
    Therefore, provided in accordance with some embodiments of the invention are kits that include wound dressings directed to a course of therapy with three types of dressings unique to the compositions designed for the target of this three wound process. For a particular injury, a regiment can be implemented for a specific number of days for which the three unique dressings are administered in sequence or repeated at some frequencies (for example, to keep microbial load low).
    Wound treatment methods
    In some embodiments of the invention, methods of treating the wound by applying a wound dressing in accordance with an embodiment of the invention are provided. Such methods can be used in combination with any other known methods of treating the wound, including the application of medications, such as those that have anti-inflammatory, pain relief, immunosuppressant, vasodilator, wound healing and / or anti-cell forming properties. . For the methods used herein, additional therapeutic agents and the methods can be used before, concurrently with or after application with a gel according to embodiments of the invention. The wound dressing according to embodiments of the invention can also be used in combination with another wound dressing known to the person skilled in the art.
    In some embodiments of the invention, the wound dressings provided therein can be used in conjunction with at least one agent that can disrupt the biopulse macrostructure before or in conjunction with the application of the wound dressing. In some embodiments, the anti-bio-film agent can disrupt the extracellular matrix of the bio-film. Examples of anti-biopellicent agents that can act in this way include lactoferrin, periodate, xylitol, DNase, protease and an enzyme that degrades extracellular polysaccharides. In some embodiments of the invention, the anti-biopellicle formulation can be acidic to promote DNase enzyme activity (e.g., mammalian DNases such as DNase II) and the acidic conditions simultaneously can also enhance the rate release of NO from diazeniodiolate modified silica. In some embodiments, the protease may include at least one of the proteinase K, trypsin, Pectinex Ultra SP (PUS) and pancreatin. In some embodiments, enzymes that degrade extracellular polysaccharides can include N acetylglucosaminidases (e.g., dispersin B).
    In some embodiments of the invention, the anti-film agent may act by affecting the transcriptional, translation and / or post-translational regulation of the sensitizing genes of the members or products of the genes in the infected organisms. For example, anti-biopellicent agents can include at least one of haamelitanin, cyclic di-GMP or sublethal concentrations of nitric oxide.
    Anti-biopellicent agents can also act by other mechanisms. For example, the anti-biopellicent agent can cause the infected organism to transition from a sessile state to a metabolically active state. As another example, the anti-biopellicle agent can act by causing the infected organism to transition from a non-mobile state to a mobile phenotype.
    In some embodiments of the invention, the wound dressings provided herein can be used in conjunction with a wound debridement procedure. For example, in some embodiments, wounds can first be treated with a debridement procedure; and then a wound dressing in accordance with an embodiment of the invention can be applied to the wound undergoing debridement. Wound dressings according to embodiments of the invention can increase the wound healing rate, decrease inflammation and / or show an antimicrobial effect. Wound dressings according to the embodiments of the invention can be used in conjunction with any suitable debridement procedure. For example, the debridement procedure can be selective or non-selective.
    In some embodiments, the debridement procedure may include at least one of the surgical, enzymatic, autolytic, sharp, mechanical and biological processes. Any suitable surgical method can be used, but in some embodiments, the surgical method may involve a surgical cut in addition to the non-viable tissue in the wound. Any suitable enzymatic method can be used, but in some embodiments, the enzymatic method may involve using one or more proteases, their required cofactors and optionally any enhancing agents, to digest the non-viable tissue in the wound. Exemplary proteases include trypsin, papain or other plant-derived proteases and collagenase. Any suitable autolytic method can be used, but in some embodiments, the autolytic method may involve maintaining a moist wound environment in order to promote the breakdown of non-viable tissue by enzymes that are naturally produced by the body. Any suitable mechanical method can be used, but in some embodiments, mechanical methods may include wet to dry gauze, irrigation, pulsating wash, water swirl therapy and / or low frequency ultrasound. Any suitable severe method can be used, but in some embodiments, the severe method may involve cutting beyond the non-viable tissue by qualified clinical staff (for example, RN or nurse). Any suitable biological method can be used, but in some embodiments, the biological method may involve the use of fly larvae, which selectively digest non-viable tissue in the wound. These debridement methods can be used alone or in combination.
    After the wound is debrided, a wound dressing in accordance with an embodiment of the invention can be applied. Additional processes can be performed and therapeutic agents can be applied. For example, after debridement, an anti-biopellicent agent can be applied to the wound before or in conjunction with the application of the wound dressing. Exemplary anti-biopellicent agents include acetylsalicylic acid (aspirin), cyclic di-GMP, lactoferrin, gallium, selenium, as described above. Other compounds, such as hamamelitanin (amaelia extract), arginine and c-di-GMP, can also be applied.
    Also provided in accordance with some embodiments of the invention are methods of using a wound dressing in accordance with an embodiment of the invention and in conjunction with negative pressure injury therapy (NPWT).
