U.S. patent application number 12/572564 was filed with the patent office on 2010-01-28 for reduction of hair growth.
This patent application is currently assigned to The Gillette Company, a Delaware corporation. Invention is credited to Cheng Shine Hwang.
Application Number | 20100021412 12/572564 |
Document ID | / |
Family ID | 37037073 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100021412 |
Kind Code |
A1 |
Hwang; Cheng Shine |
January 28, 2010 |
REDUCTION OF HAIR GROWTH
Abstract
Mammalian hair growth is reduced by applying an agonist of
farnesoid X receptor.
Inventors: |
Hwang; Cheng Shine;
(Framingham, MA) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
The Gillette Company, a Delaware
corporation
|
Family ID: |
37037073 |
Appl. No.: |
12/572564 |
Filed: |
October 2, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11141798 |
May 31, 2005 |
7618956 |
|
|
12572564 |
|
|
|
|
Current U.S.
Class: |
424/73 |
Current CPC
Class: |
A61Q 7/02 20130101; A61K
31/56 20130101; A61K 8/63 20130101; A61K 2800/70 20130101; A61P
17/00 20180101; A61K 8/361 20130101; A61K 8/342 20130101; A61K 8/37
20130101; A61K 31/20 20130101 |
Class at
Publication: |
424/73 |
International
Class: |
A61K 8/33 20060101
A61K008/33; A61Q 9/02 20060101 A61Q009/02 |
Claims
1. A method of reducing mammalian hair growth which comprises
selecting an area of skin from which reduced hair growth is
desired; and applying to said area of skin a dermatologically
acceptable composition comprising an agonist of farnesoid X
receptor in an amount effective to reduce hair growth, wherein said
agonist is not a carbamate or ester of
.alpha.-difluoromethylornithine and farnesol.
2. The method of claim 1, wherein said agonist is a bile acid.
3. The method of claim 1, wherein said agonist is an analog of a
bile acid.
4. The method of claim 1, wherein said agonist is a derivative of a
bile acid.
5. The method of claim 1, wherein said agonist interacts strongly
with the farnesoid X receptor.
6. The method of claim 1, wherein said agonist is lithocholic
acid.
7. The method of claim 1, wherein said agonist is cholic acid.
8. The method of claim 1, wherein said agonist is deoxycholic
acid.
9. The method of claim 1, wherein said agonist is chenodeoxycholic
acid.
10. The method of claim 1, wherein said agonist is ursodeoxycholic
acid.
11. The method of claim 1, wherein said agonist is 6-alpha-ethyl
chenodeoxycholic acid.
12. The method of claim 1, wherein said agonist is a farnesoid.
13. The method of claim 1, wherein said agonist is an analog of a
farnesoid.
14. The method of claim 1, wherein said agonist is a derivative of
a farnesoid.
15. The method of claim 1, wherein said agonist is farnesol.
16. The method of claim 1, wherein said agonist is farnesal.
17. The method of claim 1, wherein said agonist is farnesyl
acetate.
18. The method of claim 1, wherein said agonist is farnesoic
acid
19. The method of claim 1, wherein said agonist is methyl farnesyl
ether.
20. The method of claim 1, wherein said agonist is methyl
farnesoate.
21. The method of claim 1, wherein said agonist is ethyl farnesyl
ether.
22. The method of claim 1, wherein said agonist is ethyl
farnesoate.
23. The method of claim 1, wherein said agonist is
7-methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid
methyl ester (juvenile hormone III).
24. The method of claim 1, wherein said agonist is
7-methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid
ethyl ester.
25. The method of claim 1, wherein said agonist is
3alpha,7alpha-dihydroxy-6alpha-ethyl-5p-cholan-24-oic acid.
26. The method of claim 1, wherein said agonist is
3alpha,7alpha-dihydroxy-6alpha-propyl-5p-cholan-24-oic acid.
27. The method of claim 1, wherein said agonist is
3alpha,7alpha-dihydroxy-6alpha-allyl-5p-cholan-24-oic acid.
28. The method of claim 1, wherein said agonist is
benzenesulfonamide,
N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluorometh-
yl)ethyl]phenyl]-.
29. The method of claim 1, wherein said agonist is benzoic acid,
3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]-
methoxy]phenyl]ethenyl]-.
30. The method of claim 1, wherein said agonist is phosphonic acid,
[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-,
tetraethyl ester.
