DRESSING COMPOSITIONS AND METHODS

• US 20110033503A1
• Filed: 04/23/2008
• Published: 02/10/2011
• Est. Priority Date: 04/24/2007
• Status: Active Grant

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Sinko, Patrick J., Menjoge, Anupa R., Gunaseelan, Simi, Anumolu, Siva Naga Sree priay, Navath, Raghavandra, Stein, Stanley
• Granted Patent: US 9,211,358 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61L 15/26 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof A61L15/225 takes precedence
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/204 with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
• CPC Class Codes: A61L 2300/21 Acids
• CPC Class Codes: A61L 2300/25 Peptides having up to 20 amino acids in a defined sequence
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 26/0052 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 26/0066 Medicaments; Biocides
• CPC Class Codes: A61L 26/0076 Sprayable compositions
• CPC Class Codes: A61L 26/008 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

Described is a spray-on hydrogel comprising water-soluble PEG polymers that cross-link in situ to form a hydrogel such that the cross-links are reversible. The hydrogel can be useful as a drug delivery composition, wound dressing or surgery adjuvant. Polyethylene glycol polymer and cross-linker solutions are sprayed simultaneously through a common orifice. Cross-linking via formation of thioether or disulfide bonds is initiated upon mixing, providing rapid gelation. The hydrogel components can be derivatized with RGD peptides or analogs thereof to promote retention in/on a body compartment such as the skin, surface of the eye, or a mucosa such as the vaginal mucosa. The cross-links are reversed using a reducing solution enabling easy removal of the hydrogel by dissolution. Processes for preparation of the cross-linker, RGD derivatized PEG and RGD-linked agents are also disclosed.

Claims

1. A wound dressing, comprising

a first component comprising a hydrophilic polymer having a sulfhydryl, thiol, or mercaptan moiety;

and

a second component comprising a cross-linker, said cross-linker forming reversible cross-linkages with the hydrophilic polymer;

wherein the first and second components form a material that adheres to skin of a mammal and acts as a wound dressing.

2. The wound dressing of claim 1, wherein the polymer is polyethylene glycol.

3. The wound dressing of claim 2, wherein the polyethylene glycol comprising the sulfhydryl, thiol, or mercaptan moiety forms disulfide bonds.

4. The wound dressing of claim 1, wherein the composition further comprises a drug or a combination of drugs.

5. The wound dressing of claim 1 wherein the polyethylene glycol is derivatized to contain peptide comprising RGD.

6. The wound dressing of claim 5 wherein a drug or drugs are conjugated to the peptide comprising RGD.

7. The wound dressing of claim 5 wherein the peptide comprising RGD further comprises cysteine.

8. The wound dressing of claim 5 wherein the peptide comprising RGD is a linear peptide having an amino acid sequence selected from the group consisting of Arg-Gly-Asp-Cys, Gly-Arg-Gly-Asp-Ser, and Gly-Arg-Gly-Asp-Ser-Pro.

9. The wound dressing of claim 1, wherein the cross-linker is selected from the group consisting of H₂O₂, a maleimide terminated polyethylene glycol, and a thiopyridine terminated polyethylene glycol.

10. The wound dressing of claim 9 wherein the maleimide terminated polyethylene glycol is selected from the group consisting of bis-maleimido diethylene glycol and bis-maleimido triethylene glycol.

11. The wound dressing of claim 9 wherein the thiopyridine terminated polyethylene glycol is obtained by reacting the 2-dithiopyridine or 4-dithiopyridine with thiol terminated polyethylene glycol.

12. The wound dressing of claim 1, wherein the composition further comprises an additive selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives such as methyl cellulose, hydroxypropyl methylcelluose, hydroxypropyl cellulose, humectants such as glycerin, propylene glycol, polyethylene glycols having molecular weight in the range 100-10000, propylene glycol derivatives, and phospholipids.

13. The wound dressing of claim 1 wherein the composition provides controlled release of said drug.

28. A method of treatment for promoting healing of a wound on the skin, said method comprising the steps of:

a. applying a reversibly cross-linked hydrogel composition of claim 1 to the wound, and

b. removing the hydrogel by dissolving said cross-links in the hydrogel composition.

30. The method of claim 28 or 29, wherein removal of the hydrogel dressing comprises reversing the cross-links using a reducing agent.

31. The method of claim 30 wherein the reducing agent is selected from the group consisting of cysteine and derivatives thereof, cysteine ethyl ester, cysteine methyl ester, gluthatione, cysteine hydrocholoride, dithiothretol, N-Ethylmalemide, phosphine derivatives tetrakis-hydroxymethyl phosphonium chloride and tris-diethylaminomethyl phosphine trialkylphosphine agents, such as Tris[2-carboxyethyl]phosphine and mercaptoethanols, 2,3-dimercapto-1-propanol, dinitrobenzoic acid, a thiol, a mercaptan, a sulfite or bisulfate or ammonium or sodium salts thereof, thioglycolic acid, thiolactic acid, cysteine, thioglycerol, thioglycolic hydrazide, thioglycolamide, glycerol monothioglycolate, beta-mercapto-propionic acid, N-hydroxyethyl mercapto-acetamide, N-methyl mercapto-acetamide, beta-mercapto-ethylamine, beta-mercapto-propionamide, 2-mercapto-ethanesulfonic acid, dimercapto-adipic acid, dithiothreitol, homocysteinethiolactone, and a polythiol derivative formed by the addition of cysteamine onto a maleic anhydride-alkylvinylether copolymer.

