Wound dressings for the controlled release of therapeutic agents
A wound dressing material for controlled activation of a wound healing therapeutic compound in the presence of a protease enzyme in a wound fluid, the material comprising: a medically acceptable polymer; a wound healing therapeutic agent; an inhibitor of the protease enzyme; and a linker group which is cleavable by the protease enzyme, wherein the activities of both the wound healing therapeutic agent and the inhibitor are increased by contacting the wound dressing material with a would fluid containing the protease enzyme. For example, the enzyme may be a matrix metalloproteinase, the therapeutic agent may be a reactive oxygen scavenger, and the inhibitor may be a tissue inhibitor of metalloproteinase (TIMP).
1. A wound dressing material for controlled activation of a wound healing therapeutic compound in the presence of an enzyme, comprising:
a medically acceptable polymer;
a therapeutic agent comprising a reactive oxygen scavenger;
an inhibitor of the enzyme comprising a metalloproteinase inhibitor; and
a linker group cleavable by the enzyme, wherein the therapeutic agent is conjugated to the inhibitor by the linker group.
2. A wound dressing material according to claim 1 , wherein the reactive oxygen scavenger is selected from the group consisting of antioxidant phenol derivatives, vitamin E, methyl peroxide antioxidants, stilbenes, gallocatechins, ubiquinol, retinoids, vitamin A, vitamin C, N-acetyl cysteine, selenium and its compounds, zinc and its compounds, glutathione, carotenoids, papai, thioproline, albumin, chlorophyllin, antioxidant dyestuffs, and mixtures thereof.
3. A wound dressing material according to claim 1 , wherein the metalloproteinase inhibitor is selected from the group consisting of Tissue Inhibitor of Metalloproteinase (TIMP), Amastatin, Bestatin, Diprotin, and Ethylenediamine tetra-acetic acid (EDTA).
4. A wound dressing material according to claim 1 , wherein the linker group comprises a substrate oligopeptide for the enzyme.
5. A wound dressing material according to claim 1 , wherein the enzyme is an elastase and wherein the linker group comprises a substrate oligopeptide for an elastase.
6. A wound dressing material according to claim 1 , wherein the medically acceptable polymer comprises a synthetic polymer.
7. A wound dressing material according to claim 6 , wherein the synthetic polymer is selected from the group consisting of polyvinyl alcohol, polyethylene glycerol, PVP, polyolefins, fluoropolymers, hydropolymers from vinyl esters, vinyl esters, carboxy vinyl monomers, meth(acrylic) acid, acrylamide, N-vinyl pyrrolidone, acylamidopropanem acylamidopropane, maleic acid, NN-dimethylacrylamide diacetone acrylamide acryloyl, morpholine, non-ionic surfactants, polyalkoylated alcohols, alkyl or dialkyl polyglycerol compounds, polyethyloxylated alcohols, and polymers of acrylamide.
8. A wound dressing material according to claim 1 , wherein the medically acceptable polymer comprises a natural polymer.
9. A wound dressing material according to claim 8 , wherein the natural polymer is selected from the group consisting of carbohydrates, natural peptides or proteins, modified biopolymers, and semi synthetic peptides.
10. A wound dressing material according to claim 1 , wherein the therapeutic agent and the inhibitor are each conjugated to the medically acceptable polymer.
11. A wound dressing material according to claim 1 , wherein elevated levels of the enzyme are associated with pain, wound infection, or wound chronicity.
12. A wound dressing material according to claim 1 , wherein the enzyme is a protease, and the linker group comprises an oligopeptidic sequence which is a substrate for the protease.
13. A wound dressing material according to claim 12 , wherein the protease is a matrix metalloproteinase and wherein the oligopeptidic sequence comprises or consists of -Gly-Pro-Y-Gly-Pro-Z- (SEQ ID NO: 7), -Gly-Pro-Leu-Gly-Pro-Z- (SEQ ID NO: 8), -Gly-Pro-Ile-Gly-Pro-Z- (SEQ ID NO: 9), or -Ala-Pro-Gly-Leu-Z- (SEQ ID NO: 10), where Y and Z are amino acids.
14. A wound dressing comprising a wound dressing material according to claim 1 .
15. A wound dressing material for controlled activation of a wound healing therapeutic compound, comprising:
a medically acceptable polymer;
a wound healing therapeutic agent comprising a reactive oxygen scavenger;
an inhibitor of an enzyme; and
a linker group cleavable by the enzyme, wherein the wound healing therapeutic agent is conjugated to the inhibitor by the linker group in an agent/inhibitor conjugate;
wherein the agent/inhibitor conjugate is operable to release the wound healing therapeutic agent and the inhibitor and to thereby increase the activity of both the agent/inhibitor conjugate when the agent/inhibitor conjugate contacts a wound fluid containing the enzyme.
16. A wound dressing material according to claim 15 , wherein the reactive oxygen scavenger is selected from the group consisting of antioxidant phenol derivatives, vitamin E, methyl peroxide antioxidants, stilbenes, gallocatechins, ubiquinol, retinoids, vitamin A, vitamin C, N-acetyl cysteine, selenium and its compounds, zinc and its compounds, glutathione, carotenoids, papai, thioproline, albumin, chlorophyllin, antioxidant dyestuffs, and mixtures thereof.
17. A wound dressing material according to claim 15 , wherein the inhibitor is selected from the group consisting of Tissue Inhibitor of Metalloproteinase (TIMP), 4-(2-aminoethyl)benzenesulfonyl fluoride AEBSF, antithrombin, (p-Amidinophenyl)methanesulfonyl fluoride APMSF, Aprotinin, diisopropylfluorophosphate DFP, phenyl methyl sulfonyl fluoride PMSF, Antipain, Chymostatin, Leupeptin, Tosyl-lysine chloromethylketone TLCK, Tosyl-phenyl chloromethylketone TPCK, L-trans-epoxysuccinylleucylamido (4-guanidino) butane E-64, Amastatin, Bestatin, Diprotin, Ethylenediamine tetra-acetic acid (EDTA), pepstatin and mixtures thereof.