Treatment for dermal skin atrophy using thyroid hormone compounds or thyroid hormone-like compounds

Abstract

The present invention is directed to a method for treating dermal atrophy of the skin. The method of the invention includes applying a composition to the skin of a mammal suffering from dermal atrophy of the skin, and comprising at least one thyroid hormone compound or thyroid hormone-like compound together with a pharmacologically acceptable base suitable for topical application, wherein the thyroid hormone compound or the thyroid hormone-like compound binds to TR-α or TR-β with an equilibrium dissociation constant, K d , of at least 10 −5 M. The invention is also directed to an article of manufacture comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent is therapeutically effective for treating dermal atrophy of the skin.

What is claimed is:  
     
         1 . A method for treating dermal atrophy of the skin, comprising the step of applying a composition to the skin of a mammal suffering from dermal atrophy of the skin, said composition comprising at least one thyroid hormone compound or thyroid hormone-like compound together with a pharmacologically acceptable base suitable for topical application, wherein said thyroid hormone compound or said thyroid hormone-like compound binds to TR-α or TR-β with an equilibrium dissociation constant, K d , of at least 10 −5  M, wherein  
         K   d =( R )•( L )/( RL ),  
       where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex, and wherein said dermal atrophy of the skin is reduced.  
     
     
         2 . The method of  claim 1 , wherein said at least one thyroid hormone compound or said thyroid hormone-like compound is selected from the group consisting of Tri-iodothyronine (3,5,3′-triiodothyronine, T3); D and L thyroxine (T4); 4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-2-isopropyl-phenol, 4-(4-hydroxymethyl-2,6-diiodophenoxy)-2-iodo-phenol, 3,3′5′tri-iodothyronine (reverse T3); 3,3′-diiodothyronine; T3 and T4 analogues such as 3,5,3′,-Triiodo-L-thyronine methyl ester; 3,5,3′-Triiodo-L-thyronine hydrochloride; L-thyroxine hydrochloride; Tetrac (3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]acetic acid); Triac ([4-(4-hydroxy-3-iodophenoxy)-3,5-diiodopheny]acetic acid); Tetraprop; Triprop ([4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propionic acid); T4Bu; T3Bu; Thyroxamine; Triiodothyronamine; (5-Benzyloxy-2-methoxyphenyl)-(2-methoxypyrimidin-5-yl)-methanol; Benzyloxy-2-methoxyphenyl)-(6-methylpyridin-3-yl)methanol; (5-Benzyloxy-2-methoxyphenyl)-(5-bromo-2-methoxypyridin-4-yl)methanol; (5-benzyloxy-2-methoxyphenyl)-(2,6-difluoropyridin-3-yl)methanol; (5-Benzyloxy-2-methoxyphenyl)-(2-methoxypyridin-4-yl)methanol; 4-Methoxy-3-[(2-methoxypyrimidin-5-yl)methyl]phenol; 4-Methoxy-3-[(6-methylpyrid-3-yl)methyl]phenol; 5-Benzyloxy-2-methoxybenzyl Bromide; (5-Benzyloxy-2-methoxyphenyl-(6-chloropyridazin-3-yl)-acetonitrile; 4-Benzyloxy-2-[2-methoxythiazol-5-yl)methyl]anisole; 6-[(5-Hydroxy-2-methoxyphenyl)methyl]thiazol-2-(3H); 3′-Heteroarylmethyl-4′-)-methyl-3,5-dinitro-N-trifluoro-acetyl-L-thyronine Ethyl Esters; 3′-heteroarylmethyl-3,5-di-iodo-4′)-methyl-N-trifluoro-acetyl-L-thyronine Ethyl Esters; 3′-heteroarylmethyl analogues of 3,3′,5-tri-iodo-L-thyronine (T3); 3′-substituted derivatives of the thyroid hormone 3,3′5-triiodo-L-thyronine (T3); L-3,3′-T2; DL-Br2I; L-Br2iPr; L-Me2I; L-Me3; L-Me4; L-Me2IPr; DL-IMeI; L-3,5-Dimethyl-3′-isopropylthyronine (DIMIT); DL-BPT4; B-triac; BP-tetrac; DL-SBT3; DL-SBT4; DL-MBT3; MB-tetrac; T2F; T2Cl; T2Br; T2Me; T2Et; T2iPr; T2nPr; T2sBu; T2tBu; T2iBu; T2Phe; T2F2; T2Cl2; T2Me2; 3,5,3′-Triiodo-D-thyronine; 3,5-Diiodo-4-hydroxyphenylpropionic acid (DIHPA); Aryloxamic acids; (arylamino)acetic acids; arylpropionic acids; arylthioacetic acids; (aryloxy)acetic acid; 3,3′-T2; 3,5-T2; 3′,5′-T2; α-methyl-3,5,3′-triiodothyroacetic acid, α-methyl-3,5,3′-triiodothyropropionic acid, and α-methyl-3,5,3′,5′-tetraiodothyropropionic acid; methylene- and carbonyl-bridged analogs of iodinated thyronines or thyroacetic acids or iodinated benzofurans; 3,5-diiodo-4-(2-N,N-diethylaminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride; 2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran;] 4′-hydroxy-3′-iodo-3,5 diiodo-4-(2-N,N-dimethylamino-(ethoxy)benzophenone hydrochloride; 2-butyl-3-(3-iodo-4-hydroxybenzoyl)benzfuran; 4′,4-dihydroxy 3′3,5-triiodo-diphenylmethane; 3,5-diethyl,3′-isopropyl thyronine (DIET); and IpTA2 (3,5 diiodo-3′isopropyl thyroacetic acid) and pharmacologically acceptable salts and derivatives thereof.  
     
