U.S. patent application number 16/106503 was filed with the patent office on 2018-12-13 for peptides and their use in the treatment of hair.
This patent application is currently assigned to Avon Products, Inc.. The applicant listed for this patent is Avon Products, Inc.. Invention is credited to Jolanta Idkowiak-Baldys, Uma Santhanam.
Application Number | 20180353415 16/106503 |
Document ID | / |
Family ID | 58717641 |
Filed Date | 2018-12-13 |
United States Patent
Application |
20180353415 |
Kind Code |
A1 |
Idkowiak-Baldys; Jolanta ;
et al. |
December 13, 2018 |
Peptides and Their Use in The Treatment of Hair
Abstract
Peptides, topical compositions, and methods of improving health
and/or appearance of human integuments, such as keratinous surfaces
and fibers are provided. The peptides have from 3-12 amino acid
residues and comprise the sequence YNT (SEQ ID NO: 1) or PVG (SEQ
ID NO: 2).
Inventors: |
Idkowiak-Baldys; Jolanta;
(Montebello, NY) ; Santhanam; Uma; (Tenafly,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Avon Products, Inc. |
Suffern |
NY |
US |
|
|
Assignee: |
Avon Products, Inc.
Suffern
NY
|
Family ID: |
58717641 |
Appl. No.: |
16/106503 |
Filed: |
August 21, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15192078 |
Jun 24, 2016 |
10080714 |
|
|
16106503 |
|
|
|
|
62257366 |
Nov 19, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61Q 7/00 20130101; A61Q
5/00 20130101; A61K 8/64 20130101; A61Q 5/12 20130101; A61K 2800/57
20130101; A61Q 1/10 20130101 |
International
Class: |
A61K 8/64 20060101
A61K008/64; A61Q 5/12 20060101 A61Q005/12; A61Q 5/00 20060101
A61Q005/00; A61Q 7/00 20060101 A61Q007/00 |
Claims
1. A method for strengthening, thickening, and/or promoting growth
of human keratin fibers comprising topically applying to skin in
the area of keratin fiber follicles a composition comprising, in a
physiologically acceptable vehicle, an active agent comprising a
peptide having from 3-6 amino acid residues, comprising the
sequence YNT (SEQ ID NO: 1) or PVG (SEQ ID NO: 2).
2. The method according to claim 1, wherein said active agent
comprises the sequence YNT (SEQ ID NO: 1).
3. The method according to claim 2, wherein said active agent
comprises the sequence PVG (SEQ ID NO: 2).
4. The method according to claim 1, wherein said active agent is
peptide wherein said peptide is optionally functionalized with a
C.sub.2-24 hydrocarbon to improve lipophilicity.
5. The method according to claim 4, wherein said active agent is
palmitoyl-(YNT).
6. The method according to claim 4, wherein said active agent is
palmitoyl-(PVG).
7. The method according to claim 2, wherein said active agent is
K-Ava-YNTK (SEQ ID NO: 3).
8. The method according to claim 3, wherein said active agent is
K-Ava-PVGK (SEQ ID NO: 4).
9. The method according to claim 1, wherein said composition is
applied at least once daily for at least four weeks.
10. A composition comprising an active agent comprising a peptide
having from 3-6 amino acid residues, comprising the sequence YNT
(SEQ ID NO: 1) or PVG (SEQ ID NO: 2), and a physiologically
acceptable vehicle, wherein the active agent is present in an
amount from about 0.0001% to about 10% by weight of the
composition.
11. The composition according to claim 10, wherein said active
agent comprises the sequence YNT (SEQ ID NO: 1).
12. The composition according to claim 10, wherein said active
agent comprises the sequence PVG (SEQ ID NO: 2).
13. The composition according to claim 10, wherein said active
agent is peptide wherein said peptide is optionally functionalized
with a C.sub.2-24 hydrocarbon to improve lipophilicity.
14. The composition according to claim 13, wherein said active
agent is palmitoyl-(YNT).
15. The composition according to claim 13, wherein said active
agent is palmitoyl-(PVG).
16. The composition according to claim 10, wherein said active
agent is K-Ava-YNTK (SEQ ID NO: 3).
17. The composition according to claim 10, wherein said active
agent is K-Ava-PVGK (SEQ ID NO: 4).
18. The cosmetic composition of claim 10, wherein the active agent
is present in an amount from about 0.001% to about 1% by weight of
the composition.
19. The composition of claim 10, wherein said topically acceptable
vehicle comprises a water-in-oil, oil-in-water, silicone-in-water,
or water-in-silicone emulsion, further comprising an
emulsifier.
20. The composition of claim 10, wherein said composition is in the
form of a shampoo, conditioner, hair gel, mousse, tonic, or
lotion.
21. The composition of claim 10, wherein said composition further
includes one or more of creatine, a botanical extract from
Pouzolzia pentandra, N-biotinyl-gly-his-lys, hydrolyzed wheat
protein, saw palmetto (Serenoa) extract, Emblica officianalis
extract, and beta-glycyrrhetic acid.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation application of
U.S. Ser. No. 15/192,078, filed Jun. 24, 2016 which claims priority
to U.S. Provisional Patent Application Ser. No. 62/257,366, filed
on Nov. 19, 2015. The entirety of the aforementioned application is
incorporated herein in its entirety by reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Jun. 23, 2016, is named HC29U-US_SL.txt and is 2,904 bytes in
size.
FIELD OF INVENTION
[0003] The present invention relates generally to peptides and
derivatives thereof, topical formulations containing them, as well
as associated methods for treating human keratin fibers. In
particular, the peptides of the invention improve the health and
appearance of keratin fibers, strengthen keratin fibers, and
promote growth and thickening of keratin fibers.
BACKGROUND
[0004] Consumers continually seek to improve the appearance of
their hair. Hair loss and thinning are problems that afflict both
men and women, and may be associated with low self-esteem and
self-consciousness, and therefore can have a negative impact on
general quality of life. Various approaches have attempted to
prevent keratin fiber loss and thinning, and to enhance the growth,
fullness, and appearance of keratin fibers, but these have been
largely unsuccessful. Accordingly, there remains a need for
effective keratin fiber care products that can address the problems
of poor keratin fiber appearance, keratin fiber loss, slowed
keratin fiber growth, and the thinning of keratin fibers.
[0005] It is therefore an object of the invention to provide new
peptides and compositions containing them. It is also an object of
the invention to provide methods for improving the health and/or
appearance of hair, thickening hair, and/or promoting hair growth
with compositions comprising effective amounts of a peptide of the
invention.
[0006] The foregoing discussion is presented solely to provide a
better understanding of the nature of the problems confronting the
art and should not be construed in any way as an admission as to
prior art.
SUMMARY OF THE INVENTION
[0007] In accordance with the foregoing objectives and others, the
present invention provides peptides for provided benefits to human
keratin fibers (e.g., hair of the scalp, eyelashes, etc.) and
formulations containing such peptides. The peptides are believed to
be useful for improving health and appearance of human keratin
fibers and/or promoting growth of human keratin fibers and/or
thickening the shaft of keratin fibers and/or strengthening human
keratin fibers. The peptides are typically applied to human keratin
fibers and/or the follicles of such keratin fibers as topical
formulations comprising physiologically acceptable vehicles,
including without limitation aqueous serums and emulsions. In some
embodiments, the active peptides are capable of stimulating
proliferation of human hair germinal matrix (HHGM) cells. In some
embodiments, the active peptides of the invention are capable of
increasing the production of keratin and keratin-associated
proteins (KAP's) in the hair. In some embodiments, the active
peptides of the invention are capable of increasing the production
of cell adhesion proteins in the desmosome, including without
limitation cadherins, such as p-cadherin. Therefore, the peptides
of the invention are expected to have a beneficial effect on
improving the health and appearance of human hair and lashes (e.g.,
strengthening hair, thickening hair, promoting hair growth,
combatting age-related hair thinning, fortifying hair, protecting
hair from breakage, reducing the frizzy or brittle appearance of
hair, etc.).
[0008] In one aspect of the invention, peptides are provided
comprising the amino acid sequence YNT (SEQ ID NO: 1) and/or PVG
(SEQ ID NO: 2). The peptides may comprise, for example, from 3-12,
or from 3-10, or from 3-8, or from 3-6 amino acid residues. In some
embodiments, the peptides of the invention may have the structure
of formula (I):
R.sub.1-.PSI..sup.a-.PHI.-.PSI..sup.b-R.sub.2 (I)
wherein, .PHI. represents either the amino acid sequence YNT (SEQ
ID NO: 1) or the amino acid sequence PVG (SEQ ID NO: 2), and
.PSI..sup.a and .PSI..sup.b are independently either absent or are
selected from naturally occurring and/or non-naturally occurring
amino acid or non-proteinogenic amino acid residues or from short
peptide sequences comprising from 2-4 (e.g., two, three, or four)
naturally occurring and/or non-naturally occurring amino acid
residues; and R.sub.1 and R.sub.2 are independently either absent,
or are selected from hydrogen, or a C.sub.1-26 branched or straight
chain hydrocarbon. In some embodiments, .PSI..sup.a is absent. In
some embodiments, .PSI..sup.a comprises one, two, or three
naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In some embodiments,
.PSI..sup.b is absent. In some embodiments, .PSI..sup.b comprises
one, two, or three naturally occurring and/or non-naturally
occurring or non-proteinogenic amino acid residues. In some
embodiments, R.sub.1 and/or R.sub.2 are absent. In some
embodiments, R.sub.1 and/or R.sub.2 comprise a fatty chain,
including without limitation a C.sub.14-18 fatty chain, such as a
palmitoyl group. In some embodiments, .PSI..sup.a and/or
.PSI..sup.b comprise a lysine (K) residue. In one implementation,
.PSI..sup.a has the form -.PSI..sub.1-.PSI..sub.2-, where each of
.PSI..sub.1 and .PSI..sub.2 is independently either absent or is
selected from naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In one implementation,
.PSI..sup.a has the form -.PSI..sub.1-.PSI..sub.2- or
-.PSI..sub.1-.PSI..sub.2-.PSI..sub.3-, where each of .PSI..sub.1,
.PSI..sub.2, and .PSI..sub.3 is independently either absent or is
selected from naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In one implementation,
.PSI..sup.b has the form -.PSI..sub.4-.PSI..sub.5- or
-.PSI..sub.4-.PSI..sub.5-.PSI..sub.6-, where each of .PSI..sub.4,
.PSI..sub.5, and .PSI..sub.6 is independently either absent or is
selected from naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. For example, one or more of
.PSI..sub.1 and/or .PSI..sub.2 and/or .PSI..sub.3 and/or
.PSI..sub.4 and/or .PSI..sub.5 and/or .PSI..sub.6 may be a lysine
(K) residues, and the remaining .PSI..sub.1 and/or .PSI..sub.2
and/or .PSI..sub.3 and/or .PSI..sub.4 and/or .PSI..sub.5 and/or
.PSI..sub.6 may be absent or may be a natural or non-natural or
non-proteinogenic amino acid, including amino acids of the form
H.sub.2N--(CH.sub.2).sub.q--CO.sub.2H where "q" is an integer from
1-10, including amino valeric acid ("Ava"). In one embodiment, the
peptides of the invention will have the formula K-Ava-.PHI.-K or
K-.PHI.-Ava-K, including R.sub.1-K-Ava-YNT-.PSI..sup.b-R.sub.2 (SEQ
ID NO: 7) and R.sub.1-K-Ava-PVG-.PSI..sup.b-R.sub.2 (SEQ ID NO: 8).
