WO2004011043A1 - Pansement antimicrobien et antiproteolytique - Google Patents

Pansement antimicrobien et antiproteolytique Download PDF

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Publication number
WO2004011043A1
WO2004011043A1 PCT/US2003/023997 US0323997W WO2004011043A1 WO 2004011043 A1 WO2004011043 A1 WO 2004011043A1 US 0323997 W US0323997 W US 0323997W WO 2004011043 A1 WO2004011043 A1 WO 2004011043A1
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WO
WIPO (PCT)
Prior art keywords
composition according
substrate
immobilized
mmpi
compounds
Prior art date
Application number
PCT/US2003/023997
Other languages
English (en)
Inventor
Gregory Schultz
Original Assignee
University Of Florida
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Florida filed Critical University Of Florida
Priority to AU2003257089A priority Critical patent/AU2003257089A1/en
Publication of WO2004011043A1 publication Critical patent/WO2004011043A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/208—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • This invention pertains to the field of wound care and in particular to wound care scenarios where it is critical to maintain an aseptic environment while at the same time reducing the amount of proteolytic degradation that occurs in and around a wound.
  • the substrate is a cellulosic substrate and the atnimicrobially effective compound is a quaternary amine, or a polymer of quaternary amines.
  • matrix metalloproteinases which includes a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. These include human skin fibroblast collagenase, human skin flbroblast gelatinase, human sputum collagenase and gelatinase, and human stromelysin. These are zinc- containing metalloprotease enzymes, as are the angiotensin-converting enzymes and the enkephalinases.
  • Collagenase and related enzymes are important in mediating the symptomology of a number of diseases, including rheumatoid arthritis (Mullins, D. E., et al., Biochim Biophys Acta (1983) 695:117-214); the metastasis of tumor cells (ibid , Broadhurst, M. J., et al., EP application 276436 (1987), Reich, R., et al., Cancer Res (1988) 48:3307- 3312); and various ulcerated conditions.
  • Ulcerative conditions can result in damage to the cornea as the result of alkali burns or as a result of infection by Pseudomonas aeraginosa, Acanthamoeba, Herpes simplex and vaccinia viruses.
  • Other conditions that may be exacerbated by unwanted matrix metalloprotease activity include: periodontal disease, epidermolysis bullosa, scleritis, ulcerative conditions including but not limited to chronic wounds, leg ulcers (whether venous or arterial in origin), pressure sores, diabetes related sores and ulcers, burn injuries, and similar conditions.
  • inhibitors In view of the involvement of collagenase and related matrix metallo-proteinases (MMPs) in a number of disease conditions, attempts have been made to prepare inhibitors to this enzyme. A number of such inhibitors are disclosed in EP applications 126,974 (published 1984) and 159,396 (published 1985) assigned to G. D. Searle. These inhibitors are secondary amines which contain oxo substituents at the 2-position in both substituents bonded to the amino nitrogen. See also U.S. Pat. Nos. 4,599,361 and 4,743,587, also assigned to G. D. Searle.
  • These compounds are hydroxylarnine dipeptide derivatives which contain, as a part of the compound, a tyrosine or derivatized tyrosine residue or certain analogs thereof.
  • Other compounds that contain sulfhydryl moieties as well as residues of aromatic amino acids such as phenylalanine and tryptophan are disclosed in PCT application WO88/06890. Some of these compounds also contain i-butyl side chains.
  • MMP inhibitors have also been disclosed for the related protease, thermolysin.
  • PROMOGRAN oxidized regenerated cellulose
  • ORC oxidized regenerated cellulose
  • J&J's online literature describes this product as follows: "PROMOGRANTM Matrix is a unique advanced wound care device comprised of a sterile, freeze-dried matrix composite of 45 percent ORC and 55 percent collagen.
  • ORC is a plant material that has been chemically altered to be absorbed by the body.
  • Collagen is a natural structural protein found in all three phases of wound healing.
  • MMPs matrix metallo-proteases
  • ORC/Collagen By binding to matrix metallo-proteases (MMPs), and growth factors, ORC/Collagen creates a moist wound healing environment, which is conducive to new tissue growth....
  • MMPs matrix metallo-proteases
  • Recent scientific research has shown elevated levels of MMPs in chronic wound exudate, the fluid that bathes the wound bed. These excess MMPs cause degradation of important extracellular matrix proteins and inactivation of vital growth factors, elements that are essential in the wound healing process. This may contribute to a sub-optimal healing environment resulting in delayed wound healing (Ability of chronic wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity and diminished levels of proteinase inhibitors; D. Yager, S. Chen, S.
