U.S. patent application number 10/081397 was filed with the patent office on 2002-09-05 for treatment for dermal skin atrophy using thyroid hormone compounds or thyroid hormone-like compounds.
Invention is credited to Lavin, Thomas N..
Application Number | 20020123521 10/081397 |
Document ID | / |
Family ID | 24472066 |
Filed Date | 2002-09-05 |
United States Patent
Application |
20020123521 |
Kind Code |
A1 |
Lavin, Thomas N. |
September 5, 2002 |
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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-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.
Inventors: |
Lavin, Thomas N.; (Watchung,
NJ) |
Correspondence
Address: |
WIGGIN & DANA LLP
ATTENTION: PATENT DOCKETING
ONE CENTURY TOWER, P.O. BOX 1832
NEW HAVEN
CT
06508-1832
US
|
Family ID: |
24472066 |
Appl. No.: |
10/081397 |
Filed: |
February 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10081397 |
Feb 25, 2002 |
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09617052 |
Jul 14, 2000 |
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6380255 |
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09617052 |
Jul 14, 2000 |
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08973627 |
Mar 9, 1998 |
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6221911 |
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08973627 |
Mar 9, 1998 |
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PCT/US96/09975 |
Jun 7, 1996 |
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Current U.S.
Class: |
514/381 ;
436/501; 514/567 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61P 17/16 20180101; A61K 2300/00 20130101; A61K
31/195 20130101; A61K 31/192 20130101; A61K 31/341 20130101; A61K
31/44 20130101; A61Q 19/06 20130101; A61K 31/137 20130101; A61Q
19/00 20130101; A61K 31/195 20130101; A61K 31/137 20130101; A61P
17/02 20180101; A61P 43/00 20180101; A61K 31/341 20130101; A61K
31/53 20130101; A61K 31/505 20130101; A61P 5/12 20180101; A61K
31/343 20130101; A61K 31/505 20130101; A61K 31/425 20130101; A61P
3/10 20180101; A61Q 19/08 20130101; A61P 29/00 20180101; A61P 17/00
20180101; A61K 8/44 20130101; A61K 31/192 20130101; A61K 8/64
20130101; A61K 31/44 20130101; A61P 3/02 20180101; A61K 31/055
20130101; A61Q 19/004 20130101; A61K 31/425 20130101; A61K 31/343
20130101 |
Class at
Publication: |
514/381 ;
514/567; 436/501 |
International
Class: |
A61K 031/41; A61K
031/195; G01N 033/566 |
Claims
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-.alpha. or TR-.beta. with
an equilibrium dissociation constant, K.sub.d, of at least
10.sup.-5 M, wherein K.sub.d=(R).cndot.(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-isop-
ropyl-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]propion- ic 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-methoxybenz- yl Bromide;
(5-Benzyloxy-2-methoxyphenyl-(6-chloropyridazin-3-yl)-acetonit-
rile; 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-thyronin-
e Ethyl Esters;
3'-heteroarylmethyl-3,5-di-iodo-4')-methyl-N-trifluoro-ace-
tyl-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;
.alpha.-methyl-3,5,3'-triiodothyroacetic acid,
.alpha.-methyl-3,5,3'-trii- odothyropropionic acid, and
.alpha.-methyl-3,5,3',5'-tetraiodothyropropion- ic acid; methylene-
and carbonyl-bridged analogs of iodinated thyronines or thyroacetic
acids or iodinated benzofurans; 3,5-diiodo-4-(2-N,N-diethy-
laminoethoxy)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.times.10.sup.8 times K.sub.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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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-ylm-
ethyl)-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-dii-
odophenoxy)-3,5-diiodophenyl]acetic acid); Triac
([4-(4-hydroxy-3-iodophen- oxy)-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-m- ethoxypyrimidin-5-yl)-methanol;
Benzyloxy-2-methoxyphenyl)-(6-methylpyridi- n-3-yl)methanol;
(5-Benzyloxy-2-methoxyphenyl)-(5-bromo-2-methoxypyridin-4-
-yl)methanol;
(5-benzyloxy-2-methoxyphenyl)-(2,6-difluoropyridin-3-yl)meth- anol;
(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-methoxybenz- yl Bromide;
(5-Benzyloxy-2-methoxyphenyl-(6-chloropyridazin-3-yl)-acetonit-
rile; 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-thyronin-
e Ethyl Esters;
3'-heteroarylmethyl-3,5-di-iodo-4')-methyl-N-trifluoro-ace-
tyl-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;
.alpha.-methyl-3,5,3'-triiodothyroacetic acid,
.alpha.-methyl-3,5,3'-trii- odothyropropionic acid, and
.alpha.-methyl-3,5,3', 5'-tetraiodothyropropio- nic acid;
methylene- and carbonyl-bridged analogs of iodinated thyronines or
thyroacetic acids or iodinated benzofurans;
3,5-diiodo-4-(2-N,N-diethy-
laminoethoxy)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.times.10.sup.8 times
K.sub.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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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-phen-
ol, 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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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-phen-
ol, 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.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation-in-Part of U.S. Ser. No.
