Wound dressing for the controlled release of therapeutic agents
View Patent ↗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 wound 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 a protease enzyme in a wound fluid, the wound dressing 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 wound healing therapeutic agent and the inhibitor of the protease enzyme are each separately conjugated to the medically acceptable polymer by the linker group, wherein the linker group comprises an oligopeptidic sequence which is a substrate for the protease enzyme, wherein the therapeutic agent is a reactive oxygen scavenger, a pain relieving agent, an antiseptic, an analgesic, or a local anaesthetic, and further wherein the activities of both the wound healing therapeutic agent and the inhibitor are increased by contacting the wound dressing material with a wound fluid containing the protease enzyme;
wherein the inhibitor of the protease enzyme is selected from the group consisting of Tissue Inhibitor of Metalloproteinase (TIMP), 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSE), antithrombin, (p-Amidinophenyl)methanesulfonyl fluoride (APMSF), Aprotinin, diisopropylfluorophosphate (DFP), phenyl methyl sulfonyl fluoride (PMSF), Antipain, Chymostatin, Leupeptin, Tosyl-lysine chlorormethylketone (TLCK), Tosyl-phenyl chloromethylketone (TPCK), L-transepoxysuccinylleucylamido (4-guanidino) butane (E-64), Amastatin, Bestatin, Diprotin, Ethylenediamine tetra-acetic acid (EDTA), pepstatin and mixtures thereof.
2. A wound dressing material according to claim 1 , wherein the polymer is cross-linked. by the linker group.
3. A wound dressing material according to claim 1 wherein elevated levels of the enzyme are associated with pain, wound infection or wound chronicity.
4. A wound dressing material according to claim 1 , wherein the protease is elastase and wherein the oligopeptidic sequence comprises or consists of lys-gly-ala-ala-ala-Iys-Ala-Ala-Ala- (SEQ ID NO: 1), Ala-Ala-Pro-Val (SEQ ID NO:2), Ala-Ala-Pro-Len (SEQ ID NO: 3), Ala-Ala-Pro-Phe (SEQ ID NO: 4), Ala-Ala-Pro-Ala (SEQ ID NO: 5) or Ala-Tyr-Leu-Val (SEQ ID NO: 6).
5. A wound dressing material according to claim 1 , wherein the protease is a matrix metalloproteinase and wherein the oligopeptidic sequence comprises or consists of -Gly-Pro-Y (SEQ ID NO: 7), -Gly-Pro-Leu-Gly-Pro-Z- (SEQ ID NO: 8), -Gly-Pro-lle-Gly-Pro-Z- (SEQ ID NO: 9), or -Ala-Pro-Gly-Leu-Z- (SEQ ID NO: 10), where Y and Z are amino acids.
6. A wound dressing material according to claim 1 , wherein the protease is a collagenase and wherein the oligopeptidic sequence comprises or consists of -Pro-Leu-Gly-Pro-D-Arg-Z- (SEQ ID NO: 11), -ProLeu-Gly-Leu-Leu-Gly-Z-(SEQ ID NO: 12), Pro-Gln-Gly-lle-Ala-Gly-Trp- (SEQ ID NO: 13), -Pro-Leu-Gly-Cys (Me)-His-(SEQ ID NO: 14), -Pro-Leu-Gly-Leu-Trp-Ala- (SEQ ID NO: 15), -Pro-Leu-Ala-Leu-Trp-Ala-Arg- (SEQ ID NO: 16), or -Pro-Leu-Ala-Tyr-Trp-Ala-Arg- (SEQ ID NO: 17 ), where Z is an amino acid.
7. A wound dressing material according to claim 1 , wherein the protease is a gelatinase and wherein the oligopeptidic sequence comprises or consists of -Pro-LeuGly-Met-Trp-Ser-Arg- (SEQ ID NO: 18).
8. A wound dressing material according to claim 1 , wherein the protease is thrombin and wherein the oligopeptidic sequence comprises or consists of -Gly-Arg-Gly-Asp- (SEQ ID NO: 19),-Gly-Gly-Arg-, -Gly-Arg-Gly-Asp-Asn-Pro- (SEQ ID NO: 20), -Gly-Arg-Gly-Asp-Ser- (SEQ ID NO: 21), -Gly-Arg-Gly-Asp-Ser-Pro-Lys- (SEQ ID NO: 22), -Gly-Pro-Arg-, -Val-Pro-Arg-, or -Phe-Val-Arg-.
9. A wound dressing material according to claim 1 , wherein the protease is stromelysin and wherein the oligopeptidic sequence comprises or consists of -ProTyrAla-Tyr-Trp-Met-Arg- (SEQ ID NO: 23).
10. A wound dressing material according to claim 1 , wherein the therapeutic agent comprises a reactive oxygen scavenger.
11. A wound dressing comprising, a wound dressing material according to claim 1 .
12. A wound dressing material according to claim 1 , comprising an antioxidant wound dressing wherein the therapeutic agent is a reactive oxygen scavenger, the linker comprises a substrate oligopeptide for collagenase, elastase, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), or gelatinase, and the inhibitor of the protease enzyme is a metalloproteinase inhibitor.
13. A wound dressing material according to claim 12 , wherein the metalloproteinase inhibitor is Tissue Inhibitor of Metalloproteinase (TIMP), Amastatin, Bestatin, Diprotin, or Ethylenediamine tetra-acetic acid (EDTA).