U.S. patent application number 17/384478 was filed with the patent office on 2021-11-11 for compositions and methods for improving bruising and rejuvenating skin.
The applicant listed for this patent is Alastin Skincare, Inc.. Invention is credited to John A. GARRUTO, Alan David WIDGEROW.
Application Number | 20210346458 17/384478 |
Document ID | / |
Family ID | 1000005797224 |
Filed Date | 2021-11-11 |
United States Patent
Application |
20210346458 |
Kind Code |
A1 |
WIDGEROW; Alan David ; et
al. |
November 11, 2021 |
COMPOSITIONS AND METHODS FOR IMPROVING BRUISING AND REJUVENATING
SKIN
Abstract
Compositions and methods for improving bruising, stimulating
elastin and/or collagen production, stimulating intrinsic
hyaluronic acid production, stimulating adipogenesis, reducing
inflammation, or combinations thereof are provided herein.
Compositions and methods described herein may be used following a
cosmetic procedure.
Inventors: |
WIDGEROW; Alan David;
(Irvine, CA) ; GARRUTO; John A.; (Encinitas,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alastin Skincare, Inc. |
Carlsbad |
CA |
US |
|
|
Family ID: |
1000005797224 |
Appl. No.: |
17/384478 |
Filed: |
July 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2020/031867 |
May 7, 2020 |
|
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17384478 |
|
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62967383 |
Jan 29, 2020 |
|
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62881783 |
Aug 1, 2019 |
|
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62845063 |
May 8, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/127 20130101;
A61K 9/0014 20130101; A61P 17/00 20180101; A61K 38/40 20130101;
A61K 38/08 20130101; A61P 31/04 20180101; A61K 38/07 20130101; A61K
38/06 20130101 |
International
Class: |
A61K 38/06 20060101
A61K038/06; A61K 38/08 20060101 A61K038/08; A61K 38/07 20060101
A61K038/07; A61K 9/00 20060101 A61K009/00; A61K 9/127 20060101
A61K009/127; A61P 31/04 20060101 A61P031/04; A61P 17/00 20060101
A61P017/00; A61K 38/40 20060101 A61K038/40 |
Claims
1. A topical composition for improving bruising associated with
injection of a filler comprising: one or more ingredients
encapsulated in a liposome; a tripeptide; and a hexapeptide,
wherein the topical composition improves healing or appearance of a
bruise associated with injection of the filler.
2. The topical composition of claim 1, wherein the tripeptide is
tripeptide-1.
3. The topical composition of claim 2, wherein the tripeptide-1 is
present at 1-10 ppm.
4. The topical composition of claim 1, wherein the hexapeptide is
hexapeptide-12.
5. The topical composition of claim 4, wherein the hexapeptide-12
is present at 1-10 ppm.
6. The topical composition of claim 1, wherein a first ingredient
of the one or more ingredients encapsulated in the liposome is
hexapeptide-11.
7. The topical composition of claim 6, wherein the hexapeptide-11
is present at 50-150 ppm.
8. The topical composition of claim 6, wherein a second ingredient
of the one or more ingredients encapsulated in the liposome is
hexapeptide-38.
9. The topical composition of claim 8, wherein the hexapeptide-38
is acetyl hexapeptide-38.
10. The topical composition of claim 1, further comprising a
tetrapeptide.
11. The topical composition of claim 10, wherein the tetrapeptide
is tetrapeptide-2.
12. The topical composition of claim 1, further comprising
phosphatidylserine.
13. The topical composition of claim 12, wherein the
phosphatidylserine is present at no more than 5.0 wt %.
14. The topical composition of claim 6, wherein a third ingredient
of the one or more ingredients encapsulated in the liposome is
lactoferrin.
15. The topical composition of claim 14, wherein the lactoferrin is
present at no more than 5.0 wt %.
16. The topical composition of claim 1, further comprising Ledum
palustre extract, dill extract, Tremella fuciformis extract,
butylene glycol, glycerin, squalane, Dunaliella salina extract,
phospholipids, tocopherol, ascorbyl palmitate, xanthan gum,
betaine, propanediol, lecithin, caprylic/capric triglyceride,
caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, sodium
hyaluronate crosspolymer, xylitylglucoside, anhydroxylitol,
xylitol, hydroxymethoxyphenyl decanone, or combinations
thereof.
17. A topical composition for rejuvenating skin comprising a
liposome encapsulating: one or more peptides; and lactoferrin,
wherein the topical composition rejuvenates skin.
18. The topical composition of claim 17, wherein the one or more
peptides comprises a tripeptide-1, a hexapeptide-12, a
hexapeptide-11, a hexapeptide-38, a tetrapeptide-2, or combinations
thereof.
19. The topical composition of claim 17, further comprising
phosphatidylserine.