08/937,627 filed Mar. 9, 1998, which is a .sctn.371 filing from
International Application No. PCT/US96/09975 filed Jun. 7, 1996,
which claims the benefit of U.S. Ser. No. 08/481,698 filed Jun. 7,
1995.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to thyroid-hormone receptor binding
compounds, and more particularly to thyroid-hormone receptor
binding compounds useful as dermatologic treatments for atrophy of
the dermis.
[0004] 2. Brief Description of the Related Art
[0005] There are a considerable number of skin conditions and
diseases which significantly affect the appearance of the skin.
Examples of these skin conditions include stria, cellulite,
roughened skin, actinic skin damage, intrinsically aged skin,
photodamaged skin, lichen planus, ichtyosis acne, psoriasis,
wrinkled skin, eczema, seborrheic dermatitis, scleroderma,
hyperkeratinizing disorders, keloids and skin scarring.
[0006] A wide variety of medically useful topical skin preparations
are currently commercially available to treat many of these skin
conditions and diseases. A large number of these skin preparations
include topical steroids such as glucocorticoids, and retinoid
topical medicaments, both of which have varying side-effects and
usefulness in many patients. Particularly, eczema and psoriasis are
usually treated with topical steroids such as hydrocortisone,
betamethasone, and clobetasol propionate. The side effects of
topical steroid use, particularly in the long term are well known
and include skin atrophy consisting of atrophy of both the dermis
and epidermis, a risk for systemic absorption of the drug, and
rebound phenomena when the drug is withdrawn.
[0007] Oral glucocorticoids also produce skin atrophy with chronic
use. Therefore certain diseases and conditions which are treated
with oral or inhaled glucocorticoids are associated with atrophy.
For example, organ transplantation, asthma, rheumatic diseases, and
renal diseases are often treated with oral glucocorticoids which
results in skin atrophy.
[0008] Dermal skin atrophy results from reduced collagen in the
dermis, decreased cellularity in the dermis, and reduces the depth
of the dermis, resulting in increased fragility of the skin,
transparency of the skin, and easy bruising (Talwar et al., J. Inv.
Derm. 105:285 (1995); Uitto, H. Geriatric Dermatology 5:127
(1989)). Among the main causes of dermal skin atrophy are aging,
photodamage, topical or systemic glucocorticoids, Cushing's
disease, rheumatoid arthritis, and diabetes (see, Textbook of
Dermatology, (1997); Gilchrist, B. A. Brit. J. Dermatology 135:867
(1996); Talwar et al., J. Inv. Derm. 105:285 (1995)).
[0009] Retinoic acid has been shown to partially ameliorate the
condition of photoaging (Drugs and Aging 1:12-16 (1996)), but has
not been fully successful in reversing steroid induced dermal skin
atrophy in humans (Griffiths, Br. J. Dermatology 135:60-64 (1996)).
Other medically useful treatments involve the use of alpha hydroxy
acids as disclosed in U.S. Pat. Nos. 5,254,343; t,284,971;
5,401,772; 3,649,597; 3,357,887; 4,168,385; and 5,179097; and
European Patent Application No. 580550. Currently, there are no
treatments for dermal atrophy of the skin that are widely accepted
by the medical community or can reverse glucocorticoid-induced
dermal atrophy.
[0010] The structurally similar thyroid hormone compounds
3,3',5-triiodo-L-thyronine (T3) and L-thyroxine (T.sub.4) have a
very wide range of effects. In adult mammals they influence nearly
all organs, the metabolism of nutrients, basal metabolic rate, and
oxygen consumption. In humans, the deficiency or excess of
circulating thyroid hormone compounds results in the well
characterized syndromes, hypo- and hyperthyroidism. Small
concentrations of thyroid hormone metabolites which are also
endocrinologically active exist. Among these compounds are
tri-iodothyroacetic acid ("Triac"
[4-(4-hydroxy-3-iodophenoxy)-3,5-diodop- henyl]acetic acid) and
tri-iodopropionic acid ("Tri-prop"
[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)]propionic acid).
[0011] Thyroid hormone compounds exert many of their actions by
binding to a family of receptor proteins termed the C-erb-A family.
In humans, their receptor protein family is now known to comprise
several members, notably the human thyroid receptor .alpha.-1, the
human thyroid receptor .alpha.-2 which binds the hormone poorly or
not at all, the human thyroid receptor .beta.1, and the human
thyroid receptor .beta.-2. These proteins are part of a larger
superfamily of steroid hormone receptors which comprises the
glucocorticoid receptors, the retinoic acid receptors, the vitamin
D receptors, and the insect molting receptors (e.g., the receptors
for ecdysone and the insect juvenile hormones). Receptors for
hormone compounds are found in human skin, human fibroblasts and
keratinocytes and they are also found in many other tissues within
the human body.
[0012] In addition to the naturally occurring thyroid hormone
compounds (e.g., triiodothyronine and tetraiodothyronine), a large
number of chemical compounds which bind to the thyroid hormone
receptor and which produce thyroid hormone-like effects have been
synthesized (see, for example, U.S. Pat. No. 5,401,772).
