WO2011003172A1 - Administration contrôlée d’oxyde nitrique à partir de polymères conjugués aqueux de s-nitrosothiol et de leurs complexes - Google Patents

Administration contrôlée d’oxyde nitrique à partir de polymères conjugués aqueux de s-nitrosothiol et de leurs complexes Download PDF

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WO2011003172A1
WO2011003172A1 PCT/CA2010/000270 CA2010000270W WO2011003172A1 WO 2011003172 A1 WO2011003172 A1 WO 2011003172A1 CA 2010000270 W CA2010000270 W CA 2010000270W WO 2011003172 A1 WO2011003172 A1 WO 2011003172A1
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glu
cys
poly
maleic anhydride
aqueous solution
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Ping I. Lee
Yan Li
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University Of Toronto
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J139/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Adhesives based on derivatives of such polymers
    • C09J139/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
    • C09J139/06—Homopolymers or copolymers of N-vinyl-pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/34—Introducing sulfur atoms or sulfur-containing groups
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J135/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical, and containing at least another carboxyl radical in the molecule, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Adhesives based on derivatives of such polymers
    • C09J135/08—Copolymers with vinyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F216/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
    • C08F216/12—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an ether radical
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F222/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof
    • C08F222/04—Anhydrides, e.g. cyclic anhydrides
    • C08F222/06—Maleic anhydride
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
    • C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
    • C08F226/10—N-Vinyl-pyrrolidone

Definitions

  • This application relates to aqueous solutions containing supramacromolecular nitric oxide releasing polymer complexes of use in the treatment of healing wounds, particularly chronic ulceration caused by diabetes, and medicinal intermediate conjugates thereof.
  • RSNOs S-Nitrosothiols
  • NO nitric oxide
  • examples of endogenous RSNOs include 5-nitrosoalbumin (SNO-albumin), S-nitrosoglutathione (GSNO) and S- nitrosocysteine (SNO-cysteine), in which R is a protein, peptide and amino acid respectively.
  • SNO-albumin 5-nitrosoalbumin
  • GSNO S-nitrosoglutathione
  • SNO-cysteine S- nitrosocysteine
  • R protein, peptide and amino acid respectively.
  • RSNOs are involved in numerous biological processes including smooth muscle cell relaxation, platelet deactivation, immunosuppression, neurotransmission and host defence [2]. Because of their inherent instability, however, the use of RSNOs for clinical purposes has been greatly hindered.
  • the S-NO bond has been found to be susceptible to decomposition by a number of mechanisms, leading to the premature release of NO and the formation of disulfides.
  • the triggering activators include metal ions, enzymes, chemicals, heat and light [3].
  • the susceptibility of these existing RSNOs has led to the development of more stable analogues, in which the properties of R were modified.
  • Patent WO 2008/080934 describes the synthesis of low molecular weight S-nitrosothiol derivatives showing improved stability through structural modifications of the R groups. Similarly, a number of novel S-nitrosated dipeptides exhibiting greater vasorelaxation potency than GSNO were synthesized [4], however, they decompose much faster than GSNO in the presence of copper sulfate. On the other hand, protein RSNOs tend to be more stable than the lower molecular weight S- nitrosothiol derivatives [5]. Along this line of approach, conjugation of NO to serum albumin or other proteins has been reported [6-7].
  • this macromolecular NO donor has an equivalent of only 0.25-0.28 molecules of S-nitrosothiol per BSA molecule. Furthermore, animal results suggest that NO was quickly released from BSA shortly after injection in mice. Even after chemical conjugation with polyethylene glycol (PEG) and N-Succinimidyl S-acetylthioacetate, the number of NO molecules on this new macromolecular NO donor, PEG-poly S-NO-BSA, can only be increased to 10 [8].
  • PEG polyethylene glycol
  • N-Succinimidyl S-acetylthioacetate the number of NO molecules on this new macromolecular NO donor, PEG-poly S-NO-BSA, can only be increased to 10 [8].
  • Another method is through the general polycondensation of a diol (either ethylene glycol or PEG) with a thio-containing dicarboxylic acid (e.g. mercaptosuccinic acid) [H].
  • a diol either ethylene glycol or PEG
  • a thio-containing dicarboxylic acid e.g. mercaptosuccinic acid
  • H mercaptosuccinic acid
  • Polyesterification is well-known to be affected by temperature and the presence of catalyst. Additionally, since the reaction products contain free thiol groups, which are easily oxidized, the reaction also needs to be carried out under the protection of N 2 . Besides these difficulties in the synthesis procedures, this polynitrosated polyester is thermally unstable, necessitating it to be stored at -20 0 C. This storage restriction translates to handling difficulties during practical applications.
  • GSNO by UV/visible radiation, either in vitro [12, 13] or in vivo [14].
  • This photochemical activity of GSNO in the visible spectrum showed an enhanced cytotoxic effect on HL-60 leukemia cells.
  • RSNOs as NO carriers for in vivo targets where they can act as photochemotherapeutic agents, photo activated release of NO from GSNO and many of its derivatives are generally too fast [15-17].
