Absorbent substrate with a non-leaching antimicrobial activity and a controlled-release bioactive agent.

• US 20080206293A1
• Filed: 02/22/2008
• Published: 08/28/2008
• Est. Priority Date: 02/25/2004
• Status: Abandoned Application

• Current Assignee: Quick-Med Technologies Inc, University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: Quick-Med Technologies Inc, University of Florida Research Foundation, Incorporated (State University System of Florida)
• Inventors: Moore, David, Olderman, Gerald, Staab, Gregory, Toreki, William, Schultz, Gregory, Liesenfeld, Bernd
• Application Number:
  US12/036,107
• Publication Number:
  US 20080206293A1
• Time in Patent Office: Days
• US Class Current: 424/404
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 15/46 Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
• CPC Class Codes: A61P 31/04 Antibacterial agents

Abstract

This invention relates to antimicrobial wound dressings having a non-leaching antimicrobial activity, releasable antimicrobial and antiprotease agents, and a controlled-release bioactive agent such as doxycycline. The Wound dressing material is absorbent and acts as a substrate for antimicrobial and antiprotease agents as well as bioactive agents. More generally, this invention relates to methods and compositions for materials having a non-leaching coating that has antimicrobial properties. The coating is applied to substrates such as gauze-type wound dressings, powders and other substrates. Covalent, non-leaching, non-hydrolyzable bonds are formed between the substrate and the polymer molecules that form the coating. A high concentration of anti-microbial groups on multi-length polymeric molecules and relatively long average chain lengths, contribute to an absorbent or superabsorbent surface with a high level antimicrobial efficacy. Utilization of non-leaching coatings having a plurality of anionic or cationic sites is used according to this invention to bind a plurality of oppositely charged biologically or chemically active compounds, and to release the bound oppositely charged biologically or chemically active compounds from said substrate over a period of time to achieve desired objectives as diverse as improved wound healing to reduction in body odor.

Claims

1. A device for the treatment of wounds comprising:

a) an absorbent wound dressing material having incorporated therein inherent non-leachable antimicrobial activity and inherent non-leachable anti-protease activity; and

b) a releasable antimicrobial agent and a releasable anti-protease agent that are ionically stabilized within the device so as to be released from the device in a controlled manner.

2. The device of claim 1, further comprising one or more releasable bioactive agents which aid in wound healing, selected from the group consisting of growth factors, vitamins, antioxidants, anti-inflammatories, antimicrobials, anti-proteases, steroids and nutrients.

3. The device of claim 1, wherein the releasable antimicrobial agent and the releasable anti-protease agent are one and the same substance.

4. The device of claim 3, wherein the releasable antimicrobial agent and the releasable anti-protease agent are doxycycline.

5. The device of claim 1, wherein one or both of the inherent non-leachable antimicrobial activity and the inherent non-leachable antiprotease activity is provided by polymeric quaternary ammonium molecules.

6. The device of claim 5, wherein said polymeric quaternary ammonium molecules comprise poly(dimethyldiallylammonium chloride) also known as polyDADMAC;

quaternary ammonium derivatives of poly(acrylic) acid or of poly(methacrylic) acid;

poly(vinylbenzyl)trimethylammonium chloride;

or a polyquaternium.

7. The device of claim 5, wherein the polymeric quaternary ammonium molecules are non-leachably bonded to the wound dressing material via covalent chemical bonds.

8. The device of claim 5, wherein the polymeric quaternary ammonium molecules are non-leachably bonded to the wound dressing material via ionic bonds.

9. The device of claim 5, wherein said polymeric quaternary ammonium molecules have a crosslinked network structure that forms a hydrogel in water.

10. The device of claim 5, wherein said polymeric quaternary ammonium molecules have a crosslinked network structure formed via chemical crosslinking of said polymeric quaternary ammonium molecules.

11. The device of claim 9, wherein said polymeric quaternary ammonium molecules have crosslinked network structure which comprises a polyelectrolyte complex formed between said polymeric quaternary ammonium molecules and polymeric anionic molecules.