[0013] Thyroid hormone compounds, in many cases, act indirectly by
influencing the effects of other hormones and tissues. For example
in the rat, thyroid administration increases pituitary growth
hormone production which in turn affects hepatic protein production
including that of alpha-2 euglobulin. Functionally, in the rat,
growth hormone may act as a second message for thyroid hormone. The
biology of thyroid hormone compounds has been extensively studied
only after oral administration, which makes the relationship
between a direct effect of thyroid hormone compounds and an
indirect effect mediated by thyroid hormone modulation of other
autocrine, paracrine or endocrine factors difficult to
ascertain.
[0014] Orally administered thyroid hormones influence the
connective tissue biology of the skin. When given orally, thyroid
hormones induce an increase in neutral salt and acid soluble
collagen, but decrease insoluble collagen in the skin of guinea
pigs (Drozdzm, M. et al., Endokrinologie 73:105-111, 1979). In cell
culture, fibronectin production is decreased in human fibroblasts
and fibroblast glycosaminoglycans are either decreased or unchanged
depending on the experimental conditions used (Murata, Y. et al.,
J. Clin. Endocrinol. Metab. 64:334-339, 1987; Watxke, H. et al.,
Thrombosis Res. 46:347-353, 1987; Murata, Y. et al., JCEM
57:1233-1239, 1983; Ceccarelli, Pl, et al., JCEM 65:242-246, 1987).
Keratin gene expression for both the basal cell keratin K5 and K14
genes and the differentiation-specific K10 gene is negatively
regulated by thyroid hormones (Tomic-Canic, M. et al., J. Invest.
Dermatol. 99:842-847, 1992; Blumenberg, M. et al., J. Invest.
Dermatol. 98:42S-49S, 1992) Thyroid hormone added to fibroblasts in
culture decreases collagen production (De Ryker, FEBS Lett.
174:34-37 (1984)). Some of these effects are mirrored by similar
cell culture responses to retinoic acid or the retinoid
Tretinoin.
[0015] Histological studies of skin from individuals who have the
medical condition hyperthyroidism show an increased number of cell
layers in the skin, reflected by mean epidermal cell number,
increased protein turnover with increased proline incorporation and
generalized increases in epidermal proliferation compared to normal
skin (Holt, P. J. A. et al., Br. J. Dermatol. 95:513-518, 1976). In
human clinical biology, thyroid hormone excess leads to a general
smoothing of the skin and the loss of wrinkles especially over the
olecranon (elbow) surface.
[0016] Orally given thyroid hormone compounds in excess of normal
bodily requirements or medical conditions which are associated with
excess thyroid hormone compounds such as Grave's disease or toxic
nodular goiter produce an acceleration of heart beat with
associated heart failure, cardiac arrhythmias, osteoporosis,
increased intestinal motility leading to diarrhoea, psychiatric
abnormalities, and an increase in the basal metabolic rate.
Attempts to use oral thyroid hormone compounds for diminishing
lipid levels in man resulted in increased cardiac deaths.
[0017] What is needed in the art is a method of treating dermal
skin atrophy that does not suffer the drawbacks of current
treatment used in the art. The present invention is believed to be
an answer to that need.
SUMMARY OF THE INVENTION
[0018] In one aspect, the present invention is directed to 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, the composition 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-.alpha. or TR-.beta. with an
equilibrium dissociation constant, K.sub.d, of at least 10.sup.-5
M, wherein K.sub.d=(R).cndot.(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 the dermal atrophy of the skin is reduced.
[0019] In another aspect, the present invention is 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, and wherein the packaging
material comprises a label which indicates that the pharmaceutical
agent can be used for treating dermal atrophy of the skin, and
wherein the pharmaceutical agent comprises at least one thyroid
hormone compound or thyroid hormone-like compound in a
pharmacologically acceptable base suitable for topical application,
wherein the thyroid hormone compound or the thyroid hormone-like
compound binds to TR-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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.
[0020] In yet another aspect, the present invention is directed to
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-phen-
ol, 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.
[0021] In yet another aspect, the present invention is directed to
a method of improving healing of wounded skin of a patient,
comprising the step of applying a composition to the wounded skin
of the patient, the composition 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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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 the
healing of the wounded skin is improved.
[0022] In another aspect, the present invention is directed to a
method of dermatological surgical pretreatment of a patient with
atrophied skin, comprising the step of applying a composition to
the atrophied skin of the patient prior to dermatological surgery,
the composition 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-.alpha. or TR-.beta. with an equilibrium dissociation
constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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.
[0023] These and other aspects will become apparent from the
following drawings and detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The invention will be more fully understood from the
following detailed description taken in conjunction with the
accompanying drawings in which:
[0025] FIG. 1 is a biopsy micrograph analysis (200.times.
magnification) of mouse skin treated with betamethasone and
visualized with van Gieson, and/or hematoxylin/eosin stains;
[0026] FIG. 2 is a biopsy micrograph analysis (200.times.
magnification) of mouse skin treated with betamethasone plus 0.8 mM
Triac and visualized with van Gieson, and/or hematoxylin/eosin
stains;
[0027] FIG. 3 is biopsy micrograph analysis (100.times.