  • NO delivery system based on RSNOs which are thermally stable in the dark but which can release NO upon photo activation over an extended duration.
  • WO 09/026680 - Lee Ping I. and Li, Yan, published 5 March 2009 has shown that bioadhesive supramacromolecular complexes based on GSNO-co ⁇ jugated polyanhydride and their interpolymeric hydrogen bonding interactions with PVP not only provide a sustained NO release profile, but also exhibit significantly enhanced stability in the solid state either under ambient storage condition or upon exposure to UV light, which provides a significant advantage for potential therapeutic applications.
  • examples of these supramacromolecular complexes were prepared with high molecular weight PVP at relatively high concentrations, resulting in their precipitation out of solution. Although the resulting complexes in the solid state provided sustained release of NO they are limited in terms of ease of administration to a topical wound site.
  • Formulations in the form of powders, microparticles, fibers and film were utilized due to expected low aqueous solubility. It was expected also that the solid forms would have enhanced stability during storage and transportation over aqueous formulations. Accordingly, there remains a need to provide a more fluid administrable composition of the complex with similar NO-releasing properties and stability.
  • the invention provides an aqueous solution of a bio-adhesive, supramacromolecular nitric oxide generable polymer complex of the general formula P
  • R is an independently selected peptide linking group
  • Ri is independently selected from the group consisting of an alkane unsubstituted or substituted with alkoxy groups
  • R 2 is independently selected from the group consisting of C 1-6 alkyl
  • R 3 and R 4 are independently selected from the group consisting of optionally substituted aliphatic or aromatic alkyl
  • W is a hydrogen-bond accepting functional group-containing entity
  • Y is a carboxylic acid ester or amide linkage
  • Ti, T 2 , T 3 and T 4 are independently selected polymer residues
  • mi, m 2 , m 3) n] and n 2 are integers greater than 25; and wherein P has a molecular weight of about 1 x 10 3 to 1 x 10 7 and Q has a molecular weight of about 1 x 10 3 to 1 x 10 7 .
  • P is a maleic acid copolymer.
  • the maleic acid copolymer is selected from the group consisting of poly(methyl vinyl ether-co-maleic acid) poly(vinyl pyrrolidone-co-dimethyl maleic acid), poly(ethylene-co-maleic acid), poly(isobutylene-co-maleic acid), poly(styrene-co-maleic acid), poly(ethylene-co-ethyl acrylate-co-maleic acid), poly(maleic acid-co-octadecene), polyethylene-graft-maleic anhydride, polypropylene-graft-maleic acid, and polyisoprene-graft-maleic acid.
  • the Tj-t-Rj-Wrlni-f-Rs ⁇ -ta-t-Ra-Wr], ⁇ is polyvinyl pyrrolidone).
  • Y.R.SNO is an N-acyl-S-nitrosoglutathione or N-acyl-S-nitrosophytochelatin.
  • the invention provides an aqueous solution of a bio-adhesive, supramacromolecular nitric oxide generatable polymer complex of the general formula:
  • Ri is an alkyl vinyl ether (C 1 -C 5 ), ethylene, propylene, isobutylene, butadiene, 1-octadecene, styrene, maleic acid, or maleic anhydride unit
  • W 1 and W 2 are hydrogen-bond accepting functional group-containing entities selected from vinylpyrrolidone, ethylene oxide or propylene oxide, vinyl acetate, alkoxyl substituted glucopyranose, glucosamine, and acetylglucosamine
  • R 2 is H, a fatty acid ester, or fatty alcohol
  • R 4 is a substituted aliphatic or aromatic alkyl
  • Y is a carboxylic acid ester or amide linkage
  • RSNO is a primary amine containing S-nitrosothiol of cysteine, ⁇ -Glu-Cys, ⁇ -Glu- Cys, glutathione, homoglutathione, hydroxymethyl-glutathione, ⁇ -
  • Ti-[-R 1 -CH(COOH)-CH(Y-RSNO)-] m i-[-R 4 -] ID2 -[-R r CH(COOH)-CH (COOH)- ] m3 -T 2 is a reaction adduct of primary amine containing S-nitrosothiols as hereinabove defined and a maleic anhydride polymer or copolymer.