    Suitable patients to be treated with wound dressings or methods according to an embodiment of the invention include, but are not limited to, mammalian and avian patients. Mammals of the present invention include, but are not limited to, canines, felines, cattle, goats, horses, sheep, pigs, rodents (e.g. rats and mice), lagomorphs, primates, humans and others and mammals in utero. Any mammalian patient in need of treatment according to the present invention is suitable. Human patients are preferred. Human patients of both sexes and at any stage of development (i.e., newborn, child, youth, adolescent, adult) can be treated in accordance with the present invention.
    Illustrative poultry in accordance with the present invention include chickens, ducks, turkeys, geese, codomiz, pheasants, ratites (for example, ostrich) and domestic birds (for example, parrots and canaries) and birds in ovo.
    The invention can also be carried out on animal patients, particularly mammalian patients such as mice, rats, dogs, cats, cattle and horses for veterinary purposes and for drug evaluation and drug development purposes.
    Wound dressing methods
    The wound dressings described in this can be formed by any suitable method. However, provided in accordance with some embodiments of the invention are the methods of forming the wound dressing. In some embodiments, incorporation of polysiloxane macromolecules that release NO can be achieved through the physical fixation of the particles on the polymer surfaces, through the electrostatic association of particles on the polymeric surfaces and / or by the covalent bonding or reticulation of the particles in the groups reactive on a polymer surface, inside the polymer and / or inside the foam cells. In some embodiments, wound dressing methods include combining polysiloxane macromolecules that release NO and at least one monomer; and polymerizing at least one monomer to form a polymer matrix comprising the polysiloxane macromolecules that release NO. The monomer can be polymerized by any suitable method, but in some embodiments, the monomer is polymerized by photocure and / or moisture curing, with or without an initiator. In some embodiments, the monomer can be polymerized in contact with the wound environment, for example, through moisture in the wound. In some embodiments, a single-layer wound dressing can be formed by a method that includes a solvent that distributes a polymer solution and the polysiloxane macromolecules that release NO.
    In some embodiments, polymerization occurs through the liquid that distributes or melts the polymer extrusion. In some embodiments, a liquid monomer, polysiloxane macromolecules that release NO and an initiator are deposited on a surface and the polymerization proceeds to activate the initiator. Polymerizable groups can also be used to functionalize the exterior of the particle, after which, the particles can be co-polymerized into a polymer during the polymerization process.
    In some embodiments of the invention, methods of forming wound dressings include dispersing the polysiloxane macromolecules that release NO into a mixture of foam forming monomers; polymerization of the monomers that form the foam to form a polymer; and then foam the polymer.
    In some embodiments, wound dressing methods include the reaction of the functional groups on the polysiloxane macromolecules that release NO with at least one foaming monomer; polymerization of at least one foaming monomer to form a polymer including the polysiloxane macromolecules that release NO therein; and then foam the polymer.
    In some embodiments, polyurethane foam dressings can be prepared by reacting the polyols with added polyisocyanates in the stoichiometric excess, with other coreagents added as required. In the manufacture of conventional foam, stoichiometric amount of water is added to the reaction mixture. The water can react with the isocyanate groups to form CO2 that bubble through the polymerization mass, creating a cellular structure of the flexible foams.
    For polysiloxane macromolecules reacted with water that release NO, water cannot be used in the preparation of foam dressings that release NO as water can activate the polysiloxane macromolecules that release NO, resulting in a premature release of NO and a decrease in therapeutic value of the foam dressing.
    Entirely non-aqueous foams can be synthesized by substituting or supplementing the polyhydrols with amino alcohols or alkanolamines. Exemplary amino alcohols and alkanolamines can be seen in US Patent No. 5,859,285, the disclosure that is incorporated in this in its entirety. Alkanolamines can chemically store CO2 in its amine groups and this CO2 can be released by heating. The alkanolamines can be dissolved in a polar solvent, preferably a diol or a triol and contacted with CO 2 to form carbamates. In some embodiments, the polar solvent can be the polyol itself which can be the soft segment in the foam dressing.
    The carbamate solution can be used to react with polyisocyanate to form polyurethane foams. Carbamates can act as a catalyst in foaming, thus avoiding the need to use other catalysts.
    While any suitable alkanolamines can be used to produce carbamates, in some embodiments, carbamates can be produced by using the following alkanolamines: 2- (2aminoethylamino) ethanol, (3 - [(2-amino ethyl) amino)] propanol) , (2- [(3aminopropyl) amino] ethanol), (1 - [(2-aminoethyl) amino] -2-propanol, (2 - [(3 aminopropyl) methylamino] ethanol, l - [(2-amino-l -methylethyl) amino] -2-propanol,
    2 - [(((2-amino-2-methylpropyl) amino] -2-methyl-1-propanol, 2 - [(4-amino-3methylbutyl) amino] -2-methyl-1-propanol, 17-amino-3 , 6,9,12,15-pentaazaeptadecan-1-01 and / or 3,7,12,16-tetraazaoctadecan-1,18-diol, in particular that based on 2- (2-aminoethylamino) ethanol as alkanolamine. The carbamate solution can still be mixed with compounds containing polyhydroxyl or polyamine that has been preloaded with NO and as a result, it has a functional group that releases single or multiple NO.