magnification) of treatment of mouse skin with Triac and visualized
with van Gieson, and/or hematoxylin/eosin stains;
[0028] FIG. 4 is a photograph showing a volunteer's forearm
extensor skin surface after 5 months of control creamplacebo
formulation;
[0029] FIG. 5 is a photograph showing a volunteer's forearm
extensor skin surface after 5 months of treatment with the
composition of the invention;
[0030] FIG. 6 is a photograph showing a volunteer's forearm volar
forearm skin surface after five months of treatment with the
composition of the invention;
[0031] FIG. 7 is a photograph showing a volunteer's forearm volar
forearm skin surface after 5 months of treatment with a control
composition;
[0032] FIG. 8 is a photograph showing a volunteer's control
extensor forearm and biopsy site; and
[0033] FIG. 9 is a photograph showing a volunteer's experimental
extensor forearm and biopsy site.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Agents which improve the structure and integrity of the
dermis are not well known. It has now been found that topical
application of a composition comprising at least one thyroid
hormone compound or thyroid hormone-like compound in a
pharmacologically acceptable base is effective in treating dermal
atrophy of the skin. Thyroid hormone compounds or thyroid
hormone-like compounds have also been found to diminish easy
bruising of the skin resulting from surgical procedures and from
everyday injury. They also provide an improved cosmetic appearance
to aging, atrophied, steroid-affected, or sun damaged skin which
exhibits fragility, transparency, mottling, and appearance of
capillaries. They also reverse and prevent the dermal atrophy
induced by glucocorticoids and corticosteroids. These conditions
are improved or reversed, according to the method of the invention,
by application of the above topical composition
[0035] Medical textbooks define thyroids as those hormones that
circulate in the human body, namely T-3 (Tri-iodothyronine,
3,5,3'-triiodothyronine and T-4 (D and L thyroxine) and their
metabolites. However, it s now clear that many compounds which
possess thyroid hormone activity may have considerably different
chemical structure, including for example the loss of an amino acid
group or the elimination of iodine from the molecule. Accordingly,
for the purposes of this invention a "thyroid hormone compound" or
"thyroid hormone-like compound", which terms are used
interchangeably herein, is any chemical entity, including peptides,
which binds to thyroid hormone receptor TR-.alpha. or .beta. with a
dissociation constant, K.sub.d, of at least 10.sup.-5 Molar
(Goodman and Gilman, The Pharmacologic Basis of Therapeutics, p.
30, 1975) when measured by any of the methods known in the art.
Furthermore, the thyroid hormone receptor binding drug should be
active when applied topically at a concentration no higher than 0.1
Molar. Such ligands may be considered agonists when they have
similar agonistic effects as the natural hormone or may be
considered antagonists when the compounds antagonize the effects of
the natural hormone compounds. Partial agonist/antagonists also may
exist. Suitable ligands may be agonists or antagonists. The
thyroids may be any natural or synthetic analog of
triiodothyroacetic acid ("Triac") which binds to the thyroid
hormone receptor within the above range of K.sub.d and possesses
the biological activity of triiodothyroacetic acid.
[0036] For the purposes of this invention, the term thyroid hormone
receptor will include all of the gene products of C-erb-A and its
variants which bind thyroid hormone compounds or thyroid
hormone-like compounds. Additionally, the terms steroids,
glucocorticoids, and corticosteroids are used interchangeably for
the dermatological purposes described herein.
[0037] As indicated above, the present invention is directed to a
method for treating, reversing, or preventing dermal skin atrophy.
The method of the present invention comprises the step of apply a
composition to the skin of a mammal suffering from dermal atrophy
of the skin, the composition 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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M, wherein
K.sub.d=(R).cndot.(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 the
dermal atrophy of the skin is reduced. The present invention is
also directed to an article of manufacture comprising packaging
material and a pharmaceutical agent contained within said packaging
material. The pharmaceutical agent is therapeutically effective for
treating dermal atrophy of the skin, and 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-.alpha. or TR-.beta. with an equilibrium
dissociation constant, K.sub.d, of at least 10.sup.-5 M. The
packaging material comprises a label which indicates that the
pharmaceutical agent can be used for treating dermal atrophy of the
skin.
[0038] The thyroid hormone compound or thyroid hormone-like
compound may be any compound that meets the above definition.
Suitable thyroid hormone or thyroid hormone-like compounds include
Tri-iodothyronine (3,5,3'-triiodothyronine, T3); D and L thyroxine
(T4); 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-diiodophenyl]acetic acid);
Tetraprop; Triprop
([4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propion- ic 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-methoxybenzy- l Bromide;
(5-Benzyloxy-2-methoxyphenyl-(6-chloropyridazin-3-yl)-acetonitr-
ile; 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-thyronin-
e ethyl esters;
3'-heteroarylmethyl-3,5-di-iodo-4')-methyl-N-trifluoro-ace-
tyl-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;
.alpha.-methyl-3,5,3'-triiodothyroacetic acid,
.alpha.-methyl-3,5,3'-trii- odothyropropionic acid, and
.alpha.-methyl-3,5,3',5'-tetraiodothyropropion- ic acid; methylene-
and carbonyl-bridged analogs of iodinated thyronines or thyroacetic
acids or iodinated benzofurans; 3,5-diiodo-4-(2-N,N-diethy-
laminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride;
2-methyl-3-(3,5-diiodo-4-(2-N,N-diethylamino-ethoxy)-benzoyl)benzofuran
hydrochloride;
2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy-benzoyl)benzofura- n;
2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran;
2-methyl-3-(3,5-diiodo-4-carboymethoxy-benzyl)benzofuran;
[4'-hydroxy-3'-iodo-3,5
diiodo-4-(2-N,N-dimethylamino-ethoxy)benzophenone hydrochloride;
2-butyl-3-(3-iodo-4-hydroxybenzoyl)benzofuran; 4',4-dihydroxy
3'3,5-triiodo-diphenylmethane; 3,5-diiodo-4-(2-N,N-diethyl-
aminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride;
2-methyl-3-(3,5-diiodo-4-(2-N,N-diethylamino-ethoxy)-benzoyl)benzofuran
hydrochloride;
2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy-benzoyl)benzofura- n;
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)benzofuran;
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.