  • the maleic anhydride polymer or copolymer is selected from the group consisting of poly(methyl vinyl ether-alt-maleic anhydride), poly(maleic acid-co-maleic anhydride), poly(maleic anhydride), poly(vinylpyrrolidone-co-dimethyl maleic anhydride), poly(vinylacetate-co-maleic anhydride), poly(ethylene-alt-maleic anhydride),
  • the nitric oxide donor RSNO is selected from the group consisting of S- nitrosothiols of cysteine, ⁇ -Glu-Cys, ⁇ -Glu-Cys, glutathione, homoglutathione, hydroxymethyl- glutathione, ⁇ -Glu-Cys-Glu, ⁇ -Glu-Cys-Gly, ⁇ -Glu-Cys- ⁇ -Ala, ⁇ -Glu-Cys-Ser, ⁇ -Glu-Cys-Glu, other glutathione analog containing -SH and -NH 2 and/or -OH functional groups, or one of the following peptides: ( ⁇ -Glu-Cys) q , ( ⁇ -Glu-Cys) q -Gly, ( ⁇ -Glu-Cys) q - ⁇ -Ala, ( ⁇ -Glu-Cys) q -Ser, ( ⁇ -Glu-Cys) q -Glu, ( ⁇ -Glu-Cys)
  • T 3 -[-R 2 -W I -] n i-[-R 3 -W 2 -] n2 -[-R 2 -W ! -3 n3 -T 4 is selected from the group consisting of poly(vinyl pyrrolidone), polyethylene glycol, poly(ethylene oxide), poly(vinyl pyrrolidone-co-vinyl acetate), polyethylene oxide- polypropylene oxide block copolymers (Pluronics or Polaxomers), polyethylene glycol fatty alcohols, and polyethylene glycol fatty acids esters, ethyl cellulose, and chitosan.
  • poly(vinyl pyrrolidone) polyethylene glycol
  • poly(ethylene oxide) poly(vinyl pyrrolidone-co-vinyl acetate)
  • polyethylene oxide- polypropylene oxide block copolymers Pluronics or Polaxomers
  • polyethylene glycol fatty alcohols and poly
  • the invention provides an aqueous solution having a concentration of said polymer complex selected from 0.001% w/v to a saturation level.
  • the invention provides an aqueous solution having a concentration of > 0.01% w/v polymer complex, more, preferably, selected from 0.5% w/v to 90% w/v complex and, more preferably, selected from 1% w/v to 50% w/v.
  • the invention provides a method of making an aqueous solution of a bio- adhesive, supramacromolecular nitric oxide generatable polymer complex of the general formula:
  • Ri is independently selected from the group consisting of an alkane unsubstituted or substituted with alkoxy groups
  • R 2 is independently selected from the group consisting of Cl- 6 alkyl
  • R 3 and R 4 are independently selected from the group consisting of optionally substituted aliphatic or aromatic alkyl
  • W is a hydrogen-bond accepting functional group-containing entity
  • Y is a carboxylic acid ester or amide linkage
  • R is independently selected peptide linking group
  • T b T 2 , T 3 and T 4 are independently selected polymer residues
  • m b m 2 , m 3 , ni and n 2 are integers greater than 25; and wherein P has a molecular weight of about 1 x 10 3 to 1 x 10 7 and Q has a molecular weight of about 1 x 10 3 to 1 x 10 7 ;
  • P is a maleic acid copolymer and more preferably, the maleic acid copolymer is selected from the group consisting of poly(methyl vinyl ether-co-maleic acid) poly(vinyl pyrrolidone- co-dimethyl maleic acid), poly(ethylene-co-maleic acid), poly(isobutylene-co-maleic acid), poly(styrene-co-maleic acid), poly(ethylene-co-ethyl acrylate-co-maleic acid), poly(maleic acid-co- octadecene), polyethylene-graft-maleic anhydride, polypropylene-graft-maleic acid, and polyisoprene-graft-maleic acid.
  • the maleic acid copolymer is selected from the group consisting of poly(methyl vinyl ether-co-maleic acid) poly(vinyl pyrrolidone- co-dimethyl maleic acid), poly(ethylene-co-maleic acid), poly(isobutylene-co-male
  • T 3 -[-R 2 -W-] n i-[-R 3 -] n2 -T 4 is selected from the group consisting of polyethylene glycol, poly(ethylene oxide), poly(vinyl pyrrolidone-co-vinyl acetate), polyethylene oxide- polypropylene oxide block copolymers (Pluronics or Polaxomers), polyethylene glycol fatty alcohol esters, polyethylene glycol fatty acids esters, ethyl cellulose, chitosan and more preferably, poly(vinyl pyrrolidone).
  • Y.R.SNO is an N-acyl-S-nitrosoglutathione or N-acyl-S-nitrosophytochelatin.
  • the invention provide a method of making an aqueous solution of a bio- adhesive, supramacromolecular nitric oxide generatable polymer complex of the general formula: Ti-J L- R 1 C J H- C I H-l Jm— 1 I L- R 4 - JMm 2 I- R 1 C I H- C I H- Jl—m 3 T 2
  • Ri is an alkyl vinyl ether (Ci-C 5 ), ethylene, propylene, isobutylene, butadiene, 1- octadecene, styrene, maleic acid, or maleic anhydride unit;
  • Wi and W 2 are hydrogen-bond accepting functional group-containing entities selected from vinylpyrrolidone, ethylene oxide or propylene oxide, vinyl acetate, alkoxyl substituted glucopyranose, glucosamine, and acetylglucosamine; R 2 and
  • R 3 are independently selected from the group consisting of unsubstiruted alkyl or optionally substituted aliphatic or aromatic alkyl;
  • R 4 is a substituted aliphatic or aromatic alkyl;
  • Y is a carboxylic acid ester or amide linkage;
  • RSNO is a primary amine containing S-nitrosothiol of cysteine, ⁇ -Glu- Cys, ⁇ -Glu-Cys, glutathione, homoglutathione, hydroxymethyl-glutathione, ⁇ -Glu-Cys-Glu, ⁇ -Glu-
  • T 4 are polymer residues; In 1 , m 2 , m 3 , n if n 2 , and n 3 are integers greater than 25;
  • T T,-[-R 1 -CH(COOH)-CH(Y-RSNO)-] ml -[-R 4 -] ni2 -[-R 1 -CH(COOH)-CH (COOH)-
  • m3 -T 2 is a reaction adduct of primary amine containing S-Nitrosothiols and a maleic anhydride polymer or copolymer.