    In addition to chemically storing the blowing agent CO 2 in the above way, physical blowing agents can also be used in the production of foam. Examples of physical blowing agents include: hydrohalo-olefin (See US Patent Application Publication No. 20090099272, the contents of which are incorporated herein by reference in their entirety); alkanes, such as 2-methylbutane, pentane, heptanes (See US Patent No. 5,194,325, the contents of which are incorporated by reference in their entirety) and other low-boiling, inert compounds such as pentene and acetone. Carbon dioxide, including supercritical carbon dioxide, can be used as a physical blowing agent as well.
    In some embodiments of the invention, provided are methods of forming the dressing for multilayer wounds that include combination of one or more polymeric layers, wherein one or more layers of polymer may include the polymer matrix and polysiloxane macromolecules that release NO in this or next. The combination of the polymeric layers can be achieved by any suitable method, but in some embodiments, the polymer layers are laminated mutually. Exemplary lamination techniques include ultrasonic welding, annealing with anhydrous organic solvents and applying pressure sensitive adhesive.
    The present invention will be described in more detail with reference to the following examples. However, these examples are given for the purpose of the illustration and will not be construed as limiting the scope of the invention.
    EXAMPLES
    EXAMPLE 1
    The water absorption for the three thin-film dressings of hydrophilic polyurethanes soaked in phosphate buffered saline at physiological temperature and pH is shown in FIG. 7. Tecophilic® HP-60D-20 (T20), HP-60D-60 (T60) and HP93A-100 (T100) aliphatic thermoplastic polyurethanes from Lubrizol, Inc. gradually show an increase in the percentage of excess weight.
    EXAMPLE 2
    The water absorption for the Tecophilic® HP-60D-20 (T20) aliphatic thermoplastic polyurethane loaded with increased weight percentage of 8000 MW poly (ethylene glycol) as a porogen is shown in FIG.
    8. The weight of thin polymer films increases all the time as the hydrophilicity of a polymer matrix is increased as a function of percentage of PEG loading.
    EXAMPLE 3
    The water absorption by the TG-2000 solvent of Tecophilic® hydrogel thermoplastic polyurethane distributed in thin-film dressings of polymer films and soaked in phosphate-buffered saline at physiological temperature and pH is shown in FIG. 9. The weight of this superabsorbent polymer (SAP) rapidly increases in exposure to moisture and swells to store excess water at 2000 percent of its initial weight.
    EXAMPLE 4
    FIG. 10 illustrates the covalent storage of nitric oxide in the N-methylaminopropyltrimethoxysilane aminosilane as a NO diazeniodiolate donor, followed by co-condensation with an alkoxysilane of structure, tetraethoxysilane, to form the Nitricil 70 composition. from previous examples and tested for its antimicrobial activity against a gram negative bacterium, P. aeruginosa. A 10 6 inoculum of bacteria was deposited on a surface of the wound dressings that release NO in an agar paste and incubated for 24 hours. The percentage of reduction of P. aeruginosa versus control polyurethane materials for each composition is shown in TABLE 1. The water absorption of the polymer and the NO release kinetics corresponding to Nitricil ™ 70 directly affect bactericidal activity.
    WO 2011/022680
    PCT / US2010 / 046209
    TABLE 1
    Composition Polymer Loading of70% nitricyclic (by weight / by weight) % reduction of P. aeruginosa ATCC15442. THE T20 2.5 31 B T20 4 58 Ç T20 8 > 99.9999 D T20 10 > 99 AND T20 14 > 99'9999 F T20 16 > 99.9999 G T2O 20 > 99.9999 H T60 2.5 49 1 T60 10 > 99.99 J T100 10 98.7 K T100 16 ND L TG2OOO 10 ND
    EXAMPLE 5
    FIG. 11 describes the chemiluminescent detection of NO Release from Nitricil ™ 70 silica particles free in the solution, Composition J of the wound dressing and Composition D of the wound dressing measured in the physiological buffer, pH and temperature. The flow of NO release from the dressing surfaces is reported as loaded PPB / mg Nitricil ™. As an example of how a polymer matrix delivers the resulting NO release, the initial levels of NO release from Composition D are 20X lower than Nitricil ™ alone. Composition D also maintains a more consistent level of NO release in the first 60 minutes compared to Composition J at the equivalent 10% Nitricil ™ loading rate.
    EXAMPLE 6
    When applied to the wound, the polyurethane material of the wound dressing comes in contact with moisture in the wound layer. Polyurethane has some affinity for moisture due to the presence of soft polyether chain segments in its structure, which results in a limited amount of water being removed by the dressing. This interior diffusion within a polymer matrix leads to an increase in the distance between the polymer chains and is observed as expansion of the polymer. The increase in the distance between the chains and the concentration gradient between the water in the polymer and the volume of water in the wound layer, allows for a greater movement space for the soaked silica particles. As a result, the particles can diffuse out of the polymer, with the smaller particles having the greatest propensity. This phenomenon manifests itself as particle leaching.