In some embodiments, the peptides will have the form K-Ava-YNTK
(SEQ ID NO: 3) or K-Ava-PVGK (SEQ ID NO: 4), where either, or both,
of the N-terminus or carboxy terminus may be modified (e.g.,
through an amide or ester bond) with R.sub.1 and/or R.sub.2 (e.g.,
a biotin or palmitoyl chain).
[0009] In another aspect of the invention, formulations are
provided comprising physiologically active amounts of the peptides
of the invention, including peptides according to formula (I), such
as YNT (SEQ ID NO: 1), PVG (SEQ ID NO: 2), K-Ava-YNTK (SEQ ID NO:
3), K-Ava-PVGK (SEQ ID NO: 4), and combinations thereof. The
formulations typically comprise a physiologically acceptable
vehicle, which may be aqueous or anhydrous, but are typically in
the form of an aqueous or alcoholic serum or emulsion (e.g.,
water-in-oil or oil-in-water). The active peptide may be present in
the composition in an amount between about 0.000001% to about 10%
(e.g., 0.0001-2% or 0.001-1% or 0.01-0.5%) by weight of the
composition. The formulations may further include an additional
hair growth agent selected from the group consisting of fibroblast
growth factor receptor 1 (FGFR1) inhibitors, 5-alpha-reductase
inhibitors, vasodilators, prostaglandin F2-alpha (PGF2.alpha.)
analogs, microcirculation enhancers, creatine, biotinylated
tri-peptide (e.g., N-biotinyl-gly-his-lys), and combinations
thereof. The formulations may contain suitable adjuvants such as
organic solvents, humectants, emollients, rheology modifiers,
stabilizers, and thickeners, gelling agents, waxes, film forming
polymers, shine agents, detanglers, skin and hair conditioning
agents, emulsifiers, anti-oxidants, botanicals, peptides, amino
acids, sunscreens, colorants, fillers, vitamins and minerals,
fragrances, pH adjusters, chelating agents, preservatives, and the
like. The compositions may have the form of a mascara, shampoo,
hair rinse, hair conditioner, pomade, hair gel, mousse,
hydroalcoholic tonic, cream, spray, emulsion, serum/liquid, or any
other form that is suitable for treatment of keratin fibers. The
compositions may further comprise additional bioactive agents, such
as anti-dandruff agents, antiperspirants, retinoids, alpha-hydroxy
acids (e.g., glycolic acid), oxa-acids, salicylic acid, anti-acne
agents, ascorbic acid, etc. The additional hair growth agents,
bioactive agents, and adjuvants may be present, individually or in
the aggregate in amounts from about 0.0001% to about 25%, typically
from about 0.001% to about 10%, based on the total weight of the
composition. The vehicle may comprise from about 1% to about 99.9%,
typically from about 5% to about 95% by weight of the
composition.
[0010] In another aspect, methods are provided for improving health
and appearance of human keratin fibers and/or promoting growth of
human keratin fibers and/or thickening the shaft of keratin fibers
and/or strengthening human keratin fibers. In some embodiments, the
keratin fibers are eyelashes. In some embodiments, the keratin
fibers are hair of the scalp. In some embodiments, the keratin
fibers are hair of the face (e.g., moustache or beard). In some
embodiments, the keratin fibers are hair of the scalp that has been
damaged, for example, by sun damage, chlorine and other chemicals
from swimming pools, bleaching or lightening agents (e.g.,
peroxide), and/or treatment with colorants (e.g., reactive dyes,
such as two-part oxidative dyes). The peptides are typically
applied to human keratin fibers and/or to the follicles and/or to
the skin surrounding the follicles (e.g., the eyelid or the scalp).
Application is typically at least once daily for as long as
necessary to achieve the desired results (e.g., at least one, two,
four, eight, twelve weeks or longer).
[0011] These and other aspects of the present invention will become
apparent to those skilled in the art after a reading of the
following detailed description of the invention, including the
illustrative embodiments and examples.
DETAILED DESCRIPTION
[0012] Detailed embodiments of the present invention are disclosed
herein; however, it is to be understood that the disclosed
embodiments are merely illustrative of the invention that may be
embodied in various forms. In addition, each of the examples given
in connection with the various embodiments of the invention is
intended to be illustrative, and not restrictive. Therefore,
specific structural and functional details disclosed herein are not
to be interpreted as limiting, but merely as a representative basis
for teaching one skilled in the art to variously employ the present
invention.
[0013] All percentages given herein refer to the weight percentages
of a particular component relative to the entire composition,
including the vehicle, unless otherwise indicated. It will be
understood that the sum of all weight % of individual components
within a composition will not exceed 100%. Unless otherwise
specified, it will be understood that any components of the
formulations according to the invention may comprise from about
0.00001% to about 90% by weight, or from about 0.0001% to about 50%
by weight, or from about 0.001% to about 25% by weight, or from
about 0.01% to about 10% by weight, or from about 0.1% to about 5%
by weight of the composition.
[0014] All terms used herein are intended to have their ordinary
meaning unless otherwise provided. The phrases "physiologically
acceptable," "topically acceptable," and "dermatologically
acceptable" are used interchangeably and are intended to mean that
a particular component is generally regarded as safe and non-toxic
for application to a human integument (e.g., skin) at the levels
employed. The term "prevent," as used herein, includes delaying,
slowing or forestalling the onset of or progression of a particular
condition. The phrase "individual in need thereof" refers to a
human that could benefit from improved appearance or health of
keratin fibers, such as the hair or lashes. In some embodiments,
the individual in need thereof is a female.
[0015] As used herein, the term "consisting essentially of" is
intended to limit the invention to the specified materials or steps
and those that do not materially affect the basic and novel
characteristics of the claimed invention, as understood from a
reading of this specification. For example, a hair growth agent
"consisting essentially of" the peptides of formula (I) will
exclude effective amounts of additional hair growth agents.
[0016] As used herein, a hydrocarbon, alkyl, alkenyl, alkynyl,
aryl, aryl-alkyl, alkyl-aryl, heteroaryl, or combination of any of
those will have from 1-30 carbon atoms, unless otherwise specified.
Any of the hydrocarbon, alkyl, alkenyl, and alkynyl groups
disclosed herein, unless otherwise specified, may be
straight-chained, branched, and/or cyclic. Any hydrocarbon, alkyl,
alkenyl, alkynyl, aryl, aryl-alkyl, alkyl-aryl, or heteroaryl group
may be optionally modified with 1-20 or 1-12 or 1-8 or 1-6 or 1-4
heteroatoms selected from halogen, nitrogen, oxygen, and sulfur, or
they may be perfluorinated.
[0017] The term "amino acid" is intended to include naturally
occurring amino acids and non-proteinogenic amino acids as well as
non-naturally occurring amino acids and includes any small molecule
(MW <1,000 Daltons) having at least one carboxyl group and at
least one primary or secondary amine group capable of forming
peptide bonds. The term "peptide" is intended to include any
molecule comprising at least two amino acids joined by a peptide
bond and therefore includes di-peptides, tri-peptides,
oligopeptides, and polypeptides having up to about 20 consecutive
amino acid residues linked by peptide bonds. The term "peptide"
also embraces structures having one or more linkers, spacers,
terminal groups or other substituents or modifications which are
not amino acids.
[0018] Peptides
[0019] The peptides of the invention will typically comprise from
3-20 or from 3-12 or from 3-8 or from 3-6 or from 3-4 consecutive
amino acids linked together with peptide bonds. The peptides of the
invention may comprise, consist essentially of, or consist of the
amino acid sequences:
TABLE-US-00001 (SEQ ID NO: 1) YNT; and (SEQ ID NO: 2) PVG; and
combinations thereof
[0020] "Consisting essentially of" the specified amino acid
sequence(s) is intended to mean that additional amino acids may be
present at either terminus provided they do not substantially
impair or alter the activity of the peptide, as disclosed herein.
For example, in embodiments where a peptide "consists essentially
of" SEQ ID NOs 1 and/or 2, any additional amino acids may be
excluded from the peptide if their inclusion produces a measurable
decrease (e.g., greater than 50% reduction) of the beneficial
activity, including, without limitation, proliferation of human
hair germinal matrix (HHGM) cells, expression of keratin and
keratin-associated proteins (KAP) in hair matrix cells, and/or
expression of desmosomal components (e.g., cadherins) in hair
matrix cells.
[0021] In some embodiments, the peptides may comprise one, two,
three or more conservative substitutions of amino acids. As used
herein, a "conservative substitution" is one in which substitution
of one amino acid for another does not impair the function of the
peptide, including substitution of an amino acid having a side
chain of a certain nature (e.g., acidic, basic, aromatic, aliphatic
uncharged, non-polar uncharged, hydrophilic uncharged) by another
amino acid having a side chain of the same nature. Examples of
conservative substitutions are shown below in Table 11.
TABLE-US-00002 TABLE 1 Conservative Substitutions Acidic Residues
Asp (D) and Glu (E) Basic Residues Lys (K), Arg (R), and His (H)
Hydrophilic Uncharged Residues Ser (S), Thr (T), Asn (N), and Gln
(Q) Aliphatic Uncharged Residues Gly (G), Ala (A), Val (V), Leu
(L), and Ile (I) Non-polar Uncharged Residues Cys (C), Met (M), and
Pro (P) Aromatic Residues Phe (F), Tyr (Y), and Trp (W)
[0022] In some embodiments, the peptides of the invention may
comprise modified variants of SEQ ID NOS. 1 and 2 wherein at least
one (i.e., one, two or three) of the amino acids is replaced by the
"D" (dextrorotary) analogue of the natural "L" optical isomer.
[0023] In some embodiments the peptides according to the invention
will comprise the sequences of SEQ ID NOS. 1 and 2 with an
additional amino acid joined by a peptide bond to the N-terminus or
carboxy terminus. The active agents according to the invention may
comprise, consist essentially of, or consist of the formulas
.OMEGA.-YNT, YNT-.OMEGA., .OMEGA.-PVG, and PVG-.OMEGA., where
.OMEGA. is a naturally occurring amino acid selected from Alanine,
Cysteine, Aspartic acid, Glutamic acid, Phenylalanine, Glycine,
Histidine, Isoleucine, Lysine, Leucine, Methionine, Asparagine,
Pyrrolysine, Proline, Glutamine, Arginine, Serine, Threonine,
Selenocysteine, Valine, Tryptophan, and Tyrosine, in each case,
typically in the L optical isomer. In one embodiment, the peptides
of the invention comprise, consist essentially of, of consist of
the following sequences:
TABLE-US-00003 (SEQ ID NO. 5) YNTK; and/or (SEQ ID NO. 6) PVGK,
[0024] and derivatives thereof, including without limitation,
lipophilic derivatives (e.g., plamitoyl), hydrophilic derivatives
(e.g., PEGylated), and biotinylated derivatives thereof. For
example, the peptides of the invention can be modified to improve
the lipophilicity, stability, or to enhance penetration through the
stratum corneum. In some embodiments, the peptides are modified
with a fatty acid chain (e.g., C.sub.6-22), such as palmitoyl. In
some embodiments, at least one of the nitrogen atoms in the amide
bonds between adjacent amino acids may be methylated to improve
metabolic stability. The peptides may also be phosphorylated, for
example by forming one or more phosphoserine, phosphothreonine
and/or phosphotyrosine residues. The peptides may also be
biotinylated or modified with polyalkylene oxide chains (e.g.,
PEGylated). Peptides of the invention may have one or more
additional amino acids joined to the amino and/or carboxyl terminus
via peptide bonds.
