Methods and compositions for stimulating reepithelialisation during wound healing

1. A method for stimulating reepithelialization of skin of a subject in need thereof, comprising the steps of:

locating a wound on a dermal surface of said subject;

providing to keratinocytes at said wound of said subject a therapeutically effective amount of a mineralocorticoid receptor (MR) antagonist wherein said MR antagonist is selected from the group consisting of epoxy-steroidal mineralocorticoid receptor antagonist compounds and non-steroidal receptor antagonist compounds, wherein said step of providing is carried out during a phase of new tissue formation that includes reepithelialization; and

stimulating reepithelialization of said skin of said subject at said wound site during said phase of new tissue formation.

2. The method of claim 1 , wherein said MR antagonist is selected from the group consisting of drospirenone and eplerenone.

3. The method of claim 1 , wherein said step of providing is carried out by topical delivery or transdermal delivery.

4. The method of claim 3 , wherein said topical delivery is cutaneous.

5. The method of claim 1 wherein said wound is selected from the group consisting of a diabetic foot ulcer, a venous stasis ulcer, and a burn.

6. The method of claim 1 wherein said wound is a site of delayed wound healing selected from the group consisting of an aging defect, a surgical scar, a finger crack after cold exposure, a nail pathology, and a foot blister.

7. The method of claim 1 , wherein said epoxy-steroidal mineralocorticoid receptor antagonist compound is selected from the group consisting of Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, dimethyl ester, (7α,11α,17β), 3′ H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6β,7β,11α,17β, Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, 7-(1-methylethyl) ester, monopotassium salt, (7α,11α,17β), Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, 7-methylethyl) ester, monopotassium salt, (7α,11α,17β), 3′ H-cyclopropa[6,7]pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone(6β,7β,11α), 3′ H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, methyl ester, (6β,7β,11α,17β), 3′ H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotassium salt, (6β,7β,11α,17β), 3′ H-cyclopropa[6,7]pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone(6β,7β,11α,17β), Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, ethyl ester, (7α,11α,17β), and Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, 1-methylethyl ester (7α,11α,17β).

8. The method of claim 1 , wherein said non-steroidal receptor antagonist compound is selected from the group consisting of Dihydropyridines, imidazole carboxamides, pyrrole carboxamides, dibenzosuberanes, 3,3-bisaryl oxindoles, 4-aryl-1,4-dihydropyridines, 3-benzyl indoles, benzoxazinethiones, tetrahydroquinolines, aryl benzoxazinones/thiones, and aryl benzoxazinethiones.

9. A method for stimulating reepithelialization of a cornea of a subject in need thereof, comprising the steps of:

locating a wound on said cornea of said subject;

providing to epithelium at said cornea of said subject a therapeutically effective amount consisting of a mineralocorticoid receptor (MR) antagonist wherein said MR antagonist is selected from the group consisting of epoxy-steroidal mineralocorticoid receptor antagonist compounds and non-steroidal receptor antagonist compounds, wherein said step of providing is carried out during a phase of new tissue formation that includes reepithelialization; and

stimulating reepithelialization of said corneal epithelium of said subject at said wound site during said phase of new tissue formation.

10. The method of claim 9 wherein said wound is selected from the group consisting of a corneal ulcer, a site of corneal erosion or trauma, and a site of a keratoplasty.

11. The method of claim 9 wherein said wound is dry eye.

12. The method of claim 9 , wherein said MR antagonist is selected from the group consisting of drospirenone and eplerenone.

13. The method of claim 9 , wherein said step of providing is carried out by topical delivery or transdermal delivery.

14. The method of claim 13 , wherein said topical delivery is ophthalmic.

15. The method of claim 9 , wherein said epoxy-steroidal mineralocorticoid receptor antagonist compound is selected from the group consisting of Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, dimethyl ester, (7α,11α,17β), 3′ H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6β,7β,11α,17β), Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, 7-(1-methylethyl) ester, monopotassium salt, (7α,11α,17β), Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, 7-methylethyl) ester, monopotassium salt, (7α,11α,17β), 3′ H-cyclopropa[6,7]pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone(6β,7β,11α), 3′ H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, methyl ester, (6β,7β, 11α,17β), 3′ H-cyclopropa[6,7]pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotassium salt, (6β,7β,11α,17β), 3′ H-cyclopropa[6,7]pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone(6β,7β,11α,17β), Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, ethyl ester, (7α,11α,17β), and Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, 1-methylethyl ester (7α,11α,17β).

16. The method of claim 9 , wherein said non-steroidal receptor antagonist compound is selected from the group consisting of Dihydropyridines, imidazole carboxamides, pyrrole carboxamides, dibenzosuberanes, 3,3-bisaryl oxindoles, 4-aryl-1,4-dihydropyridines, 3-benzyl indoles, benzoxazinethiones, tetrahydroquinolines, aryl benzoxazinones/thiones, and aryl benzoxazinethiones.