U.S. patent application number 11/091037 was filed with the patent office on 2005-07-28 for method of treating scarring.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Lee, James H., Miller, Richard L., Owens, Mary L..
Application Number | 20050165043 11/091037 |
Document ID | / |
Family ID | 32990886 |
Filed Date | 2005-07-28 |
United States Patent
Application |
20050165043 |
Kind Code |
A1 |
Miller, Richard L. ; et
al. |
July 28, 2005 |
Method of treating scarring
Abstract
Methods of treating scarring are disclosed. Generally, the
methods include topically administering an IRM compound to the site
of a surgical wound for a period of time and in an amount effective
for preventing, reversing, or reducing the formation of a scar.
Suitable IRM compound compounds include agonists of one or more
TLRs.
Inventors: |
Miller, Richard L.;
(Maplewood, MN) ; Lee, James H.; (St. Paul,
MN) ; Owens, Mary L.; (Cottage Grove, MN) |
Correspondence
Address: |
3M INNOVATIVE PROPERTIES COMPANY
PO BOX 33427
ST. PAUL
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
32990886 |
Appl. No.: |
11/091037 |
Filed: |
March 28, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11091037 |
Mar 28, 2005 |
|
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10799999 |
Mar 12, 2004 |
|
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60454245 |
Mar 13, 2003 |
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Current U.S.
Class: |
514/292 |
Current CPC
Class: |
A61K 31/4745 20130101;
A61P 37/02 20180101; A61P 43/00 20180101; A61P 17/16 20180101; A61K
31/397 20130101; A61Q 19/08 20130101; A61K 8/4946 20130101; A61P
35/00 20180101; A61P 17/00 20180101; A61P 17/12 20180101; Y10S
514/844 20130101; Y10S 514/878 20130101; A61P 17/02 20180101; A61K
2800/70 20130101 |
Class at
Publication: |
514/292 |
International
Class: |
A61K 031/4745 |
Claims
What is claimed is:
1. A method of preventing scarring of a subject's skin resulting
from a surgical wound, the method comprising topically applying to
the skin at the site of the surgical wound an IRM compound in an
amount effective to improve the quality of the skin.
2. The method of claim 1 wherein the IRM compound is an agonist of
at least one TLR.
3. The method of claim 2 wherein the IRM compound is an agonist of
TLR7, TLR8, or both TLR7 and TLR8.
4. The method of claim 1 wherein the IRM compound is administered
via a topical application vehicle.
5. The method of claim 4 wherein the topical application vehicle
comprises a cream, a foam, a gel, a spray, an ointment, a lotion, a
solution, a suspension, a dispersion, an emulsion, a microemulsion,
a paste, a powder, a wipe, or an oil.
6. The method of claim 1 wherein the IRM compound is an
imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an
imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a
6,7-fused cycloalkylimidazopyridine amine, an imidazonaphthyridine
amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline
amine, a thiazoloquinoline amine, an oxazolopyridine amine, a
thiazolopyridine amine, an oxazolonaphthyridine amine, a
thiazolonaphthyridine amine, or a combination thereof.
7. The method of claim 1 wherein applying an IRM compound in an
amount effective comprises providing a dose of 100 ng/kg to 50
mg/kg to the subject.
8. The method of claim 7 wherein applying an IRM compound in an
amount effective comprises providing a dose of 10 .mu.g/kg to 5
mg/kg to the subject.
9. The method of claim 7 wherein applying an IRM compound in an
amount effective comprises providing a dose of 100 .mu.g/kg to 1
mg/kg to the subject.
10. The method of claim 1 wherein the IRM compound is applied at
least two times per week.
11. A method of reversing or reducing scarring of a subject's skin
resulting from a surgical wound, the method comprising topically
applying to the scarred skin at the site of the surgical wound an
IRM compound in an amount effective to improve the quality of the
skin.
12. The method of claim 11 wherein the IRM compound is an agonist
of at least one TLR.
13. The method of claim 12 wherein the IRM compound is an agonist
of TLR7, TLR8, or both TLR7 and TLR8.
14. The method of claim 11 wherein the IRM compound is administered
via a topical application vehicle.
15. The method of claim 14 wherein the topical application vehicle
comprises a cream, a foam, a gel, a spray, an ointment, a lotion, a
solution, a suspension, a dispersion, an emulsion, a microemulsion,
a paste, a powder, a wipe, or an oil.
16. The method of claim 11 wherein the IRM compound is an
imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an
imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a
6,7-fused cycloalkylimidazopyridine amine, an imidazonaphthyridine
amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline
amine, a thiazoloquinoline amine, an oxazolopyridine amine, a
thiazolopyridine amine, an oxazolonaphthyridine amine, a
thiazolonaphthyridine amine, or a combination thereof.
17. The method of claim 11 wherein applying an IRM compound in an
amount effective comprises providing a dose of 100 ng/kg to 50
mg/kg to the subject.
18. The method of claim 17 wherein applying an IRM compound in an
amount effective comprises providing a dose of 10 .mu.g/kg to 5
mg/kg to the subject.
19. The method of claim 17 wherein applying an IRM compound in an
amount effective comprises providing a dose of 100 .mu.g/kg to 1
mg/kg to the subject.
20. The method of claim 1 wherein the IRM compound is applied at
least two times per week.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/799,999, filed Mar. 12, 2004, which claims
priority to U.S. Provisional Patent Application No. 60/454,245,
filed Mar. 13, 2003.