31. The method of claim 1, wherein said agonist is phosphonic acid,
[2-[3,5-bis(1-dimethylethyl)-4-hydroxyphenyl]ethylidene]bis-,
tetrakis(1-methylethyl) ester.
32. The method of claim 1, wherein said agonist is phosphonic acid,
[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethylidene]bis-,
tetraethyl ester.
33. The method of claim 1, wherein said agonist is phosphonic acid,
[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-,
tetrakis(1-methylethyl) ester.
34. The method of claim 1, wherein the concentration of said
agonist in said composition is between 0.1% and 30%.
35. The method of claim 1, wherein the composition provides a
reduction in hair growth of at least 30% when tested in the Human
Hair Follicle assay.
36. The method of claim 1, wherein the agonist is applied to the
skin in an amount of from 10 to 3000 micrograms of said agonist per
square centimeter of skin.
37. The method of claim 1, wherein said area of skin is on the face
of a human.
38. The method of claim 37, wherein the composition is applied to
the area of skin in conjunction with shaving.
39. The method of claim 1, wherein said area of skin is on a leg of
the human.
40. The method of claim 1, wherein said area of skin is on an arm
of the human.
41. The method of claim 1, wherein said area of skin is in an
armpit of the human.
42. The method of claim 1, wherein said area of skin is on the
torso of the human.
43. The method of claim 1, wherein said hair growth comprises
androgen stimulated hair growth.
44. The method of claim 1, wherein the composition further includes
a second component that also causes a reduction in hair growth.
45. A method of reducing mammalian hair growth, which comprises
selecting an area of skin including hair follicles from which
reduced hair growth is desired; and applying to the area of skin a
dermatologically acceptable composition comprising a compound
selected from the group consisting of bile acids, bile acid
analogues, and bile acid derivatives in an amount effective to
reduce hair growth.
46. A method of reducing mammalian hair growth, which comprises
selecting an area of skin including hair follicles from which
reduced hair growth is desired; and applying to the area of skin,
in an amount effective to reduce hair growth, a dermatogically
acceptable composition comprising a compound, other than a
carbamate or ester of .alpha.-difluoromethylomithine and farnesol,
selected from the group consisting of compounds that increase the
formation of FXR-RXR heterodimer, compounds that promote
coactivator recruitment and interaction with FXR-RXR, and compounds
that increase the expression of farnesoid X receptor.
47. A method of reducing mammalian hair growth, which comprises
selecting an area of skin from which reduced hair growth is
desired; and applying to the area of skin a dermatologically
acceptable composition comprising a compound selected from the
group consisting of farsenoids, analogues of farsenoids, and
derivatives of farsenoids in an amount effective to reduce hair
growth.
48. A method of treating an area of exfoliated skin, comprising
applying an agonist of farnesoid X receptor to the area of
exfoliated skin.
49. The method of claim 48, wherein the area of exfoliated skin has
been shaved prior to application of the agonist of farnesoid X
receptor.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/141,798, filed May 31, 2005, which is
incorporated herein by reference in its entirety.
BACKGROUND
[0002] The invention relates to reducing hair growth in mammals,
particularly for cosmetic purposes.
[0003] A main function of mammalian hair is to provide
environmental protection. However, that function has largely been
lost in humans, in whom hair is kept or removed from various parts
of the body essentially for cosmetic reasons. For example, it is
generally preferred to have hair on the scalp but not on the
face.
[0004] Various procedures have been employed to remove unwanted
hair, including shaving, electrolysis, depilatory creams or
lotions, waxing, plucking, and therapeutic antiandrogens. These
conventional procedures generally have drawbacks associated with
them. Shaving, for instance, can cause nicks and cuts, and can
leave a perception of an increase in the rate of hair regrowth.
Shaving also can leave an undesirable stubble. Electrolysis, on the
other hand, can keep a treated area free of hair for prolonged
periods of time, but can be expensive, painful, and sometimes
leaves scarring. Depilatory creams, though very effective,
typically are not recommended for frequent use due to their high
irritancy potential. Waxing and plucking can cause pain,
discomfort, and poor removal of short hair. Finally,
antiandrogens--which have been used to treat female hirsutism--can
have unwanted side effects.
[0005] It has previously been disclosed that the rate and character
of hair growth can be altered by applying to the skin inhibitors of
certain enzymes. These inhibitors include inhibitors of 5-alpha
reductase, ornithine decarboxylase, S-adenosylmethionine
decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase.