[0025] In some embodiments, the modified peptides will have the
structure according to Formula (I):
R.sub.1-.PSI..sup.a-.PHI.-.PSI..sup.b-R.sub.2 (I)
where .PHI. represents a peptide sequence of the invention (e.g.,
comprising SEQ IDs 1 or 2), R.sub.1 and R.sub.2 are independently
either absent or are selected from hydrogen or C.sub.1-26
(C.sub.1-6 or C.sub.6-12 or C.sub.12-18 or C.sub.18-22)
hydrocarbons (e.g., acyl group, such as palmitoyl), and where
.PSI..sup.a and .PSI..sup.b are, independently, absent or are amino
acids or peptides (e.g., comprising from 2-6 or from 2-4 or from
2-3 amino acid residues). In some embodiments, .PSI..sup.a and
.PSI..sup.b are independently either absent or are selected from
naturally occurring and/or non-naturally occurring amino acid or
non-proteinogenic amino acid residues or from short peptide
sequences comprising from 2-4 (e.g., two, three, or four) naturally
occurring and/or non-naturally occurring or non-proteinogenic amino
acid residues. In some embodiments, .PSI..sup.a is absent. In some
embodiments, .PSI..sup.b is absent. In some embodiments,
.PSI..sup.a comprises one, two, or three naturally occurring and/or
non-naturally occurring or non-proteinogenic amino acid residues.
In some embodiments, .PSI..sup.b comprises one, two, or three
naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In some embodiments,
.PSI..sup.a and/or .PSI..sup.b comprises or consists of a lysine
(K) residue. In one implementation, .PSI..sup.a has the form
-.PSI..sub.1-.PSI..sub.2, where each of .PSI..sub.1 and .PSI..sub.2
is independently either absent or is selected from naturally
occurring and/or non-naturally occurring or non-proteinogenic amino
acid residues. In one implementation, .PSI..sup.a has the form
-.PSI..sub.1-.PSI..sub.2-.PSI..sub.3-, where each of .PSI..sub.1,
.PSI..sub.2, and .PSI..sub.3 is independently either absent or is
selected from naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In one implementation,
.PSI..sup.b has the form -.PSI..sub.4-.PSI..sub.5-, where each of
.PSI..sub.4 and .PSI..sub.5 is independently either absent or is
selected from naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In one implementation,
.PSI..sup.b has the form -.PSI..sub.4-.PSI..sub.5-.PSI..sub.6-,
where each of .PSI..sub.4, .PSI..sub.5, and .PSI..sub.6 is
independently either absent or is selected from naturally occurring
and/or non-naturally occurring or non-proteinogenic amino acid
residues. For example, one or more of .PSI..sub.1 and/or
.PSI..sub.2 and/or .PSI..sub.3 and/or .PSI..sub.4 and/or
.PSI..sub.5 and/or .PSI..sub.6 may be a lysine (K) residue, and the
remaining .PSI..sub.1 and/or .PSI..sub.2 and/or .PSI..sub.3 and/or
.PSI..sub.4 and/or .PSI..sub.5 and/or .PSI..sub.6 may be absent or
may be a natural or non-natural or non-proteinogenic amino acid,
including amino acids of the form
H.sub.2N--(CH.sub.2).sub.q--CO.sub.2H where "q" is an integer from
1-10, including amino valeric acid ("Ava"). In some embodiments,
R.sub.1 and R.sub.2 are independently either absent, or are
selected from hydrogen, or a C.sub.1-26 branched or straight chain
hydrocarbon. In some embodiments, R.sub.1 and/or R.sub.2 are
absent. In some embodiments, R.sub.1 and/or R.sub.2 comprise a
fatty chain, including without limitation a C.sub.14-18 fatty
chain.
[0026] In one embodiment, the peptides of formula (I) will comprise
the peptide sequence of formula (II):
R.sub.1-.PSI..sub.1-.PSI..sub.2-.PHI.-K-R.sub.2 (II)
where .PHI. represents a peptide sequence of the invention (e.g.,
comprising SEQ IDs 1 or 2), R.sub.1 and R.sub.2 are independently
either absent or are selected from hydrogen or C.sub.1-26
(C.sub.1-6 or C.sub.6-12 or C.sub.12-18 or C.sub.18-22)
hydrocarbons (e.g., acyl group, such as palmitoyl), and where each
of .PSI..sub.1 and .PSI..sub.2 is independently either absent or is
selected from naturally occurring and/or non-naturally occurring or
non-proteinogenic amino acid residues. In some embodiments
according to Formula (II), .PSI..sub.1 is a naturally occurring
amino acid selected from Alanine, Cysteine, Aspartic acid, Glutamic
acid, Phenylalanine, Glycine, Histidine, Isoleucine, Lysine,
Leucine, Methionine, Asparagine, Pyrrolysine, Proline, Glutamine,
Arginine, Serine, Threonine, Selenocysteine, Valine, Tryptophan,
and Tyrosine, in each case, typically in the L optical isomer, but
optionally in the "D" isomer. In one embodiment, .PSI..sub.1 is
lysine or a conservative substitution therefor. In one embodiment,
.PSI..sub.2 is a non-natural or non-proteogenic amino acid.
[0027] The non-natural amino acid or non-proteinogenic amino acids
used in the peptides of the invention may, for example, have the
structures of formula (III) or (IV):
##STR00001##
[0028] where X is selected from X.sub.1, C.sub.1-26 (C.sub.1-6 or
C.sub.6-12 or C.sub.12-18 or C.sub.18-22) hydrocarbons, optionally
substituted with a group X.sub.1 or with from 1-20 (or 1-10 or 1-6
or 1-3) heteroatoms selected from halogen (e.g., fluorine,
chlorine, bromine, iodine), oxygen, nitrogen, phosphorous, sulfur,
silicon and combinations thereof. In some embodiments, X is ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, optionally substituted with X.sub.1 or with from 1-20 (or
1-10 or 1-6 or 1-3) heteroatoms selected from halogen (e.g.,
fluorine, chlorine, bromine, iodine), oxygen, nitrogen,
phosphorous, sulfur, silicon and combinations thereof. In some
embodiments, X is C.sub.1-12 or C.sub.6-20 or C.sub.12-26 alkyl,
akenyl, akynyl, aryl, aryl-alkyl, alkyl-aryl, alkyl-aryl-alkyl,
heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl,
alkyl-heteroaryl-alkyl, etc., optionally substituted with X.sub.1,
or with 1-20 (or 1-10 or 1-6 or 1-3) heteroatoms selected from
halogen (e.g., fluorine), oxygen, nitrogen, phosphorous, sulfur,
and combinations thereof. In some embodiments, X comprises a fused
ring system having two, three, or more 5- or 6-membered rings,
X.sub.1 or with from 1-20 (or 1-10 or 1-6 or 1-3) heteroatoms
selected from halogen (e.g., fluorine, chlorine, bromine, iodine),
oxygen, nitrogen, phosphorous, sulfur, silicon and combinations
thereof. In some embodiments, X, together with the nitrogen atom in
Formula (III) forms a 3-13 (e.g., 2-8 or 4-6) membered ring,
wherein the amino acid is other than proline.
[0029] L.sub.1 is a hydrocarbon spacer comprising from 1-20 (or
from 2-12 or from 2-8 or from 2-6) carbon atoms and optionally
substituted with a group X.sub.1 or from 1-20 (or 1-10 or 1-6 or
1-3) heteroatoms selected from halogen (e.g., fluorine, chlorine,
bromine, iodine), oxygen, nitrogen, phosphorous, sulfur, silicon
and combinations thereof, including perfluorinated derivatives of
L.sub.1. In some embodiments, L.sub.1 will comprise a branched,
straight chained, or cyclic hydrocarbon. In some embodiments,
L.sub.1 will have the form --(CH.sub.2)p- where "p" is an integer
from 1-20 or from 1-10 or from 2-8 or from 3-6, including
embodiments where p is 1, 2, 3, 4, 5, 6, 7, or 8. In some
embodiments, L.sub.1 will comprise from 1-6 oxo or oxa groups. In
some embodiments, L.sub.1 will have the form
--(OCH.sub.2CH.sub.2)p- or --(CH.sub.2CH.sub.2O)p- where "p" is an
integer from 1-20 or from 1-10 or from 2-8 or from 3-6, including
embodiments where p is 1, 2, 3, or 4. In one embodiment, the amino
acid of formula (IV) is aminoethanoic acid, aminopropionic acid,
aminobutyric acid, aminovaleric acid, aminocaproic acid,
aminoenanthic acid, aminocaprylic acid, amino pelargonicacid, or
aminocapric acid. In one embodiment, .PSI..sub.1 and/or .PSI..sub.2
comprises aminovaleric acid. In one embodiment, one of .PSI..sub.1
and/or .PSI..sub.2 comprises aminovaleric acid and the other
comprises lysine (K) joined by a peptide bond to the aminovaleric
acid. In some embodiments, .PSI..sub.2 is an amino acid of the form
H.sub.2N--(CH.sub.2).sub.q--CO.sub.2H where "q" is an integer from
1-10 or 2-8 or 3-6, including amino valeric acid. In some
embodiments, -.PSI..sub.1-.PSI..sub.2- is lysine-amino valeric acid
(-K-Ava-).
[0030] In some embodiments, R.sub.1 and R.sub.2 are hydrogen (i.e.,
they are absent). In some embodiments, one of R.sub.1 and R.sub.2
is a C.sub.1-26 hydrocarbon, optionally substituted with a group
X.sub.1 or from 1-20 (or 1-10 or 1-6 or 1-3) heteroatoms selected
from halogen (e.g., fluorine, chlorine, bromine, iodine), oxygen,
nitrogen, phosphorous, sulfur, silicon and combinations thereof,
including perfluorinated derivatives. In some embodiments, R.sub.1
and/or R.sub.2 may comprise a straight chained, branched, or cyclic
hydrocarbon group. In some embodiments, only one of R.sub.1 and
R.sub.2 is a C.sub.1-26 (or C.sub.2-24 or C.sub.4-22 or C.sub.6-20
or C.sub.12-18) hydrocarbon and the other is absent (or is
hydrogen). In some embodiments, one of R.sub.1 and R.sub.2 is a
C.sub.1-26 hydrocarbon selected from the group consisting of alkyl,
alkenyl, alkynyl, aryl, alkyl-aryl (e.g., benzyl), and aryl-alkyl
optionally substituted with 1-20 (or 1-10 or 1-6 or 1-3)
heteroatoms selected from halogen (e.g., fluorine), oxygen,
nitrogen, phosphorous, sulfur, and combinations thereof, and
perfluorinated derivates thereof. In some embodiments, R.sub.1
and/or R.sub.2 may comprise a group of the form R.sup.a--(C.dbd.O),
where R.sub.2 is a C.sub.1-25 (or C.sub.2-24 or C.sub.4-22 or
C.sub.6-20 or C.sub.12-18) hydrocarbon (e.g., straight chain or
branched alkyl) as described above. In one embodiment, R.sub.1
and/or R.sub.2 may comprise an acyl group, for example, one having
the form CH.sub.3--(CH.sub.2)n-(C.dbd.O) where "n" is an integer
from 0-25 (e.g., zero or from 1-24 or 2-22 or 10-20 or 12-16),
including embodiments where n is 10, 11, 12, 13, 14, 15, or 16. In
one embodiment, R.sub.1 and/or R.sub.2 may comprise an acetyl group
of the form CH.sub.3--(C.dbd.O)--. In one embodiment, R.sub.1
and/or R.sub.2 may comprise a palmitoyl group of the form
CH.sub.3--(CH.sub.2).sub.14--(C.dbd.O)--. R.sub.1 and/or R.sub.2
may be attached to a nitrogen atom on the peptide so as to thereby
form an amide bond of the form .OMEGA.-NH--(C.dbd.O)--R.sup.a,
formed, for example, through the reaction of an acid of the form
R.sup.a--(C.dbd.O)--OH (or activated derivative of the acid) with a
nitrogen atom on the N-terminal amino group of the peptide or a
nitrogen atom on a side chain (e.g., lysine) of the peptide. In
some embodiments, R.sub.1 and/or R.sub.2 may be attached to the
peptide through an amide bond of the form
.OMEGA.-(C.dbd.O)--NH--R.sup.b, formed, for example, by reaction of
an amine of the form R.sup.b--NH with the carboxyl terminus of the
peptide or on a carboxyl-containing side chain (e.g., aspartic acid
or glutamic acid) where R.sup.b can be any of the groups defined
for R.sup.a. In some embodiments, R.sub.1 and/or R.sub.2 may be
attached to the peptide through an ester bond of the form
.OMEGA.-(C.dbd.O)--O--R.sup.b, formed, for example, through the
reaction of an alcohol of the form R.sup.b--OH with the carboxyl
terminus of the peptide or carboxyl side chain (e.g., aspartic acid
or glutamic acid). In some embodiments, R.sub.1 and/or R.sub.2 may
be attached to the peptide through an ester bond of the form
.OMEGA.-O--(C.dbd.O)--R.sup.a, formed, for example, by the reaction
of an acid of the form R.sup.a(C.dbd.O)--OH with a hydroxyl group
on an amino acid side chain (e.g., serine or threonine). In any
case where an acid is reacted, the acid may first be activated
according to conventional practice by first converting it to an
anhydride, acid halide, or activated ester, such as an
N-hydroxysuccinimide ester, etc. It is also contemplated that
R.sub.1 and/or R.sub.2 may be attached to the peptide through
thioester bonds of the form .OMEGA.-S--(C.dbd.O)--R.sup.a,
thioether bonds of the form .OMEGA.-S--R.sup.b, ether bonds of the
form .OMEGA.-O--R.sup.b, and amines of the form of the form
.OMEGA.-NR.sup.N--R.sup.b, to name but a few non-limiting examples.