[0039] Other suitable thyroid hormone-like compounds are disclosed
for example in U.S. Pat. Nos. 5,284,971; 3,649,679; 3,357,887;
4,168,385; 5,179,097, EP 0580550, EP 018351 and H. A. Selenkow and
S. P. Asper, Jr., Physiol. Rev. 35 426 (1955); C. S. Pitman and J.
A. Pitman in Handbook of Physiology, Section 7: Endocrinology, Vol.
3, R. O. Greep and E. B. Astwood, Eds., Thyroid American
Physiological Society, Washington, D.C., 1974, p. 233; E. C.
Jorgensen, Pharm. Ther. B, 2, 661 (1976); and E. C. Jorgensen,
"Thyroid Hormones and Analogs. II. Structure-Activity
Relationships," in Hormonal Proteins and Peptides, Vol. 6, Thyroid
Hormones, C. H. Li, Ed., Academic, New York, 1978, p. 108., all of
which are incorporated by reference herein. The choice of other
suitable thyroid hormone-like compounds for use in the compositions
and methods of the present invention is within the scope of the
skilled worker.
[0040] The thyroid hormone compound or thyroid hormone-like
compound is preferably in pure form, i.e., not contaminated with
other compounds greater than about 0.1%.
[0041] The thyroid hormone compound or thyroid hormone-like
compound is preferably at least partially dissolved in a solvent.
The solvent is preferably an organic solvent selected from alcohol
and alcohol and water solutions. More preferably, the organic
solvent is selected from isopropanol, isopropanol and water,
ethanol, and ethanol and water solutions containing at least 20%
alcohol.
[0042] As described above, the thyroid hormone compound or thyroid
hormone-like compound is mixed with a pharmacologically acceptable
base that is suitable for topical application. Examples of suitable
pharmacologically acceptable bases include oil in water (or water
in oil) emulsions, sprays, liposomes, creams, lotions, solutions,
and combinations thereof. The composition may also include suitable
epidermal penetration-enhancing agents. The pharmacologically
acceptable base is preferably an oil in water emulsion, a cream, or
an alcoholic solution with glycerol. One particularly preferred
pharmacologically acceptable base composition is a cream that
includes linoleic, oleic, palmitic, and linolenic fatty acids or
esters thereof and/or combined with triglycerides. This composition
is preferably combined with one or more additional substituents
including glyceryl stearate, safflower oil, sorbitol, cetyl
alcohol, stearic acid, triethanolamine, and the like.
[0043] Preferably, the composition comprises less than about 200
mg/100 ml, more preferably less than about 50 mg/100 ml of the
thyroid hormone compound or thyroid hormone-like compound.
Preferably the composition comprises a concentration
5.times.10.sup.8 times or less the receptor dissociation constant,
K.sub.d, of the said at least one thyroid hormone compound or
thyroid hormone-like compound. Preferably the composition is used
to supply an effective amount of the thyroid hormone compound or
thyroid hormone-like compound which generally ranges from 500
mg/m.sup.2 to 0.1 mg/m.sup.2 in one or more applications,
preferably 250 mg/m.sup.2 to 1 mg/m.sup.2 per day in one or more
applications. A useful amount to apply is 100 .mu.l-1000 .mu.l at
the above concentrations. As will be appreciated by those skilled
in the art, the effective concentration of the thyroid hormone
compound or thyroid hormone-like compound will depend on factors
such as metabolism of the compound, the pharmaceutical or cosmetic
base employed, and the like.
[0044] The composition of the invention may also include other
additional ingredients such as Vitamin D, estrogens,
glucocorticoids and retinoids or analogues thereof to potentiate
and modify the effects of the thyroid hormone compound or thyroid
hormone-like compound for increased benefit. The composition may
also include BHT (butylated hydroxy toluene) or BHA (butylated
hydroxy anisole) as a hindered phenol to decrease iodine
decomposition or oxidation. Furthermore, the composition may
include compounds which facilitate passage of the thyroid hormone
through the skin and compounds which act as sunscreens such as
PABA. Preferably, the composition also includes a suitable
antioxidant such as Tinuvin P or vitamin E. The choice of such
compounds is within the scope of the skilled addressee. See for
example Hermens W. A. J. J Pharmaceutisch Weekblad Scientific
Edition 14(4A) 1992. Preferably, the thyroid hormone compound or
thyroid hormone-like compound is not halogenated as such compounds
are less prone to photodecomposition.