20. The topical composition of claim 17, further comprising Ledum
palustre extract, dill extract, Tremella fuciformis extract,
butylene glycol, glycerin, squalane, Dunaliella salina extract,
phospholipids, tocopherol, ascorbyl palmitate, xanthan gum,
betaine, propanediol, lecithin, caprylic/capric triglyceride,
caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, sodium
hyaluronate crosspolymer, xylitylglucoside, anhydroxylitol,
xylitol, hydroxymethoxyphenyl decanone, or combinations thereof.
Description
CROSS-REFERENCE
[0001] This application is a continuation of International
Application No. PCT/US2020/031867, filed May 7, 2020, which claims
the benefit of U.S. Provisional Patent Application No. 62/967,383
filed on Jan. 29, 2020; U.S. Provisional Patent Application No.
62/881,783 filed on Aug. 1, 2019; and U.S. Provisional Patent
Application No. 62/845,063 filed on May 8, 2019, each of which is
incorporated herein by reference in its entirety.
BACKGROUND
[0002] A bruise may appear hours after injury to the tissues below
the skin's surface or in some instances, a bruise appears instantly
when a blood vessel is breached such as during the injection
process. Red blood cells extravasate into the surrounding tissue,
and breakdown of these cells by macrophages results in loss of
oxygen, giving the red blood cells a bluish hue. The byproducts of
hemoglobin breakdown (heme, biliverdin, bilirubin, and hemosiderin)
transmit the different colors to the skin that slowly resolve once
these pigments are absorbed by the macrophages and digested. Due to
the negative aesthetics of the skin discoloration that can occur
for multiple days, there is a need for resolving the bruising
process more quickly.
BRIEF SUMMARY
[0003] Described herein are compositions and methods for improving
bruising. In some instances, the bruising is caused by an
injection. Compositions and methods as described herein can improve
bruising by improving macrophage function. Compositions and methods
as described herein may further stimulate elastin and/or collagen
production, intrinsic hyaluronic acid production, adipogenesis, or
reduce inflammation.
[0004] Efficacy of an active ingredient depends on several factors
including its bioavailability. For topical compositions, skin
penetration ability is important for bioavailability of the active
ingredient. Some methods for improving skin penetration and
bioavailability can be too aggressive such as methods employing a
skin barrier disrupter like an alcohol. Delivery systems employing
liposomes may improve delivery and skin penetration of topical
compositions in a safe and efficacious manner. Described herein are
liposomal compositions for improved distribution, efficacy,
bioavailability, and/or activity. Liposomal compositions may
improve distribution, efficacy, bioavailability, and/or activity by
improving delivery and skin penetration.
[0005] An aspect described herein are topical compositions for
improving bruising following injection of a filler comprising: one
or more ingredients encapsulated in a liposome; a tripeptide-1; and
a hexapeptide-12, wherein the topical composition improves healing
or appearance of a bruise following injection of the filler. In one
feature, the tripeptide-1 is present at 1-10 ppm. In one feature,
the tripeptide-1 comprises palmitoyl tripeptide-1, myristoyl
tripeptide-1, or a combination thereof. In one feature, the
hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl
hexapeptide-12, or a combination thereof. In one feature, the
hexapeptide-12 is present at 1-10 ppm. In one feature, a first
ingredient of the one or more ingredients encapsulated in the
liposome is hexapeptide-11. In one feature, the hexapeptide-11 is
present at 50-150 ppm. In one feature, a second ingredient of the
one or more ingredients encapsulated in the liposome is
hexapeptide-38. In one feature, the hexapeptide-38 is acetyl
hexapeptide-38. In one feature, the topical compositions further
comprise a tetrapeptide. In one feature, the tetrapeptide is
tetrapeptide-2. In one feature, the tetrapeptide-2 is acetyl
tetrapeptide-2. In one feature, the topical compositions further
comprise phosphatidylserine. In one feature, the phosphatidylserine
is present at no more than 0.050% by weight (wt. %). In one
feature, the phosphatidylserine is present in a range of about
0.005 wt. % to about 0.1 wt. %. In one feature, the
phosphatidylserine is present at no more than 5.0 wt %. In one
feature, the phosphatidylserine is present at 0.1 wt %. In one
feature, a third ingredient of the one or more ingredients
encapsulated in the liposome is lactoferrin. In one feature, the
lactoferrin is present at no more than 0.050 wt. %. In one feature,
the lactoferrin is present in a range of about 0.005 wt. % to about
0.1 wt. %. In one feature, the lactoferrin is present at no more
than 5.0 wt %. In one feature, the topical compositions further
comprise Ledum palustre extract. In one feature, the Ledum palustre
extract is present in a range of about 0.1 wt. % to about 2.5 wt.