In various embodiments, R.sup.a and R.sup.b may be branched (e.g.,
ethylhexyl, isoalkyl, etc.), cyclic, or straight chained. R.sup.a
and R.sup.b and R.sup.N may be, without limitation methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, or C.sub.13, or C.sub.14, or C.sub.15, or C.sub.16, or
C.sub.17, or C.sub.18, or C.sub.19, or C.sub.20, or C.sub.21, or
C.sub.22, or C.sub.23, or C.sub.24, or C.sub.25, or C.sub.26 alkyl,
akenyl (having one, two, three or more double bonds in the cis
and/or trans configuration), or akynyl, etc. Any of the groups
R.sup.a, R.sup.b, R.sub.1, R.sub.2 and R.sup.N may be further
substituted with from 1-3 groups X.sub.1 or with from 1-20 (or 1-10
or 1-6 or 1-3) heteroatoms selected from halogen (e.g., fluorine),
oxygen, nitrogen, phosphorous, sulfur, and combinations
thereof.
[0031] Optional substituent X.sub.1 is selected independently at
each occurrence from hydrogen, --F; --Cl; --Br; --I; --OH, --OR*;
--NH.sub.2; --NHR*; --N(R*).sub.2; --N(R*).sub.3.sup.-;
--N(R*)--OH; --N(.fwdarw.O)(R*).sub.2; --O--N(R*).sub.2;
--N(R*)--O--R*; --N(R*)N(R*).sub.2; --C.dbd.N--R*;
--N.dbd.C(R*).sub.2; --C.dbd.N--N(R*).sub.2;
--C(.dbd.NR*)--N(R*).sub.2; --SH; --SR*; --CN; --NC;
--(C.dbd.O)--R*; --CHO; --CO.sub.2H; --CO.sub.2; --CO.sub.2R*;
--(C.dbd.O)--S--R*; --O--(C.dbd.O)--H; --O--(C.dbd.O)--R*;
--S--(C.dbd.O)--R*; --(C.dbd.O)--NH.sub.2;
--(C.dbd.O)--N(R*).sub.2; --(C.dbd.O)--NHNH.sub.2;
--O--(C.dbd.O)--NHNH.sub.2; --(C.dbd.S)--NH.sub.2;
--(C.dbd.S)--N(R*).sub.2; --N(R*)--CHO; --N(R*)--(C.dbd.O)--R*;
--(C.dbd.NR)--O--R*; --O--(C.dbd.NR*)--R*, --SCN; --NCS; --NSO;
--SSR*; --N(R*)--C(.dbd.O)--N(R*).sub.2;
--N(R*)--C(.dbd.S)N(R*).sub.2; --SO.sub.2--R*;
--O--S(.dbd.O).sub.2--R*; --S(.dbd.O).sub.2--OR*;
--N(R*)--SO.sub.2--R*; SO.sub.2--N(R*).sub.2; --O--SO.sub.3--R*;
--O--S(.dbd.O).sub.2--OR*; --O--S(.dbd.O)--OR*; --O--S(.dbd.O)--R*;
--S(.dbd.O)--OR*; --S(.dbd.O)--R*; --NO; --NO.sub.2; --NO.sub.3;
--O--NO; --O--NO.sub.2; --N.sub.3; --N.sub.2--R*;
--N(C.sub.2H.sub.4); --Si(R*).sub.3; --CF.sub.3; --O--CF.sub.3;
--PR*.sub.2; --O--P(.dbd.O)(OR*).sub.2; --P(.dbd.O)(OR*).sub.2;
C.sub.1-C.sub.8 perfluoroalkyl; an aliphatic C.sub.1-C.sub.8
hydrocarbon radical; a C.sub.1-C.sub.8 aromatic hydrocarbon
radical; or a C.sub.1-C.sub.8 heteroaryl radical. R* is a
C.sub.1-10 hydrocarbon, such as methyl, ethyl, propyl, butyl,
pentyl, hexyl, benzyl, phenyl, etc. Any two of R, R*, R.sup.N,
R.sub.1, and R.sub.2 may together form a 3-8 membered, optionally
heterocyclic ring.
[0032] In some embodiments, R.sub.1 or R.sub.2 is attached
covalently to the terminal carboxyl group. In some embodiments,
R.sub.1 and/or R.sub.2 is attached covalently to the terminal amino
group. In some embodiments, R.sub.1 and/or R.sub.2 is attached to a
side chain having a nitrogen, oxygen, or sulfur atom. In some
embodiments, the terminal amino groups of the peptides contain one
or two methyl groups covalently attached thereto. In one embodiment
the terminal carboxyl group is esterified with methanol or ethanol
to form a methyl or ethyl ester.
[0033] In some embodiments, R.sub.1 and/or R.sub.2 promotes
adhesion to or penetration of an integument. For example,
polyarginine (n=2-15 or 2-6) may be beneficially used to enhance
penetration of the peptide into skin. In some embodiments, R.sub.1
and/or R.sub.2 comprise biotin (e.g., attached through the carboxy
functionality of the biotin molecule to form an amide bond with the
N-terminus of the peptide), or a keto-ester such as a beta-keto
ester. The peptide can be PEGylated to enhance water-solubility. In
some embodiments, R.sub.1 and/or R.sub.2 have the form
--(OCH.sub.2CH.sub.2)y-Z or --(CH.sub.2CH.sub.2O)y-Z, where "y" is
an integer from 1-20 (or from 1-10 or from 1-6 or from 1-3) and Z
is H, R.sub.3, X.sub.1, or R.sub.4--X.sub.1, where R.sub.3 and
R.sub.4 are independently branched, straight chained, or cyclic
C.sub.1-6 hydrocarbons (e.g., methyl, ethyl, propyl, methylene,
--(CH.sub.2).sub.n-- (n=1-6), etc.). In some embodiments, R.sub.1
and/or R.sub.2 comprise mini-PEG (i.e.,
11-amino-3,6,9-trioxaundecanoic acid).
[0034] In some embodiments, the peptides will comprise a
hydrocarbon chain on the amino and/or carboxyl terminus, including,
without limitation, C.sub.1-24 or C.sub.6-18 or C.sub.12-18
aliphatic hydrocarbons, which may be straight chained or branched
or cyclic. In some embodiments, the peptides include the reaction
product of a peptide with a fatty acid or fatty alcohol. A fatty
acid or alcohol, as used herein, contains 6-26 (or 12-18) carbon
atoms. For example, the N-terminus may be reacted with a C.sub.6-24
fatty acid (e.g., palmitic acid) to form an amide bond. The
carboxyl terminus may be reacted with a C.sub.6-24 fatty alcohol
(e.g., cetyl alcohol) to form an ester. These fatty derivatives may
improve the lipophilicity of the peptide.
[0035] In one embodiment, the peptides of the invention will have
the structure of formulas (V)-(VIII):
CH.sub.3--(CH.sub.2).sub.14--(C.dbd.O)-YNT (V)
CH.sub.3--(CH.sub.2).sub.14--(C.dbd.O)-TNY (VI)
CH.sub.3--(CH.sub.2).sub.14--(C.dbd.O)-PVG (VII)
CH.sub.3--(CH.sub.2).sub.14--(C.dbd.O)-GVP (VIII)
[0036] where the group --(C.dbd.O)-- is typically attached to the
amino group of the adjacent amino acid.
[0037] Topically acceptable salts and prodrugs (collectively
"derivatives") of the peptides of the invention are also suitable.
Salts will typically be acid addition salts formed by the reaction
of the peptide with an inorganic or an organic acid. Inorganic
acids include mineral acids such as HCl and H.sub.2SO.sub.4, and
the like. Organic acids include citric, benzoic, tartaric, malic,
maleic, succinic, acetic, and propionic acid. The peptides may
exist in zwitterionic form. Prodrugs include any esters or amides
that hydrolyze in vivo to yield the peptide. Examples of suitable
prodrugs can be found in the book entitled "Prodrugs and Targeted
Delivery: Towards Better ADME Properties," Volume 47 (2011),
published by WILEY-VCH Verlag & Co, which is herein
incorporated by reference in its entirety. As used herein, a
"prodrug" is a derivative which yields the peptide in vivo, for
example through hydrolysis or cleavage of a functional group such
as an ester. In one embodiment, the prodrug is formed by reacting
the peptide with glyoxylic acid to produce
peptidyl-.alpha.-hydroxylglycine derivatives having improved
stability. In other embodiment the prodrugs may include terminal
N-acetyl derivatives, side chain N-acetyl derivatives, N-hydroxy
methylation or N-phthalidation of its N-terminus and/or side
chain.
[0038] It is within the skill in the art to prepare peptides using,
for example, conventional protection and activation chemistry.