[0045] The composition used in the method of the invention is
preferably applied to the skin of a mammal suffering from dermal
atrophy of the skin, and more preferably to the skin of a human
suffering from dermal atrophy of the skin. Preferably, the
composition is applied from twice a day to every three days.
[0046] Topical administration of thyroid hormone to the skin allows
direct thyroid hormone to modulation of the skin without influence
by modulating factors produced in the pituitary, liver, or other
organs. Further, the extensive metabolism by the liver and kidney
of thyroid hormones into inactive metabolites is avoided by topical
application. However, the dermatological effect of topically
applied thyroid hormones in humans and animals is for the most part
entirely unknown, and no medical publications appear which relate
to this topic.
[0047] The topically-applied thyroid hormone compounds, or thyroid
hormone-like compounds, used in the compositions and methods of the
present invention are advantageous in that they enable the use of
these chemical compounds to treat dermal skin atrophy, to improve
the appearance of the skin, or normalize the physiology of the skin
under pathophysiologic conditions without causing the undue adverse
effects of orally administered thyroid hormone compounds, and
avoids renal and hepatic metabolism of the thyroid hormone receptor
binding chemical entity. In particular, the method of delivery of
the thyroid hormone compounds and thyroid hormone-like compounds
avoids liver and kidney metabolism of the hormones, blood
circulation of the hormones to other tissue and binding to blood
carrier proteins which can alter efficacy. Moreover, topical
administration of the composition of the invention should not cause
a hyperthyroid state.
[0048] The compositions and methods of the present invention are
also useful for improving healing of wounded skin of a patient, as
shown in detail in Example 2 below. The compositions and methods of
the present invention are also useful for pretreatment a patient's
atrophied skin prior to dermatologic surgery. It has been found
that application of the composition of the present invention to the
skin prior to dermatologic surgery results in faster healing of the
skin in the weeks following the surgery. While not wishing to be
bound by any particular theory, it is thought that the
topically-applied thyroid hormone compounds or thyroid hormone-like
compounds treat dermal skin atrophy by increasing the cellularity
and thickness of the dermis and by an associated increase in
collagen fibers, among other biological substances.
EXAMPLES
[0049] The invention is further described by the following
Examples, but is not intended to be limited by the Examples. All
parts and percentages are by weight and all temperatures are in
degrees Celsius unless explicitly stated otherwise.
Example 1
Prevention of Glucocorticoid-Induced Atrophy in Normal Mice
[0050] Normal Balb/c mice were used for the experiments. 100 .mu.l
solution of either betamethasone (0.2 mM in 50% isopropanol/water),
topical thyroid agonist (Triac, Triprop,
4-[2,6-dibromo-4-(1H-tetrazol-5--
ylmethyl)-phenoxy]-2-isopropyl-phenol (KB-067),
4-(4-hydroxymethyl-2,6-dii- odophenoxy)-2-iodo-phenol (KB-026) in
50% isopropanol/water at various concentrations, or both were
applied daily to the shaved back of the animals for one week.
Biopsies were taken and the thickness of the dermal layer was
measured microscopically after staining of collagen with Van Gieson
stain. Five mice were used for each measurement at each
concentration of test material and 5 sections were averaged from
each mouse. Therefore each averaged measurement represents 25
determinations. FIGS. 1-3 and Tables 1 and 2 show the effects of a
range of doses of Triac or Triac cream in preventing
betamethasone-induced atrophy after one week.
[0051] In FIGS. 1-3, the arrows show the dermal layer which is
predominantly collagen fibers. In some of the Experiments, Triac
was formulated as a 0.1% or 0.03% cream and 100 .mu.l was applied
to the mice.
[0052] FIG. 1 shows a biopsy micrograph analysis (200.times.
magnification) of mouse skin treated with betamethasone alone for
one week, which is known to cause dermal skin atrophy. As shown in
FIG. 1, the dermis appears to be very thinned, and some of the deep
dermis has pulled away from the fat and muscle layer of the
subcutaneaous tissues (a biopsy fixation artifact).
[0053] FIG. 2 shows a biopsy micrograph analysis (200.times.
magnification) of mouse skin treated with 0.2 mM betamethasone plus
0.8 mM Triac, both in 50% isopropanol/water for one week. As shown
in FIG. 2, the collagen layer (dermis) is almost double the
thickness of the skin treated with betamethasone alone shown in
FIG. 1. Thus, the Triac appears to be preventing
betamethasone-induced dermal skin atrophy.
[0054] FIG. 3 shows a biopsy micrograph analysis (100.times.
magnification) of treatment of mouse skin with Triac alone for one
week. As shown in FIG. 3, the dermis is very dense and thicker than
that shown in FIG. 2. Compared to normal mouse skin, the collagen
layers are very thick and dense. Additionally, as shown in Table 2
below, Triac treated skin increased from 0.54 mm to 0.79 mm in a
mouse treated with isopropanol/water alone. Therefore, Triac by
itself can improve skin thickness in the absence of
betamethasone-induced atrophy.