  • the maleic anhydride polymer or copolymer is selected from the group consisting of poly(methyl vinyl ether-alt-maleic anhydride), poly(maleic acid-co-maleic anhydride), poly(maleic anhydride), poly(vinylpyrrolidone-co-dimethyl maleic anhydride), poly(vinylacetate-co-maleic anhydride), poly(ethylene-alt-maleic anhydride), poly(isobutylene-alt-maleic anhydride), poly(styrene-alt-maleic anhydride), poly(ethylene-co-ethyl acrylate-co-maleic anhydride), and poly(maleic anhydride-alt-1-octadecene).
  • the nitric oxide donor RSNO is preferably selected from the group consisting of S- nitrosothiols of cysteine, ⁇ -Glu-Cys, ⁇ -Glu-Cys, glutathione, homoglutathione, hydroxymethyl- glutathione, ⁇ -Glu-Cys-Glu, ⁇ -Glu-Cys-Gly, ⁇ -Glu-Cys- ⁇ -Ala, ⁇ -Glu-Cys-Ser, ⁇ -Glu-Cys-Glu, other glutathione analog containing -SH and -NH 2 and/or -OH functional groups, or one of the following peptides: ( ⁇ -Glu-Cys) q , ( ⁇ -Glu-Cys) q -Gly, ( ⁇ -Glu-Cys) q - ⁇ -Ala, ( ⁇ -Glu-Cys) q -Ser, ( ⁇ -Glu-Cys) q -Glu, ( ⁇ -Glu-Cys
  • T3-[-R2-Wi-] n i-[-R3-W2-]n2-[-R2- Wi-Jn 3 -T 4 is selected from the group consisting of polyethylene glycol, poly(ethylene oxide), poly(vinyl pyrrolidone-co-vinyl acetate), polyethylene oxide- polypropylene oxide block copolymers (Pluronics or Polaxomers), polyethylene glycol fatty alcohols, and polyethylene glycol fatty acids esters, ethyl cellulose, chitosan, and more preferably, poly(vinyl pyrrolidone).
  • the present invention preferably, provides for the production of supramacromolecular polymer hydrogen bonded complexes in aqueous solution from the interaction of GSNO- polyanhydride conjugate with low molecular weight PVP or similar biocompatible compound such as, for example, PEG, HMPC, Pluronic and the like.
  • the aprotic solvent is selected from acetone, dimethyl sulfoxide, N,N-dimethyl fornamide, N-methyl pyrrolidone, N,N-dimethyl acetamide and more preferably dimethyl sulfoxide.
  • the invention provides an aqueous solution of a bio-adhesive, supramacromolecular nitric oxide generatable polymer complex made by a method as hereinabove defined.
  • the aqueous solution is essentially clear and/or pure. It will be understood by those skilled in the art, that the aforesaid aqueous solutions as defined of the supramacromolecular polymer complex also contains a proportion of the conjugate carrier and the hydrogen bond-accepting polymer species in distinct, non-hydrogen bonded form in equilibrium with the hydrogen bonded polymer complex.
  • the invention provides a use of a nitric oxide polymeric conjugate carrier of the general formula P for the treatment of healing wounds
  • R is an independently selected peptide linking group
  • R 1 is independently selected from the group consisting of an alkane unsubstituted or substituted with alkoxy groups
  • R 4 is independently selected from the group consisting of optionally substituted aliphatic or aromatic alkyl
  • Y is a carboxylic acid ester or amide linkage
  • Ti and T 2 are independently selected polymer residues
  • mi, m 2 and ni 3 are integers greater than 25; and wherein P has a molecular weight of about 1 x 10 3 to 1 x 10 7 .
  • the use is wherein P is a maleic acid copolymer.
  • said maleic acid copolymer is selected from the group consisting of poly(methyl vinyl ether-co-maleic acid) polyvinyl pyrrolidone-co-dimethyl maleic acid), poly(ethylene-co-maleic acid), poly(isobutylene-co-maleic acid), poly(styrene-co-maleic acid), poly(ethylene-co-ethyl acrylate-co-maleic acid), poly(maleic acid-co-octadecene), polyethylene-graft- maleic anhydride, polypropylene-graft-maleic acid, and polyisoprene-graft-maleic acid.