    The wound dressing comprising NO-releasing silica particles is designed to minimize leaching on exposure to moisten the wound layer. The curative polymer composition and silica loading by weight / weight affect the accumulated leached amount. Light scattering is a technique commonly used to characterize particle suspensions, particularly for measuring micrometer size and polydispersity and nanometer particle sizes. In the static light scattering mode, the average time intensity of the light dispersed by a particle suspension is measured and is highly dependent on the particle size, its concentration and molecular weight. Thus, for a regularly diluted suspension of the monodisperse particles, the average light intensity of time must be directed proportional to the particle concentration and the static light scattering is said to occur in Rayleigh mode. A plot of intensity vs. intensity dispersion. Particle concentration produces a straight line and provides an exact method for determining the concentrations of unknown particles that leach into the solution from the wound dressing prototypes.
    To measure the potential concentrations of silica that releases NO that accumulates in the solution following incubation under physiologically buffered solutions for 24 and 48 hours, the light scattering intensity of each unknown particle sample was measured and converted to its concentration using a curve calibration The polyurethane dressings I release nitric oxide loaded with silica were cut into three 0.75 x 0.75 square samples. The samples were weighed and placed in polypropylene vials and 10 mL of filtered phosphate buffered saline (PBS, 10 mM sodium dihydrogen phosphate, 137 mM NaCl, 2.3 mM KC1, pH 7.4) pre -heated to 37 ° C was added to all. The flasks were then incubated in a 37 ° C water bath. After 24 hours, each flask was shaken and an aliquot was removed, which was transferred to a polystyrene crucible. The dispersion of the static light intensity of this aliquot was determined against PBS filtered as void. The silica concentration of the leachate was then determined using the calibration curve to convert the obtained kcps value to mg / ml and the obtained mg / ml values were expressed as a percentage of the calculated amount of silica to be initially loaded into the dressing sample.
    The leaching values for the representative compositions are shown below and illustrate the dependence on polymer hydrophilicity and homogeneity of the silica polyurethane compound: 5% w / v T20 in tetrahydrofuran, 80 mg silica / g polymer, paste prepared using magnetic stirring (TABLE 2), 5% w / v T20 in tetrahydrofuran, 80 mg silica / g polymer, paste prepared by sonication, (TABLE 3), 10% w / v TI00 in tetrahydrofuran, 160 mg of silica / polymer g, paste prepared by magnetic stirring (TABLE 4), 10% w / v T20 in tetrahydrofuran, 160 mg silica / g polymer, paste prepared through sonification (TABLE 5). All wound dressing polymers were solvents distributed on thin films and dried under vacuum.
    TABLE 2
    Day Average Standard deviation i 11.01% 1.58% 2 9.23% 1.37%
    TABLE 3
    Day Average Standard deviation 1 0.62% 0.31% 2 0.34% 0.01%
    TABLE 4
    Day Average Standard deviation 1 21.1% 6.73% 2 23.72% 9.14%
    TABLE 5
    Day Average Standard deviation 1 0.50% 0.22% 2 1.23% 0.65%
    EXAMPLE 7
    The biopellicles of P. aeruginosa were developed for 48 hours in partial thickness wounds in a porcine animal model. After 2 days of development, baseline levels of the bacteria from a wound flow with sterile tampon and a vigorous tissue / bacterial wound rub in the sterile tampon were recorded. At
    Q planktonic bacteria were approximately 10 CFU / mL and the bacteria embedded in the bio-film are above 10 10 CFU / mL prior to treatment with dressings for wounds that release NO. The efficacy of various wound dressing compositions that release NO on both levels of planktonic bacteria flowing from the wound and the scraped bio-film bacteria levels from the wound are shown in comparison to the Tegaderm ™ covered controls in FIG. 12. Wound dressings comprising different polymer matrices and varying percentages of Nitricil ™ loading elicit different results when tested against an in vivo bio-film model.
    EXAMPLE 8
    A medical grade, aliphatic polyether polyurethane that absorbs less water in the amount of 20% of its dry weight is combined with 14% w / w Nitricil ™ 70 (precipitated silica charged by nitric oxide) such that Nitricil ™ is permanently incorporated throughout the polyurethane matrix. The resulting polyurethane film device is transparent. The polymer blend is distributed in a clear, siliconized PET release liner (FRA-308, Fox River Associates, LLC), which is pre-printed with a square grid 1.
    The test performed to evaluate the project and the technical characteristics is summarized in TABLE 6.
    TABLE 6
    Performance characteristics Measured value Film thickness 98 ± 10 pm Water absorption% 6.8 ± 2.9% MVTR 31 ± 16 g / m 2 '24 h Oxygen permeability 206 ± 91 mL 02 @ STP / 100 in 2 Tensile strength 9.57 ± 2.02 lcg / in 2 Residual solvent 3.31 pLTHF / g Storage of nitric oxide 1.2 ± 0.1 pmoles NO / cm 2 Leach analysis <0.5% (<3 ppm)
    The chemiluminescent detection of NO was used to characterize the behavior of the release of nitric oxide from the polyurethane film device. The nitric oxide in the device is released upon exposure to moisture. FIGS. 13A and 13B describe the NO behavior of the finished device soaked in the buffer at physiological temperature and pH (37 ° C, 7.4). The maximum flow at the device surface never exceeds 850 pmol NO cm 's' (FIG. 13A) and the total NO loaded on the measured device 1.2 + 0.1 pmols NO / cm (FIG. 13B) for all tested devices . A surface flow of nitric oxide from the proposed device has been optimized to assist in providing a barrier to microbial penetration.