%. In one feature, the topical compositions further comprise dill
extract. In one feature, the dill extract is present in a range of
about 0.01 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise hydroxymethoxyphenyl decanone. In one
feature, the hydroxymethoxyphenyl decanone is present in a range of
about 0.001 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise Tremella fuciformis extract. In one
feature, the Tremella fuciformis extract is present in a range of
about 0.001 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise sodium hyaluronate crosspolymer. In
one feature, the sodium hyaluronate crosspolymer is present in a
range of about 0.0001 wt. % to about 2.5 wt. %. In one feature, the
topical compositions further comprise xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof. In one feature,
the xylitylglucoside, anhydroxylitol, xylitol, or combinations
thereof is present in a range of about 0.25 wt. % to about 5 wt. %.
In one feature, the topical compositions further comprise butylene
glycol, glycerin, squalane, Dunaliella salina extract,
phospholipids, tocopherol, ascorbyl palmitate, xanthan gum,
betaine, propanediol, lecithin, caprylic/capric triglyceride,
caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, or
combinations thereof. In one feature, the topical composition is
aqueous. In one feature, a viscosity of the topical composition is
in a range of about 8,000 centipoise (cps) to about 30,000 cps. In
one feature, the filler is a soft tissue filler. In one feature,
the filler is a dermal filler.
[0006] An aspect described herein are topical compositions for
improving bruising comprising: one or more ingredients encapsulated
in a liposome, wherein a first ingredient of the one or more
ingredients encapsulated in the liposome is hexapeptide-11; a
tripeptide-1; and a hexapeptide-12, wherein the topical composition
improves healing or appearance of a bruise. In one feature, the
tripeptide-1 is present at 1-10 ppm. In one feature, the
tripeptide-1 comprises palmitoyl tripeptide-1, myristoyl
tripeptide-1, or a combination thereof. In one feature, the
hexapeptide-12 comprises palmitoyl hexapeptide-12, myristoyl
hexapeptide-12, or a combination thereof. In one feature, the
hexapeptide-12 is present at 1-10 ppm. In one feature, the
hexapeptide-11 is present at 50-150 ppm. In one feature, a second
ingredient of the one or more ingredients encapsulated in the
liposome is hexapeptide-38. In one feature, the hexapeptide-38 is
acetyl hexapeptide-38. In one feature, the topical compositions
further comprise a tetrapeptide. In one feature, the tetrapeptide
is tetrapeptide-2. In one feature, the tetrapeptide-2 is acetyl
tetrapeptide-2. In one feature, the topical compositions further
comprise phosphatidylserine. In one feature, the phosphatidylserine
is present at no more than 0.050% by weight (wt. %). In one
feature, the phosphatidylserine is present in a range of about
0.005 wt. % to about 0.1 wt. %. In one feature, the
phosphatidylserine is present at no more than 5.0 wt %. In one
feature, the phosphatidylserine is present at 0.1 wt %. In one
feature, a third ingredient of the one or more ingredients
encapsulated in the liposome is lactoferrin. In one feature, the
lactoferrin is present at no more than 0.050 wt. %. In one feature,
the lactoferrin is present in a range of about 0.005 wt. % to about
0.1 wt. %. In one feature, the lactoferrin is present at no more
than 5.0 wt %. In one feature, the topical compositions further
comprise Ledum palustre extract. In one feature, the Ledum palustre
extract is present in a range of about 0.1 wt. % to about 2.5 wt.
%. In one feature, the topical compositions further comprise dill
extract. In one feature, the dill extract is present in a range of
about 0.01 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise hydroxymethoxyphenyl decanone. In one
feature, the hydroxymethoxyphenyl decanone is present in a range of
about 0.001 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise Tremella fuciformis extract. In one
feature, the Tremella fuciformis extract is present in a range of
about 0.001 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise sodium hyaluronate crosspolymer. In
one feature, the sodium hyaluronate crosspolymer is present in a
range of about 0.0001 wt. % to about 2.5 wt. %. In one feature, the
topical compositions further comprise xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof. In one feature,
the xylitylglucoside, anhydroxylitol, xylitol, or combinations
thereof is present in a range of about 0.25 wt. % to about 5 wt. %.
In one feature, the topical compositions further comprise butylene
glycol, glycerin, squalane, Dunaliella salina extract,
phospholipids, tocopherol, ascorbyl palmitate, xanthan gum,
betaine, propanediol, lecithin, caprylic/capric triglyceride,
caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, or
combinations thereof. In one feature, the topical composition is
aqueous. In one feature, a viscosity of the topical composition is
in a range of about 8,000 centipoise (cps) to about 30,000 cps. In
one feature, the bruise appears following a cosmetic procedure. In
one feature, the cosmetic procedure is an injection of a filler. In
one feature, the cosmetic procedure is an injection of a
neurotoxin. In one feature, the cosmetic procedure is an invasive
surgery. In one feature, the bruise appears following a medical
procedure. In one feature, the medical procedure is a therapeutic
injection. In one feature, the medical procedure is an intravenous
injection. In one feature, the medical procedure is an invasive
surgery. In one feature, the bruise appears following a trauma.