BACKGROUND OF THE INVENTION
[0002] Skin condition is continuously affected by various factors
including, for example, humidity, UV-light, cosmetics, aging,
diseases, stress, cigarette smoking, and eating habits, each of
which can result in various skin changes. Additionally, certain
changes appear on the skin that are characteristic of aging, many
of which are reflected, in particular, by a change in the skin's
structure. The main clinical signs of aging of the skin are, in
particular, the appearance of fine lines and deep wrinkles, each of
which can increase with age. Wrinkles can be caused by both the
chronological aging of the skin and photoaging of skin due to
exposure of the skin to sunlight, UV-radiation and other forms of
actinic radiation.
[0003] In young skin, the collagen just beneath the surface of the
skin forms an organized lattice with good elasticity and
flexibility. During aging, the collagen structure can change, thus
causing changes in the cosmetic appearance of the skin that many
find undesirable. Current methods of improving skin quality include
the application of cosmetic products containing active agents such
as moisturizers, alpha-hydroxy acids, beta-hydroxy acids and
retinoids. However, other methods are still sought after.
SUMMARY OF THE INVENTION
[0004] It has been found that certain immune response modifier
(IRM) compounds can be used to improve skin quality.
[0005] In some aspects, the present invention provides methods of
improving skin quality by topically applying to the skin an IRM
compound in an amount effective to improve the quality of the
skin.
[0006] In some aspects, the present invention provides methods of
visibly reducing a skin change associated with aging by topically
applying to skin exhibiting an age-associated change an IRM
compound, wherein the IRM compound is applied in an amount and for
a period of time sufficient to visibly reduce the skin change
associated with aging.
[0007] In other aspects, the present invention includes methods of
visibly reducing a human skin wrinkle by topically applying to the
human skin wrinkle an IRM compound in an amount and for a period of
time sufficient to visibly reduce the wrinkle.
[0008] In other aspects, the present invention includes methods of
treating aging related skin conditions by topically applying to the
skin an IRM compound for a period of time and in an amount
sufficient to effect changes in the dermis.
[0009] In still other aspects, the present invention includes
methods for reducing the appearance of skin changes associated with
aging by topically applying to an area of skin exhibiting skin
changes associated with aging an IRM compound in an amount and for
a period of time sufficient to reduce the appearance of skin
changes associated with aging.
[0010] In yet other aspects, the present invention includes methods
for improving the quality of facial skin by topically applying to
the facial skin an IRM compound in an amount and for a period of
time sufficient to reverse or prevent changes in the dermis, where
the changes in the dermis result from natural or innate aging or
exposure to actinic radiation, and the changes in the dermis
include diminution in the number and diameter of elastic fibers in
the papillary dermis, atrophy of the dermis, reduction in
subcutaneous adipose tissue, deposition of abnormal elastic
materials in the upper dermis, and combination thereof.
[0011] In some embodiments of the methods of the present invention,
the IRM compound may be an agonist of at least one TLR; including
an agonist of TLR7, TLR8 or both TR7 and TR8.
[0012] In some embodiments of the methods of the present invention,
the IRM compound may be administered via a topical application
vehicle including a cream, a foam, a gel, a spray, an ointment, a
lotion, a solution, a suspension, a dispersion, an emulsion, a
microemulsion, a paste, a powder, a wipe, or an oil.
[0013] In the some embodiments of the methods of the present
invention, the IRM compound may be an imidazoquinoline amine, a
tetrahydroimidazoquinoline amine, an imidazopyridine amine, a
1,2-bridged imidazoquinoline amine, a 6,7-fused
cycloalkylimidazopyridine amine, an imidazonaphthyridine amine, a
tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a
thiazoloquinoline amine, an oxazolopyridine amine, a
thiazolopyridine amine, an oxazolonaphthyridine amine, or a
thiazolonaphthyridine amine, or a combination thereof.
[0014] Various other features and advantages of the present
invention should become readily apparent with reference to the
following detailed description, examples, and claims. In several
places throughout the specification, guidance is provided through
lists of examples. In each instance, the recited list serves only
as a representative group and should not be interpreted as an
exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION
[0015] The present invention provides methods of improving skin
quality by the topical administration of an immune response
modifier (IRM) compound to the skin in an amount effective to
improve the quality of skin.
[0016] IRM compounds have previously been shown to be useful for
treating many different types of conditions. It has now been found
that when topically applied to the skin such as, for example, to
treat a dermatological condition, certain IRM compounds provide a
secondary benefit of improving the quality of skin treated with the
IRM. That is, treatment of skin with an IRM compound not only, for
example, clears lesions associated with the condition being
treated, but also leaves the treated skin in even better condition
than skin unaffected by the condition and, therefore, left
untreated.
[0017] IRM compounds include compounds that possess potent
immunomodulating activity including but not limited to antiviral
and antitumor activity. Certain IRMs modulate the production and
secretion of cytokines. For example, certain IRM compounds induce
the production and secretion of cytokines such as, e.g., Type I
interferons, TNF-.alpha., IL-1, IL-6, IL-8, IL-10, IL-12, MIP-1,
and/or MCP-1. As another example, certain IRM compounds can inhibit
production and secretion of certain T.sub.H2 cytokines, such as
IL-4 and IL-5. Additionally, some IRM compounds are said to
suppress IL-1 and TNF (U.S. Pat. No. 6,518,265).