See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander,
U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007;
Ahluwalia et al., U.S. Pat. No. 5,096,911; and Shander et al., U.S.
Pat. No. 5,132,293.
[0006] Farnesoid X receptor (also known as "FXR", "RIP14", "bile
acid receptor", "BAR", "HRR1" and "NR1H4") is a member of the
family of ligand-activated transcription factors that bind to
specific cis-acting regulatory elements in the promoters of their
target genes and modulate gene expression in response to ligands.
Some of these receptors bind to their target genes as dimers
consisting of two molecules of the same receptor homodimers), while
others bind to as dimers consisting of one molecule each of two
different receptors (heterodimers). Farnesoid X receptor forms a
heterodimer with the retinoid X receptor (RXR) and binds to an
inverted hexanucleotides repeat spaced by one nucleotide in the
promoters of its target genes. Farnesoid X receptor is activated
through interaction with ligands such as farnesoids and bile acids.
In addition, coactivators (DRIP205/TRAP220, SRC-1 and PGC-1alpha)
that bridge between the ligand-activated farnesoid X receptors and
the basal transcription machinery, and/or influence the chromatin
structure, can enhance the transcriptional activity of farnesoid X
receptor.
[0007] Farnesoid X receptor helps maintain bile acid homeostasis by
modulating the expression of genes involved in the synthesis and
transport of bile acid. Bile acids are the end product of
cholesterol catabolism. Synthesis of bile acid is the predominant
mechanisms for the excretion of excess cholesterol. Most bile acids
in human are chenodeoxycholic acid, cholic acid, deoxycholic acid,
ursodeoxycholic acid and lithocholic acid. While the level of bile
acids is increased, farnesoid X receptor is activated and
upregulates the expression of the bile salt export pump that is
responsible for bile acid excretion. In addition to bile acid
excretion, bile acid-activated farnesoid X receptor represses the
transcription of cholesterol 7alpha-hydroxylase (CYP7A1), which the
rate-limiting enzyme in the bile acid biosynthesis pathway.
SUMMARY
[0008] In one aspect, the invention provides a method (typically a
cosmetic method) of reducing unwanted mammalian (preferably human)
hair growth by applying to the skin an agonist of farnesoid X
receptor in an amount effective to reduce hair growth. Preferably,
the agonist interacts strongly with the farnesoid X receptor. The
unwanted hair growth may be undesirable from a cosmetic
standpoint.
[0009] In another aspect, the invention provides a method of
reducing unwanted mammalian hair growth by applying to the skin a
compound selected from the group consisting of bile acids, analogs
of bile acids, and derivatives of bile acids.
[0010] In another aspect, the invention provides a method of
reducing unwanted mammalian hair growth by applying to the skin a
compound selected from the group consisting of farnesoids, analogs
of farnesoids, and derivatives of farnesoids.
[0011] In a another aspect, the invention provides a method of
reducing unwanted mammalian hair growth by applying to the skin a
compound that increases the formation of FXR-RXR heterodimer, the
expression of farnesoid X receptor, or promotes coactivator
recruitment and interaction with FXR-RXR heterodimer.
[0012] In a further aspect, the invention provides a method of
providing a benefit to exfoliated skin by applying any of the above
agonists/compounds.
[0013] Typically, in practicing the aforementioned methods, the
agonist/compound will be included in a topical composition along
with a dermatologically or cosmetically acceptable vehicle.
Accordingly, the present invention also relates to topical
compositions comprising a dermatologically or cosmetically
acceptable vehicle and an agonist of farnesoid X receptor. The
present invention further relates to topical compositions
comprising a dermatologically or cosmetically acceptable vehicle
and (a) a compound selected from the group consisting of bile
acids, analogs or derivatives of bile acids; (b) a compound
selected from the group consisting of farnesoids, analogs or
derivatives of farnesoids; and/or (c) a compound that increases the
formation of FXR-RXR heterodimer, the expression of farnesoid X
receptor, or promotes coactivator recruitment and interaction with
FXR-RXR heterodimer.
[0014] In addition, the present invention relates to the use of an
agonist of farnesoid X receptor for the manufacture of a
therapeutic topical composition for reducing hair growth. Further,
the present invention relates to the use of a compound for the
manufacture of a therapeutic topical composition for reducing hair
growth, wherein the compound is (a) a compound that selected from
the group consisting of bile acids, analogs or derivatives of bile
acids; (b) a compound selected from the group consisting of
farnesoids, analogs or derivatives of farnesoids; and/or (c) a
compound that increases the formation of FXR-RXR heterodimer, the
expression of farnesoid X receptor, or promotes coactivator
recruitment and interaction with FXR-RXR heterodimer.