    EXAMPLE 9
    The wound dressing that releases nitric oxide from Example 9 was used to treat partial thickness wounds in a porcine model. This study was designed to assess the healing potential of whether or not the proposed device has a negative impact on normal wound repair compared to previously listed topical nitric oxide formulations (evidenced by healing of the delayed wound or significant erythema / edema). 160 rectangular wounds measuring 10 mm x 7 mm x 0.5 mm deep were divided into four groups (40 wounds each). The wounds were healed immediately after the wounds and dressings were changed on days 2, 3, 5 and 7. Five wounds from each of the four groups were taxed each day starting on day 4 after injury and prepared according to the jumping technique. split sodium bromide to assess epidermal migration. Epithelialization is considered complete (cured) if no defects or holes are present after the separation of the dermis and epidermis. The wounds in each group were assessed until 100% complete epithelialization was observed. The test materials were not adherent to the wound layer on removal (no damage was seen again) and none of the wounds in either treatment group developed erythema, swelling or signs of infection. On day 4, none of the treatment groups were completely re-epithelialized on day 6, 100% of injuries in the nitric oxide treated group were re-epithelialized compared to just 60% of the occlusive wound environment covered by Tegaderm (FIGURE 14). The MVTR average of the wound dressing in Example 9 crosses n = 6 batches is 31 ± 16 g / m -24 hours, representing 9 MVTR greater folds than that of 3M Tegaderm barrier wound dressing, measured under identical conditions (3, 34 g / m 24 hours). In addition, the wound dressing in Example 9 has an MVTR <4% of value 840 g / m -24 hours below which the dressings are considered to be occlusive and is <1% of 3000 to 5000 g / m -24 hours MVTR damaged skin (Rennekampff, 1996). Untreated controls (exposed to air) do not completely heal until day 10 illustrating the importance of maintaining a moist wound environment.
    EXAMPLE 10
    The test was performed by an independent laboratory, according to Good Laboratory Practices, to assess the biocompatibility of the wound dressing in Example 9, as recommended by FDA's Blue Book Memo, G95-1, Use of International Standards ISO-10993 and Biological
    Evaluation of Medical Devices Part 1: Evaluation and testing. Following are the tests that were conducted along with a brief summary of the results.
    • Cytotoxicity (in vitro): NON-TOXIC
    The MEM eluting extract was prepared from dressing extracts and applied to mouse fibroblasts. Fibroblasts were stored for signs of cytotoxicity in a 72-hour test period. The wound dressing extract received a cytotoxicity count of 0 at all time points.
    • Awareness (in vivo): NO SENSITIZATION
    Normal saline and cottonseed oil extracts were prepared from the dressing extracts and tested using the guinea pig maximization sensitization test. Both extracts elicited at 0% sensitization response.
    • Irritation / Intracutaneous reactivity (in vivo): NON-IRRITANT Normal saline and cottonseed oil extracts were prepared from the wound dressing and injected into the rabbits. The injection sites were stored for reactivity in a 72-hour test period. For each extract, the difference between the average reactivity count for the wound dressing extract and an average reactivity count for vehicle control was <1.0.
    • Systemic (acute) toxicity (in vivo): NON-TOXIC
    The normal saline solution and extracts of cottonseed oil were prepared from the wound dressing and injected into mice. The animals were observed for mortality and signs of pharmacological and toxicological effects over a 72-hour test period. Both extracts result in zero animal fatalities, zero animals that show clinical signs of toxicity and zero animals with changes in body weight outside acceptable parameters:
    • Sub-acute (Sub-chronic) toxicity (in vivo): NO
    TOXIC
    The normal saline solution and extracts of cottonseed oil were prepared from the wound dressing and injected intravenously (saline) or intraperitoneally (oil) into mice once daily for 14 days. The animals were observed for mortality and signs of toxicity during the test period. There are no fatalities, no statistically significant weight difference between the control and test animals and no abnormal clinical signs noticed by any of the animals during the test period. No clinically abnormal observations were noted during the animal's necropsy. Clinical chemistry and hematology data have not been indicated as a source of toxicity.
    • Implantation (in vivo): NOT IRRITANT
    Two implantation studies were completed by the wound dressing in which parts were implanted intramuscularly in albino rabbits for one or four weeks of study. At the end of a week of implantation, the irritating rating count for the wound dressing was calculated to be 1.2. At the end of the fourth week of implantation, the irritating classification score by the wound dressing was calculated to be 2.6.
    • LAL endotoxin test for pyrogens (in vitro, GMP): PASSAGE
    The kinetic chromogenic LAL test system has been validated for use with the wound dressing. Samples from three production batches of the finished, sterilized device, all contained <0.200 EU / device.