[0018] Certain IRMs are small organic molecules (e.g., molecular
weight under about 1000 Daltons, preferably under about 500
Daltons, as opposed to large biological molecules such as proteins,
peptides, and the like) such as those disclosed in, for example,
U.S. Pat. Nos. 4,689,338; 4,929,624; 4,988,815; 5,037,986;
5,175,296; 5,238,944; 5,266,575; 5,268,376; 5,346,905; 5,352,784;
5,367,076; 5,389,640; 5,395,937; 5,446,153; 5,482,936; 5,693,811;
5,741,908; 5,756,747; 5,939,090; 6,039,969; 6,083,505; 6,110,929;
6,194,425; 6,245,776; 6,331,539; 6,376,669; 6,451,810; 6,525,064;
6,541,485; 6,545,016; 6,545,017; 6,558,951; 6,573,273; 6,656,938;
6,660,735; 6,660,747; 6,664,260; 6,664,264; 6,664,265; 6,667,312;
6,670,372; 6,677,347; 6,677,348; 6,677,349; 6,683,088; European
Patent 0 394 026; U.S. Patent Publication Nos. 2002/0016332;
2002/0055517; 2002/0110840; 2003/0133913; 2003/0199538; and
2004/0014779; and International Patent Publication Nos. WO
01/74343; WO 02/46749 WO 02/102377; WO 03/020889; WO 03/043572; WO
03/045391; and WO 03/103584.
[0019] Additional examples of small molecule IRMs include certain
purine derivatives (such as those described in U.S. Pat. Nos.
6,376,501, and 6,028,076), certain imidazoquinoline amide
derivatives (such as those described in U.S. Pat. No. 6,069,149),
certain imidazopyridine derivatives (such as those described in
U.S. Pat. No. 6,518,265), certain benzimidazole derivatives (such
as those described in U.S. Pat. No. 6,387,938), certain derivatives
of a 4-aminopyrimidine fused to a five membered nitrogen containing
heterocyclic ring (such as adenine derivatives described in U.S.
Pat. Nos. 6,376,501; 6,028,076 and 6,329,381; and in WO 02/08595),
and certain 3-.beta.-D-ribofuranosylthiaz- olo[4,5-d]pyrimidine
derivatives (such as those described in U.S. Publication No.
2003/0199461).
[0020] Other IRMs include large biological molecules such as
oligonucleotide sequences. Some IRM oligonucleotide sequences
contain cytosine-guanine dinucleotides (CpG) and are described, for
example, in U.S. Pat. Nos. 6,194,388; 6,207,646; 6,239,116;
6,339,068; and 6,406,705. Some CpG-containing oligonucleotides can
include synthetic immunomodulatory structural motifs such as those
described, for example, in U.S. Pat. Nos. 6,426,334 and 6,476,000.
Other IRM nucleotide sequences lack CpG sequences and are
described, for example, in International Patent Publication No. WO
00/75304.
[0021] Other IRMs include biological molecules such as aminoalkyl
glucosaminide phosphates (AGPs) and are described, for example, in
U.S. Pat. Nos. 6,113,918; 6,303,347; 6,525,028; and 6,649,172.
[0022] Certain IRMs can function as Toll-like receptor (TLR)
agonists, i.e., their immunomodulating influence is exerted through
a TLR-mediated cellular pathway. For example, some small molecule
IRMs have been identified as agonists of one or more members of the
TLR receptor family, TLR2, TLR4, TLR6, TLR7, and TLR8; certain AGPS
have been identified as agonists of TLR4; and, certain CpGs have
been identified as a agonists of TLR9. In many cases, activating a
TLR-mediated pathway results in gene transcription, cytokine or
co-stimulatory marker expression regardless of the particular TLR
that is activated.
[0023] In certain embodiments of the present invention, the IRM is
an agonist of at least one TLR. In particular embodiments, the IRM
compound can be an agonist of TLR7, TLR8, and/or TLR9. In
alternative embodiments, the IRM compound is an agonist of TLR4. In
certain specific embodiments, the IRM is an agonist of TLR8 or an
agonist of both TLR7 and TLR8. The IRM may induce the production of
one or more cytokines, including but not limited, to Type I
interferons, TNF-.alpha., IL-10, and IL-12. See, for example,
Gibson et al., Cell Immunol. 218(1-2): 74-86 (2002). The IRM may
effect the maturation, activation, and/or migration of cells of the
myeloid lineage, including, but not limited to, macrophages,
dendritic cells, and Langerhans cells.
[0024] Suitable IRM compounds include, but are not limited to, the
small molecule IRM compounds described above having a
2-aminopyridine fused to a five membered nitrogen-containing
heterocyclic ring. Such compounds include, for example,
imidazoquinoline amines including but not limited to amide
substituted imidazoquinoline amines, sulfonamide substituted
imidazoquinoline amines, urea substituted imidazoquinoline amines,
aryl ether substituted imidazoquinoline amines, heterocyclic ether
substituted imidazoquinoline amines, amido ether substituted
imidazoquinoline amines, sulfonamido ether substituted
imidazoquinoline amines, urea substituted imidazoquinoline ethers,
thioether substituted imidazoquinoline amines, and 6-, 7-, 8-, or
9-aryl or heteroaryl substituted imidazoquinoline amines;
tetrahydroimidazoquinoline amines including but not limited to
amide substituted tetrahydroimidazoquinoline amines, sulfonamide
substituted tetrahydroimidazoquinoline amines, urea substituted
tetrahydroimidazoquinoline amines, aryl ether substituted
tetrahydroimidazoquinoline amines, heterocyclic ether substituted
tetrahydroimidazoquinoline amines, amido ether substituted
tetrahydroimidazoquinoline amines, sulfonamido ether substituted
tetrahydroimidazoquinoline amines, urea substituted
tetrahydroimidazoquinoline ethers, and thioether substituted
tetrahydroimidazoquinoline amines; imidazopyridine amines including
but not limited to amide substituted imidazopyridine amines,
sulfonamido substituted imidazopyridine amines, urea substituted
imidazopyridine amines, aryl ether substituted imidazopyridine
amines, heterocyclic ether substituted imidazopyridine amines,
amido ether substituted imidazopyridine amines, sulfonamido ether
substituted imidazopyridine amines, urea substituted
imidazopyridine ethers, and thioether substituted imidazopyridine
amines; 1,2-bridged imidazoquinoline amines; 6,7-fused
cycloalkylimidazopyridine amines; imidazonaphthyridine amines;
tetrahydroimidazonaphthyridine amines; oxazoloquinoline amines;
thiazoloquinoline amines; oxazolopyridine amines; thiazolopyridine
amines; oxazolonaphthyridine amines; thiazolonaphthyridine amines;
and 1H-imidazo dimers fused to pyridine amines, quinoline amines,
tetrahydroquinoline amines, naphthyridine amines, or
tetrahydronaphthyridine amines. Various combinations of IRMs can be
used if desired.