Typically, the amino functionality of a first amino acid is
protected with a removable amino protecting group and the carboxyl
functionality of a second amino acid is protected with a removable
carboxyl protecting group. Suitable amine protecting groups
include, without limitation, benzoyloxycarbonyl (Cbz),
tert-butoxycarbonyl (t-Boc), and 9-flourenylmethloxycarbonyl
(FMOC). The carboxyl group may be protected by forming an acid or
base labile ester such as a methyl, ethyl, benzyl, or
trimethylsilyl esters. After protection, the first and second amino
acids are reacted in a suitable solvent such as water or DMF in the
presence of an in situ activating agent such as
N,N'-dicyclohexylcarbodiimide (DCCI), diisopropylcarbodiimide
(DIPCDI), or 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI)
to effect peptide bond formation. Reactive moieties on the side
chains of either amino acid are protected with protecting groups
such as tent-butyl or benzyl for OH and SH; methyl, ethyl,
tert-butyl or benzyl for carboxyl groups, and
2,2,5,7,8-pentamethylchroman-6-sulphonyl for the
--NHC(NH.sub.2).dbd.NH functionality of Arg. Following the coupling
reaction, selective deprotection of the amino group of the first
amino acid is accomplished by acid hydrolysis under conditions that
do not remove the carboxyl protecting group of the second amino
acid. The procedure is repeated with additional amino protected
amino acids. Solid phase synthesis, such as the well-known
Merrifield method, is especially useful for synthesizing the
peptides of the invention. Lysine-amino valeric acid (K-ava)
derivatives are described in U.S. Pat. No. 8,551,956, the
disclosure of which is hereby incorporated by reference.
[0039] Topical Compositions
[0040] The compositions according to the invention may be
formulated in a variety of forms for topical application and will
typically comprise from about 0.00001% by weight to about 20% by
weight of the peptide. More typically, the peptide will comprise
from about 0.0001% by weight to about 10% by weight, and more
preferably from about 0.001% by weight to about 5% by weight of the
composition. In one embodiment, the active peptide or a fragment or
derivative thereof will comprise from about 0.001% by weight to
about 1% by weight or from about 0.001% by weight or to about 0.1%
by weight of the composition. The compositions may comprise an
effective amount of the peptide, by which is meant an amount
sufficient to stimulate hair matrix cell proliferation, keratin
production, KAP production, and/or production of desmosomal
proteins (e.g., cadherins). In other embodiments, the amount of
peptide or derivative thereof will be sufficient to promote hair
growth and/or thicken the hair shafts and/or strengthen hair when
topically applied to the hair and/or scalp daily for a period of at
least four, or at least eight weeks.
[0041] The peptides of the invention (e.g., comprising any of SEQ
ID NOs:1-4) are provided in physiologically acceptable vehicles or
carriers. The vehicle may be either hydrophobic or hydrophilic.
Suitable, hydrophobic carriers include, for example, hydrocarbons,
paraffins, isoparafins, waxes, silicone oils, fatty alcohols, fatty
esters and ethers of fatty alcohols and of fatty acids, with carbon
chain length from C.sub.4 to C.sub.22, typically from C.sub.8 to
C.sub.18, or from C.sub.12 to C.sub.18. Examples of fatty
hydrophobic carriers include isopropyl myristate, isopropyl
palmitate, octyl palmitate, isopropyl lanolate, acetylated lanolin
alcohol, the benzoate of C.sub.12-C.sub.15 alcohols, cetearyl
octanoate, cetyl palmitate, myristyl myristate, myristyl lactate,
cetyl acetate, propylene glycol dicaprylate/caprate, decyl oleate,
acetylated lanolin, stearyl heptanoate, diisostearyl malate, octyl
hydroxystearate, octyl hydroxystearate, isopropyl isostearate, and
the like.
[0042] Suitable hydrophilic carriers may comprise, for example,
water, lower alcohols (C.sub.1-6) such as ethanol, mixtures of
ethanol and water, glycols (e.g., glycerin, propylene glycol,
butylene glycol, etc.), and alkoxylated glycols, including ethylene
glycol, diethylene glycol, triethylene glycol, propylene glycol,
dipropylene glycol, and the like. In one embodiment, the carrier
comprises water and/or ethanol.
[0043] The physiologically acceptable vehicle may be in the form of
an emulsion. Non-limiting examples of suitable emulsions include
water-in-oil emulsions, oil-in-water emulsions, silicone-in-water
emulsions, water-in-silicone emulsions, wax-in-water emulsions,
water-oil-water triple emulsions or the like having the appearance
of a cream, gel or microemulsions. As used herein, the term "oil"
includes silicone oils unless otherwise indicated. The emulsion may
include an emulsifier, such as a nonionic, anionic or amphoteric
surfactant, or a gellant, typically in an amount from about 0.001%
to about 10% by weight.
[0044] The vehicle may include water; vegetable oils; mineral oils;
ester oils; ethers such as dicapryl ether and dimethyl isosorbide;
alcohols such as ethanol and isopropanol; fatty alcohols such as
cetyl alcohol, cetearyl alcohol, stearyl alcohol and behenyl
alcohol; isoparaffins such as isooctane, isododecane (IDD) and
isohexadecane; silicone oils such as cyclomethicone, dimethicone,
dimethicone cross-polymer, polysiloxanes and their derivatives,
including PDMS, dimethicone copolyol, dimethiconols, and
amodimethiconols; hydrocarbon oils such as mineral oil, petrolatum,
isoeicosane and polyolefins, e.g., (hydrogenated) polyisobutene;
polyols such as propylene glycol, glycerin, butylene glycol,
pentylene glycol, hexylene glycol, caprylyl glycol; waxes such as
beeswax, carnauba, ozokerite, microcrystalline wax, polyethylene
wax, and botanical waxes; or any combinations or mixtures of the
foregoing. Aqueous vehicles may include one or more solvents
miscible with water, including lower alcohols, such as ethanol,
isopropanol, and the like. The vehicle may comprise, for example,
from about 50% to about 99.99% by weight of the composition, more
typically from about 75% to about 97.5% by weigh of the
composition. In some embodiments, the compositions are anhydrous,
by which is meant no water is deliberately added to the
formulation. The term "anhydrous" as used herein, does not preclude
minor amounts of water that are picked up from the atmosphere or
found in trace amounts in the raw ingredients.
[0045] In some embodiments, the compositions comprise a penetration
enhancer. The penetration enhancer may, for example, be selected
from one or more of the group consisting of lower alcohols (e.g.,
ethanol), fatty alcohols, glycols, polyethylene glycols, fatty
acids, fatty esters, fatty ethers, occlusive agents (e.g., waxes,
oils, silicones, paraffins, petrolatum, etc.), surface active
agents, dimethylaminopropionic acid derivatives, terpenes,
sulfoxides, cyclic ethers, amides, urea and amines. Surface active
agents include without limitation nonionic, anionic, and cationic
agents, and combinations thereof, such as polysorbates, sodium
dodecyl sulfate (SDS), macrogol, hydroxystearate, polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer,
lecithin, lysolecithin, nonylphenoxypolyoxyethylene,
lysophosphatidylcholine, polyethyleneglycol 400, polyoxyethylene
ethers, polyglycol ether surfactants, sodium laurate, sodium lauryl
sulfate, cetyltrimethylammonium bromide, docusate sodium, and
benzalkonium chloride, etc. Other penetration enhancers that may be
useful include dimethylaminopropionic acid derivatives, such as
2-dimethylaminopropionic acid dodecyl ester (DDAIP); terpenes,
including terpinolene, limonene, nerol, cineol; sulfoxides such as
DMSO; cyclic ethers; amides and amines, such as
Didecyldimethylammonium bromide (DDAB), sodium taurodeoxycholate,
triethylamine; octyl (e.g., ethylhexyl) salicylate, dimethyl
isosorbide, ethoxydiglycol and combinations thereof. Penetrations
enhancers may be included in amount from about 0.001-20% by weight.
In other embodiments, the peptides may be included in liposomes to
improve penetration of the scalp and hair follicle.
[0046] The formulations may further include an additional hair
growth agent selected from the group consisting of fibroblast
growth factor receptor 1 (FGFR1) inhibitors, 5-alpha-reductase
inhibitors, prostaglandin F2-alpha (PGF2.alpha.) analogs,
microcirculation enhancers, creatine, biotinylated tri-peptide
(e.g., N-biotinyl-gly-his-lys), aminexil, FP receptor agonists and
vasodilators and combinations thereof. Representative additional
hair growth agents include aminexil, minoxidil, latanoprost and
travoprost. The compositions according to the invention may also
optionally comprise one or more 5-alpha reductase inhibitors. Such
compounds are known to assist in promotion of hair growth, and
include, but are not limited to, saw palmetto (Serenoa) extract,
Emblica officianalis extract, beta-glycyrrhetic acid, estradiol,
estrone, progesterone, or azasteroids, such as finasteride or
dutasteride. Potassium channel openers, such as Minoxidil, are also
contemplated. Saw Palmetto and Pygeum africanum. Other agents that
may have such activity are beta-sisterol, licorise powder or
extract, gamma-linolenic acid and other unsaturated fatty acids,
Zinc and Zinc salts, green tea catechin (-)-epigallocatechin
gallate (EGCG) and other polyphenols, grape and grape seed
extracts, etc. Additional hair growth actives, if present, will
typically comprise, individually or in the aggregate, from about
0.0001-10% by weight of the formulation.
[0047] Other agents that may be optionally added to the
compositions of the invention comprise those that act as an
exfoliant, such as lactic acid. The compositions useful in the
methods of the invention may also optionally comprise agents that
act on stearoyl coenzyme A desaturase, such as extracts of Eclipta
prostrata, which is believed to reduce sebum production, thereby
improving the health and appearance of, for example, the scalp.
[0048] The compositions according to the invention may also
optionally comprise one or more vasodilators. Use of one or more
vasodilation agents can supplement the activity of the peptides and
enhance the overall efficacy of the formulation. Examples of useful
vasodilation agents include, but are not limited to, arginine,
ginseng extracts, gingko extracts, swertia extracts, calpronium
chloride, diphenhydramine hydrochloride, gamma-oryzanol,
prostaglandins, vitamin E derivatives such as vitamin E nicotinate,
pinacidil, minoxidil, phthalides, quina extracts, Capsicum
extracts, orange peel extracts, and citron extracts. The
vasodilators may be used in the compositions of the invention in
the amount of about 0.001 to about 10% based on the total weight of
the composition.
[0049] The compositions according to the invention may also
optionally comprise one or more microcirculation enhancers.
Apigenin is a citrus-derived flavonoid believed to promote
microcirculation when topically applied, and may be included in the
compositions of the invention. The compositions according to the
invention may also optionally comprise prostaglandin F2.alpha.
analogs. The compositions useful in the methods of the invention
may also optionally comprise creatine. Creatine is a
naturally-occurring amino acid derivative that is thought to play a
role in cellular energy metabolism. Creatine may be used, for
example, use at a concentration of from about 0.01-10% by weight,
or from 0.5-1.4 weight % based on the total weight of the
composition.
[0050] The compositions useful in the methods of the invention may
also optionally comprise algae extracts. An algae extract, as used
herein, refers to an extract of marine algae. Preferred marine
algae include, for example, Pelvetia canaliculata and/or Laminara
digitata. The compositions of the instant invention may comprise an
amount of algae extract from about 0.001-10 weight % based on the
total weight of the composition, or from about 0.01-3 weight %; or
from about 0.02-1 weight %, based on the total weight of the
composition. It is believed that the algae extract may also act to
maintain healthy structure and function of keratin fiber proteins
by stimulating "heat shock proteins" (HSPs). Heat shock proteins
(HSPs), also known as "stress proteins," are a family of highly
conserved proteins found in all organisms. HSPs are induced by a
wide variety of stresses, such as increased temperature, oxygen
deprivation, pH changes, chemical insult, UV radiation, and the
like. These stresses modify the folding structure of proteins.