12. The device of claim 11, wherein said polymeric anionic molecules comprise one or more of carboxymethyl cellulose, also known as CMC, alginate, or polyacrylate.

13. The device of claim 1, wherein said wound device comprises one or more of cellulose, a cellulose-based material, a polysaccharide, a textile fabric, gauze, fibers, a synthetic polymer, a superabsorbent material, or a protein.

14. The device of claim 13, wherein the cellulose-based material is one or more of cotton, rayon, CMC, hydroxyethyl cellulose, paper, or woodpulp, and wherein the polysaccharide is one or more of dextran, chitosan, alginate, or starch, and wherein the protein is collagen.

15. The device of claim 1, wherein said inherent non-leachable anti-protease activity is provided by a polymer with a multiplicity of anionic sites.

16. The device of claim 15, where said polymer with a multiplicity of anionic sites is one or more of CMC, alginate, collagen or polyacrylate.

17. The device of claim 1, wherein said releasable antimicrobial agent comprises an antibiotic or polymeric quaternary ammonium molecule.

18. The device of claim 17, wherein said releasable antimicrobial agent is one or more of tetracycline, doxycycline and poly(DADMAC).

19. The device of claim 1, wherein said releasable antiprotease agent is one or more of ilomastat, doxycycline, minocycline, collagen, CMC or poly(DADMAC).

20. The device of claim 1, wherein said inherent non-leachable antimicrobial agent and said inherent non-leachable anti-protease agent is one and the same.

21. The device of claim 1, wherein said releasable bioactive agent is one or more growth factors, vitamins, nutritive factors, and anti-inflammatories.

22. The device of claim 21, wherein the growth factor is epidermal growth factor (EGF), platelet derived growth factor (PDGF), or vascular endothelial growth factor (VEGF).

23. An absorbent antimicrobial material comprising a substantially carboxymethylated cellulosic substrate and poly(DADMAC) non-leachably attached to said substrate, wherein a sufficient amount of said poly(DADMAC) is attached to said substrate to form a polyelectrolyte network, and wherein said polyelectrolyte network permits the degree of swelling of said material to range from about 10 times up to about 20 times of the dry material, and wherein said polyelectrolyte network diminishes the dissolution of the substantially carboxymethylated cellulosic substrate upon exposure to aqueous fluids, and wherein said polyelectrolyte network permits the incorporation and release of a bioactive agent in a controlled manner.

24. A method for the preparation of a non-leaching antimicrobial-coated device, comprising the steps of:

a. immersing all or a portion of a substrate into a solution comprising a sufficient quantity of monomer bearing at least one antimicrobial group per monomer molecule, and a sufficient quantity of catalyst to sustain polymerization reactions to sufficiently coat said substrate to impart an antimicrobial characteristic;

b. maintaining the contact of said substrate with said solution under acceptable conditions for a sufficient period of time to complete said reaction, wherein said reactions comprise forming polymers of varying lengths, and forming covalent, non-siloxane bonds between the majority of said polymers of varying lengths and binding sites on said substrate;

c. rinsing said substrate sufficiently to remove non-polymerized monomer molecules, non-stabilized polymeric molecules, and catalyst;

d. drying said substrate to a desired low moisture content, such that the substrate is not a hydrogel; and

e. contacting the thus prepared substrate with sufficient anionic or cationic biologically or chemically active compound to achieve ionic association between said compound and said substrate.

25. The method of claim 24, additionally comprising the step of maintaining the solution and gases in contact with the solution free of oxygen by sparging with an inert gas.

26. The method of claim 24, wherein said rinsing is with an aqueous solution, and additionally comprising the step of dewatering the substrate after the rinsing step.

27. The method of claim 24, wherein the catalysts is selected from the group consisting of a cerium salt, a peroxide, a persulfate, and, an Azo catalyst, and a photolabile or thermolabile catalyst.