[0025] In some embodiments, the IRM compound is an imidazoquinoline
amine such as, for example,
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amin- e or
4-amino-.alpha.,.alpha.-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quin-
olin-1-ethanol. In one particular embodiment, the IRM compound is
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.
[0026] In an alternative embodiment, the IRM compound is an
imidazonaphthyridine amine such as, for example,
2-methyl-1-(2-methylprop-
yl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine or
1-(2-methylpropyl)-1H-im-
idazo[4,5-c][1,5]naphthyridin-4-amine.
[0027] In another alternative embodiment, the IRM compound is a
sulfonamide substituted imidazoquinoline amine such as, for
example,
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfona-
mide.
[0028] In another alternative embodiment, the IRM compound is an
amide substituted imidazoquinoline amine such as, for example,
N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimeth-
ylethyl} cyclohexanecarboxamide.
[0029] In another alternative embodiment, the IRM compound is a
thioether substituted imidazoquinoline amine such as, for example,
2-butyl-1-[2-(propylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine.
[0030] In yet another alternative embodiment, the IRM compound is
an imidazopyridine amine such as, for example,
N-{2-[4-amino-2-(ethoxymethyl-
)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]ethyl}benzamide.
[0031] In certain embodiments, the IRM compound may be an
imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine,
an oxazoloquinoline amine, a thiazoloquinoline amine, an
oxazolopyridine amine, a thiazolopyridine amine, an
oxazolonaphthyridine amine, or a thiazolonaphthyridine amine.
[0032] In certain embodiments, the IRM compound may be a
substituted imidazoquinoline amine, a tetrahydroimidazoquinoline
amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline
amine, a 6,7-fused cycloalkylimidazopyridine amine, an
imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine,
an oxazoloquinoline amine, a thiazoloquinoline amine, an
oxazolopyridine amine, a thiazolopyridine amine, an
oxazolonaphthyridine amine, or a thiazolonaphthyridine amine.
[0033] As used herein, a substituted imidazoquinoline amine refers
to an amide substituted imidazoquinoline amine, a sulfonamide
substituted imidazoquinoline amine, a urea substituted
imidazoquinoline amine, an aryl ether substituted imidazoquinoline
amine, a heterocyclic ether substituted imidazoquinoline amine, an
amido ether substituted imidazoquinoline amine, a sulfonamido ether
substituted imidazoquinoline amine, a urea substituted
imidazoquinoline ether, a thioether substituted imidazoquinoline
amine, or a 6-, 7-, 8-, or 9-aryl or heteroaryl substituted
imidazoquinoline amine. As used herein, substituted
imidazoquinoline amines specifically and expressly exclude
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and
4-amino-.alpha.,.alpha.-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-
-1-ethanol.
[0034] Unless otherwise indicated, reference to a compound can
include the compound in any pharmaceutically acceptable form,
including any isomer (e.g., diastereomer or enantiomer), salt,
solvate, polymorph, and the like. In particular, if a compound is
optically active, reference to the compound can include each of the
compound's enantiomers as well as racemic mixtures of the
enantiomers.
[0035] An IRM compound may be provided in any formulation suitable
for administration to a subject. Suitable types of formulations are
described, for example, in U.S. Pat. No. 5,736,553; U.S. Pat. No.
5,238,944; U.S. Pat. No. 5,939,090; U.S. Pat. No. 6,365,166; U.S.
Pat. No. 6,245,776; U.S. Pat. No. 6,486,186; European Patent No. EP
0 394 026; and U.S. Patent Publication No. 2003/0199538. The
compound may be provided in any suitable form including but not
limited to a solution, a suspension, an emulsion, or any form of
mixture. The compound may be delivered in formulation with any
pharmaceutically acceptable excipient, carrier, or vehicle. For
example, the formulation may be delivered in a conventional topical
dosage form such as, for example, a cream, an ointment, an aerosol
formulation, a non-aerosol spray, a gel, a foam, a solution, a
suspension, a dispersion, an emulsion, a microemulsion, a paste, a
powder, a solid stick (e.g., wax- or petroleum-based sticks), a
wipe, an oil, a lotion, and the like. In one particular embodiment,
the IRM compound is provided in a cream formulation suitable for
topical administration.