1TABLE 1 Effect of Various Concentrations of TriAc on
Corticosteroid-Induced Skin Atrophy in a Mouse Model Thickness of
dermis (mm) in no of Group 5 low power fields (.times.10) mean (mm)
SD mice *p Betamethasone 0.2 mM 0.38 0.37 0.36 0.40 0.35 0.37 0.01
5 Bet. + 0.0008 mM TriAc 0.40 0.40 0.36 0.38 0.36 0.38 0.02 4 Bet.
+ 0.008 mM TriAc 0.40 0.47 0.48 0.44 0.46 0.45 0.02 5 Bet. + 0.08
mM TriAc 0.50 0.48 0.53 0.49 0.50 0.50 0.02 5 <0.05 Bet. + 0.8
mM TriAc 0.49 0.54 0.51 0.48 0.48 0.50 0.02 5 <0.05 Bet. + 8 mM
TriAc 0.52 0.50 0.47 0.52 0.49 0.50 0.02 5 <0.05 Vehicle (50%
0.53 0.45 0.52 0.51 0.49 0.50 0.01 5 <0.05
isopropanol/water)
[0055]
2TABLE 2 Effect of Various Concentrations of TriAc and TriAc Cream
on Betamethasone-induced Skin Atrophy in a Mouse Model Thickness of
dermis (mm) no of Group in 5 low power fields (.times.10) mean (mm)
SD mice *p Betamethasone 0.2 mM 0.39 0.41 0.37 0.37 0.4 0.39 0.02 5
Bet. + TriAc 0.0008 mM 0.4 0.37 0.4 0.43 0.4 0.40 0.02 4 Bet. +
TriAc 0.008 mM 0.41 0.37 0.4 0.43 0.4 0.40 0.02 5 Bet. + TriAc 0.08
mM 0.52 0.53 0.45 0.5 0.52 0.50 0.03 5 <0.05 Bet. + TriAc 0.8 mM
0.54 0.6 0.6 0.56 0.62 0.58 0.03 5 <0.05 TriAc 0.8 mM 0.72 0.82
0.84 0.76 0.82 0.79 0.05 5 <0.05 Bet. + placebo cr. 0.35 0.4
0.37 0.39 0.4 0.38 0.02 5 Bet. + TriAc cr. (0.01 0.46 0.48 0.5 0.49
0.5 0.49 0.02 5 <0.05 % TriAc) Bet. + TriAc cr. (0.03 0.5 0.58
0.56 0.55 0.58 0.55 0.03 5 <0.05 % TriAc) Vehicle (50% 0.6 0.58
0.57 0.59 0.58 0.58 0.01 4 <0.05 propanol/water) *p is defined
as the probability that the result is due to chance alone. "cr."=
hydrophilic cream
[0056] As can be seen in Tables 1 and 2, a gradual increase in
effectiveness occurs as the concentration of Triac increases from
0.0008 to 8 mM, with the effect saturating at approximately 0.8
mM.
[0057] Table 3 shows the effects of Triac alone, Triac cream,
TriProp,
4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-2-isopropyl-phenol,
4-(4-hydroxymethyl-2,6-diiodophenoxy)-2-iodo-phenol on
betamethasone-induced skin atrophy in a mouse model.
3TABLE 3 Effect of Various Concentrations of Triac cream, TriProp,
4-[2,6-dibromo-4-(1H-tetrazol-5-
ylmethyl)-phenoxy]-2-isopropyl-phenol (KB-067),
4-(4-hydroxymethyl-2,6-di- iodophenoxy)- 2-iodo-phenol (KB-026) on
Betamethasone-Induced Skin Atrophy in a Mouse Model Thickness of
dermis (mm) in no of Group 5 low power fields (mm) mean (mm) SD
mice *p Triac 0.8 mM 0.72 0.82 0.84 0.76 0.82 0.079 Betamethasone
0.2 mM 0.50 0.38 0.41 0.42 0.39 0.42 0.05 4 Bet. 0.2 mM + placebo
0.40 0.42 0.38 0.40 0.39 0.40 0.01 5 cr. Bet. + TriAc cr. (0.01%
0.50 0.52 0.45 0.53 0.50 0.50 0.03 5 <0.05 TriAc) Bet. + TriAc
cr. (0.03%) 0.50 0.55 0.60 0.56 0.57 0.56 0.04 5 <0.05 Bet. +
0.0008 mM 0.40 0.41 0.40 0.42 0.41 0.41 0.01 4 KB-026 Bet. + 0.008
mM 0.45 0.42 0.46 0.44 0.45 0.44 0.01 4 KB-026 Bet. + 0.08 mM
KB-026 0.44 0.50 0.49 0.46 0.50 0.48 0.03 4 Bet. + 0.8 mM KB-026
0.50 0.52 0.48 0.51 0.50 0.50 0.01 4 <0.05 Bet. + 0.0008 mM 0.41
0.40 0.46 0.40 0.41 0.42 0.03 4 TriProp Bet. + 0.008 mM 0.45 0.50
0.40 0.42 0.48 0.45 0.04 4 TriProp Bet. + 0.08 mM TriProp 0.50 0.48
0.47 0.50 0.44 0.48 0.02 4 Bet. + 0.8 mM TriProp 0.50 0.45 0.47
0.48 0.52 0.48 0.03 4 Bet. + 0.0008 mM 0.42 0.39 0.40 0.39 0.40
0.40 0.01 4 KB-067 Bet. + 0.008 mM 0.40 0.39 0.41 0.40 0.39 0.40
0.01 4 KB-067 Bet. + 0.08 mM KB-067 0.40 0.40 0.41 0.39 0.41 0.04
0.01 4 Bet. + 0.8 mM KB-067 0.45 0.46 0.47 0.45 0.48 0.46 0.01 4
Vehicle (50% 0.52 0.55 0.53 0.56 0.55 0.54 0.02 4 <0.05
propanol/water) *p is defined as the probability that the result is
due to chance alone. cr. = hydrophilic cream
[0058] As shown in Table 3, all compounds were capable of
preventing betamethasone-induced atrophy and thinning of the
dermis. Each was effective at a slightly different concentration
range. From the above tables, one can therefore conclude that
topical thyroids including tri-iodothryoacetic acid (triac) and
others are effective at preventing glucocorticoid-induced dermal
skin atrophy in mice.