[0015] In some embodiments, the agonist/compound is not a carbomate
or ester of .alpha.-difluoromethylornithine. Carbamates, esters,
and other conjugates of .alpha.-difluoromethylornithine are
described in U.S. Ser. No. 10/397,132, which was filed on Mar. 26,
2003, is owned by the same owner as the present application, and is
hereby incorporated herein by reference.
[0016] "Agonist of farnesoid X receptor", as used herein, means a
compound that activates farnesoid X receptor.
[0017] An agonist that "interacts strongly" with the farnesoid X
receptor is one that binds the receptor with such affinity that it
elicits a response that is at least approximately comparable to (in
magnitude) to that elicited by farnesoids.
[0018] Specific compounds include both the compound itself and
pharmacologically acceptable salts of the compound.
[0019] Other features and advantages of the invention may be
apparent from the detailed description and from the claims.
DETAILED DESCRIPTION
[0020] An example of a preferred composition includes at least one
agonist of farnesoid X receptor in a cosmetically and/or
dermatologically acceptable vehicle. The composition may be a
solid, semi-solid, or liquid. The composition may be, for example,
a cosmetic and dermatologic product in the form of an, for example,
ointment, lotion, foam, cream, gel, or solution. The composition
may also be in the form of a shaving preparation, an aftershave or
an antiperspirant. The vehicle itself can be inert or it can
possess cosmetic, physiological and/or pharmaceutical benefits of
its own.
[0021] Examples of agonists of farnesoid X receptor include bile
acids, farnesoids, their analogs and derivatives, and other
compounds.
[0022] Derivatives and analogs of bile acids are known. For
example, J. Med. Chem. (2004), 47, 4559-4569 describes bile acid
derivatives. J. Biol. Chem. (2004), 279(10), 8856-8861. describes
various bile acids. Derivatives and analogs of farnesoids are
known. For example, U.S. Pat. No. 6,187,814 describes farnesoid
derivatives. Other examples of agonists of farnesoid X receptor are
disclosed in WO2004007521, WO03015771, WO2004048349, WO03076418,
WO2004046162, WO03060078, WO02072598, WO03080803, WO2003086303, WO
2004046068, U.S. Pat. 20030187042, U.S. Pat. 0040176426, U.S. Pat.
20040180942, U.S. Pat. No. 6,452,032, U.S. Pat. 2003203939, U.S.
Pat. 2005004165, J. med. Chem. (2000), 43(6), 2971-2974, Mol. Gen.
Met. (2004), 83, 184-187, Drugs for the future 91999), 24(4),
431-438, Current Pharmaceutical Design (2001), 7, 231-259. Examples
of coactivators involved in FXR-RCR hetrodimer are disclosed in
Genes & Dev. (2004), 18, 157-169 and J. Biol. Chem. (2004),
279(35), 36184-36191. All of these references are incorporated by
reference.
[0023] Specific examples of agonists of farnesoid X receptor are
provided in Tables I.
TABLE-US-00001 TABLE I Examples of Farnesoid X receptor agonists
Farnesol Farnesal Farnesyl acetate Farnesoic acid Methyl farnesyl
ether Methyl farnesoate Ethyl farnesyl ether Ethyl farnesoate
7-Methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid
methyl ester (also known as Juvenile hormone III) Lithocholic acid
Cholic acid Deoxycholic acid Chenodeoxycholic acid Ursodeoxycholic
acid 6-alpha-Ethyl chenodeoxycholic acid Benzenesulfonamide,
N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-
hydroxy-1-(trifluoromethyl)ethyl]phenyl]-(also known as T0901317)
Benzoic acid,
3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-
4-isoxazolyl]methoxy]phenyl]ethenyl]-(also known as GW4064)
Phosphonic acid, [[3,5-bis(1,1-dimethylethyl)-4-
hydroxyphenyl]ethenylidene]bis-,tetraethyl ester (also known as
SR-12813) Phosphonic acid, [2-[3,5-bis(1,1-dimethylethyl)-4-
hydroxyphenyl]ethylidene]bis-,tetrakis(1-methylethyl) ester (also
known as SR-45023A or apomine) Phosphonic acid,
[2-[3,5-bis(1,1-dimethylethyl)-4-
hydroxyphenyl]ethylidene]bis-,tetraethyl ester (also known as
SR-9213) Phosphonic acid, [[3,5-bis(1,1-dimethylethyl)-4-
hydroxyphenyl]ethenylidene]bis-,tetrakis(1-methylethyl) ester (also
known as SR-12823i)
7-Methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid
ethyl ester
3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5p-cholan-24-oic acid
3.alpha.,7.alpha.-dihydroxy-6.alpha.-propyl-5p-cholan-24-oic acid
3.alpha.,7.alpha.-dihydroxy-6.alpha.-allyl-5p-cholan-24-oic
acid
[0024] The composition may include more than one agonist of
farnesoid X receptor. In addition, the composition may include one
or more other types of hair growth reducing agents, such as those
described in U.S. Pat. No. 4,885,289; U.S. Pat. No. 4,720,489; U.S.