    The wound dressing of Example 9 passed the requirements of all biocompatibility tests; thus, it can be concluded that the product is biocompatible and non-toxic, providing a topical nitric oxide release solution with demonstrated safety and effectiveness.
    EXAMPLE 11
    This example describes a process for making flexible polyurethane foam that releases NO 100 kg starting 2- (2aminoethylamino) ethanol as a base. The foam is prepared using Desmodur N-100 (22% from NCO groups, Bayer Material Science, Pittsburgh, PA) as the polyisocyanate and Desmodur N and Desmophen-R-221-75 (3.3% from OH groups, Bayer Material Science , Pittsburgh, PA) as the polyol. Nitricil ™ -70 (Novan, Inc.) as a macromolecule that releases NO is incorporated into the foam in a 1% (w / w) load.
    1. CO 2 is bubbled into 100 kg 2- (2-aminoethylamino) ethanol to prepare 2- (2-aminoethylamino) ethanol carbamate
    2. The 2- (2-aminoethylamino) ethanol carbamate is dissolved in 200 kg of Desmophen-R-221-75 polyol
    3. Nitricil ™ -70, the blowing agent and gel catalysts are added to the mixture (see USP 4173691)
    4. The mixture is reacted with a stoichiometric excess of Desmodur N-100, with stirring and heating to 50 ° C.
    5. The reaction mixture is cured at 50 ° C to release the chemical CO 2 bond.
    Calculations for:
    1. Amount of CO 2 needs to be bubbled
    2. Amount of Desmodur N-100 to be added
    3. Amount of Nitricil ™ -70 to be added to a nominal 1% w / w load
    Calculation for adding CCb
    There are two moles of NH per mole of 2- (2aminoethylamino) ethanol. The number of moles of 2- (2-aminoethylamino) ethanol in
    100 kg = 961.54. The mole number of NH = 2 * 961.54 = 1923.07 moles. Thus, the required CO 2 weight = 1923.07 moles * 44 g / mol = 84.6 kg. A gas in excess of 1.2 fold to ensure complete conversion of the carbamates. Thus, the amount of CO 2 required = 101.52 kg.
    Calculation for adding catalyst
    Two types of catalyst are used in combination, a gel catalyst to accelerate the urethane-forming reaction and a blowing catalyst to reduce the time for foam to rise. The gel catalyst (e.g., stannous octoate) is present as 0.3 parts per 100 parts of polyol (w / w). The blowing catalyst (for example, antimony tris 2-ethylexoate) is present as 0.3 parts per 100 parts of polyol (w / w). Therefore, the catalyst calculation is based on the total mass reacting the hydroxyl compounds and includes the hydroxyls in 2- (2aminoethylamino) ethanol. Thus, the weight of the gel catalyst = 300 kg / 100 kg * 0.3 = 9 kg. The weight of the blowing catalyst = 9 kg.
    Calculation for adding Desmodur N-100
    Desmodur N-100 enough needs to be added such that the NCO are suitable for reacting with OH in 2- (2-aminoethylamino) ethanol and in Desmophen. The equivalent of OH groups in Desmophen-R-221-75 (3.3% OH) = 17 * 100 / 3.3 = 515. The moles of OH groups in 100 kg 2- (2aminoethylamino) ethanol = 961.54. The 200 kg equivalents = 200/515 = 0.388. The equivalent NCO groups in Desmodur N-100 (22% NCO) = 42 * 100/22 = 191. The NCO equivalents required for 1: 1 reaction with 200 kg Desmophen-R-221-75 = 191 * 0.388 = 74 , 2 kg. The percent OH in 2- (2-aminoethylamino) ethanol = 17/104 = 16.3%. The OH group equivalent = 17 * 100 / 16.3 = 104. The 100 kg equivalents = 100/104 = 0.9615. The NCO equivalents required by reaction 1: 1 = 0.9615 * 191 = 183.65 kg. Thus, the total required = 183.65 6+ 74.2 = 257.83 kg. An excess of 2% is used to guarantee the complete reaction. Therefore, the total requirement
    Desmodur Ν-100 = 1.02 * 257.83 = 262.985kg.
    Calculation for Nitricil ™ 70
    Total reagent weight (not including CO 2 ) = 262,985 kg (Desmodur N-100) + 200 kg (Desmophen-R-221-75 polyol) + 100 kg (2- (25 aminoethylamino) ethanol) + 18 kg (weight of blowing catalyst and gel catalyst) = 580.985 kg. Thus, 1% Nitricil ™ -70 = 5.81 kg.
    Summary:
    Material Quantity to be used (kg) 2- (2-aminoetdammo) ethanol 100 Desmophen-R-221-75 . 200 Desmodur N-100 262,985 Nitricil M -7Q 5.81 Tinous octoate 9 antimony tris 2-ethylexoate 9
    In the drawings and specification, typical embodiments of the invention have been disclosed and, although specific terms are used, 10 these are used in a generic and descriptive sense only and not for the purposes of the limitation, the scope of the invention being presented in the following claims .