Improperly folded proteins lead to loss of function and potentially
cell death. HSPs bind to proteins during stress to help maintain
and/or restore protein structure and function. Without wishing to
be bound by theory, it is believed that the algae extract increases
activity of HSP27 and HSP70 at the gene level, thereby further
protecting keratin fiber proteins, especially during periods of
stress. Stresses to keratin fibers may include, for example,
stresses from curling the keratin fibers, heat, brushing or combing
hair, and shampooing and conditioning hair. Suitable agents for
modulating HSPs include, for example, Gynostemma, coconut water,
Azadiracta, and Rhodeola, described, for example, in U.S. Published
Patent Application US2005/0147578, the contents of which are herein
incorporated by reference.
[0051] The composition of the invention may optionally further
comprise one or more cell differentiation activators. Examples of
such agents are extracts of sage, for example clary sage, and/or
any differentiation-active compounds, such as sclareolide,
obtainable therefrom. Other examples of useful differentiation
active compounds are forskolin, 7-dehydrocholesterol, and Vitamin
D3 analogs. Specifically, a clary sage fermented extract is
commercially available from Avoca/RJ Reynolds. Such agents may be
used in the compositions of the invention in the amount of about
0.001 to about 10% based on the total weight of the
composition.
[0052] The compositions of the invention may also optionally
comprise one or more firming components, which promote the support
in the basement membrane and dermis to encourage and support the
keratin fiber structure. Examples of finning components are
compounds that enhance the amount of collagen and/or elastin in the
skin, for example, collagenase and or elastase inhibitors, or
collagen or elastin synthesis enhancers. Such compounds include,
but are not limited to triterpenoid-containing extracts and refined
compounds, for example, white birch bark extract, silver birch bark
extract, Boswellia extract, bearberry extract, Centella asiatica
extract, Mimosa tenuiflora bark extract, or Pygeum (Prunus)
africanum extract and individual active compounds that may be
present in these extracts, including betulinol (betulin), betulinic
acid, boswellic acid, ursolic acid, oleanolic acid, oleanol,
asiaticoside, asiatic acid, and madagassic acid;
phenolic-containing extracts, such as green tea extracts and apple
extracts, and compounds contained therein, such as EGCG, ECG,
catechins, phenylpropanoids, and phloretin; and Vitamin C and
derivatives thereof for enhancing collagen synthesis. The firming
agents may be used in the compositions of the invention in the
amount of about 0.001 to about 10% based on the total weight of the
composition.
[0053] The formulations may include one or more vitamins,
including, but not limited to, vitamin A, vitamin B's, such as
vitamin B.sub.3, vitamin B.sub.5, and vitamin B.sub.12, vitamin C,
vitamin K, vitamin E such as alpha, gamma or delta-tocopherol, and
derivatives (such as salts and C.sub.1-16 esters) and mixtures
thereof. Vitamins, if present, will typically comprise,
individually or in the aggregate, from about 0.0001-10% by weight
of the formulation.
[0054] In one embodiment of the invention, the compositions may
include one or more additional skin actives, including but not
limited to, retinoids, botanicals, keratolytic agents, desquamating
agents, keratinocyte proliferation enhancers, collagenase
inhibitors, elastase inhibitors, depigmenting agents,
anti-inflammatory agents, steroids, anti-acne agents, antioxidants,
and advanced glycation end-product (AGE) inhibitors, to name but a
few. The amounts of these various ingredients are those
conventionally used in the cosmetic field to achieve their intended
purpose, and range individually or collectively typically from
about 0.001 wt % to about 20 wt % by weight of the composition. The
nature of these ingredients and their amounts must be compatible
with the production and function of the compositions of the
disclosure.
[0055] Exemplary anti-aging components include, without limitation,
botanicals (e.g., Butea frondosa extract, Tiliacora triandra
extract, Portulaca oleracea, Melicope elleryana, etc.); phytol;
phytonic acid; retinoids; hydroxy acids (including alpha-hydroxy
acids and beta-hydroxy acids), salicylic acid and alkyl
salicylates; exfoliating agents (e.g., glycolic acid,
3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase
stimulating compounds (e.g., caffeine and derivatives); compounds
capable of inhibiting 5 alpha-reductase activity (e.g., linolenic
acid, linoleic acid, finasteride, and mixtures thereof); and
barrier function enhancing agents (e.g., ceramides, glycerides,
cholesterol and its esters, alpha-hydroxy and omega-hydroxy fatty
acids and esters thereof, etc.), to name a few.
[0056] Exemplary retinoids include, without limitation, retinoic
acid (e.g., all-trans, or 9-cis, or 13-cis), and derivatives
thereof, retinaldehyde, retinol (Vitamin A) and esters thereof,
such as retinyl palmitate, retinyl acetate and retinyl propionate,
and salts thereof. Particular mention may be made of retinol. When
present, the retinoids will typically be included in amounts from
about 0.0001% to about 5% by weight, more typically from about
0.01% to about 2.5% by weight, or from about 0.1% to about 1.0% by
weight. Compositions according to this embodiment will typically
include an antioxidant such as ascorbic acid and/or BHT and/or a
chelating agent such as EDTA or a salt thereof (e.g., disodium
EDTA) in amounts effective to stabilize the retinoid (e.g.,
0.0001%-5%). The composition may include from 0.001-10% by weight
phytol.
[0057] In another embodiment, the topical compositions of the
present invention may also include one or more of the following: a
skin penetration enhancer; an emollient, such as isopropyl
myristate, petrolatum, volatile or non-volatile silicones oils
(e.g., methicone, dimethicone), ester oils, mineral oils, and fatty
acid esters; a humectant, such as glycerin, hexylene glycol or
caprylyl glycol; a skin plumper, such as palmitoyl oligopeptide,
collagen, collagen and/or glycosaminoglycan (GAG) enhancing agents;
an exfoliating agent; and an antioxidant.
[0058] Suitable exfoliating agents include, for example,
alpha-hydroxy acids, beta-hydroxy acids, oxa-acids, oxadiacids, and
their derivatives such as esters, anhydrides and salts thereof.
Suitable hydroxy acids include, for example, glycolic acid, lactic
acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic
acid, mandelic acid, salicylic acid and derivatives thereof. One
exemplary exfoliating agent is glycolic acid. When present, the
exfoliating agent may comprise from about 0.001% to about 20% by
weight of the composition.
[0059] Examples of antioxidants that may be used in the present
compositions include compounds having phenolic hydroxy functions,
such as ascorbic acid and its derivatives/esters; beta-carotene;
catechins; curcumin; ferulic acid derivatives (e.g., ethyl
ferulate, sodium ferulate); gallic acid derivatives (e.g., propyl
gallate); lycopene; reductic acid; rosmarinic acid; tannic acid;
tetrahydrocurcumin; tocopherol and its derivatives, including
tocopheryl acetate; uric acid; or any mixtures thereof. Other
suitable antioxidants are those that have one or more thiol
functions (--SH), in either reduced or non-reduced form, such as
glutathione, lipoic acid, thioglycolic acid, and other sulfhydryl
compounds. The antioxidant may be inorganic, such as bisulfites,
metabisulfites, sulfites, or other inorganic salts and acids
containing sulfur. In one embodiment, the composition comprises
thiodipropionic acid or a mono- or diester thereof such as dilauryl
thiodipropionic acid. Antioxidants may comprise, individually or
collectively, from about 0.001% to about 10% (w/w), or from about
0.01% to about 5% (w/w) of the total weight of the composition.
[0060] Other additives include: vitamins, such as tocopherol and
ascorbic acid; vitamin derivatives such as ascorbyl monopalmitate,
tocopheryl acetate, and Vitamin E palmitate; thickeners such as
hydroxyalkyl cellulose, carboxymethylcellulose, carbombers, and
vegetable gums such as xanthan gum; gelling agents, such as
ester-terminated polyester amides; structuring agents; metal
chelating agents such as EDTA or salts thereof; fillers and
powders, colorants, pH adjusters (citric acid, ethanolamine, sodium
hydroxide, etc.); film formers, moisturizers, minerals, viscosity
and/or rheology modifiers, anti-acne agents, anti-inflammatories,
depigmenting agents, pharmaceutical agents, surfactants,
botanicals, sunscreens, insect repellents, skin cooling compounds,
skin protectants, conditioners, lubricants, fragrances, excipients,
preservatives, stabilizers, emulsifiers, and mixtures thereof. The
foregoing may individually or collectively comprise from about
0.0001% to about 20% by weight of the composition.
[0061] Details with respect to these and other suitable cosmetic
ingredients can be found in the "International Cosmetic Ingredient
Dictionary and Handbook," 10th Edition (2004), published by the
Cosmetic, Toiletry, and Fragrance Association (CTFA), at pp.
2177-2299, which is herein incorporated by reference in its
entirety. The amounts of these various substances are those that
are conventionally used in the cosmetic or pharmaceutical fields,
for example, they can constitute individually or in the aggregate,
from about 0.01% to about 20% of the total weight of the
composition.
[0062] A sunscreen may be included to protect the skin from
damaging ultraviolet rays. The sunscreen may provide both UVA and
UVB protection, by using either a single sunscreen or a combination
of sunscreens. Among the sunscreens that can be employed in the
present compositions are avobenzone, cinnamic acid derivatives
(such as octylmethoxy cinnamate), octyl salicylate, homosalate,
oxybenzone, octocrylene, titanium dioxide, zinc oxide, or any
mixtures thereof. The sunscreen may be present from about 1 wt % to
about 30 wt % of the total weight of the composition.
[0063] The compositions may include one or more oil-phase and/or
water phase gelling agents or thickeners. Hydrophilic gelling
agents include carboxyvinyl polymers (carbomer), acrylic copolymers
such as acrylate-(alkyl)acrylate copolymers and Acryalates
Copolymer (INCI), polyacrylamides, polysaccharides, such as
hydroxypropylcellulose, hydroxypropylmethylcellulose, silica,
alumina, gums and hydrocolloids, such as xanthan, gaur, veegum,
carrageenan, gelatin, karaya, pectin and locust beans gum, etc.,
and clays, and, as lipophilic gelling agents, representative are
the modified clays such as bentones, fatty acid metal salts such as
aluminum stearates and hydrophobic silica, or ethylcellulose and
polyethylene. Other suitable oil-phase gellants include dibutyl
lauryl glutamide, dibutyl ethylhexyl glutamide, ethylene block
copolymers (ethylene/propylene/butylene block copolymers),
polyamides capable of forming a gel with an oil, for example,
ester-terminated polyamides (ETPA), ester-terminated
poly(ester-amide) polymeric gellants (ETPEA) (e.g., Bis-Stearyl
Ethylenediamine/Neopentyl Glycol/Stearyl Hydrogenated Dimer
Dilinoleate copolymer (INCI)), tertiary amide terminated polyamides
(ATPA), polyalkyleneoxy terminated polyamides (PAOPA), and
polyether polyamides (PEPA).
[0064] In one embodiment, the topical composition will have a pH
range from 1 to 13, with a pH in the range of from 2 to 12 being
typical. In some embodiment, the composition will have a pH in the
range of from 3.5 to 7 or from 7 to 10.5. In some embodiments, the
pH will be in the range of 3-4, or 4-5, or 5-6, or 6-7, or 7-8, or
8-9, or 9-10, or 10-11, or 11-12. Suitable pH adjusters such as
sodium hydroxide, citric acid and triethanolamine may be added to
bring the pH within the desired range.
[0065] Another embodiment of the present disclosure is directed to
the delivery of the described compositions by the use of targeted
delivery systems, for example, liposomes, microspheres (see, e.g.,
U.S. Pat. No. 5,770,222 to Unger et al.), and the like, so that the
components and/or active constituents can more readily reach and
affect the subcutaneous layer of the area of application, e.g.,
face or neck, or the other area of the skin.