Pat. No. 5,132,293; U.S. Pat. No. 5,096,911; U.S. Pat. No.
5,095,007; U.S. Pat. No. 5,143,925; U.S. Pat. No. 5,328,686; U.S.
Pat. No. 5,440,090; U.S. Pat. No. 5,364,885; U.S. Pat. No.
5,411,991; U.S. Pat. No. 5,648,394; U.S. Pat. No. 5,468,476; U.S.
Pat. No. 5,475,763; U.S. Pat. No. 5,554,608; U.S. Pat. No.
5,674,477; U.S. Pat. No. 5,728,736; U.S. Pat. No. 5,652,273; WO
94/27586; WO 94/27563; and WO 98/03149, all of which are
incorporated herein by reference.
[0025] The concentration of the agonist in the composition may be
varied over a wide range up to a saturated solution, preferably
from 0.1% to 30% by weight or even more; the reduction of hair
growth increases as the amount of agonist applied increases per
unit area of skin. The maximum amount effectively applied is
limited only by the rate at which the agonist penetrates the skin.
The effective amounts may range, for example, from 10 to 3000
micrograms or more per square centimeter of skin.
[0026] The vehicle can be inert or can possess cosmetic,
physiological and/or pharmaceutical benefits of its own. Vehicles
can be formulated with liquid or solid emollients, solvents,
thickeners, humectants and/or powders. Emollients include stearyl
alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate,
polyethylene glycol, petroleum jelly, palmitic acid, oleic acid,
and myristyl myristate. Solvents include ethyl alcohol,
isopropanol, acetone, diethylene glycol, ethylene glycol, dimethyl
sulfoxide, and dimethyl formamide.
[0027] The composition optionally can include components that
enhance the penetration of the agonist into the skin and/or to the
site of action. Examples of penetration enhancers include urea,
polyoxyethylene ethers (e.g., Brij-30 and Laureth-4),
3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene, terpenes, cis-fatty
acids (e.g., oleic acid, palmitoleic acid), acetone, laurocapram,
dimethylsulfoxide, 2-pyrrolidone, oleyl alcohol,
glyceryl-3-stearate, propan-2-ol, myristic acid isopropyl ester,
cholesterol, and propylene glycol. A penetration enhancer can be
added, for example, at concentrations of 0.1% to 20% or 0.5% to 5%
by weight.
[0028] The composition also can be formulated to provide a
reservoir within or on the surface of the skin to provide for a
continual slow release of the agonist. The composition also may be
formulated to evaporate slowly from the skin, allowing the agonist
extra time to penetrate the skin.
[0029] A topical cream composition containing an agonist of
farnesoid X receptor may be prepared by mixing together water and
all water soluble components in a mixing vessel-A. The pH is
adjusted in a desired range from about 3.5 to 8.0. In order to
achieve complete dissolution of ingredients the vessel temperature
may be raised to up to 45.degree. C. The selection of pH and
temperature will depend on the stability of the agonist. The oil
soluble components, except for the preservative and fragrance
components, are mixed together in another container (B) and heated
to up to 70.degree. C. to melt and mix the components. The heated
contents of vessel B are poured into the water phase (container A)
with brisk stirring. Mixing is continued for about 20 minutes. The
preservative components are added at temperature of about
40.degree. C. Stirring is continued until the temperature reaches
about 25.degree. C. to yield a soft cream with a viscosity of
8,000-12,000 cps, or a desired viscosity. The fragrance components
are added at about 25.degree. C.-30.degree. C. while the contents
are still being mixed and the viscosity has not yet built up to the
desired range. If it is desired to increase the viscosity of the
resulting emulsion, shear can be applied using a conventional
homogenizer, for example a Silverson L4R homogenizer with a square
hole high sheer screen. The topical composition can be fabricated
by including the agonist in the water phase during formulation
preparation or can be added after the formulation (vehicle)
preparation has been completed. The agonist can also be added
during any step of the vehicle preparation. The components of come
cream formulations are described in the examples below.