[0007] An aspect described herein are topical compositions for
rejuvenating skin comprising a liposome encapsulating: one or more
peptides; and lactoferrin, wherein the topical composition
rejuvenates skin. In one feature, the topical compositions further
comprise tripeptide-1. In one feature, the tripeptide is
tripeptide-1. In one feature, the tripeptide-1 is present at 1-10
ppm. In one feature, the tripeptide-1 comprises palmitoyl
tripeptide-1, myristoyl tripeptide-1, or a combination thereof. In
one feature, the topical compositions further comprise
hexapeptide-12. In one feature, the hexapeptide-12 comprises
palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a
combination thereof. In one feature, the hexapeptide-12 is present
at 1-10 ppm. In one feature, a first peptide of the one or more
peptides comprises hexapeptide-11. In one feature, the
hexapeptide-11 is present at 50-150 ppm. In one feature, a second
peptide of the one or more peptides comprises hexapeptide-38. In
one feature, the hexapeptide-38 is acetyl hexapeptide-38. In one
feature, the topical compositions further comprise a tetrapeptide.
In one feature, the tetrapeptide is tetrapeptide-2. In one feature,
the tetrapeptide-2 is acetyl tetrapeptide-2. In one feature, the
topical compositions further comprise phosphatidylserine. In one
feature, the phosphatidylserine is present at no more than 0.050%
by weight (wt. %). In one feature, the phosphatidylserine is
present in a range of about 0.005 wt. % to about 0.1 wt. %. In one
feature, the phosphatidylserine is present at no more than 5.0 wt
%. In one feature, the phosphatidylserine is present at 0.1 wt %.
In one feature, the lactoferrin is present at no more than 0.050
wt. %. In one feature, the lactoferrin is present in a range of
about 0.005 wt. % to about 0.1 wt. %. In one feature, the
lactoferrin is present at no more than 5.0 wt %. In one feature,
the topical compositions further comprise Ledum palustre extract.
In one feature, the Ledum palustre extract is present in a range of
about 0.1 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise dill extract. In one feature, the
dill extract is present in a range of about 0.01 wt. % to about 2.5
wt. %. In one feature, the topical compositions further comprise
hydroxymethoxyphenyl decanone. In one feature, the
hydroxymethoxyphenyl decanone is present in a range of about 0.001
wt. % to about 2.5 wt. %. In one feature, the topical compositions
further comprise Tremella fuciformis extract. In one feature, the
Tremella fuciformis extract is present in a range of about 0.001
wt. % to about 2.5 wt. %. In one feature, the topical compositions
further comprise sodium hyaluronate crosspolymer. In one feature,
the sodium hyaluronate crosspolymer is present in a range of about
0.0001 wt. % to about 2.5 wt. %. In one feature, the topical
compositions further comprise xylitylglucoside, anhydroxylitol,
xylitol, or combinations thereof. In one feature, the
xylitylglucoside, anhydroxylitol, xylitol, or combinations thereof
is present in a range of about 0.25 wt. % to about 5 wt. %. In one
feature, the topical compositions further comprise butylene glycol,
glycerin, squalane, Dunaliella salina extract, phospholipids,
tocopherol, ascorbyl palmitate, xanthan gum, betaine, propanediol,
lecithin, caprylic/capric triglyceride, caprylyl glycol, caprylyl
methicone, phenoxyethanol, ethylhexylglycerin, polyacrylate-13,
polyisobutene, polysorbate 20, caprylhydroxamic acid, disodium
EDTA, Arnica Montana extract, sorbitan isostearate, pentylene
glycol, glucose, sunflower seed oil, radish root ferment filtrate,
potassium sorbate, or combinations thereof. In one feature, the
topical composition is aqueous. In one feature, a viscosity of the
topical composition is in a range of about 8,000 centipoise (cps)
to about 30,000 cps.
[0008] An aspect described herein are methods for improving
bruising in an individual, comprising administering a topical
composition as described herein. In one feature, the bruising is
improved by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or more than 90%. In one feature, the bruising is
improved by at least 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times.. In one feature, the bruising is
improved at least 1 day after administering the topical
composition. In one feature, the bruising is improved at least 2
days after administering the topical composition. In one feature,
improvements in bruising comprises accelerated resolution of a
bruise, reduced size of a bruise, reduced discoloration of skin,
reduced swelling, or combinations thereof.
[0009] An aspect described herein are methods for improving
macrophage function in an individual, comprising administering a
topical composition as described herein. In one feature, the
improved macrophage function comprises improved phagocytosis. In
one feature, the improved macrophage function comprises improved
hemosiderin clearance. In one feature, the macrophage function is
improved by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or more than 90%. In one feature, the macrophage
function is improved by at least 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 3.5.times.,
4.0.times., 5.0.times., 6.0.times., 7.0.times., 8.0.times.,
9.0.times., 10.times., or more than 10.times..