77. The method according to claim 24 wherein said sufficient anionic or cationic biologically or chemically active compound to achieve ionic association between said compound and said substrate are selected from the group consisting of:

antibiotics, analgesics, anti-inflammatories, strong oxidizing agents, matrix metalloproteinase inhibitors, proteins, peptides, fragrances, and antifungal.

28. A material comprising a substrate and an enhanced surface area, said enhanced surface area comprising a multitude of non-hydrolyzable, non-leachable polymeric molecules covalently bonded by non-siloxane bonds to said substrate;

wherein said non-hydrolyzable, non-leachable polymeric molecules comprise a multitude of antimicrobial groups attached to said non-hydrolyzable, non-leachable polymeric molecules by covalent bonds; and

wherein a sufficient number of said non-hydrolyzable, non-leachable polymeric molecules are covalently bonded to sites of said substrate to render the material antimicrobial, or receptive to avid binding of negatively charged dye molecules, when exposed to aqueous fluids, menses, bodily fluids, skin, cosmetic compositions, or wound exudates, wherein said material has associated therewith a plurality of anionically charged biologically or chemically active compounds.

29. The material of claim 28, wherein said antimicrobial groups comprise at least one quaternary ammonium structure.

30. The material of claim 28, wherein said antimicrobial groups comprise at least one non-ionic structure.

31. The material of claim 30, wherein said at least one non-ionic structure comprises a biguanide.

32. The material of claim 28, wherein said non-hydrolyzable, non-leaching polymeric molecules have an average degree of polymerization selected from about 5 to 1000, 10 to 500, and 10 to 100.

33. The material of claim 28, wherein said material comprises all or part of a wound dressing, sanitary pad, a tampon, an intrinsically antimicrobial absorbent dressing, a diaper, toilet paper, a sponge, a sanitary wipe, isolation and surgical gowns, gloves, surgical scrubs, sutures, sterile packaging, floor mats, lamp handle covers, burn dressings, gauze rolls, blood transfer tubing or storage container, mattress cover, bedding, sheet, towel, underwear, socks, cotton swabs, applicators, exam table covers, head covers, cast liners, splint, paddings, lab coats, air filters for autos, planes or HVAC systems, military protective garments, face masks, devices for protection against biohazards and biological warfare agents, lumber, meat or fish packaging material, apparel for food handling, paper currency, powder, and other surfaces required to exhibit a non-leaching antimicrobial property and to release over time portions of said biologically or chemically active compound.

34. The material of claim 28, wherein said substrate is comprised, in whole or in part, of cellulose, or other naturally-derived polymers.

35. The material of claim 28, wherein said substrate is comprised, in whole or in part, of synthetic polymers including, but not limited to:

polyethylene, polypropylene, nylon, polyester, polyurethane, or silicone.

36. The material of claim 28, wherein said attachment of said non-hydrolyzable, non-leachable polymer to said substrate is via a carbon-oxygen-carbon bond, also known as an ether linkage, a carbon-carbon bond, and mixtures thereof.

37. The material of claim 36, wherein a cerium-containing catalyst, a peroxide containing catalyst, an Azo catalyst, a redox initiator, a thermolabile or photolabile catalyst catalyzes formation of said ether linkage or said carbon-carbon bond.

38. The material of claim 28, wherein said non-hydrolyzable, non-leachable polymeric molecules are formed by polymerization of allyl- or vinyl-containing monomers.

39. The material of claim 38, wherein said allyl- or vinyl-monomers are selected from the group consisting of:

styrene derivatives, allyl amines, and ammonium salts.

40. The material of claim 38, wherein said allyl- or vinyl-monomers are selected from the group consisting of:

acrylates, methacrylates, acrylamides, and methacrylamides.