EXAMPLE # 1
Cream
TABLE-US-00002 [0030] INCI Name W/w (%) DI Water 61.00-75.00
Agonist of farnesoid X receptor 1.00-15.00 Mineral oil 1.90
Glyceryl stearate 3.60 PEG 100 stearate 3.48 Cetearyl alcohol 2.59
Ceteareth-20 2.13 Dimethicone, 100 ct 0.48 Lipidure PMB.sup.a 3.00
Advanced moisture complex.sup.b 5.00 Stearyl alcohol 1.42
Preservative, fragrance and color pigment qs Total 100.00
.sup.apolyquartinium-51 (Collaborative Labs, NY); .sup.bglycerin
and water and sodium PCA and urea and trehalose and
polyqauternium-51 and sodium hyaluronate (Collaborative Labs,
NY)
EXAMPLE # 2
Cream
TABLE-US-00003 [0031] INCI Name w/w (%) Agonist of farnesoid X
receptor 0.5-15.00 Glycerol (glycerin) 0-5 Isoceteth-20 3-7
Glyceryl isostearate 1.5-5 Dicaprylyl ether 3-15 Glyceryl
triacetate (triacetin) 0.5-10 Preservative, fragrance and color
pigment q.s. Water q.s. to 100.00
EXAMPLE # 3
Cream
TABLE-US-00004 [0032] INCI Name w/w (%) Agonist of farnesoid X
receptor 0.5-15.00 Glycerol (glycerin) 0-5 Isoceteth-20 3-7
Glyceryl isostearate 1.5-5 Dicaprylyl ether 3-15
1-dodecyl-2-pyrrolidanone 0.5-10% Preservative, fragrance and color
q.s. Water to 100.00
EXAMPLE #4
Cream
TABLE-US-00005 [0033] INCI Name w/w (%) Water 70 Glyceryl stearate
4 PEG-100 4 Cetearyl alcohol 3 Ceteareth-20 2.5 Mineral oil 2
Stearyl alcohol 2 Dimethicone 0.5 Preservatives 0.43
1-Dodecyl-2-pyrrolidanone 1-10 Total 100.00
An agonist of farnesoid X receptor is added to the example 4
formulation and mixed until solubilized.
EXAMPLE 5
Cream
TABLE-US-00006 [0034] INCI Name w/w (%) Water 70-80 Glyceryl
stearate 4 PEG-100 4 Cetearyl alcohol 3 Ceteareth-20 2.5 Mineral
oil 2 Stearyl alcohol 2 Dimethicone 0.5 Preservatives 0.43
Monocaprylate/Caprate (Estol 3601, Uniquema, NJ) 1-10 Total
100.00
An agonist of farnesoid X receptor is added to the example 5
formulation and mixed until solubilized.
EXAMPLE 6
Cream
TABLE-US-00007 [0035] INCI Name w/w (%) Water 70-80 Glyceryl
stearate 4 PEG-100 4 Cetearyl alcohol 3 Ceteareth-20 2.5 Mineral
oil 2 Stearyl alcohol 2 Dimethicone 0.5 Preservatives 0.43 cis
Fatty acids 1-10 Total 100.00
An agonist of farnesoid X receptor is added to the example 6
formulation and mixed until solubilized.
EXAMPLE 7
Cream
TABLE-US-00008 [0036] INCI Name w/w (%) Water 70-80% Glyceryl
stearate 4 PEG-100 4 Cetearyl alcohol 3 Ceteareth-20 2.5 Mineral
oil 2 Stearyl alcohol 2 Dimethicone 0.5 Preservatives 0.43
Terpene(s) 1-10 Total 100.00
An agonist of farnesoid X receptor is added to the example 7
formulation and mixed until solubilized.