  • said maleic acid copolymer is selected from the group consisting of poly(methyl vinyl ether-co-maleic acid) polyvinyl pyrrolidone-co-dimethyl maleic acid), poly(ethylene-co-maleic acid), poly(isobutylene-co-maleic acid), poly(styrene-co-maleic acid), poly(
  • Y.R.SN0 is an N-acyl-S-nitrosoglutathione or N-acyl-S- nitrosophytochelatin.
  • Ri is an alkyl vinyl ether (Ci-C 5 ), ethylene, propylene, isobutylene, butadiene, 1-octadecene, styrene, maleic acid, or maleic anhydride unit;
  • R 4 is a substituted aliphatic or aromatic alkyl;
  • Y is a carboxylic acid ester or amide linkage;
  • RSNO is a primary amine containing S-nitrosothiol of cysteine, ⁇ -Glu-Cys, ⁇ -Glu-Cys, glutathione, homoglutathione, hydroxymethyl-glutathione, ⁇ -Glu-Cys-Glu, ⁇ -Glu-Cys-Gly, ⁇ -Glu-Cys- ⁇ -Ala, ⁇ - Glu-Cys-Ser, ⁇ -Glu-Cys-Glu, other glutathione analog containing -SH and -NH 2 and/or -OH functional groups,
  • T 1 -[-R 1 -CH(COOH)-CH(Y-RSNO)-] ml -[-R 4 -] m2 -[-Ri- CH(COOH)-CH(COOH)-] n , 3 -T 2 is a reaction adduct of primary amine containing S-Nitrosothiols of claim 7 and a maleic anhydride polymer or copolymer.
  • said maleic anhydride polymer or copolymer is selected from the group consisting of poly(methyl vinyl ether-alt-maleic anhydride), poly(maleic acid-co-maleic anhydride), poly(maleic anhydride), poly(vinylpyrrolidone-co-dimethyl maleic anhydride), poly(vinylacetate-co-maleic anhydride), poly(ethylene-alt-maleic anhydride), poly(isobutylene-alt- maleic anhydride), poly(styrene-alt-maleic anhydride), poly(ethylene-co-ethyl acrylate-co-maleic anhydride), and poly(maleic anhydride-alt- 1-octadecene).
  • nitric oxide donor RSNO is selected from the group consisting of S-nitrosothiols of cysteine, ⁇ -Glu-Cys, ⁇ -Glu-Cys, glutathione, homoglutathione, hydroxymethyl-glutathione, ⁇ -Glu-Cys-Glu, ⁇ -Glu-Cys-Gly, ⁇ -Glu-Cys- ⁇ -Ala, ⁇ -Glu-Cys-Ser, ⁇ - Glu-Cys-Glu, other glutathione analog containing -SH and -NH 2 and/or -OH functional groups, or one of the following peptides: ( ⁇ -Glu-Cys) q , ( ⁇ -Glu-Cys) q -Gly, ( ⁇ -Glu-Cys) q - ⁇ -Ala, ( ⁇ -Glu-Cys) q -Ser, ( ⁇ -Glu-Cys) q -Glu, ( ⁇ -Glu-Cys) q
  • Typical molecular weight values are PVP (up to MW 1.3 x 10 6 ), polyethylene oxide (PEO; up to MW 7 x 10 6 ); and PVMMA (up to MW 2 x 10 6 ).
  • Y-RSNO is an N-acyl-S-nitrosoglutathione or N-acyl-S- nitrosophytochelatin.
  • Preferred formulations of use in the practice of the invention for both the conjugate and the complex compounds comprise gels, creams and the like based on gel excipients known in the art for medicinal and cosmetic formulations.
  • examples are Poloxamer 407 (polyethylene oxide- polypropylene oxide block copolymer) and Natrosol 250 HR (hydroxyethylcellulose) listed in the examples herein, and other applicable hydrophilic gelling excipients, such as, polyethylene glycol (PEG 400, 1500, 4000, 6000, and the like) and Carbomers (Carbopol 934P or 97 IP; lightly crosslinked polyacrylic acid).
  • the invention provides a use as hereinabove defined wherein said polymeric conjugate carrier is in a formulation in the form of a pharmaceutically-acceptable gel, cream or the like.
  • the invention provides, a method of enhancing the healing of a skin wound or infection comprising applying an effective amount of a nitric oxide polymeric conjugate carrier as hereinabove defined to said skin wound or infection to provide an applied wound.
  • the method may further comprise irradiating said applied wound with suitable light radiation for an effective period of time.
  • the invention provides, a medicinal skin covering for application to the skin of a mammal in wound healing need thereof, said covering incorporating an effective wound healing amount of a conjugate carrier.