[0036] A formulation suitable for practicing the invention may
include one or more additional active ingredients such as, for
example, another IRM compound, acyclovir, valcyclovir, pencyclovir,
amphotericins, chlorhexidine, clotrimazole, ketoconazole,
econazole, miconazole, metronidazole, minocycline, nystatin,
neomycin, kanamycin, phenyloin, octyl dimethyl PABA, octyl
methoxycinnamate, PABA and other esters, octyl salicylate,
oxybenzone, dioxybenzone, tocopherol, tocopheryl acetate, selenium
sulfide, zinc pyrithione, soluble elastin, diphenhydramine,
pramoxine, lidocaine, procaine, erythromycin, tetracycline,
clindamycin, crotamiton, hydroquinone and its monomethyl and benzyl
ethers, naproxen, ibuprofen, cromolyn, retinoic acid, retinol,
retinyl palmitate, retinyl acetate, coal tar, griseofulvin,
hydrocortisone, hydrocortisone 21-acetate, hydrocortisone
17-valerate, hydrocortisone 17-butyrate, betamethasone valerate,
betamethasone dipropionate, triamcinolone acetonide, fluocinonide,
clobetasol propionate, minoxidil, dipyridamole, diphenylhydantoin,
benzoyl peroxide, 5-fluorouracil, vitamin A acetate (retinyl
acetate) and vitamin E acetate (tocopheryl acetate). In some
embodiments, additional beneficial effects may also be found when a
skin-bleaching agent, such as a hydroquinone (including glycolic
acid, lactic acid, methyllactic acid, mandelic acid, pyruvic acid,
methylpyruvate, ethyl pyruvate, benzilic acid, gluconolactone,
malic acid, tartaric acid, citric acid, and tropic acid) or a
monobenzone, is incorporated into an IRM composition. In some
embodiments, the IRM compound may be incorporated into, for
example, a sunscreen, a skin lotion, a skin moisturizer, or other
cosmetic.
[0037] The composition of a suitable formulation may depend at
least in part on many factors known in the art including but not
limited to the physical and chemical nature of the IRM compound;
the nature of the carrier; the dosing regimen; the state of the
subject's immune system (e.g., suppressed, compromised,
stimulated); the method of administering the IRM compound; and the
desired result (e.g., wrinkle reduction, hydration, scar
prevention, etc.). Accordingly it is not practical to set forth
generally a single formulation suitable for improving skin quality
for all possible applications. Those of ordinary skill in the art,
however, can readily determine a suitable formulation with due
consideration of such factors.
[0038] A suitable formulation may contain, for example, about
0.001%, about 0.002%, about 0.005%, about 0.01%, about 0.015%,
about 0.02%, about 0.025%, about 0.05%, about 0.1%, about 0.25%,
about 0.5%, about 0.75%, about 1%, about 2.5%, about 5%, about
7.5%, about 10%, about 25%, or about 50% active IRM compound. In
one particular embodiment, the composition includes about 5% IRM
compound.
[0039] Skin treated by practicing the invention can include facial
skin, skin on the neck, hands, arms, legs, or torso, and skin of
other body regions.
[0040] Improving skin quality includes reversing, slowing the
progression of, or preventing skin changes associated with natural
or innate aging. As used herein, "prevent" and variations thereof
refer to any degree of delaying the onset of skin changes. For
example, improving skin quality includes the reversal, slowing the
progression of, or prevention of skin changes associated with sun
damage or photoaging--i.e., skin changes associated with exposure
to sunlight or other forms of actinic radiation (for example, such
as UV radiation and tanning booths). As another example, improving
skin quality also can include reversing, slowing the progression
of, or preventing skin changes resulting from extrinsic factors,
including, but not limited to, radiation, air pollution, wind,
cold, dampness, heat, chemicals, smoke, cigarette smoking, and
combinations thereof.
[0041] Improving skin quality also can include reversing,
preventing or reducing scarring the can result, for example, from
certain skin conditions (e.g., acne), infections (i.e.,
leishmaniasis), or injury (e.g., abrasions, punctures, lacerations,
or surgical wounds).
[0042] Skin changes treatable by practicing the invention include,
for example, wrinkles (including, but not limited to, human facial
wrinkles), deepening of skin lines, thinning of skin, reduced
scarring, yellowing of the skin, mottling, hyperpigmentation,
appearance of pigmented and/or non-pigmented age spots,
leatheriness, loss of elasticity, loss of recoilability, loss of
collagen fibers, abnormal changes in the elastic fibers,
deterioration of small blood vessels of the dermis, formation of
spider veins, and combinations thereof.
[0043] Skin changes in the dermis also can be treated by practicing
the invention. Such changes in the dermis include, but are not
limited to, a reduction in the number and diameter of elastic
fibers in the papillary dermis, atrophy of the dermis, reduction in
subcutaneous adipose tissue, deposition of abnormal elastic
materials in the upper dermis, and combinations thereof.
[0044] Improving skin quality includes decreasing, reducing, and/or
minimizing one or more of the skin changes discussed above.
Improving skin quality may result in the skin having a more
youthful appearance. Improving skin quality may result in the skin
having a smoother, hydrated (i.e., less dry), or less scaly
appearance.
[0045] In some embodiments, an IRM compound may be administered to
treat--i.e., reverse or slow the progression of--one or more skin
changes. Thus, the IRM compound may be administered after one or
more skin changes have occurred. In other embodiments, an IRM
compound may be administered to prevent one or more skin changes.
Thus, the IRM compound may be administered before one or more skin
changes have occurred, to prevent or slow the onset of such skin
changes.
[0046] For example, in certain embodiments, improving skin quality
can include a reduction in roughness, dryness, or scaliness. Skin
quality assessments, performed in conjunction with efficacy trials
in which cancerous (basal cell carcinoma, BCC) or pre-cancerous
(actinic keratosis, AK) dermal lesions were treated with an IRM
compound (5% imiquimod cream ALDARA, 3M Pharmaceuticals) indicate
that treatment with the IRM compound not only cleared the lesions,
but also improved skin quality of the treated area.