     
         3 . The method of  claim 1 , wherein said composition comprises a concentration of 5×10 8  times K d  or less of said at least one thyroid hormone compound or said thyroid hormone-like compound.  
     
     
         4 . The method of  claim 1 , wherein said at least one thyroid hormone compound or said thyroid hormone-like compound is in chemically pure form.  
     
     
         5 . The method of  claim 1 , wherein said pharmacologically acceptable base is selected from the group consisting of oil in water emulsions, water in oil emulsions, sprays, liposomes, creams, lotions, solutions, and combinations thereof.  
     
     
         6 . The method of  claim 1 , wherein said pharmacologically acceptable base comprises one or more fatty acids, esters, or triglycerides selected from the group consisting of linoleic, oleic, palmitic, and linolenic fatty acids, esters, or triglycerides.  
     
     
         7 . The method of  claim 1 , wherein said at least one thyroid hormone compound or said thyroid hormone-like compound is at least partially dissolved in a solvent.  
     
     
         8 . The method of  claim 7 , wherein said solvent is an organic solvent.  
     
     
         9 . The method of  claim 8 , wherein said organic solvent comprises water and an alcohol.  
     
     
         10 . The method of  claim 9 , wherein said alcohol is selected from the group consisting of isopropanol, ethanol, and combinations thereof.  
     
     
         11 . The method of  claim 1 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 200 mg/100 ml of said composition.  
     
     
         12 . The method of  claim 11 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 50 mg/100 ml of said composition.  
     
     
         13 . An article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein said pharmaceutical agent is therapeutically effective for treating dermal atrophy of the skin, and wherein said packaging material comprises a label which indicates that the pharmaceutical agent can be used for treating dermal atrophy of the skin, and wherein said pharmaceutical agent comprises at least one thyroid hormone compound or thyroid hormone-like compound in a pharmacologically acceptable base suitable for topical application, wherein said thyroid hormone compound or said thyroid hormone-like compound binds to TR-α or TR-β with an equilibrium dissociation constant, K d , of at least 10 −5  M, wherein  
         K   d =( R )•( L )/( RL ),  
       where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex.  
     