32. The method of claim 30 wherein the reducing agent is glutathione or cysteine.

35. The dressing of claim 1 or 14 wherein the dressing further comprises a growth factor.

36. The dressing of claim 35 wherein the growth factor is selected from the group consisting of a cytokine, epidermal growth factor (EGF), an EGF protein having one or more repeats of the conserved amino acid sequence:

CX7CX4-5CX10-13CXCX8GXRC (where X represents any amino acid), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-b), keratinocyte growth factor (KGF-2), fibroblast growth factor, fibronectin, fibrinogen, Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF) and platelet-derived growth factor (PDGF).

41. The dressing of claim 1 or 14 wherein the hydrogel is bioadhesive.

42. The dressing of claim 1 or 14 wherein the ratio of polymer to cross-linker is in the range of about 5:

1 to 1;

5 w/w.

43. The dressing of claim 1 or 14 wherein polymer and cross-linker are provided as a solution having a concentration of less than 30% w/v.

14. An ocular dressing, comprising

a first component comprising a hydrophilic polymer having a sulfhydryl, thiol, or mercaptan moiety;

and

a second component comprising a cross-linker, said cross-linker forming reversible cross-linkages with the hydrophilic polymer;

wherein the first and second components form a material that adheres to the ocular surface of an eye of a mammal.

15. The composition of claim 14 wherein the ocular dressing comprises a drug or combination of drugs for topical administration of the drug or drugs to the eye.

16. The ocular dressing of claim 14, wherein the polymer is polyethylene glycol.

17. The ocular dressing of claim 14, wherein the polyethylene glycol comprising the sulfhydryl, thiol, or mercaptan moiety forms disulfide bonds.

18. The ocular dressing of claim 14 wherein the polyethylene glycol is derivatized to contain a peptide comprising RGD.

19. The ocular dressing of claim 18 wherein a drug or drugs are conjugated to the peptide comprising RGD.

20. The ocular dressing of claim 18 wherein the peptide comprising RGD further comprises cysteine.

21. The ocular dressing of claim 18 wherein the peptide comprising RGD is a linear peptide having an amino acid sequence selected from the group consisting of Arg-Gly-Asp-Cys, Gly-Arg-Gly-Asp-Ser, and Gly-Arg-Gly-Asp-Ser-Pro.

22. The ocular dressing of claim 14, wherein the cross-linker is selected from the group consisting of H₂O₂, a maleimide terminated polyethylene glycol, and a thiopyridine terminated polyethylene glycol.

23. The ocular dressing of claim 22 wherein the maleimide terminated polyethylene glycol is selected from the group consisting of bis-maleimido diethylene glycol and bis-maleimido triethylene glycol.

24. The ocular dressing of claim 22 wherein the thiopyridine terminated polyethylene glycol is obtained by reacting the 2-dithiopyridine or 4-dithiopyridine with thiol terminated polyethylene glycol.

25. The ocular dressing of claim 14, wherein the composition further comprises an additive selected from the group consisting of polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives such as methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, humectants such as glycerin, propylene glycol, polyethylene glycols having molecular weight in the range 100-10000, propylene glycol derivatives, and phospholipids.

26. The ocular of claim 14 wherein the composition provides controlled release of said drug.

27. A drug delivery device for delivering drug for treatment of the eye, said drug delivery device comprising a composition of claim 14.

29. A method of treatment for delivering a drug to a corneal surface of an eye, said method comprising the steps of:

a. providing a reversibly cross-linked hydrogel composition of claim 14, and

b. removing the hydrogel by dissolving said cross-links in the hydrogel composition.

33. The dressing of claim 4 or 15 comprising a drug selected from the group consisting of a topical anesthetic, antibiotic, antiseptic, analgesic, anti-inflammatory and a wound healing therapeutic agent.

34. The composition of claim 33 wherein the drug is lidocaine, benzocaine, butamben, dibucaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, novocaine, procaine, tetracaine, doxycycline, minocycline, oxytetracycline, sancycline, dedimethylamino tetracycline, indomethacin, diclofenac, ibuprofen, naproxen, ketoprofen, dexamethasone, a vallinoid, olvanil, capsaicin, benzalkonium chloride, an antiglaucoma medication, pilocarpine, timolol, levobunolol, betaxolol, or carbacol.

37. A method of preparing a cross-linked hydrogel composition for application to the skin, said method comprising:

a. providing a polymer in solution,

b. providing in a separate solution a cross-linker that forms reversible cross-links,

c. administering both solutions concomitantly from at least one nozzle permitting mixing of the polymer and cross-linking solutions in order to provide rapid gelation of the reversibly cross-linked hydrogel at the site of administration.

38. The method of claim 37 wherein the rapid gelation occurs within less than 3 minutes.

39. The method of claim 37 wherein the solutions are administered as a spray.

40. The method of claim 37 wherein the method comprises administering the polymer and cross-linking solutions from a dual-barreled syringe.

44. A wound or ocular dressing kit, comprising

a first component comprising a hydrophilic polymer having a sulfhydryl, thiol, or mercaptan moiety;

a second component comprising a cross-linker capable of forming a reversible cross-linkages with the hydrophilic polymer,

said first and second components being supplied as separate solutions and being mixed together during administration to a wound site such that a reversible cross-linked gel matrix forms as a wound dressing on the surface of the wound in less than about 30 minutes.

45. The kit of claim 44 further comprising a drug, a growth factor, or both.

46. The kit of claim 44 further comprising a reducing agent for reversing the reversible cross-links of the formed hydrogel for dissolution and removal of the dressing from a wound.