[0047] The IRM compound was administered once daily either 5.times.
per week or 7.times. per week for six weeks for treating BCC.
Subjects in each treatment group completed both an initiation
(prior to the 6-week treatment period) skin surface assessment and
a follow-up (twelve weeks after completion of the treatment period)
skin surface assessment. Skin quality was assessed on a scale of 1
(none) to 4 (severe). The assessment from the initiation visit
established a baseline against which the follow-up assessment was
compared. Both of the IRM-treated groups (5.times. per week and
7.times. per week) showed a substantial decrease in the degree of
rough/dry/scaly skin surface over the treatment area. The results
(see Table 1) were statistically significant over the baseline as
well as statistically significant over the placebo-treated control
group.
[0048] In a separate study, the IRM was administered once daily
either 2.times. per week or 3.times. per week for sixteen weeks for
treating AK. Subjects in each treatment group completed both an
initiation (prior to the 16-week treatment period) skin surface
assessment and a follow-up (eight weeks after completion of the
treatment period) skin surface assessment. Skin quality was
assessed on a scale of 1 (none) to 4 (severe). The assessment from
the initiation visit established a baseline against which the
follow-up assessment was compared. Both of the IRM-treated groups
(2.times. per week and 3.times. per week) showed a substantial
decrease in the degree of rough/dry/scaly skin surface over the
treatment area. The results (see Table 2) for both groups were
statistically significant against both the baseline assessments and
the placebo-treated control group.
[0049] The particular amount of IRM compound necessary to improve
skin quality may depend, at least in part, on one or more factors.
Such factors include, but are not limited to, the particular IRM
compound being administered; the state of the subject's overall
health; the state of the subject's immune system (e.g., suppressed,
compromised, stimulated); the route of administering the IRM; and
the desired result (e.g., wrinkle reduction, reducing dryness,
etc.). Accordingly, it is not practical to set forth generally the
amount that constitutes an amount of an IRM compound effective for
improving skin quality. Those of ordinary skill in the art,
however, can readily determine the appropriate amount with due
consideration of such factors.
[0050] In some embodiments, the methods of the present invention
include administering sufficient IRM compound to provide a dose of,
for example, from about 100 ng/kg to about 50 mg/kg to the subject,
although in some embodiments the method may be performed by
administering IRM compound in a dose outside this range. In some of
these embodiments, the method includes administering sufficient IRM
compound to provide a dose of from about 10 .mu.g/kg to about 5
mg/kg to the subject, for example, a dose of from about 100
.mu.g/kg to about 1 mg/kg.
[0051] The dosing regimen may depend at least in part on many
factors known in the art such as, for example, the physical and
chemical nature of the IRM compound; the nature of the carrier; the
amount of IRM being administered; the period over which the IRM
compound is being administered; the state of the subject's immune
system (e.g., suppressed, compromised, stimulated); the method of
administering the IRM compound; and the desired result. Accordingly
it is not practical to set forth generally the dosing regimen
effective for improving skin quality for all possible applications.
Those of ordinary skill in the art, however, can readily determine
an appropriate dosing regimen with due consideration of such
factors.
[0052] In some embodiments of the invention, the IRM compound may
be administered, for example, from a single dose to multiple doses
administered multiple times per day. In certain embodiments, the
IRM compound may be administered from about once per week to about
once per day. In one particular embodiment, the IRM compound is
administered once per day, two days per week. In an alternative
embodiment, the IRM compound is administered once per day, three
times per week. In another alternative embodiment, the IRM compound
is administered one per day, five days per week. In yet another
alternative embodiment, the IRM compound is administered once per
day, seven days per week.
[0053] The period of time that is sufficient for practicing the
invention may depend, at least in part, on factors such as, for
example, the physical and chemical nature of the IRM compound; the
nature of the carrier; the amount of IRM being administered; the
frequency with which the IRM compound is being administered; the
state of the subject's immune system (e.g., suppressed,
compromised, stimulated); the method of administering the IRM
compound; and the desired result. Accordingly it is not practical
to set forth generally the period of time necessary to improve skin
quality for all possible applications. Those of ordinary skill in
the art, however, can readily determine an appropriate period of
time with due consideration of such factors.
[0054] In some embodiments, a sufficient period of time may range
from at least one day to about six months, although in some
embodiments the invention may be practiced by administering IRM
compound for a period outside this range. In some embodiments, the
IRM compound may be administered for at least one week. In an
alternative embodiment, the IRM compound may be administered for at
least about four weeks. In another alternative embodiment, the IRM
compound may be administered for at least about eight weeks. In
another alternative embodiment, the IRM compound may be
administered for at least about sixteen weeks.
[0055] The methods of the present invention may be performed on any
suitable subject. Suitable subjects include, but are not limited
to, animals such as, but not limited to, humans, non-human
primates, rodents, dogs, cats, horses, pigs, sheep, goats, or
cows.
EXAMPLES
[0056] The following examples have been selected merely to further
illustrate features, advantages, and other details of the
invention. It is to be expressly understood, however, that while
the examples serve this purpose, the particular materials and
amounts used as well as other conditions and details are not to be
construed in a matter that would unduly limit the scope of this
invention. Unless otherwise indicated, all percentages and ratios
are by weight.