[0010] An aspect described herein are methods for stimulating
production of elastin, collagen, or a combination thereof in an
individual, comprising administering a topical composition as
described herein. In one feature, the production of elastin,
collagen, or a combination thereof is stimulated by at least 5%,
10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than
90%. In one feature, the production of elastin, collagen, or a
combination thereof is stimulated by at least 0.5.times.,
1.0.times., 1.5.times., 2.0.times., 2.5.times., 3.0.times.,
3.5.times., 4.0.times., 5.0.times., 6.0.times., 7.0.times.,
8.0.times., 9.0.times., 10.times., or more than 10.times..
[0011] An aspect described herein are methods for stimulating
intrinsic hyaluronic acid production in an individual, comprising
administering a topical composition as described herein. In one
feature, the intrinsic hyaluronic acid production is stimulated by
at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
or more than 90%. In one feature, the intrinsic hyaluronic acid
production is stimulated by at least 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 3.5.times.,
4.0.times., 5.0.times., 6.0.times., 7.0.times., 8.0.times.,
9.0.times., 10.times., or more than 10.times..
[0012] An aspect described herein are methods for increasing
adipogenesis in an individual, comprising administering a topical
composition as described herein. In one feature, adipogenesis is
increased by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or more than 90%. In one feature, adipogenesis is
increased by at least 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times..
[0013] An aspect described herein are methods for reducing
inflammation in an individual, comprising administering a topical
composition as described herein. In one feature, inflammation is
reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or more than 90%. In one feature, inflammation is
reduced by at least 0.5.times., 1.0.times., 1.5.times., 2.0.times.,
2.5.times., 3.0.times., 3.5.times., 4.0.times., 5.0.times.,
6.0.times., 7.0.times., 8.0.times., 9.0.times., 10.times., or more
than 10.times..
[0014] An aspect described herein are methods for administering a
topical composition. In one feature, the topical composition is
administered following a cosmetic procedure. In one feature, the
topical composition is administered prior to a cosmetic procedure.
In one feature, the cosmetic procedure comprises injection of a
filler. In one feature, the filler is a soft tissue filler. In one
feature, the filler is a dermal filler. In one feature, the
cosmetic procedure is a microneedling procedure. In one feature,
the microneedling procedure is a radiofrequency microneedling
procedure. In one feature, the topical composition is administered
at least 1 day prior to the microneedling procedure. In one
feature, the topical composition is administered at least 1 week
prior to the microneedling procedure. In one feature, the topical
composition is administered at least 2 weeks prior to the
microneedling procedure. In one feature, the topical composition is
administered at least 1 day following the microneedling procedure.
In one feature, the topical composition is administered at least 1
week following the microneedling procedure. In one feature, the
topical composition is administered at least 2 weeks following the
microneedling procedure. In one feature, the topical composition is
administered immediately prior to the injection of the filler. In
one feature, the topical composition is administered at least 1 day
prior to the injection of the filler. In one feature, the topical
composition is administered at least 1 week prior to the injection
of the filler. In one feature, the topical composition is
administered at least 2 weeks prior to the injection of the filler.
In one feature, the topical composition is administered immediately
following the injection of the filler. In one feature, the topical
composition is administered at least 1 day following the injection
of the filler. In one feature, the topical composition is
administered at least 1 week following the injection of the filler.
In one feature, the topical composition is administered at least 2
weeks following the injection of the filler. In one feature, the
cosmetic procedure is an injection of a neurotoxin. In one feature,
the cosmetic procedure is an invasive surgery. In one feature, the
topical composition is administered following a medical procedure.
In one feature, the topical composition is administered prior to a
medical procedure. In one feature, the medical procedure is a
therapeutic injection. In one feature, the medical procedure is an
intravenous injection. In one feature, the medical procedure is an
invasive surgery. In one feature, the topical composition is
administered following a trauma. In one feature, the topical
composition is administered prior to a trauma. In one feature, the
topical composition is administered 1, 2, 3, 4, 5, 6, 7, or 8 times
a day. In one feature, the topical composition is administered 4
times a day. In one feature, the individual is a human.
INCORPORATION BY REFERENCE
[0015] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0017] FIG. 1A illustrates a schematic of a macrophage phagocytosis
assay.
[0018] FIG. 1B illustrates macrophage phagocytosis prior to red
blood cell washout.
[0019] FIG. 1C illustrates macrophage phagocytosis following red
blood cell washout.
[0020] FIG. 2 illustrates a graph of phagocytosis of human red
blood cells (RBCs) with the following groups: no treatment positive
control, no treatment negative control, hexapeptide-11
(Hex11-Peptide), hexapeptide-12 (Hex12-peptide), tripeptide-1
(Tri-peptide), Oct-peptide, and blood only.
[0021] FIG. 3A illustrates a graph of a red blood cell (RBC)
standard curve with absorbance on the y-axis and number of RBCs on
the x-axis.