41. The material of claim 40, wherein said allyl- or vinyl-containing monomers are selected from the group consisting of:

compounds of the structure CH₂═

CR—

(C═

O)—

X—

(CH2)_n—

N⁺R′

R″

R′

″

//Y⁻

;

wherein, R is hydrogen or methyl, n equals 2 or 3, X is either O, S, or NH, R′

, R″

, and R′

″

are independently selected from the group consisting of H, C1 to C16 alkyl, aryl, arylamine, alkaryl, and aralkyl, and Y−

is an acceptable anionic counterion to the positive charge of the quaternary nitrogen;

diallyldimethylammonium salts;

vinyl pyridine and salts thereof; and

vinylbenzyltrimethylammonium salts.

42. The material of claim 41, where said allyl- or vinyl-containing monomers are selected from the group consisting of:

dimethylaminoethyl methacrylate;

methyl chloride quaternary; and

dimethylaminoethyl methacrylate;

benzyl chloride quaternary.

43. The material of claim 33, wherein said powder is mica.

78. The composition according to claim 28, wherein said plurality of anionically charged biologically or chemically active compounds are selected from the group consisting of:

antibiotics, analgesics, anti-inflammatories, strong oxidizing agents, matrix metalloproteinase inhibitors, proteins, peptides, fragrances, and antifungals.

44. A superabsorbent material for absorbing biological fluids, comprising a substrate and an enhanced surface area, said enhanced surface area comprising a multitude of non-hydrolyzable, non-leachable polymeric molecules covalently bonded by non-siloxane bonds to said substrate;

wherein said non-hydrolyzable, non-leachable polymeric molecules comprise a multitude of antimicrobial groups attached to said non-hydrolyzable, non-leachable polymeric molecules by covalent bonds; and

wherein a sufficient number of said non-hydrolyzable, non-leachable polymeric molecules are covalently bonded to sites of said flexible substrate to render the material antimicrobial when exposed to aqueous fluids, menses, bodily fluids, or wound exudates;

wherein said superabsorbent material is capable of absorbing about 30 or more times its own weight of water or other fluids in a single instance; and

wherein said absorbing capacity is the result of branching or crosslinking of said non-hydrolyzable, non-leachable polymeric molecules, wherein said material has associated therewith a plurality of anionically charged biologically or chemically active compounds.

45. The material of claim 44, wherein said antimicrobial groups comprise at least one quaternary ammonium structure.

46. The material of claim 44, wherein said antimicrobial groups comprise at least one non-ionic structure.

47. The material of claim 46, wherein said at least one non-ionic structure comprises a biguanide.

48. The material of claim 44, wherein said material comprises all or part of a wound dressing, sanitary pad, a tampon, an intrinsically antimicrobial absorbent dressing, a diaper, toilet paper, a sponge, a sanitary wipe, food preparation surfaces, gowns, gloves, surgical scrubs, sutures, needles, sterile packings, floor mats, lamp handle covers, burn dressings, gauze rolls, blood transfer tubing or storage container, mattress cover, bedding, sheet, towel, underwear, socks, cotton swabs, applicators, exam table covers, head covers, cast liners, splint, paddings, lab coats, air filters for autos planes or HVAC systems, military protective garments, face masks, devices for protection against biohazards and biological warfare agents, lumber, meat packaging material, paper currency, powders, and other surfaces required to exhibit a non-leaching antimicrobial or enhanced dye binding properties, and to release over time portions of said biologically or chemically active compound.

49. The material of claim 44, wherein said substrate is comprised, in whole or in part, of cellulose, or other naturally-derived polymers.

50. The material of claim 44, wherein said substrate is comprised, in whole or in part, of synthetic polymers including, but not limited to:

polyethylene, polypropylene, nylon, polyester, polyurethane, or silicone.

51. The material of claim 44, wherein said attachment of said non-hydrolyzable, non-leachable polymer to said substrate is via a carbon-oxygen-carbon bond, also known as an ether linkage, a carbon-carbon bond, or mixtures thereof.

52. The material of claim 51, wherein a cerium-containing catalyst, a peroxide containing catalyst, an Azo catalyst, a thermolabile or photolabile catalyst catalyzes formation of said ether linkage or said carbon-carbon linkage, or mixtures thereof.