  • This invention comprises a novel wound dressing and a method for making and using the wound dressing comprising an immobilized matrix metalloproteinase inhibitor (MMPI) with or without immobilized microbicidal or other biologically active compounds grafted onto the wound dressing.
  • MMPI matrix metalloproteinase inhibitor
  • the microbicidal function may comprise quaternary amines or polymers of quaternary amines grafted onto a cellulosic substrate.
  • the composition of the present invention comprises a matrix metalloproteinase inhibitor (MMPI) immobilized on a substrate which is used as a wound covering, particularly for a chronic wound such as a leg ulcer or the like.
  • the substrate in one embodiment of this invention is a superabsorbent substrate as is known in the art, which is capable of absorbing many times its own weight in wound exudate.
  • the immobilized MMPIs bound to the substrate preferably has nanomolar, micromolar or millimolar affinity for various matrix metalloproteinases present in wound exudate. As wound exudate is absorbed onto the substrate, the matrix metalloproteases are bound and inhibited by the immobilized MMPFs.
  • the composition of the present invention comprises an MMPI immobilized on a substrate useable as a bandage for a wound, wherein, in addition to the immobilized MMPI, there is immobilized additional biologically active molecules, selected from the group including but not limited to: antimicrobial compounds, serine protease inhibitory compounds, hemostatic agents, anti- hemostatic agents (such as heparin), analgesic compounds, and antineoplastic compounds.
  • additional biologically active molecules selected from the group including but not limited to: antimicrobial compounds, serine protease inhibitory compounds, hemostatic agents, anti- hemostatic agents (such as heparin), analgesic compounds, and antineoplastic compounds.
  • the composition of the present invention comprises an MMPI bound to a polymer which is grafted onto a substrate which is used as a wound dressing.
  • the composition of this invention comprises an MMPI bound to a polymer comprising additional biologically active molecules, including but not limited to: antimicrobial compounds, serine protease inhibitory compounds, hemostatic agents, anti-hemostatic agents (such as heparin), analgesic compounds, and antineoplastic compounds.
  • additional biologically active molecules including but not limited to: antimicrobial compounds, serine protease inhibitory compounds, hemostatic agents, anti-hemostatic agents (such as heparin), analgesic compounds, and antineoplastic compounds.
  • soluble factors such as MMPFs, collagen, antibiotics, analgesics, serine protease inhibitors, hemostatic agents, anti-hemostatic agents, antineoplastic agents, or the like.
  • composition of this invention may be prepared, in one embodiment, by grafting quaternary amines to a cellulosic substrate utilizing cerium ion as a free-radical polymerization catalyst, and utilizing monomeric quaternary amines such as those known in the art, selected from, but not limited to: diallyldimethylammonium chloride (DADMAC), vinylbenzyltriethyl ammonium chloride (VBC), N,N,N-trimethyl-N- (meth)acryloyloxyethylammonium chloride (TMMC), also known as the methyl chloride quaternary salt of dimethylaminoethyl methacrylate, and the like.
  • DADMAC diallyldimethylammonium chloride
  • VBC vinylbenzyltriethyl ammonium chloride
  • TMMC N,N,N-trimethyl-N- (meth)acryloyloxyethylammonium chloride
  • TMMC methyl chlor
  • MMPFs may be immobilized, or co-polymerized.
  • Both of these groups can easily be used to couple the MMPI to either a cellulosic backbone or to pendant acrylate chains which are grafted onto the surface.
  • Standard coupling chemistry is used, such as the reaction of an ester with an amine.
  • the AM form is reacted with the substrate directly to form an amide bond from reaction with the acrylate ester group.
  • the substrate is esterified, and then reacted with the AM-form.
  • a more active substrate is formed by reacting the cellulose with cyanogen bromide, a diisocyanate or a bis-epoxide, and that reacted with the AM-form.
  • the bis-epoxide modified cellulose is also susceptible to reaction with the CA-form.
  • Ilomastat is attached to an acrylate monomer, and simply polymerized in a grafting reaction.
  • the AM-form is reacted with acrylochloride, and the resulting monomer used for free radical induced grafting. Spacers are added as needed, such as polyethylene glycol units.
  • the cellulosic component of PROMOGRAN is utilized as a substrate, onto which is immobilized Ilomastat.
  • both Ilomastat and TMMC are grafted onto the cellulosic component.
  • Ilomastat is co-polymerized onto the cellulosic substrate with quaternary amines. In this fashion, a wound dressing is produced which is not only beneficial because of its matrix metalloproteinase inhibitory activity, but the dressing also exhibits anti-microbial efficacy.
  • MMPFs used may be used as the MMPI, or a derivative or analog thereof may be utilized.
  • Other MMPFs known in the art may have desirable properties and may be used in addition to Ilomastat or in place of Ilomastat.
  • combinations of different MMPFs, different antimicrobial compounds and the like may be utilized.