  • Fig. 1 shows the stability of GSNO-PVMMA conjugate at different concentrations in PBS stored at ambient temperature (22 0 C) and in the dark;
  • Fig. 2 shows the solution decomposition kinetics of (a) GSNO and (b) GSNO-PVMMA conjugate in the presence of different concentrations of CuSO 4 in PBS (O. IM, pH 7.4) at ambient temperature (22 0 C) and in the dark;
  • Fig. 3 illustrates the degradation of GSNO in the presence of different concentrations of CuSO 4 in hydrolyzed PVMMA solution in PBS (O. IM, pH 7.4) at ambient temperature (22 °C) and in the dark;
  • Fig. 4 shows the solution decomposition kinetics of (a) GSNO (b) GSNO-PVMMA conjugate in
  • Fig. 5 shows the decomposition kinetics of low concentrations ( ⁇ M) of GSNO and GSNO-
  • PVMMA conjugate in PBS at ambient temperature (22 0 C) under exposure to ambient light condition normal day/night cycle in the laboratory with no special lighting control
  • Fig. 6 shows the decomposition of high concentrations (mM) of GSNO and GSNO-PVMMA conjugate in PBS at ambient temperature (22 0 C) under continuous irradiation from a cool white fluorescence lamp (4100K) at a light intensity of 480 lux..
  • Inset comparison of different decay rates between GSNO and GSNO-PVMMA conjugate at low concentrations ( ⁇ M);
  • Fig. 7 illustrates the improved stability of high concentrations (mM) of GSNO-PVMMA/PVP (1:6) complex in PBS at ambient temperature (22 0 C), as compared with that of GSNO-PVMMA conjugate solution alone, under continuous irradiation from a cool white fluorescence lamp (4100K) at a light intensity of 950 lux;
  • Fig. 8 presents a schematic illustration of the potential molecular association in the GSNO- PVMMA/PVP supramacromolecular complex in solution during the release of NO;
  • Fig. 9 shows programmable NO release patterns from GSNO-PVMMA/PVP complexes in aqueous solution (pH 5) at 22 0 C under controlled lighting conditions from a cool white fluorescence lamp (4100K) at a light intensity of either 480 lux or 950 lux, as compared with that of a control exposed under ambient light condition. Changes in the absorption intensities at 336 nm of GSNO- PVMMA/PVP solutions were monitored as a function of light exposure; and
  • Fig. 10 illustrates controlled NO release patterns from GSNO-PVMMA conjugates in aqueous solutions (pH 4) at 22 0 C and 37 0 C under continuous exposure lighting conditions from a daylight fluorescence lamp (6500K) at a light intensity of either 200 lux or 800 lux. Changes in the absorption intensities at 336 nm of GSNO-PVMMA solutions were monitored as a function of light intensity.
  • PVMMA and PVP used in the following examples are PVMMA AN-139, PVMMA AN-169, PVP K-25, PVP K-29/32 and PVP K-90.
  • GS ⁇ O reduced glutathione
  • GSH C 10 H 17 N 3 O 6 S Mw.307.33
  • GSH glutathione
  • 5 ml of 0.1 N HCl was added briefly a portion OfNaNO 2 (35 mg, 0.5 mmol).
  • This reaction gives GSNO in a high yield of more than 80%.
  • the final red solution (appx. 0.1 M) was protected from light with aluminum foil and stable in the dark, which allow it to be used directly after synthesis without purification.
  • another concentrated GSNO solution (appx. 0.2 M) was prepared in 2.5 ml of 0.1 N HCl.
  • the conjugation of GSNO to PVMMA can be achieved via the acetylation reaction between pendant maleic anhydride moieties in PVMMA and primary amine groups in GSNO.
  • This reaction can be performed homogeneously in a mixture of an aprotic solvent and aqueous medium under generally mild conditions.
  • RSNO should be prepared first before conjugation with PVMMA because the thiol group is more reactive than the amine group with respect to reacting with the anhydride group.
  • the mixture was dialyzed (membrane MW cut-off 12-14,000) against water in the dark for 1 day with frequently replacement of the external dialysate with fresh D.I. water to remove the residual HCl, unreacted GSNO, GSSG, nitrite and other extractables.
  • the dialysis process was deemed complete when the UV absorbance at 336 run of the external dialysate was reduced to below the detection limit.
  • the content of the dialysis tube was then transfered to an amber bottle and stored in the dark at room temperature.
  • a 10 wt% PVP solution was prepared by first dissolving a selected grade of PVP in distilled water.
  • the pH value of GSNO-PVMMA/PVP complex was prepared by first dissolving a selected grade of PVP in distilled water.
  • PVMMA solution of Example 2F was adjusted from 3 to 5. Subsequently, a measured amount of PVP solution was quickly poured into the aqueous GSNO-PVMMA solution of Example 2F under vigorous stirring in an ice bath. As the complex formation took place through intermolecular hydrogen bonding, the resultant mixture showed slight increase in viscosity but remained in the solution state. These procedures were repeated for PVP selected from:
  • Poloxamer 407 polyethylene oxide-polypropylene oxide block copolymer
  • Typical composition of a gel formulation based on a soluble GSNO-PVMMA/PVP (1:1 ratio) complex from Example 3C is shown below: INGREDIENT FUNC ⁇ ON CONCENTRATION (wrw%)
  • Natrosol 250 HR hydroxyethylcellulose; Hercules-Aqualon
  • GSNO-PVMMA/PVP (1: 1) solution from Example 3 C was first dissolved in a measured amount of purified water and mixed slowly with the GSNO-PVMMA/PVP (1: 1) solution from Example 3 C to reach the desired composition. This resulted in a clear red gel.