53. The material of claim 44, wherein said non-hydrolyzable, non-leachable polymeric molecules are formed by polymerization of allyl- or vinyl-containing monomers.

54. The material of claim 53, wherein said allyl- or vinyl-monomers are selected from the group consisting of:

styrene derivatives; and

allyl amines or ammonium salts.

55. The material of claim 53, wherein said allyl- or vinyl-monomers are selected from the group consisting of:

acrylates, methacrylates, acrylamides, and methacrylamides.

56. The material of claim 55, wherein said allyl- or vinyl-containing monomers are selected from the group consisting of:

compounds of the structure CH₂═

CR—

(C═

O)—

X—

(CH2)_n—

N⁺R′

R″

R′

″

/Y⁻

;

wherein, R is hydrogen or methyl, n equals 2 or 3, X is either O, S, or NH, R′

, R″

, and R′

″

are independently selected from the group consisting of H, C1 to C16 alkyl, aryl, arylamine, alkaryl, and aralkyl, and Y−

is an acceptable anionic counterion to the positive charge of the quaternary nitrogen;

diallyldimethylammonium salts;

vinyl pyridine and salts thereof; and

vinylbenzyltrimethylammonium salts.

57. The material of claim 56, where said allyl- or vinyl-containing monomers are selected from the group consisting of:

dimethylaminoethyl methacrylate;

methyl chloride quaternary; and

dimethylaminoethyl methacrylate;

benzyl chloride quaternary.

79. The composition according to claim 44, wherein said plurality of anionically charged biologically or chemically active compounds are selected from the group consisting of:

antibiotics, analgesics, anti-inflammatories, strong oxidizing agents, matrix metalloproteinase inhibitors, proteins, peptides, fragrances, and antifungals.

58. An inherently antimicrobial composition comprising:

a. a substrate;

b. a coating, layer, or enhanced surface area on said substrate, comprised of a plurality of polymeric molecules of variable lengths bearing antimicrobial groups, wherein said polymeric molecules are covalently, non-leachably bound to said substrate, and wherein said coating, layer, or enhanced surface area exhibits antimicrobial activity due to the presence of said antimicrobial groups; and

c. ionically associated biologically or chemically active compounds which are released from said substrate and coating layer over a period of time.

59. The composition of claim 58, wherein said antimicrobial groups comprise at least one quaternary ammonium structure.

60. The composition of claim 58, wherein said antimicrobial groups comprise at least one non-ionic structure.

61. The composition of claim 60, wherein said at least one non-ionic structure comprises a biguanide.

62. The composition of claim 58, wherein said material comprises all or part of a wound dressing, sanitary pad, a tampon, an intrinsically antimicrobial absorbent dressing, a diaper, toilet paper, a sponge, a sanitary wipe, food preparation surfaces, gowns, gloves, surgical scrubs, sutures, needles, sterile packings, floor mats, lamp handle covers, burn dressings, gauze rolls, blood transfer tubing or storage container, mattress cover, bedding, sheet, towel, underwear, socks, cotton swabs, applicators, exam table coves, head covers, cast liners, splint, paddings, lab coats, air filters for autos, planes or HVAC systems, military protective garments, face masks, devices for protection against biohazards and biological warfare agents, lumber, meat packaging material, paper currency, powders, and other surfaces required to exhibit a non-leaching antimicrobial or enhanced dye binding properties, and to release over time portions of said biologically or chemically active compound.

63. The composition of claim 58, wherein said substrate is comprised, in whole or in part, of cellulose, or other naturally-derived polymers.

64. The composition of claim 58, wherein said substrate is comprised, in whole or in part, of synthetic polymers including, but not limited to:

polyethylene, polypropylene, nylon, polyester, polyurethane, or silicone.

65. The composition of claim 58, wherein said attachment of said non-hydrolyzable, non-leachable polymeric molecule to said substrate is via a carbon-oxygen-carbon bond, also known as an ether linkage, via a carbon-carbon bond, or mixtures thereof.