Example 1
Treatment of Rough, Dry, or Scaly Skin
[0057] Volunteer subjects with superficial basal cell carcinoma
(BCC) were randomized to either the 5% imiquimod cream formulation
(ALDARA, 3M Pharmaceuticals, St. Paul, Minn.) or a placebo cream
(Vehicle) in one of two treatment regimens: (1) once daily for
seven days per week (7.times./week), and (2) once daily for five
consecutive days per week and no treatment for the remaining two
days (5.times./week). Subjects in each group received treatment for
six weeks.
[0058] Subjects were instructed to administer a single application
of cream (Vehicle or 5% imiquimod, as assigned) to a target tumor
just prior to normal sleeping hours according to the dosing regimen
to which they were assigned. The subjects were instructed to wash
the tumor lesion prior to applying the cream, and then rub the
cream into the tumor and into extramarginal skin about 1 cm around
the tumor. The subjects were instructed to leave the cream in place
for at least eight hours without occlusion.
[0059] Subjects completed interval visits 1, 3, and 6 weeks after
treatment was initiated and at twelve weeks after the end of
treatment. At the 12-weeks post-treatment visit, the treatment area
was clinically and histologically evaluated for evidence of
BCC.
[0060] In addition, the treatment area was evaluated for skin
quality. Skin quality was assessed on a scale of 1 (none) to 4
(severe). The assessment from the Initiation visit established a
baseline against which the Follow-up assessment was compared. Both
IRM-treated groups (5.times. per week and 7.times. per week) showed
a substantial decrease in the degree of rough/dry/scaly skin
surface over the treatment area. The results were statistically
significant over the baseline as well as statistically significant
over the placebo-treated control group. Results are shown in Table
1.
1TABLE 1 Treat- ment Visit N= None Mild Moderate Severe IRM
5.times. Initiation 185 76 (41%) 93 (50%) 16 (9%) 0 (0%) Follow-up
178 41 (79%) 36 (20%) 1 (1%) 0 (0%) Vehicle Initiation 178 53 (30%)
105 (59%) 20 (11%) 0 (0%) 5.times. Follow-up 173 82 (47%) 82 (47%)
8 (5%) 1 (1%) IRM 7.times. Initiation 179 66 (36%) 96 (54%) 16 (9%)
1 (1%) Follow-up 168 139 (83%) 27 (16%) 2 (1%) 0 (0%) Vehicle
Initiation 181 56 (31%) 106 (59%) 19 (10%) 0 (0%) 7.times.
Follow-up 169 88 (52%) 73 (43%) 7 (4%) 1 (1%)
[0061] Separately, volunteer subjects with actinic keratoses (AK)
were randomized to either the 5% imiquimod cream formulation
(ALDARA, 3M Pharmaceuticals, St. Paul, Minn.) or a placebo cream
(Vehicle) in one of two treatment regimens: (1) once daily for two
days per week (2.times./week), and (2) once daily for three days
per week (3.times./week). Subjects in each group received treatment
for sixteen weeks.
[0062] Subjects were instructed to administer a single application
of cream (Vehicle or 5% imiquimod, as assigned) to a 25 cm.sup.2
treatment area just prior to normal sleeping hours according to the
dosing regimen to which they were assigned. The subjects were
instructed to wash the treatment area prior to applying the cream,
and then rub the cream into the treatment area. The subjects were
instructed to leave the cream in place for at least eight hours
without occlusion.
[0063] Subjects completed interval throughout 16-week the treatment
and at eight weeks after the end of treatment. At the 8-weeks
post-treatment visit, the treatment area was clinically and
histologically evaluated for evidence of AK.
[0064] In addition, the treatment area was evaluated for skin
quality. Skin quality was assessed on a scale of 1 (none) to 4
(severe). The assessment from the Initiation visit established a
baseline against which the Follow-up assessment was compared. Both
IRM-treated groups (2.times. per week and 3.times. per week) showed
a substantial decrease in the degree of rough/dry/scaly skin
surface over the treatment area. The results were statistically
significant over the baseline as well as statistically significant
over the placebo-treated control group. Results are shown in Table
2.
2TABLE 2 Treatment Visit N= None Mild Moderate Severe IRM 2.times.
Initiation 215 26 135 50 4 (12.1%) (62.8%) (23.3%) (1.9%) Follow-up
205 116 76 13 0 (56.6%) (37.1%) (6.3%) (0%) Vehicle 2.times.
Initiation 221 33 141 44 3 (14.9%) (63.8%) (19.9%) (1.4%) Follow-up
210 45 123 38 4 (21.4%) (58.6%) (18.1%) (1.9%) IRM 3.times.
Initiation 242 43 147 51 1 (17.8%) (60.7%) (21.1%) (0.4%) Follow-up
226 132 88 6 0 (58.4%) (38.9%) (2.7%) (0%) Vehicle 3.times.
Initiation 250 46 144 57 3 (18.4%) (57.6%) (22.8%) (1.2%) Follow-up
233 58 138 36 1 (24.9%) (59.2%) (15.5%) (0.4%)
Example 2
[0065] Subjects having cutaneous leishmaniasis received standard
care for leishmaniasis: meglumine antimonate (GLUCANTIME, Aventis
Pharma, 20 mg/Kg) for 20 consecutive days. Subjects were randomized
to received, in addition to the meglumine antimonate, either 5%
imiquimod cream (ALDARA, 3M Pharmaceuticals, St. Paul, Minn.) or a
placebo cream. A thin layer of cream was applied to each lesion
every other day for 20 days (i.e., ten total applications). Doses
of cream were applied by study personnel blinded to group
assignments. Cream was applied with a gentle rubbing action over
areas of involved but intact skin--i.e., the whole area of nodular
lesions and including the periphery of ulcerative lesions (up to
0.5 cm beyond the edge of each lesion).