[0022] FIG. 3B illustrates a graph of red blood cell (RBC) standard
curve (log 2) with absorbance (log 2) on the y-axis and number of
RBCs (log 2) on the x-axis.
[0023] FIG. 4 illustrates a graph of absorbance for no treatment
control samples with absorbance on the y-axis and time (24 hours,
48 hours, and 72 hours) on the x-axis.
[0024] FIG. 5 illustrates a graph of a time course of phagocytosis
following various treatments. The treatments included the
following: no treatment (NT), tripeptide-1 (Tri), hexapeptide-11
(Hex11), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-11
(Tri+Hex11), and tripeptide-1, hexapeptide-11, and hexapeptide-12
(Tri+Hex11+Hex12).
[0025] FIG. 6 illustrates a graph of phagocytosis following various
treatments including: No treatment (NT), tripeptide-1 (Tri),
hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1 and
hexapeptide-11 (Tri+Hex11), and tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12).
[0026] FIG. 7 illustrates a graph of phagocytosis following various
treatments including: No treatment (NT), tripeptide-1 (Tri),
hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1 and
hexapeptide-11 (Tri+Hex11), tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12), phosphatidylserine at 10 ug/mL
(PS_10 ug/mL), phosphatidylserine at 50 ug/mL (PS_50 ug/mL),
tripeptide-1, hexapeptide-11, hexapeptide-12, and
phosphatidylserine at 10 ug/mL (Pep_PS_10 ug/mL), tripeptide-1,
hexapeptide-11, hexapeptide-12, and phosphatidylserine at 50 ug/mL
(Pep_PS_50 ug/mL), tripeptide-1, hexapeptide-11, hexapeptide-12,
and phosphatidylserine at 100 ug/mL (Pep_PS_100 ug/mL), and
tripeptide-1, hexapeptide-11, hexapeptide-12, and
phosphatidylserine at 500 ug/mL (Pep_PS_500 ug/mL).
[0027] FIG. 8 illustrates a graph of phagocytosis following various
treatments including: No treatment (NT), tripeptide-1 (Tri),
hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1 and
hexapeptide-11 (Tri+Hex11), tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12), tripeptide-1, hexapeptide-11,
hexapeptide-12, and lactoferrin at 10 ug/mL (Pep_Lac_10 ug/mL),
tripeptide-1, hexapeptide-11, hexapeptide-12, and lactoferrin at 50
ug/mL (Pep_Lac_50 ug/mL), tripeptide-1, hexapeptide-11,
hexapeptide-12, and lactoferrin at 100 ug/mL (Pep+Lac 100 ug/mL),
tripeptide-1, hexapeptide-11, hexapeptide-12, and lactoferrin at
500 ug/mL (Pep_Lac_500 ug/mL), tripeptide-1, hexapeptide-11,
hexapeptide-12, phosphatidylserine and lactoferrin at 50 ug/mL
(Pep+PS+Lac50 ug/mL), tripeptide-1, hexapeptide-11, hexapeptide-12,
phosphatidylserine and lactoferrin at 100 ug/mL (Pep+PS+Lac100
ug/mL), and tripeptide-1, hexapeptide-11, hexapeptide-12,
phosphatidylserine and lactoferrin at 500 ug/mL (Pep+PS+Lac500
ug/mL).
[0028] FIG. 9 illustrates a graph of phagocytosis following various
treatments including: No treatment (NT), tripeptide-1 (Tri),
hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1 and
hexapeptide-11 (Tri+Hex11), tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12), hydroxysuccinimide at 1 mg/mL
(HS_1 mg/mL), hydroxysuccinimide at 2 mg/mL (HS 2 mg/mL),
tripeptide-1, hexapeptide-11, hexapeptide-12, and
hydroxysuccinimide at 1 mg/mL (Pep_HS_1 mg/mL), and tripeptide-1,
hexapeptide-11, hexapeptide-12, and hydroxysuccinimide at 2 mg/mL
(Pep_HS_2 mg/mL).
[0029] FIG. 10 illustrates a graph of phagocytosis following
various treatments including: No treatment (NT), tripeptide-1
(Tri), hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1
and hexapeptide-11 (Tri+Hex11), tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12), tripeptide-1, hexapeptide-11,
hexapeptide-12 and phosphatidylserine at 500 ug/mL (Pep_PS_500
ug/mL), and tripeptide-1, hexapeptide-11, hexapeptide-12,
phosphatidylserine at 500 ug/mL, and lactoferrin at 500 ug/mL
(Pep+PS+Lac500 ug/mL).
[0030] FIGS. 11A-1B show schematics for preparation of
liposomes.
[0031] FIG. 12 shows an image of a liposome.
[0032] FIG. 13A shows a graph of diffusion of Molecule A through
human skin.
[0033] FIG. 13B shows a graph of skin distribution of Molecule
A.
[0034] FIG. 13C shows a graph of skin distribution of Molecule B
after 24 hours.