     
         14 . The article of manufacture of  claim 13 , wherein said at least one thyroid hormone compound or said thyroid hormone-like compound is selected from the group consisting of Tri-iodothyronine (3,5,3′-triiodothyronine, T3); D and L thyroxine (T4); 3,3′5′tri-iodothyronine (reverse T3); 4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-2-isopropyl-phenol, 4-(4-hydroxymethyl-2,6-diiodophenoxy)-2-iodo-phenol, 3,3′-diiodothyronine; T3 and T4 analogues such as 3,5,3′,-Triiodo-L-thyronine methyl ester; 3,5,3′-Triiodo-L-thyronine hydrochloride; L-thyroxine hydrochloride; Tetrac (3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]acetic acid); Triac ([4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]acetic acid); Tetraprop; Triprop ([4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propionic acid); T4Bu; T3Bu; Thyroxamine; Triiodothyronamine; (5-Benzyloxy-2-methoxyphenyl)-(2-methoxypyrimidin-5-yl)-methanol; Benzyloxy-2-methoxyphenyl)-(6-methylpyridin-3-yl)methanol; (5-Benzyloxy-2-methoxyphenyl)-(5-bromo-2-methoxypyridin-4-yl)methanol; (5-benzyloxy-2-methoxyphenyl)-(2,6-difluoropyridin-3-yl)methanol; (5-Benzyloxy-2-methoxyphenyl)-(2-methoxypyridin-4-yl)methanol; 4-Methoxy-3-[(2-methoxypyrimidin-5-yl)methyl]phenol; 4-Methoxy-3-[(6-methylpyrid-3-yl)methyl]phenol; 5-Benzyloxy-2-methoxybenzyl Bromide; (5-Benzyloxy-2-methoxyphenyl-(6-chloropyridazin-3-yl)-acetonitrile; 4-Benzyloxy-2-[2-methoxythiazol-5-yl)methyl]anisole; 6-[(5-Hydroxy-2-methoxyphenyl)methyl]thiazol-2-(3H); 3′-Heteroarylmethyl-4′-)-methyl-3,5-dinitro-N-trifluoro-acetyl-L-thyronine Ethyl Esters; 3′-heteroarylmethyl-3,5-di-iodo-4′)-methyl-N-trifluoro-acetyl-L-thyronine Ethyl Esters; 3′-heteroarylmethyl analogues of 3,3′,5-tri-iodo-L-thyronine (T3); 3′-substituted derivatives of the thyroid hormone 3,3′5-triiodo-L-thyronine (T3); L-3,3′-T2; DL-Br2I; L-Br2iPr; L-Me2I; L-Me3; L-Me4; L-Me2IPr; DL-IMeI; L-3,5-Dimethyl-3′-isopropylthyronine (DIMIT); DL-BPT4; B-triac; BP-tetrac; DL-SBT3; DL-SBT4; DL-MBT3; MB-tetrac; T2F; T2Cl; T2Br; T2Me; T2Et; T2iPr; T2nPr; T2sBu; T2tBu; T2iBu; T2Phe; T2F2; T2Cl2; T2Me2; 3,5,3′-Triiodo-D-thyronine; 3,5-Diiodo-4-hydroxyphenylpropionic acid (DIHPA); Aryloxamic acids; (arylamino)acetic acids; arylpropionic acids; arylthioacetic acids; (aryloxy)acetic acid; 3,3′-T2; 3,5-T2; 3′,5′-T2; α-methyl-3,5,3′-triiodothyroacetic acid, α-methyl-3,5,3′-triiodothyropropionic acid, and α-methyl-3,5,3′, 5′-tetraiodothyropropionic acid; methylene- and carbonyl-bridged analogs of iodinated thyronines or thyroacetic acids or iodinated benzofurans; 3,5-diiodo-4-(2-N,N-diethylaminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride; 2-n-butyl-3- (3,5-diiodo-4-carboxymethoxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran;] 4′-hydroxy-3′-iodo-3,5 diiodo-4-(2-N,N-dimethylamino-(ethoxy)benzophenone hydrochloride; 2-butyl-3-(3-iodo-4-hydroxybenzoyl)benzfuran; 4′,4-dihydroxy 3′3,5-triiodo-diphenylmethane; 3,5-diethyl,3′-isopropyl thyronine (DIET); and IpTA2 (3,5 diiodo-3′isopropyl thyroacetic acid) and pharmacologically acceptable salts and derivatives thereof.  
     
     
         15 . The article of manufacture of  claim 13 , wherein said composition comprises a concentration of 5×10 8  times K d  or less of said at least one thyroid hormone compound or said thyroid hormone-like compound.  
     
     
         16 . The article of manufacture of  claim 13 , wherein said at least one thyroid hormone compound or said thyroid hormone-like compound is in chemically pure form.  
     
     
         17 . The article of manufacture of  claim 13 , wherein said pharmacologically acceptable base is selected from the group consisting of oil in water emulsions, water in oil emulsions, sprays, liposomes, creams, lotions, solutions, and combinations thereof.  
     
     
         18 . The article of manufacture of  claim 13 , wherein said pharmacologically acceptable base comprises one or more fatty acids, esters, or triglycerides selected from the group consisting of linoleic, oleic, palmitic, and linolenic fatty acids, esters, or triglycerides.  
     
     
         19 . The article of manufacture of  claim 13 , wherein said at least one thyroid hormone compound or said thyroid hormone-like compound is at least partially dissolved in a solvent.  
     
     
         20 . The article of manufacture of  claim 19 , wherein said solvent is an organic solvent.  
     
     
         21 . The article of manufacture of  claim 20 , wherein said organic solvent comprises water and an alcohol.  
     