  • GSNO is well-known as a highly labile, small molecular species, wherein the inherent instability poses a number of challenges for the isolation and characterization of this compound in the pure solid state. So far, the X-ray crystallography data for GSNO is still not available due to this difficulty [18]. The majority of researchers concentrate their studies on the influence of substitutions at the ⁇ or ⁇ carbon atoms of the S-NO bond [19].
  • GSNO-PVMMA conjugate was evaluated by monitoring the UV absorbance decay at 336 nm for three concentrations (from low to high) of the conjugate solution in phosphate buffered saline (PBS) obtained from EXAMPLE 2E and stored in the dark at ambient temperature.
  • Fig. 1 shows favourable stability of GSNO-PVMMA conjugate in aqueous solutions at relatively high concentrations. In contrast to the less than desired stability of GSNO, S-NO bonds are greatly stabilized in the GSNO-PVMMA conjugate.
  • the conjugate unexpectedly shows a substantially enhanced stability over that of unconjugated GSNO in the presence of copper.
  • Degradation of the conjugate is almost negligible even at high concentrations OfCu 2+ . Without being bound by theory, this may be attributed to the chelating effect of the carboxylic acid polymer resulted from the hydrolysis of polyanhydride in buffer.
  • Fig. 3 shows a decreasing decay trend similar to that of GSNO alone (Fig. 2a) in physical blends of GSNO (obtained from EXAMPLE 1) with the hydrolyzed poly anhydride solution.
  • the addition of the resulting carboxylic polymer is seen to reduce significantly the degradation of GSNO in the presence of copper. This suggests that hydrolyzed polyanhydride may act as an efficient copper chelator.
  • the chelating effect is proportional to the concentration ratio of hydrolyzed PVMMA to Cu 2+ .
  • GSH reduced glutathione
  • GSNO obtained from EXAMPLE 1
  • GSH mM concentration, which is close to the physiological level
  • GSNO-PVMMA conjugate obtained from EXAMPLE 2E
  • free GSH mM concentration, which is close to the physiological level
  • Fig. 4 marked differences are observed between the decomposition rate of GSNO and GSNO-PVMMA conjugate as a function of the concentration of GSH in solution. Comparing with GSNO, the GSNO-PVMMA conjugate exhibits a significantly enhanced stability in the presence of GSH under otherwise identical experimental conditions.
  • GSNO-PVMMA conjugate and GSNO-PVMMA/PVP complex (1:6) at relatively high concentrations were compared in the same manner as in EXAMPLE 9.
  • GSNO- PVMMA conjugate (obtained from EXAMPLE 2E) and GSNO-PVMMA/PVP complex (obtained from EXAMPLE 3A) were incubated at ambient temperature (22 0 C) under continuous irradiation from a cool white fluroescence lamp (4100K) with a light intensity of 950 lux (at the sample surface) for up to 6 days. Samples were removed at predetermined time intervals, and their absorbance at 336 nm measured.
  • soluble GSNO-PVMMA/PVP complexes in the solution state exhibit sustained NO generation at high initial GSNO concentrations and are more stable to light induced decomposition as compared with the GSNO-PVMMA conjugate in solution alone.
  • FIG. 9 illustrates the modulation of NO release under controlled conditions where programmable NO release patterns were generated from an aqueous solution (pH 5) of GSNO- PVMMA/PVP (1:1) complex of EXAMPLE 3 A at ambient temperature (22 0 C) under a cool white fluorescence lamp (4100K) with a light intensity of either 480 lux or 950 lux (at the sample surface).
  • the NO release profile of a control sample under ambient light (normal day/night cycle in the laboratory with no special lighting control; combination of fluorescence lighting/reflected sunlight during the day cycle gave a light intensity ⁇ 480 lux at the sample surface) for up to 15 days is also included in Fig. 9 for comparison. Changes in the UV absorbance intensities at 336 run of GSNO- PVMMA/PVP solution samples were monitored as a function of time and light exposure.
  • Controlled NO release profiles from GSNO-PVMMA conjugate can also be obtained by varying the light intensity.
  • Fig. 10 shows adjustable NO release patterns from an aqueous solution (pH 4) of GSNO-PVMMA conjugate of EXAMPLE 2H maintained at 22 0 C and 37 0 C in an incubator under continuous exposure to a daylight fluorescence lamp (6500K) at a light intensity of either 200 lux or 800 lux (at the sample surface). Changes in the UV absorbance intensities at 336 nm of GSNO- PVMMA solutions were monitored as a function of time, temperature, and light intensity.
  • this supramacromolecular complex system provides a controllable means of delivering NO to a specific in vivo site via photoactivation by UV- Vis irradiation. Depending on the experimental conditions, photomodulation of NO release can be easily achieved from this solution.