    权利要求:
    Claims (31)
    [1]
    1. Wound dressing characterized by the fact that it comprises a polymeric matrix comprising a foam, and polysiloxane macromolecules of nitric oxide release 5 (NO) inside and / or in the polymeric matrix, in which the polymeric matrix comprises a hydrophilic polyurethane, in whereas nitric oxide (NO) release polysiloxane macromolecules are NO-releasing particles, and
    10 in which the wound dressing is non-toxic and stably stores NO.
    [2]
    2. Wound dressing according to claim 1, characterized by the fact that the polysiloxane macromolecules that release NO comprise functional groups of N-diazenziodiolate.
    15
    [3]
    3. Wound dressing according to claim 1, characterized in that the polysiloxane macromolecules that release NO comprise functional groups of S-nitrosothiol.
    [4]
    4. Wound dressing, according to claim 1, characterized by the fact that the concentration of the macromolecules of
    NO-releasing polysiloxane is in the range of about 0.1 to about 20 weight percent.
    [5]
    5. Wound dressing according to claim 1, characterized by the fact that it still comprises a water-soluble progeny selected from the group consisting of sodium chloride, sucrose, glucose,
    25 lactose, sorbitol, xylitol, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
    [6]
    6. Wound dressing according to claim 1, characterized by the fact that it still comprises at least one therapeutic agent selected from the group consisting of antimicrobial compounds,
    Petition 870180149313, of 11/08/2018, p. 8/15 anti-inflammatory agents, pain relievers, immunosuppressants, vasodilators, wound healing agents, anti-bio-film agents and mixtures thereof.
    [7]
    7. Wound dressing according to claim 1, characterized by the fact that the polymeric matrix comprises an aliphatic polyurethane polyether that absorbs water in an amount ranging from 10 percent to 60 percent of its dry weight.
    [8]
    8. Wound dressing according to claim 1, characterized by the fact that the polymer is a super-absorbent polymer.
    [9]
    9. Wound dressing according to claim 1, characterized in that the polymeric matrix is a flexible open cell polyurethane foam comprising at least one polyisocyanate segment and at least one polyol segment.
    [10]
    10. Wound dressing according to claim 9, characterized in that the at least one polyisocyanate segment is formed from a polyisocyanate selected from the group consisting of tolylene diisocyanate, methylphenylene diisocyanate, modified diisocyanates and / or mixtures thereof.
    [11]
    11. Wound dressing according to claim 9, characterized in that the at least one polyol segment is formed from at least one diol having from 2 to 18 carbon atoms.
    [12]
    12. Wound dressing according to claim
    11, characterized by the fact that at least one diol having from 2 to 18 carbon atoms is selected from the group consisting of 2-ethanediol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,5 -pentanediol, 1,10decanediol, 2-methyl-1,3-propanediol, 2-methyl-2-butyl-1,3-propanediol, 2,2dimethyl-1,3-propanediol, 2,2-dimethyl-1,4 -butanediol, 2-ethyl-2-butyl-1,3propanediol, neopentyl glycol hydroxypivalate, diethylene glycol, triethylene glycol and mixtures thereof.
    Petition 870180149313, of 11/08/2018, p. 9/15
    [13]
    13. Wound dressing according to claim 9, characterized by the fact that the macromolecules that release NO are present inside and, optionally, cross-linked to the polymeric matrix of the polymeric foam.
    [14]
    14. Wound dressing according to claim 1, characterized by the fact that the wound dressing is a single layer with a thickness ranging from 10 microns to 5000 microns.
    [15]
    15. Wound dressing according to claim 1, characterized by the fact that the wound dressing is substantially transparent.
    [16]
    16. Wound dressing according to claim 1, characterized by the fact that the flow of nitric oxide released from the hydrated dressing surface is in the range of 0.1 pmol of NO cm -2 to 100 pmol of NO cm - 2 .
    [17]
    17. Wound dressing according to claim 1, characterized by the fact that the storage of nitric oxide in the dressing is in the range of 100 pmol NO cm -2 to 1000 pmol NO cm -2 .
    [18]
    18. Wound dressing according to claim 1, characterized by the fact that the storage of nitric oxide in the dressing is in the range of 1 nmol NO cm -2 to 10 pmol NO cm -2 .
    [19]
    19. Method for forming a wound dressing characterized by the fact that it comprises:
    combining the NO-releasing polysiloxane macromolecules and at least one monomer, where the nitric oxide-releasing polysiloxane (NO) macromolecules are NO-releasing particles; and polymerize the at least one monomer to form a polymeric matrix comprising the NO-releasing polysiloxane macromolecules, wherein the polymeric matrix comprises a foam in which to combine the polysiloxane macromolecules which
    Petition 870180149313, of 11/08/2018, p. 10/15 releases NO and at least one monomer comprises dispersing the macromolecules that release NO in a mixture of foam-forming monomers;
    wherein polymerizing the at least one monomer to form a polymeric matrix comprises polymerizing the foaming monomers to form a polymer and foaming the polymer to form the polymeric matrix.