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  • Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Cette invention concerne un nouveau pansement antimicrobien et antiprotéolytique, et un procédé de fabrication et d'utilisation du pansement, qui comprend un inhibiteur de métalloprotéinase matricielle immobilisé (MMPI) avec ou sans composés microbicides ou autres biologiquement actifs immobilisés greffés sur le pansement. Dans un mode de réalisation, la fonction microbicide peut comprendre des amines quaternaires ou des polymères d'amines quaternaires greffés sur un substrat cellulosique.
PCT/US2003/023997 2002-07-31 2003-07-31 Pansement antimicrobien et antiproteolytique WO2004011043A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003257089A AU2003257089A1 (en) 2002-07-31 2003-07-31 Antimicrobial and antiproteolytic wound dressing

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US39977502P 2002-07-31 2002-07-31
US60/399,775 2002-07-31

Publications (1)

Publication Number Publication Date
WO2004011043A1 true WO2004011043A1 (fr) 2004-02-05

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Application Number Title Priority Date Filing Date
PCT/US2003/023997 WO2004011043A1 (fr) 2002-07-31 2003-07-31 Pansement antimicrobien et antiproteolytique

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AU (1) AU2003257089A1 (fr)
WO (1) WO2004011043A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007137733A2 (fr) * 2006-05-26 2007-12-06 Paul Hartmann Ag Pansement comprenant du polyacrylates et son utilisation
WO2008148174A1 (fr) * 2007-06-08 2008-12-11 Queensland University Of Technology Composition de réparation de blessure et procédé

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5189178A (en) * 1990-11-21 1993-02-23 Galardy Richard E Matrix metalloprotease inhibitors
EP0712635A1 (fr) * 1994-05-13 1996-05-22 Kuraray Co., Ltd. Gel polymere a usage medical
GB2314842A (en) * 1996-06-28 1998-01-14 Johnson & Johnson Medical Protein/oxidised regenerated cellulose complexes
WO2000056283A1 (fr) * 1999-03-24 2000-09-28 The B.F.Goodrich Company Inhibition des metalloproteinases matrices par des polymeres et applications pharmaceutiques correspondantes
WO2002055121A1 (fr) * 2001-01-11 2002-07-18 Biocompatibles Uk Limited Apport de medicament en provenance de stent
WO2003016520A1 (fr) * 2001-08-16 2003-02-27 Kimberly-Clark Worldwide, Inc. Composes anti-age et de cicatrisation de plaies

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5189178A (en) * 1990-11-21 1993-02-23 Galardy Richard E Matrix metalloprotease inhibitors
EP0712635A1 (fr) * 1994-05-13 1996-05-22 Kuraray Co., Ltd. Gel polymere a usage medical
GB2314842A (en) * 1996-06-28 1998-01-14 Johnson & Johnson Medical Protein/oxidised regenerated cellulose complexes
WO2000056283A1 (fr) * 1999-03-24 2000-09-28 The B.F.Goodrich Company Inhibition des metalloproteinases matrices par des polymeres et applications pharmaceutiques correspondantes
WO2002055121A1 (fr) * 2001-01-11 2002-07-18 Biocompatibles Uk Limited Apport de medicament en provenance de stent
WO2003016520A1 (fr) * 2001-08-16 2003-02-27 Kimberly-Clark Worldwide, Inc. Composes anti-age et de cicatrisation de plaies

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007137733A2 (fr) * 2006-05-26 2007-12-06 Paul Hartmann Ag Pansement comprenant du polyacrylates et son utilisation
WO2007137733A3 (fr) * 2006-05-26 2008-11-06 Hartmann Paul Ag Pansement comprenant du polyacrylates et son utilisation
WO2008148174A1 (fr) * 2007-06-08 2008-12-11 Queensland University Of Technology Composition de réparation de blessure et procédé
JP2010529047A (ja) * 2007-06-08 2010-08-26 クィーンズランド ユニバーシティ オブ テクノロジー 創傷修復組成物および方法
AU2008258285B2 (en) * 2007-06-08 2013-03-21 Queensland University Of Technology Wound repair composition and method
US8747830B2 (en) 2007-06-08 2014-06-10 Queensland University Of Technology Wound repair composition and method
CN101754775B (zh) * 2007-06-08 2015-07-01 昆士兰技术大学 创伤修复组合物及方法

Also Published As

Publication number Publication date
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