EXAMPLE 8
Cream
TABLE-US-00009 [0037] INCI Name w/w (%) Water 70-80% Glyceryl
stearate 4 PEG-100 4 Cetearyl alcohol 3 Ceteareth-20 2.5 Mineral
oil 2 Stearyl alcohol 2 Dimethicone 0.5 Preservatives 0.43
Polyoxyethylene sorbitans (tween) 1-10 Total 100.00
An agonist of farnesoid X receptor is added to the example 8
formulation and mixed until solubilized.
[0038] A hydroalcoholic formulation containing an agonist of
farnesoid X receptor is prepared by mixing the formulation
components in a mixing vessel. The pH of the formulation is
adjusted to a desired value in the range of 3.5-8.0. The pH
adjustment can also be made to cause complete dissolution of the
formulation ingredients. In addition, heating can be applied to up
to 45.degree. C., or even up to 70.degree. C. depending on the
stability of the agonist to achieve dissolution of the formulation
ingredients. The components of two hydroalcoholic formulations are
listed below.
EXAMPLE #9
Hydro-Alcoholic
TABLE-US-00010 [0039] INCI Name w/w (%) Water 48.00-62.50 An
agonist of farnesoid X receptor 0.5-15.00 Ethanol 16.00 Propylene
glycol 5.00 Dipropylene glycol 5.00 Benzyl alcohol 400 Propylene
carbonate 2.00 Captex-300.sup.a 5.00 Total 100.00
.sup.acaprylic/capric triglyceride (Abitec Corp., OH).
EXAMPLE #10
Hydro-Alcoholic
TABLE-US-00011 [0040] INCI Name w/w (%) Water 53.00-67.9 An agonist
of farnesoid X receptor 0.1-15.00 Ethanol 16.00 Propylene glycol
5.00 Dipropylene glycol dimethyl ether 5.00 Benzyl alcohol 4.00
Propylene carbonate 2.00 Total 100.00
EXAMPLE #11
Hydro-Alcoholic
TABLE-US-00012 [0041] INCI Name w/w (%) Ethanol (alcohol) 80 Water
17.5 Propylene glycol dipelargonate 2.0 Propylene glycol 0.5 Total
100.00
An agonist of farnesoid X receptor is added to the example 11
formulation and mixed until solubilized.
[0042] The composition should be applied topically to a selected
area of the body from which it is desired to reduce hair growth.
For example, the composition can be applied to the face,
particularly to the beard area of the face, i.e., the cheek, neck,
upper lip, and chin. The composition also may be used as an adjunct
to other methods of hair removal including shaving, waxing,
mechanical epilation, chemical depilation, electrolysis and
laser-assisted hair removal. Other actions that make their concept
appearance are concurrent skin benefits in addition to hair
reduction.
[0043] The composition can also be applied to the legs, arms, torso
or armpits. The composition is suitable, for example, for reducing
the growth of unwanted hair in women. In humans, the composition
should be applied once or twice a day, or even more frequently, to
achieve a perceived reduction in hair growth. Perception of reduced
hair growth could occur as early as 24 hours or 48 hours (for
instance, between normal shaving intervals) following use or could
take up to, for example, three months. Reduction in hair growth is
demonstrated when, for example, the rate of hair growth is slowed,
the need for removal is reduced, the subject perceives less hair on
the treated site, or quantitatively, when the weight of hair
removed (i.e., hair mass) is reduced.
[0044] Human Hair Follicle Growth Assay:
[0045] Human hair follicles in growth phase (anagen) were isolated
from face-lift tissue (obtained from plastic surgeons) under
dissecting scope using a scalpel and watchmakers forceps. The skin
was sliced into thin strips exposing 2-3 rows of follicles that
could readily be dissected. Follicles were placed into 0.5 ml
William's E medium (Life Technologies, Gaithersburg, Md.)
supplemented with 2 mM L-glutamine, 10 .mu.g/ml insulin, 10 ng/ml
hydrocortisone, 100 units of penicillin, 0.1 mg/ml streptomycin and
0.25 .mu.g/ml amphotericin B. The follicles were incubated in
24-well plates (1 follicle/well) at 37.degree. C. in an atmosphere
of 5% CO.sub.2 and 95% air. Compounds are dissolved into dimethyl
sulfoxide as 100-fold stock solution. The control hair follicles
were treated with dimethyl sulfoxide without prostaglandin. The
follicles were photographed in the 24-well plates under the
dissecting scope at a power of 10.times.. Typically, image
recordings were made on day 0 (day follicles were placed in
culture), and again on day 7. The length of hair follicle was
assessed using an image analysis software system. The growth of
hair fiber was calculated by the subtracting the follicle length on
day 0 from that determined on day 7.