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Abstract

La présente invention concerne un procédé de fabrication d’une solution aqueuse d’un complexe polymère bio-adhésif et supramoléculaire pouvant libérer de l’oxyde nitrique et présentant la formule suivante (I) : dans laquelle R1 est indépendamment choisi dans le groupe constitué par un alcane non substitué ou substitué par des groupes alcoxy ; R2 est indépendamment choisi dans le groupe constitué par un groupe alkyle en C1-6 ; R3 et R4 sont indépendamment choisis dans le groupe constitué par un groupe alkyle aliphatique ou aromatique facultativement substitué ; W est une entité contenant un groupe fractionné accepteur de liaison hydrogène ; Y est une liaison ester ou amide d’acide carboxylique ; R est un groupe de liaison peptidique indépendamment choisi ; T1, T2, T3 et T4 sont des résidus polymères indépendamment choisis ; et m1, m2, m3, n1, et n2 sont des nombres entiers supérieurs à 25 ; et dans laquelle P a un poids moléculaire allant d’environ 1 x 103 à 1 x 107 et Q a un poids moléculaire allant d’environ 1 x 103 à 1 x 107 ; le procédé consistant à (a) lier de façon covalente un composé S-nitrosothiol ayant un groupe de liaison amino avec un composé polyanhydride hydrophobe bio-adhésif, pour former un véhicule conjugué polymère donneur d’oxyde nitrique ; consistant à (i) traiter le composé polyanhydride dissous dans un solvant aprotique avec une solution aqueuse dudit composé S-nitrosothiol pendant une période de temps efficace et à l’abri de la lumière ; (ii) éliminer le solvant aprotique pour produire une solution sensiblement aqueuse du véhicule conjugué ; et (b) mélanger la solution du véhicule conjugué avec un polymère à structure intermoléculaire pouvant accepter une liaison hydrogène pour produire une solution aqueuse du complexe. Les solutions sont destinées à être utilisées dans le traitement de plaies en voie de cicatrisation. L’invention concerne également le véhicule conjugué polymère destiné à être utilisé dans le traitement de plaies en voie de cicatrisation par le biais de la libération d’oxyde nitrique. L’invention est également utile lorsqu’elle est utilisée en photo-irradiation de systèmes contenant le véhicule conjugué et le complexe pour améliorer la cicatrisation des plaies cutanées.
PCT/CA2010/000270 2009-07-09 2010-02-26 Administration contrôlée d’oxyde nitrique à partir de polymères conjugués aqueux de s-nitrosothiol et de leurs complexes WO2011003172A1 (fr)

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WO2018067838A1 (fr) * 2016-10-07 2018-04-12 The University Of North Carolina At Chapel Hill Polyesters hyperramifiés médiés par un s-nitrosothiol
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014066684A1 (fr) * 2012-10-24 2014-05-01 Kci Licensing, Inc. Compositions de polymère à fonctionnalité sulfhydryle pour dispositifs médicaux
EP3611205A1 (fr) * 2012-10-24 2020-02-19 KCI Licensing, Inc. Compositions polymères fonctionnalisées de sulfhydryle pour dispositifs médicaux
CN106574005A (zh) * 2014-08-14 2017-04-19 罗门哈斯公司 具有可释放气体的聚合物
WO2018067838A1 (fr) * 2016-10-07 2018-04-12 The University Of North Carolina At Chapel Hill Polyesters hyperramifiés médiés par un s-nitrosothiol
US11186681B2 (en) 2016-10-07 2021-11-30 The University Of North Carolina At Chapel Hill S-Nitrosothiol-mediated hyperbranched polyesters
US11072668B2 (en) 2017-01-03 2021-07-27 The University Of North Carolina At Chapel Hill Nitric oxide-releasing alginates as biodegradable antibacterial scaffolds and methods pertaining thereto
US11697693B2 (en) 2017-01-03 2023-07-11 The University Of North Carolina At Chapel Hill Nitric oxide-releasing alginates as biodegradable antibacterial scaffolds and methods pertaining thereto
US11723914B2 (en) 2017-03-28 2023-08-15 The University Of North Carolina At Chapel Hill Nitric oxide-releasing polyaminoglycosides as biodegradable antibacterial scaffolds and methods pertaining thereto
US11026965B2 (en) 2018-03-06 2021-06-08 The University Of North Carolina At Chapel Hill Nitric oxide-releasing cyclodextrins as biodegradable antibacterial scaffolds and methods pertaining thereto
US11672818B2 (en) 2018-03-06 2023-06-13 The University Of North Carolina At Chapel Hill Nitric oxide-releasing cyclodextrins as biodegradable antibacterial scaffolds and methods pertaining thereto
US11421044B2 (en) 2018-12-28 2022-08-23 The University Of North Carolina At Chapel Hill Nitric oxide-releasing antibacterial polymers and scaffolds fabricated therefrom and methods pertaining thereto

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