    [20]
    20. Method, according to claim 19, characterized by the fact that the monomer is polymerized by photocure.
    [21]
    21. Method according to claim 19, characterized in that the polymer occurs by a method which comprises depositing the liquid monomer, polysiloxane macromolecules that release NO and an initiator and polymerizing the liquid monomer.
    [22]
    22. Method according to claim 19, characterized in that combining the polysiloxane macromolecules that releases NO and at least one monomer further comprises reacting functional groups in the macromolecules that release NO with at least one foam forming monomer.
    [23]
    23. Method according to claim 19, characterized by the fact that the polymeric foam is formed by the use of a blowing agent selected from at least one of the groups consisting of carbon dioxide, hydroaloolefins and alkanes.
    [24]
    24. Method according to claim 23, characterized in that the blowing agent includes carbon dioxide generated from carbamates that are formed from alkanolamines selected from at least one of the groups consisting of 2- (2 -aminoethylamino) ethanol, (3 [(2-aminoethyl) amino)] propanol), (2 - [(3-aminopropyl) amino] ethanol), (1 - [(2aminoethyl) amino] -2-propanol, (2- [(3-aminopropyl) methylamino] ethanol, 1 - [(2 amino-1-methylethyl) amino] -2-propanol, 2 - [((2-amino-2-methylpropyl) amino] -2
    Petition 870180149313, of 11/08/2018, p. 11/15 methyl-1-propanol, 2 - [(4-amino-3-methylbutyl) amino] -2-methyl-1-propanol, 17 amino-3,6,9,12,15- pentaazaeptadecan- 1-ol e 3,7,12,16-tetraazaoctadecane1,18-diol.
    [25]
    25. Wound dressing kit characterized by the fact that it comprises one or more of a first wound dressing that releases low concentrations of nitric oxide from 0 to 7 days in the range of 0.5 pmol of NO cm -2 s -1 to 20 pmol of NO cm -2 s -1 in the initial application to the patient;
    a second wound dressing that releases intermediate concentrations of nitric oxide from 0 to 7 days in the range of 20 pmol of NO cm -2 s -1 to 1000 pmol of NO cm -2 s -1 in the initial application to the patient and a third dressing for wound that releases high levels of nitric oxide from 0 to 48 hours in the range of 1 nmol NO m -2 s -1 to 1 pmol NO cm -2 s-1 in the initial application to the patient, in which each of the wound dressings comprises a polymeric matrix and polysiloxane macromolecules that release NO within and / or in the polymeric matrix, wherein the nitric oxide releasing polysiloxane (NO) macromolecules are NO releasing particles and the polymeric matrix comprises a foam, and each of which wound dressing is non-toxic and can stably store nitric oxide.
    [26]
    26. Wound dressing kit according to claim 25, characterized in that the second wound dressing still includes an anti-inflammatory agent.
    [27]
    27. Wound dressing kit according to claim 25, characterized in that the third wound dressing still includes an anti-microbial agent.
    [28]
    28. Wound dressing according to claim 1, characterized by the fact that the wound dressing comprises a first layer that contacts the wound layer and is
    Petition 870180149313, of 11/08/2018, p. 12/15 not interactive with the wound and a second layer on the first layer.
    [29]
    29. Wound dressing according to claim
    28, characterized by the fact that the first layer is substantially free of macromolecules that release NO and comprises at least one therapeutic agent and in which the second layer comprises the polymeric matrix having polysiloxane macromolecules that release NO therein.
    [30]
    30. Method according to claim 19, characterized by the fact that the polymeric matrix comprises a polymer selected from the
    10 group consisting of polyurethanes, acrylate polymers, acrylic acid polymers, copolymers thereof and mixtures thereof.
    [31]
    31. Wound dressing according to claim
    25, characterized by the fact that the polymer matrix comprises a polymer selected from the group consisting of polyurethanes, acrylate polymers, acrylic acid polymers, copolymers thereof and mixtures thereof.
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    同族专利:
    公开号 | 公开日
    EP2467173B1|2019-04-24|
    CN102695528B|2016-07-13|
    CN102695528A|2012-09-26|
    US20180214598A1|2018-08-02|
    US9919072B2|2018-03-20|
    BR112012003804A2|2015-09-01|
    CA2771389C|2019-04-09|
    DK2467173T3|2019-07-29|
    WO2011022680A3|2011-07-07|
    CA2771389A1|2011-02-24|
    WO2011022680A2|2011-02-24|
    EP2467173A2|2012-06-27|
    US20120136323A1|2012-05-31|
    EP2467173B8|2019-06-19|
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    法律状态:
    2018-04-03| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2018-08-14| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|
    2019-01-15| B09A| Decision: intention to grant|
    2019-02-19| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/08/2010, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/08/2010, OBSERVADAS AS CONDICOES LEGAIS |
    优先权:
    申请号 | 申请日 | 专利标题
    US23592709P| true| 2009-08-21|2009-08-21|
    US23594809P| true| 2009-08-21|2009-08-21|
    US61/235,927|2009-08-21|
    US61/235,948|2009-08-21|
    PCT/US2010/046209|WO2011022680A2|2009-08-21|2010-08-20|Wound dressings, methods of using the same and methods of forming the same|
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