[0046] Hamster Hair Mass Assay:
[0047] Hamster hair mass was determined using a method similar to
that described in previous patent (US2004/0198821).
[0048] The agonists of farnesoid X receptor demonstrated a
significant reduction of human hair follicle growth. All of the six
agonists of farnesoid X receptor tested significantly reduced hair
growth. The results are provided in Table II. The hair growth
inhibition profile by the agonists of farnesoid X receptor was
found to be dose-dependent. The results are provided in Table
III.
TABLE-US-00013 TABLE II Inhibition of human hair follicle growth by
the agonists of farnestoid X receptor. Dose Hair follicle length
increase (mm) FXR agonists (.mu.M) Treated Control % Inhibition
Deoxycholic acid 100 0.06 .+-. 0.05 1.07 .+-. 0.14 94.3 .+-. 4.7
Ursodeoxycholic 200 0.20 .+-. 0.11 1.07 .+-. 0.14 81.3 .+-. 10.3
acid Chenodeoxycholic 100 0.05 .+-. 0.06 1.07 .+-. 0.14 95.3 .+-.
5.6 acid Lithocholic acid 50 0.02 .+-. 0.02 1.07 .+-. 0.14 98.1
.+-. 1.9 Farnesol 100 0.04 .+-. 0.07 0.87 .+-. 0.23 95.4 .+-. 8.0
Juvenile 100 0.21 .+-. 0.15 0.87 .+-. 0.23 75.9 .+-. 17.2 hormone
III
TABLE-US-00014 TABLE III Dose-dependent reduction of human hair
follicle growth by the agonists of farnestoid X receptor. Dose
Growth of follicle (mm) FXR agonists (.mu.M) Treated Control %
Reduction Deoxycholic acid 10 1.20 .+-. 0.49 1.76 .+-. 0.36 31.8
.+-. 18.1 50 0.54 .+-. 0.34 1.76 .+-. 0.36 69.3 .+-. 13.6 100 0.54
.+-. 0.34 1.76 .+-. 0.36 69.3 .+-. 13.6 Ursodeoxycholic acid 50
1.12 .+-. 0.24 1.76 .+-. 0.36 36.3 .+-. 13.6 100 0.86 .+-. 0.20
1.76 .+-. 0.36 51.1 .+-. 11.4 150 0.61 .+-. 0.20 1.76 .+-. 0.36
65.3 .+-. 11.4 Chenodeoxycholic 5 1.53 .+-. 0.29 1.55 .+-. 0.02 1.3
.+-. 18.7 acid 25 0.79 .+-. 0.27 1.55 .+-. 0.02 49.0 .+-. 17.4 50
0.13 .+-. 0.10 1.55 .+-. 0.02 91.6 .+-. 6.5 Lithocholic acid 2 0.82
.+-. 0.14 1.24 .+-. 0.23 33.9 .+-. 11.3 10 0.44 .+-. 0.16 1.24 .+-.
0.23 64.5 .+-. 12.9 20 0.03 .+-. 0.06 1.24 .+-. 0.23 97.6 .+-.
4.8
[0049] Furthermore, the agonists of farnestoid X receptor were
tested in the hamster hair mass assay. The agonists reduced hair
mass in vivo as shown in Table IV.
TABLE-US-00015 TABLE IV Reduction of hamster hair mass by the
agonists of farnestoid X receptor. Dose Hair mass (mg) FXR agonists
(w/v) Vehicle* Treated Control % Inhibition Lithocholic acid 4%
ethanol 1.01 .+-. 0.12 1.96 .+-. 0.19 46.4 .+-. 6.0
Chenodeoxycholic acid 5% ethanol 0.54 .+-. 0.08 2.28 .+-. 0.19 76.4
.+-. 2.6 Deoxycholic acid 5% ethanol 0.92 .+-. 0.14 2.66 .+-. 0.28
63.6 .+-. 6.0 Ursodeoxycholic acid 5% ethanol 1.02 .+-. 0.16 2.43
.+-. 0.31 56.8 .+-. 3.8 *The vehicle contains 90% ethanol and 10%
propylene glycol.
[0050] Accordingly, other embodiments are within the scope of the
following claims.
* * * * *