Example 2
Treatment of Glucocorticoid-Induced Atrophy in Human
[0059] A 78-year old volunteer displayed tissue paper thin
transparent skin, with atrophy of the dermis and subcutaneous fat,
and easy bruisability. The patient had a history of rheumatoid
arthritis treated with oral prednisone, but was currently receiving
only a maintenance dose (5 mg) of prednisone. Multiple bruises
covered each forearm extensor surface. Surface capillaries were
visible through the skin and the forearms had a brown cast (FIG.
4).
[0060] A hydrophilic vanishing cream containing 30 mg of Triac per
100 ml vehicle alone was prepared as follows. Triac was added in 10
ml of 70% isopropanol per 120 ml vehicle and mixed to produce a 29
mg Triac per 100 ml cream. The cream was diluted with vehicle (a
mixture of glyceryl stearate, safflower oil containing linoleic,
oleic, palmitic, linolenic, and other fatty acid substituents,
sorbitol, cetyl alcohol, stearic acid, triethanolamine) to produce
the 10 mg/ml cream one part plus two parts vehicle, and
subsequently diluted again in the same manner.
[0061] The above preparations were applied to the other forearm of
the patient in a blinded fashion for a period of approximately six
months. Due to the effects of the cream, patient blinding became
impossible after approximately eight weeks. The following dose
schedule was used in a consecutive manner: (1) Eight weeks of 30 mg
Triac per 100 ml vehicle, followed by (2) 4 weeks of 10 mg Triac
per 100 ml vehicle, followed by (3) 12 weeks of 3.3 mg Triac per
100 ml vehicle.
[0062] At the 30 mg/ml, 5.6% isopropanol dose some pruritus
occurred which was minor and did not prevent cream application. No
pruritus occurred at the lowered dosages. During the treatment
period, the patient had intermittent courses of prednisone ranging
from 10 to 30 mg per day for periods up to two weeks.
[0063] Clinically, a change in the skin could be seen in eight
weeks, and was remarked upon by untrained observers. Purpura
(bruising) was markedly decreased in the treated arm (FIG. 5).
After a total of six months of treatment, the patient was examined
by a dermatologist. On blinded clinical examination, the treated
arm (FIGS. 5, 6, and 9) appeared healthier with more even
pigmentation, less brown cast, less wrinkling and slightly higher
turgor and elasticity than the control arm (FIGS. 4, 7, and 8).
Superficial veins were also more difficult to detect.
[0064] After six months of treatment, 3 mm punch biopsies were
taken to identical depths. Biopsy of the extensor surface of the
control forearm revealed solar elastosis, orthokeratosis, with
epidermal and prominent dermal atrophy and reduced collagen. Biopsy
of the extensor surface of the treated arm revealed no dermal
atrophy and increased cellularity, and continued solar elastosis,
orthokeratosis, and evidence for hyperkeratosis. Physically the
treated specimen was thicker than the untreated one. Trichrome
staining revealed an increase in collagen fibers in the reticular
dermis in the treated specimen. Eccrine glands were situated far
more superficially in the untreated side.
[0065] After the biopsy, bruising around the biopsy occurred in the
control forearm associated with the biopsy site and also with the
bandage (FIG. 8). It did not develop in the treated arm (FIG. 9).
The treated arm also has a greatly reduced purpuric response to
injury and the biopsy site healed more readily (FIG. 9).
[0066] Skin thickness measurements were performed with a
springloaded micrometer during skin tenting. The results are show
in Table 4.
4TABLE 4 Skin Thickness Measurements Double Skin Calculated Site
Measurement Thickness Treated Extensor 2.16 mm 1.08 mm Forearm
Untreated Extensor 1.65 mm 0.83 mm Forearm
[0067] As shown in Table 4, double thickness skin measurements were
taken from the extensor surface of each forearm, revealing a 0.25
mm single skin thickness difference in apparent skin thickness, or
a 30% increase in the thickness of the skin.
[0068] While the invention has been described in combination with
embodiments thereof, it is evident that many alternatives,
modifications and variations will be apparent to those skilled in
the art in light of the foregoing description. Accordingly, it is
intended to embrace all such alternatives, modifications and
variations as fall within the spirit and broad scope of the
appended claims. All patent applications, patents, and other
publications cited herein are incorporated by reference in their
entireties.
* * * * *