[0035] FIGS. 14A-14B show graphs of size distribution of acetyl
hexapeptide-38 in a first experiment.
[0036] FIGS. 14C-14D show graphs of size distribution of acetyl
hexapeptide-38 in a second experiment.
[0037] FIG. 15A shows a graph of bruise color intensity over time
following administration of the topical product and the bland
moisturizer.
[0038] FIG. 15B shows images of bruising resolution of a first
subject administered the topical product on the right arm and the
bland moisturizer on the left arm.
[0039] FIG. 15C shows images of bruising resolution of a second
subject administered the topical product on the left arm and the
bland moisturizer on the right arm.
[0040] FIG. 15D shows images of bruising resolution of a third
subject administered the topical product on the left arm and the
bland moisturizer on the right arm.
[0041] FIG. 15E shows images of bruising resolution of a fourth
subject administered the topical product on the right arm and the
bland moisturizer on the left arm.
[0042] FIG. 15F shows images of bruising resolution of a fifth
subject administered the topical product on the left arm and the
bland moisturizer on the right arm.
[0043] FIG. 15G shows images of bruising resolution following
administration of the topical product or the bland moisturizer.
[0044] FIG. 16A shows images of swelling in a first subject
administered the topical product as compared to the bland
moisturizer at Day 1, Day 2, Day 3, and Day 4.
[0045] FIG. 16B shows images of swelling in a second subject
administered the topical product as compared to the bland
moisturizer at Day 1, Day 2, Day 3, and Day 4.
[0046] FIG. 16C shows images of bruising resolution in a subject
treated with radiofrequency (RF) needling and administered the
topical product.
[0047] FIG. 16D shows images of bruising resolution following
administration of the topical product.
[0048] FIG. 16E shows images of a Herovici stain (40.times.
magnification) demonstrating new mucopolysaccharide formation
(denoted by blue areas in papillary dermis). The left panel is
pretreatment and the right panel is 2 weeks after use of the
topical product.
[0049] FIG. 16F shows images of a fibrillin stain (10.times.
magnification) in brown demonstrating regeneration of elastin
fibers. The left panel is pretreatment and the right panel is 2
weeks after use of the topical product.
[0050] FIG. 17 shows results from the Antimicrobial Effectiveness
Test of the topical product.
DETAILED DESCRIPTION
Definitions
[0051] Throughout this disclosure, various embodiments are
presented in a range format. It should be understood that the
description in range format is merely for convenience and brevity
and should not be construed as an inflexible limitation on the
scope of any embodiments. Accordingly, the description of a range
should be considered to have specifically disclosed all the
possible subranges as well as individual numerical values within
that range to the tenth of the unit of the lower limit unless the
context clearly dictates otherwise. For example, description of a
range such as from 1 to 6 should be considered to have specifically
disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5,
from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual
values within that range, for example, 1.1, 2, 2.3, 5, and 5.9.
This applies regardless of the breadth of the range. The upper and
lower limits of these intervening ranges may independently be
included in the smaller ranges, and are also encompassed within the
disclosure, subject to any specifically excluded limit in the
stated range. Where the stated range includes one or both of the
limits, ranges excluding either or both of those included limits
are also included in the disclosure, unless the context clearly
dictates otherwise.
[0052] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
any embodiment. As used herein, the singular forms "a," "an" and
"the" are intended to include the plural forms as well, unless the
context clearly indicates otherwise. It will be further understood
that the terms "comprises" and/or "comprising," when used in this
specification, specify the presence of stated features, integers,
steps, operations, elements, and/or components, but do not preclude
the presence or addition of one or more other features, integers,
steps, operations, elements, components, and/or groups thereof. As
used herein, the term "and/or" includes any and all combinations of
one or more of the associated listed items.
[0053] Unless specifically stated or obvious from context, as used
herein, the term "about" in reference to a number or range of
numbers is understood to mean the stated number and numbers +/-10%
thereof, or 10% below the lower listed limit and 10% above the
higher listed limit for the values listed for a range.
Compositions
[0054] A bruise is caused by bleeding under the skin due to trauma
to capillaries under the skin. As a result of the trauma, there can
be an extravasation of blood to the surrounding tissue. Generally,
bruising results in a visible discoloration on the skin. The
discoloration caused by bruising can take days to disappear and is
resolved through the function of macrophages. Accordingly,
compositions are needed for improving the bruising process.
[0055] Described herein are compositions and methods for improving
bruising. Compositions and methods as described herein can improve
bruising by improving macrophage function. Compositions and methods
as described herein may further stimulate elastin and/or collagen
production, intrinsic hyaluronic acid production, adipogenesis, or
reduce inflammation.
[0056] Liposomes
[0057] Described herein are liposomal compositions for improved
distribution, efficacy, bioavailability, and/or activity. Liposomal
compositions may improve distribution, efficacy, bioavailability,
and/or activity of the active ingredient by improving delivery and
tissue (e.g. skin) penetration. In some instances, improved
delivery and skin penetration result from the active ingredient
being incorporated (e.g. encapsulated) in a liposome. In some
instances, the active ingredient is a peptide that is encapsulated
in a liposome.