[0066] The compositions may be formulated in a variety of product
forms, such as, for example, a shampoo, conditioner, mousse, hair
tonic, styling gel, mascara, lotion, cream, serum, spray, aerosol,
cake, ointment, essence, gel, paste, patch, pencil, towelette,
mask, stick, foam, elixir, concentrate, and the like, particularly
for topical administration. The composition is typically formulated
as an emulsion comprising from 0.01-10% by weight of an emulsifier
for stabilizing the emulsion.
[0067] Methods of Treatment
[0068] The invention provides methods for enhancing and/or
promoting growth of hair, including hair of the scalp and
eyelashes. Methods for thickening hair, including increasing
follicle density, are also provided. In some embodiments, the
invention provides methods for increasing the diameter of the hair
shaft are also provided. In some embodiments, the invention
provides methods for increasing the tensile strength of hair
fibers. In some embodiments, methods are provided for improving the
condition, health, and/or appearance of keratin fibers (e.g., hair
of the scalp). Non-limiting examples of improvements in keratin
fibers imparted by use of the compositions of the invention
comprise: (a) improvement in root sheath thickness; (b) improvement
in fiber anchorage; (c) decrease in keratin fiber loss; (d)
reduction in keratin fiber breakage; (e) increase in keratin fiber
strength; (f) improvement in keratin fiber growth rate; (g)
improvement in shine; (h) improvement in the number of visible
keratin fibers; (i) improvement in keratin fiber length; and/or (j)
improvement in keratin fiber volume. The methods of the invention
comprise the step of topically applying the compositions of the
invention to the hair and/or scalp and/or area of skin surrounding
a hair follicle. The compositions of the invention are preferably
applied to affected skin areas once or twice daily for as long as
is necessary to achieve desired anti-aging results. The treatment
may be at least once or twice daily and may last for a period of at
least four weeks, typically at least eight weeks, twelve weeks, or
longer. In one embodiment, the compositions of the invention will
be applied in an amount from about 0.001 to about 1000 mg/cm.sup.2,
more typically from about 0.01 to about 200 mg/cm.sup.2, or from
about 0.1 to about 100 mg/cm.sup.2.
[0069] In particular, the composition for application to the scalp
or hair can be provided in the form of a hair care lotion, for
example for daily or twice-weekly application, of a shampoo or of a
hair conditioner, in particular for twice-weekly or weekly
application, of a liquid or solid soap for cleaning the scalp for
daily application, of a product for shaping the hairstyle (lacquer,
hair setting product, styling gel), of a treatment mask, of a cream
or of a foaming gel for cleaning the hair. It can also be provided
in the form of a hair dye or mascara to be applied with a brush or
comb.
[0070] In some preferred embodiments, a method for stimulating hair
growth comprises administering to the skin of a patient, said skin
comprising hair follicles, an effective amount of a peptide of the
invention, or formulation containing said peptide, wherein the
administration causes increased hair growth. The composition may be
applied to the scalp. The composition may be applied at least once
daily. In some embodiments, the composition is applied to the scalp
for treatment of a condition selected from the group consisting of
alopecia areata, telogen effluvium, anagen effluvium, cicatricial
alopecia, scarring alopecia; hair shaft abnormalities, trichorrexis
nodosa, loose anagen syndrome, trichotillomania, traction alopecia;
infectious hair disorders, tiniea capitis, sebohorreic dermatitis,
follicullitus of the scalp, and androgenetic alopecia. In some
embodiments, the composition is applied to one or both of the scalp
and the eyebrows, including for patients experiencing hair loss due
to chemotherapy, hormonal imbalance, fungal infection of the scalp,
anti-coagulants, medicine for gout, depression, high blood pressure
and heart disease. In some embodiments, the peptides are applied to
slow or arrest the loss of hair.
[0071] In another aspect of the invention, the compositions are
applied topically to improve the aesthetic appearance of human
skin. The method comprises topically applying to an area of the
skin in need thereof a composition comprising an effective amount
of a peptide of the invention (e.g., comprising any of SEQ ID NOs:
1 or 2) for a time sufficient to improve the aesthetic appearance
of said human skin. The composition may optionally further comprise
a retinoid (e.g., from 0.0001-5%) and/or an alpha-hydroxy acid
(e.g., glycolic acid) (e.g., from 0.0001-25%) and/or a beta-hydroxy
acid (e.g., salicylic acid or a derivative) (e.g., from
0.0001-15%).
[0072] As used herein, "aesthetic improvement" may be measured by
evaluation of before and after pictures by panels of
dermatologists, or by other objective measures known in the
art.
[0073] In a related implementation, a method is provided for the
treatment of wrinkles and/or fine lines on the skin human skin
(typically, skin of the face) comprising topically applying to an
area of the skin in need thereof (e.g., applying to a wrinkle or
fine line) a composition comprising a peptide of the invention
(e.g., comprising any of SEQ ID NOs: 1-2), for a time sufficient to
reduce the visibility, number, or depth of said wrinkles and/or
fine lines. The treatment may be a least once or twice daily and
may last for a period of at least four weeks, typically at least
eight weeks, twelve weeks, or longer. The composition may
optionally further comprise a retinoid (e.g., retinol or retinyl
palmitate) and/or an alpha-hydroxy acid (e.g., glycolic acid)
and/or a beta-hydroxy acid (e.g., salicylic acid or derivative) in
amounts effective to improve the appearance of skin. In some
embodiments, methods reduce the severity of, reduce the number of,
or prevent or forestall the onset of, wrinkles or fine lines on
human skin. The composition may be topically applied to an area of
the skin in need thereof (e.g., directly to wrinkled skin), an
effective amount (e.g., 0.000001%-1% by weight, w/w) of a peptide
of the invention (e.g., comprising any of SEQ ID NOs: 1 or 2) in
combination with an effective amount (e.g., 0.01%-5% by weight,
w/w) of retinol and/or an effective amount (e.g., 0.001%-20% by
weight, w/w) of an alpha-hydroxy acid (e.g., glycolic acid) and/or
a beta-hydroxy acid (e.g., salicylic acid). The effect of a
composition on the formation or appearance of fine lines and
wrinkles can be evaluated qualitatively, e.g., by visual
inspection, or quantitatively, e.g., by microscopic or computer
assisted measurements of wrinkle morphology (e.g., the number,
depth, length, area, volume and/or width of wrinkles per unit area
of skin).
[0074] Topically application of a composition comprising a peptide
comprising any of SEQ ID NOs: 1 or 2, typically in a
physiologically acceptable vehicle, over an affected area of skin
may remediate, reverse, reduce, ameliorate, or prevent
dermatological signs of aging. Generally, the improvement in the
condition and/or appearance of skin is selected from the group
consisting of: reducing dermatological signs of chronological
aging, photo-aging, hormonal aging, and/or actinic aging;
preventing and/or reducing the appearance of lines and/or wrinkles;
reducing the noticeability of facial lines and wrinkles, facial
wrinkles on the cheeks, forehead, perpendicular wrinkles between
the eyes, horizontal wrinkles above the eyes, and around the mouth,
marionette lines, and particularly deep wrinkles or creases;
improving the appearance of suborbital lines and/or periorbital
lines; reducing the appearance of crow's feet; rejuvenating and/or
revitalizing skin, particularly aging skin; reducing skin
fragility; preventing and/or reversing of loss of
glycosaminoglycans and/or collagen; ameliorating the effects of
estrogen imbalance; preventing skin atrophy; preventing, reducing,
and/or treating hyperpigmentation or hypopigmentation; minimizing
skin discoloration; improving skin tone, radiance, clarity and/or
tautness; preventing, reducing, and/or ameliorating skin sagging;
improving skin firmness, plumpness, suppleness and/or softness;
improving procollagen and/or collagen production; improving skin
texture and/or promoting retexturization; improving skin barrier
repair and/or function; improving the appearance of skin contours;
restoring skin luster and/or brightness; minimizing dermatological
signs of fatigue and/or stress; resisting environmental stress;
replenishing ingredients in the skin decreased by aging and/or
menopause; improving communication among skin cells; increasing
cell proliferation and/or multiplication; increasing skin cell
metabolism decreased by aging and/or menopause; retarding cellular
aging; improving skin moisturization; enhancing skin thickness;
slowing or halting skin thinning; increasing skin elasticity and/or
resiliency; enhancing exfoliation; improving microcirculation;
decreasing and/or preventing cellulite formation; and any
combinations thereof. In some embodiments, each of the forgoing is
associated with female skin.
[0075] The improvement in aesthetic appearance of human skin also
may be an improvement of any attribute or characteristic of skin,
including without limitation:
[0076] (a) treatment, reduction, and/or prevention of fine lines or
wrinkles;
[0077] (b) reduction of skin pore size;
[0078] (c) improvement in skin thickness, plumpness, and/or
tautness;
[0079] (d) improvement in skin smoothness, suppleness and/or
softness;
[0080] (e) improvement in skin tone, radiance, and/or clarity;
[0081] (f) improvement in procollagen, and/or collagen
production;
[0082] (g) improvement in maintenance and remodeling of
elastin;
[0083] (h) improvement in skin texture and/or promotion of
retexturization;
[0084] (i) improvement in skin barrier repair and/or function;
[0085] (j) improvement in appearance of skin contours;
[0086] (k) restoration of skin luster and/or brightness;
[0087] (l) replenishment of essential nutrients and/or constituents
in the skin;
[0088] (m) improvement of skin appearance decreased by aging and/or
menopause;
[0089] (n) improvement in skin moisturization;
[0090] (o) increase in skin elasticity and/or resiliency;
[0091] (p) treatment, reduction, and/or prevention of skin
sagging;
[0092] (q) improvement in skin firmness; and
[0093] (r) reduction of pigment spots and/or mottled skin; and
[0094] (s) improvement of optical properties of skin by light
diffraction or reflection.
[0095] It is also contemplated that the compositions of the
invention will be useful for treating thin skin by topically
applying the composition comprising the active peptides (e.g.,
comprising any of SEQ ID NOs: 1 or 2) to thin skin of an individual
in need thereof. "Thin skin" is intended to include skin that is
thinned due to chronological aging, menopause, or photo-damage and
skin that is thinning prematurely. In some embodiments, the
treatment is for thin skin in men, whereas other embodiments treat
thin skin in women, pre-menopausal or post-menopausal, as it is
believed that skin thins differently with age in men and women, and
in particular in women at different stages of life.
[0096] The method of the invention may be employed prophylactically
to forestall aging including in individuals that have not
manifested signs of skin aging, most commonly in individuals under
25 years of age. The method may also reverse or treat signs of
aging once manifested as is common in individuals over 25 years of
age, or to slow the progression of dermatological aging in such
individuals.
[0097] In one embodiment, the compositions of the invention
comprising active peptides (e.g., comprising any of SEQ ID NOs: 1
or 2) are applied to human skin to reduce sebum production or
improve the appearance of skin affected by cellulite, and/or reduce
unwanted lipogenesis or increase lipolysis. In this embodiment, the
peptides of the invention can be formulated in topically acceptable
vehicles (as described herein) and may include one or more
additional agents such as anti-acne ingredients (e.g., salicylic
acid, benzoyl peroxide and other peroxides, sulfur, retinoids,
etc.) in the case of a facial composition, or, in the case of a
cellulite treatment, the formulation may comprise any ingredients
suitable for treatment of cellulite, including without limitation,
perilla oil and other unsaturated fatty oils and omega-3 fatty
acids such as alpha-linolenic acid; caffeine; theophylline;
xanthines; retinoids (e.g., retinol); and the like. A cellulite
treatment according to the invention will typically be applied
topically to skin suffering from cellulite, including skin of the
buttocks and thighs for a period of time sufficient to improve the
appearance thereof, including for example, daily treatment for at
least four weeks, at least eight weeks, at least twelve weeks, or
longer. In one embodiment, the compositions are topically applied
to treat acne.