66. The composition of claim 65, wherein a cerium-containing catalyst, a peroxide containing catalyst, an Azo catalyst, a thermolabile or photolabile catalyst catalyzes formation of said ether linkage or said carbon-carbon linkage, or mixtures thereof.

67. The composition of claim 58, wherein said non-hydrolyzable, non-leachable polymeric molecules are formed by polymerization of allyl- or vinyl-containing monomers.

68. The composition of claim 67, wherein said allyl- or vinyl-monomers are selected from a group consisting of:

styrene derivatives;

allyl amines and ammonium salts.

69. The composition of claim 67, wherein said allyl- or vinyl-monomers are selected from the group consisting of:

acrylates, methacrylates, acrylamides, and methacrylamides.

70. The composition of claim 69, wherein said allyl- or vinyl-containing monomers are selected from the group consisting of:

compounds of the structure CH₂═

CR—

(C═

O)—

X—

(CH2)_n—

N⁺R′

R″

R′

″

//Y⁻

;

wherein, R is hydrogen or methyl, n equals 2 or 3, X is either O, S, or NH, R′

, R″

, and R′

″

are independently selected from the group consisting of H, C1 to C16 alkyl, aryl, arylamine, alkaryl, and aralkyl, and Y−

is an acceptable anionic counterion to the positive charge of the quaternary nitrogen;

diallyldimethylammonium salts;

vinyl pyridine and salts thereof; and

vinylbenzyltrimethylammonium salts.

71. The composition of claim 70, where said allyl- or vinyl-containing monomers are selected from the group consisting of:

dimethylaminoethyl methacrylate;

methyl chloride quaternary; and

dimethylaminoethyl methacrylate;

benzyl chloride quaternary.

72. The antimicrobial composition of claim 71, wherein said substrate is selected from the group consisting of:

woven or nonwoven flexible matrices, wherein said composition is formed into the shape of a wound dressing and a powder.

73. The antimicrobial composition of claim 71, wherein said coating absorbs aqueous liquids.

74. The antimicrobial composition of claim 71, wherein said substrate is wood, lumber, or an extract or a derivative of wood fiber.

80. The composition according to claim 58, wherein said ionically associated biologically or chemically active compounds which are released from said substrate and coating layer over a period of time are selected from the group consisting of:

antibiotics, analgesics, anti-inflammatories, strong oxidizing agents, matrix metalloproteinase inhibitors, proteins, peptides, fragrances, and antifungals.

75. An antimicrobial-coated composition for destruction of microbes contacting said composition, comprising:

a. a substrate onto which a coating of antimicrobial polymers is bonded;

b. said coating, formed of an effective amount of polymeric molecules having a multiplicity of quaternary ammonium groups, wherein said polymeric molecules are non-leachably and covalently bonded to surface sites of said substrate, wherein said polymers do not form using siloxane bonds, and wherein said coating is absorbent of aqueous liquids, and

c. associated anionic biologically active or chemically active compound;

whereby said multiplicity of quaternary ammonium groups act to destroy microbes coming in contact with said groups as well as to bind and release said anionic biologically active or chemically active compound.

81. The composition according to claim 75 wherein said associated anionic biologically active or chemically active compound is selected from the group consisting of antibiotics, analgesics, anti-inflammatories, strong oxidizing agents, matrix metalloproteinase inhibitors, proteins, peptides, fragrances, and antifungals.

76. A composition comprising mica which has been subjected to coating, grafting, binding or adhesion of a quaternary amine polymer, followed by association of anionic biologically or chemically active compounds with said quaternary amine polymer.

82. The composition according to claim 76 wherein said anionic biologically or chemically active compounds associated with said quaternary amine polymer is selected from the group consisting of antibiotics, analgesics, anti-inflammatories, strong oxidizing agents, matrix metalloproteinase inhibitors, proteins, peptides, fragrances, and antifungals.