     
         22 . The article of manufacture of  claim 21 , wherein said alcohol is selected from the group consisting of isopropanol, ethanol, and combinations thereof.  
     
     
         23 . The article of manufacture of  claim 13 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 200 mg/100 ml of said composition.  
     
     
         24 . The article of manufacture of  claim 23 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 50 mg/100 ml of said composition.  
     
     
         25 . A composition for treating dermal atrophy of the skin, comprising: 
 at least one thyroid hormone compound or thyroid hormone-like compound selected from the group consisting of tri-iodothyroacetic acid, tri-iodopropionic acid, 4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-2-isopropyl-phenol, 4-(4-hydroxymethyl-2,6-diiodophenoxy)-2-iodo-phenol, and combinations thereof; and    a pharmacologically acceptable base comprising oil in water emulsions, water in oil emulsions, sprays, liposomes, creams, lotions, solutions, and combinations thereof.    
     
     
         26 . The composition of  claim 25 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 200 mg/100 ml of said composition.  
     
     
         27 . The composition of  claim 26 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 50 mg/100 ml of said composition.  
     
     
         28 . The composition of  claim 25 , wherein said pharmacologically acceptable base further comprises one or more fatty acids, esters, or triglycerides selected from the group consisting of linoleic, oleic, palmitic, and linolenic fatty acids, esters, or triglycerides.  
     
     
         29 . A method of improving healing of wounded skin of a patient, comprising the step of applying a composition to the wounded skin of said patient, said composition comprising at least one thyroid hormone compound or thyroid hormone-like compound together with a pharmacologically acceptable base suitable for topical application, wherein said thyroid hormone compound or said thyroid hormone-like compound binds to TR-α or TR-β with an equilibrium dissociation constant, K d , of at least 10 −5  M, wherein  
         K   d =( R )•( L )/( RL ),  
       where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex, and wherein said healing of said wounded skin is improved.  
     
     
         30 . The method of  claim 29 , wherein said composition comprises at least one thyroid hormone compound or thyroid hormone-like compound selected from the group consisting of tri-iodothyroacetic acid, tri-iodopropionic acid, 4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-2-isopropyl-phenol, 4-(4-hydroxymethyl-2,6-diiodophenoxy)-2-iodo-phenol, and combinations thereof; and a pharmacologically acceptable base comprising oil in water emulsions, water in oil emulsions, sprays, liposomes, creams, lotions, solutions, and combinations thereof.  
     
     
         31 . The method of  claim 30 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 200 mg/100 ml of said composition.  
     
     
         32 . The method of  claim 31 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 50 mg/100 ml of said composition.  
     
     
         33 . The method of  claim 29 , wherein said pharmacologically acceptable base further comprises one or more fatty acids, esters, or triglycerides selected from the group consisting of linoleic, oleic, palmitic, and linolenic fatty acids, esters, or triglycerides.  
     
     
         34 . A method of dermatological surgical pretreatment of a patient with atrophied skin, comprising the step of applying a composition to the atrophied skin of said patient prior to dermatological surgery, said composition comprising at least one thyroid hormone compound or thyroid hormone-like compound together with a pharmacologically acceptable base suitable for topical application, wherein said thyroid hormone compound or said thyroid hormone-like compound binds to TR-α or TR-β with an equilibrium dissociation constant, K d , of at least 10 −5  M, wherein  
         K   d =( R )•( L )/( RL ),  
       where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex.  
     
     
         35 . The method of  claim 34 , wherein said composition comprises at least one thyroid hormone compound or thyroid hormone-like compound selected from the group consisting of tri-iodothyroacetic acid, tri-iodopropionic acid, 4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-2-isopropyl-phenol, 4-(4-hydroxymethyl-2,6-diiodophenoxy)-2-iodo-phenol, and combinations thereof; and a pharmacologically acceptable base comprising oil in water emulsions, water in oil emulsions, sprays, liposomes, creams, lotions, solutions, and combinations thereof.  
     
     
         36 . The method of  claim 35 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 200 mg/100 ml of said composition.  
     
     
         37 . The method of  claim 36 , wherein said at least one thyroid hormone compound or thyroid hormone-like compound comprises less than 50 mg/100 ml of said composition.  
     
     
         38 . The method of  claim 34 , wherein said pharmacologically acceptable base further comprises one or more fatty acids, esters, or triglycerides selected from the group consisting of linoleic, oleic, palmitic, and linolenic fatty acids, esters, or triglycerides.