[0098] In certain embodiments, the compositions described herein
comprising active peptides (e.g., comprising any of SEQ ID NOs: 1
or 2) can be used to treat and/or prevent hyper-pigmentation of
skin and/or of the hair, for example, to lighten skin or hair. In
some embodiments, the compositions are topically applied to the
skin or hair, for example to an area of hyper-pigmented skin or
hair. Hyper-pigmentation includes any coloration of an individual's
skin or hair that is darker than desired by the individual and that
is caused by melanocytes. Hyper-pigmented areas of the skin include
areas of discrete or mottled hyper-pigmentation. Areas of discrete
hyper-pigmentation can be distinct, uniform areas of darker color
and may appear as brown spots or freckles on the skin, including
marks commonly called pigment spots or "age spots." Areas of
mottled hyper-pigmentation of the skin can be dark blotches that
are larger and more irregular in size and shape than areas of
discrete pigmentation. Areas of hyper-pigmentation also include
areas of tanned skin, for example, skin tanned due to UV exposure.
Hyper-pigmented hair includes any shade of hair that is darker than
desired.
[0099] Treating hyper-pigmentation or hyper-pigmented skin/hair
refers to eradicating, reducing, ameliorating, or reversing one or
more of the unwanted features associated with hyper-pigmentation,
such as producing a perceptible lightening of the skin or hair in
the affected area. Lightening hyper-pigmented areas of the skin may
be effective in diminishing age spots; lightening a suntan; evening
or optimizing skin tones, e.g., in areas of mottled
hyper-pigmentation; in treating melasmic and chloasmic patches,
freckles, after-burn scars, and post-injury hyper-pigmentation.
Preventing hyper-pigmentation or hyper-pigmented skin refers to
affording skin, not yet affected by hyper-pigmentation, a benefit
that serves to avoid, delay, forestall, or minimize one or more
unwanted features associated with skin hyper-pigmentation, such as
reducing the darkness or size of hyper-pigmented areas that
eventually develop.
[0100] In some embodiments, the compositions of the invention are
used in a rotational, alternating, or sequential treatment regimen
comprising topical application of the compositions of the invention
for a first period of time (e.g., at least once daily for at least
one day), followed by a second period of time in which at least one
additional treatment modality is administered for at least one
additional day following said first period of time. The second
treatment modality may comprise topical application of any hair or
skin benefit agent, such as a hair growth agent (e.g., finesteride,
Minoxidil, cis-6-nonenol, thiazolyl alanine, botanical extracts
from Pouzolzia pentandra, etc.), retinoid (e.g., retinol), phytol,
antioxidants (e.g., ascorbic acid or TDPA or esters thereof),
botanicals, such as Tiliacora triandra, niacinamide, vitamins such
as Vitamin E and Vitamin E acetate, salicylic acid, salicylates and
derivatives thereof, moisturizers, emollients, etc.
[0101] In another embodiment, the peptides of the invention (e.g.,
comprising any of SEQ ID NOs: 1 or 2) are intended for oral use,
including for pharmaceutical use. Pharmaceutical formulations will
include pharmaceutically acceptable carriers (i.e., diluents and
excipients). The pharmaceutical compositions may be included in
solid dosage forms, including compressed tablets and capsules, or
in liquid or powder forms (including lyophilized powders of the
peptide suitable for reconstitution with water). Pharmaceutical
compositions may also be in the form of creams, serums, etc., or
formulated for injection. Pharmaceutical dosage forms will
typically include from about 0.1 mg to about 200 mg, or from about
1 mg to about 100 mg of the peptides of the invention. Solid dosage
forms may be immediate release, in which case they will typically
comprise a water-soluble or dispersible carrier such as
microcrystalline cellulose, mannitol, hydroxypropyl methyl
cellulose, PVP or the like, or may be delayed, sustained, or
modified release, in which case they may comprise water-insoluble
polymers such as cellulose ethers (e.g., ethylcellulose), alone or
in combination with water soluble or dispersible polymers, to
regulate the rate of dissolution of the dosage form in the
stomach.
[0102] In one embodiment, the composition is intended for use as a
non-therapeutic treatment. In another embodiment, the composition
is an article intended to be rubbed, poured, sprinkled, or sprayed
on, introduced into, or otherwise applied to the human body for
cleansing, beautifying, promoting attractiveness, or altering the
appearance, in accordance with the US FD&C Act, .sctn.
201(i).
EXAMPLES
[0103] The following example illustrates a specific aspect of the
instant description. The example should not be construed as
limiting, as the example merely provides specific understanding and
practice of the embodiments and its various aspects.
Example 1
[0104] Proliferation of Hair Matrix Cells
[0105] Hair Germinal Matrix Cells (ScienCell, Carlsbad, CA) were
grown in 96-well tissue culture plate (5000 cells/well) in MSCM
medium supplemented with growth factors (ScienCell, Carlsbad, CA).
Cells were incubated overnight at 37.degree. C. and 5% CO.sub.2.
Next, media were aspirated and cells were incubated in MSCM medium
without growth supplement for 4-6 h, followed by treatment with
given concentration of peptides for 24 h. After treatment cells
were incubated with BrdU for 4 h and proliferation rate was
evaluated using BrdU proliferation kit from Cell Signaling
(Danvers, Mass.). The results are summarized in Table 2 below as
percent change cell proliferation relative to vehicle control
(peptide concentrations provided in parentheses) using the
following key: 0: <10%, +: 11-20%, ++:21-40%, +++:41-60%, ++++:
>60%.
TABLE-US-00004 TABLE 2 Peptide Sequence Wt. % Proliferation (%) YNT
(SEQ ID NO: 1) 0.0001 ++ 0.00001 0 K-Ava-YNTK (SEQ ID 0.0001 0 NO:
3) 0.00001 0 PVG (SEQ ID NO: 2) 0.0001 + 0.00001 0 K-Ava-PVGK (SEQ
ID 0.0001 0 NO: 4) 0.00001 0
[0106] As shown in Table 2, tripeptides YNT (SEQ ID NO: 1) and PVG
(SEQ ID NO: 2) of the invention effectively increase Hair Germinal
Matrix Cell proliferation. Surprisingly, the hydrolytically more
stable K-Ava- derivatives of these tripeptides did not have an
effect on cell proliferation at the concentrations tested. Based on
these results, it is contemplated that tripeptides YNT (SEQ ID NO:
1) and PVG (SEQ ID NO: 2), and lipophilic plamitoyl derivatives
thereof, will have benefit in promoting growth of hair, including
hair of the scalp and eyelashes, as well as retarding hair loss,
and promoting hair shaft thickness.
Example 2
[0107] Expression of Keratin, Keratin Associated Proteins (KAPs),
P-cadherin
[0108] Hair Germinal Matrix Cells (ScienCell, Carlsbad, CA) were
grown in 6-well tissue culture plate (1.5.times.10.sup.5
cells/well) in MSCM medium supplemented with growth factors
(ScienCell, Carlsbad, CA). Cells were incubated overnight at
37.degree. C. and 5% CO.sub.2. Next day, cells were changed into
fresh media and treated with given concentration of peptides for 48
h. After treatment, cells were washed with ice cold PBS, collected
into RLT lysis buffer and RNA was extracted using RNeasy Mini Kit
(Qiagen, Valencia, Calif.) following manufactures recommendations.
200 ng of RNA was used for cDNA synthesis using High Capacity cDNA
Reverse Transcription Kit (Life Technologies, Carlsbad, CA). 1
.mu.L of undiluted cDNA was used per qPCR reaction. Primers used
were purchased from Life technologies (Carlsbad, CA). Following
primers were used: Keratin35 (Hs0060557_g1), KAP8 (Hs00545666_s1),
KAP11 (Hs00545667_s1), P-cadherin (Hs00999925_m1). Expression was
normalized to GAPDH. The conditions of q-PCR were: an incubation
step at 50.degree. C. for 2 minutes and an enzyme activation step
at 95.degree. C. for 10 minutes; followed by 45 cycles of
95.degree. C. for 30 seconds and 60.degree. C. for 1 minute. CT
value was obtained from the software of the Stratagene MX2005P. The
results are summarized in Table 2 below as percent change in mRNA
expression relative to vehicle control using the following key: 0:
<10%, +: 11-20%, ++:21-40%, +++:41-60%, ++++: >60%
TABLE-US-00005 TABLE 3 Peptide Sequence Wt. % Keratin 35 KAP 8 KAP
11 P-cadherin YNT (SEQ ID NO: 1) 0.0001 0 ++++ ++++ + K-Ava-YNTK
(SEQ ID 0.0001 0 0 0 +++ NO: 3) PVG (SEQ ID NO: 2) 0.0001 0 ++++ 0
0 K-Ava-PVGK (SEQ ID 0.0001 +++ ++++ +++ 0 NO: 4)
[0109] As shown in Table 2, tripeptides YNT (SEQ ID NO: 1) and PVG
(SEQ ID NO: 2) of the invention effectively increase mRNA
expression for Keratin Associated Protein 8. Interestingly, the
hydrolytically more stable K-Ava- derivative K-Ava-PVGK (SEQ ID NO:
4) was effective in upregulating expression of mRNA for Keratin 35,
KAP8 and KAP11, whereas the K-Ava- derivative K-Ava-YNTK (SEQ ID
NO: 3) was not effective at the concentration tested. Tripeptide
YNT (SEQ ID NO: 1) was effective in boosting levels of the
desmosomal protein P-cadherein. The effect was enhanced in the
K-Ava- derivative K-Ava-YNTK (SEQ ID NO: 3).
[0110] As various changes can be made in the above-described
subject matter without departing from the scope and spirit of the
present invention, it is intended that all subject matter contained
in the above description, or defined in the appended claims, be
interpreted as descriptive and illustrative of the present
invention. Many modifications and variations of the present
invention are possible in light of the above teachings.
Accordingly, the present description is intended to embrace all
such alternatives, modifications, and variances which fall within
the scope of the appended claims.
Sequence CWU 1
1
813PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 1Tyr Asn Thr 1 23PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 2Pro
Val Gly 1 36PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptideMOD_RES(2)..(2)Amino valeric acid 3Lys
Xaa Tyr Asn Thr Lys 1 5 46PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(2)..(2)Amino valeric
acid 4Lys Xaa Pro Val Gly Lys 1 5 54PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 5Tyr
Asn Thr Lys 1 64PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 6Pro Val Gly Lys 1 79PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(2)..(2)AvaMOD_RES(6)..(9)Any naturally occurring,
non-naturally occurring or non-proteinogenic amino acid
residueMISC_FEATURE(6)..(9)This region may encompass 1 to 4 amino
acids wherein some positions may be absentSee specification as
filed for detailed description of substitutions and preferred
embodiments 7Lys Xaa Tyr Asn Thr Xaa Xaa Xaa Xaa 1 5
89PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideMOD_RES(2)..(2)AvaMOD_RES(6)..(9)Any naturally
occurring, non-naturally occurring or non-proteinogenic amino acid
residueMISC_FEATURE(6)..(9)This region may encompass 1 to 4 amino
acids wherein some positions may be absentSee specification as
filed for detailed description of substitutions and preferred
embodiments 8Lys Xaa Pro Val Gly Xaa Xaa Xaa Xaa 1 5
* * * * *