[0066] Treatment efficacy was evaluated at follow-up visits one,
two, three, six, and twelve months after the completion of
treatment. Scar quality was not an original outcome of the study
and thus, no well-standardized scale for the assessment of scar
quality was established. Nevertheless, study personnel blinded to
group assignment throughout the treatment period and follow-up
visits were able, prior to unblinding, to identify which subjects
had received imiquimod during the treatment period.
Example 3
Treatment of Wrinkles
[0067] Wrinkles of skin may be due to natural aging and/or sun
damage. Most fine wrinkles on the face are due to natural or innate
aging, while coarse wrinkles on the face are the consequence of
actinic or sun damage. Although the real mechanism of wrinkles
formation in the skin is still unknown, it has been shown that
visible fine wrinkles are due to diminution in the number and
diameter of elastic fibers in the papillary dermis, and also due to
atrophy of dermis as well as reduction in subcutaneous adipose
tissue. Histopathology and electron microscopy studies indicate
that coarse wrinkles are due to excessive deposition of abnormal
elastic materials in the upper dermis and thickening of the
skin.
[0068] A 5% cream of imiquimod, the imidazoquinoline amine
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, marketed as
ALDARA (3M Pharmaceuticals, St. Paul, Minn.), is provided to a
randomized segment of volunteer subjects having facial wrinkles
lateral and inferior to the lateral canthus. The remaining subjects
receive a placebo formulation. The subjects are instructed to apply
the formulation provided to them (ALDARA or placebo) at least daily
on areas of facial wrinkles for 4 to 12 months. All subjects are
told to avoid sun exposure, and to use sunscreen products if
exposure to sunlight is unavoidable.
[0069] Evaluations are performed at the beginning of the study to
establish a baseline, and at three month intervals during the study
period. Evaluations include examination of the treatment area and
photographing each side the subject's face. The subjects are asked
not to wear any facial make-up at the time of each photographic
session. Standardized photographic conditions are used. At the end
of the study, clinical evaluations and review of photographs
reveals substantial reductions in facial wrinkles. Clinical
evaluations are performed using to the following scale:
[0070] None (0): No evidence of wrinkling.
[0071] Mild (1): Minimal evidence of wrinkles beyond lateral
canthus, wrinkles are fine and shallow.
[0072] Moderate (2): Superficial wrinkles that extend beyond
orbital rim, wrinkles do not fold onto each other.
[0073] Severe (3): Deep folds that extend beyond orbital rim,
wrinkles begin to fold onto each other.
[0074] Evaluation scores are analyzed to establish statistical
significance of changes in evaluation scores (a) over the course of
the study (baseline vs. end of study), and (b) with respect to
placebo (ALDARA vs. placebo). The degree of improvement and
reduction in wrinkles is evaluated and determined to range from
mild improvement in some subjects, to very substantial improvement
in other subjects.
Example 4
Treatment of Mottled Pigmentation
[0075] Many small and large discolored lesions such as, for
example, age spots (solar lentigines) develop on the face and the
back of the hands with aging.
[0076] A 5% cream of imiquimod, the imidazoquinoline amine
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, marketed as
ALDARA (3M Pharmaceuticals, St. Paul, Minn.), is provided to a
randomized segment of volunteer subjects having age spots and/or
other pigmented lesions. The remaining subjects receive a placebo
formulation. The subjects are instructed to apply the formulations
provided to them (ALDARA or placebo) to the age spots and/or other
pigmented lesions. Specific instructions are given to the subjects
that the medications are to be applied at least daily to the
lesions of age spots and/or other pigmented lesions.
[0077] Evaluations are performed at the beginning of the study to
establish a baseline and throughout the study period. Evaluations
include examination of the treatment area and photographing the
treatment area. Standardized photographic conditions are used. At
the end of the study, clinical evaluations and review of
photographs reveals substantial reduction of irregular
pigmentation. Clinical evaluations are performed using to the
following scale:
[0078] None (1): No evidence of irregular pigmentation changes.
[0079] Mild (2): Minimal evidence--in both extent and noticeability
in contrast with surrounding normal skin--of diffuse reticulated,
irregular pigmentation changes, solar lentigines, or discrete
hypo/hyperpigmentated macules.
[0080] Moderate (3): Moderate evidence of one or more of the
following findings: moderate diffuse reticulated, irregular
pigmentation changes, solar lentigines, or discrete
hypo/hyperpigmentated macules.
[0081] Severe (4): One or more of the following findings: Extensive
reticulated background irregular pigmentation changes, large
discrete hypo/hyperpigmentated macules, or solar lentigines.
[0082] Evaluation scores are analyzed to establish statistical
significance of changes in evaluation scores (a) over the course of
the study (baseline vs. end of study), and (b) with respect to
placebo (ALDARA vs. placebo). At the end of 4 to 8 weeks,
improvement of age spots is clinically discernible. After 4 to 6
months of topical treatment, substantial improvement of age spots
is observed in the majority of subjects tested. Complete
eradication of age spots is observed after 6 to 9 months of topical
administration with the IRM compositions of the instant
inventions.
[0083] The complete disclosures of the patents, patent documents
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. In case
of conflict, the present specification, including definitions,
shall control. Various modifications and alterations to this
invention will become apparent to those skilled in the art without
departing from the scope and spirit of this invention. Illustrative
embodiments and examples are provided as examples only and are not
intended to limit the scope of the present invention. The scope of
the invention is limited only by the claims set forth as
follows.
* * * * *