[0058] Liposomal compositions as described herein may comprise a
peptide encapsulated in a liposome. In some embodiments, the
peptide is tripeptide-1. In some embodiments, the peptide is
hexapeptide-12. In some embodiments, the peptide is hexapeptide-11
In some embodiments, the peptide is hexapeptide-38. In some
embodiments, the peptide is tetrapeptide-2. In some embodiments,
the peptide is functionalized with a palmitoyl group. In some
embodiments, the peptide is functionalized with an acetyl group.
For example, the peptide is acetyl hexapeptide-38.
[0059] Liposomal compositions as described herein may comprise
various ingredients encapsulated in a liposome. In some
embodiments, the ingredient is lactoferrin. In some embodiments,
the ingredient is phosphatidylserine. In some embodiments, the
ingredient is Ledum Palustre extract. In some embodiments, the
ingredient is Arnica Montana extract. In some embodiments, the
ingredient is sodium hyaluronate. In some embodiments, the
ingredient is larger than 50 kDa.
[0060] Lecithin and other phospholipids may be used to prepare
liposomes containing the peptide compositions as described herein.
In some embodiments, liposomes are used to prepare one or more
peptides. In some embodiments, the peptide is functionalized with
an acetyl group. Formation of lipid vesicles occurs when
phospholipids such as lecithin are placed in water and consequently
form one bilayer or a series of bilayers, each separated by water
molecules, once enough energy is supplied. Liposomes can be created
by sonicating phospholipids in water. Low shear rates create
multilamellar liposomes. Continued high-shear sonication tends to
form smaller unilamellar liposomes. Hydrophobic chemicals can be
dissolved into the phospholipid bilayer membrane. The lipid
bilayers of the liposomes deliver the peptide compositions as
described herein.
[0061] The phospholipids used to prepare the liposomal compositions
described herein may comprise a transition phase temperature of
about 10.degree. C. to about 25.degree. C. In some instances, the
phospholipids comprise a transition phase temperature of about
10.degree. C., 12.degree. C., 14.degree. C., 16.degree. C.,
18.degree. C., 20.degree. C., 22.degree. C., 24.degree. C.,
26.degree. C., 28.degree. C., 30.degree. C., 32.degree. C.,
34.degree. C., 36.degree. C., 38.degree. C., 40.degree. C., or more
than 40.degree. C. In some instances, the phospholipids comprise a
transition phase temperature in a range of about 10.degree. C. to
about 40.degree. C., about 12.degree. C. to about 36.degree. C.,
about 14.degree. C. to about 32.degree. C., about 16.degree. C. to
about 20.degree. C., or about 21.degree. C. to about 25.degree.
C.
[0062] The topical composition may contain micelles, or an
aggregate of surfactant molecules dispersed in an aqueous solution.
Micelles may be prepared by dispersing an oil solvent in an aqueous
solution comprising a surfactant, where the surfactant
concentration exceeds the critical micelle concentration. The
resulting composition contains micelles, i.e., spherical oil
droplets.
[0063] The liposomal composition may contain micelles, or an
aggregate of surfactant molecules dispersed in an aqueous solution.
Micelles may be prepared by dispersing an oil solvent in an aqueous
solution comprising a surfactant, where the surfactant
concentration exceeds the critical micelle concentration. The
resulting formulation contains micelles, i.e., spherical oil
droplets surrounded by a membrane of polar surfactant molecules,
dispersed in the aqueous solvent.
[0064] Described herein, in some embodiments, are methods for
preparing a composition comprising a peptide encapsulated in a
liposome, comprising: combining the peptide and a solvent to form a
mixture; and contacting the mixture with an aqueous solution
comprising liposomes. In some instances, the contacting occurs at a
temperature between about 10.degree. C. and about 25.degree. C. In
some instances, the contacting occurs at a temperature of about
10.degree. C., 12.degree. C., 14.degree. C., 16.degree. C.,
18.degree. C., 20.degree. C., 22.degree. C., 24.degree. C.,
26.degree. C., 28.degree. C., 30.degree. C., 32.degree. C.,
34.degree. C., 36.degree. C., 38.degree. C., 40.degree. C., or more
than 40.degree. C. In some instances, the contacting occurs at a
temperature in a range of about 10.degree. C. to about 40.degree.
C., about 12.degree. C. to about 36.degree. C., about 14.degree. C.
to about 32.degree. C., about 16.degree. C. to about 20.degree. C.,
or about 21.degree. C. to about 25.degree. C.
[0065] Methods for preparing a composition comprising a peptide
encapsulated in a liposome may comprise use of a solvent. In some
instances, the solvent is water. In some instances, the solvent is
an organic solvent. Exemplary organic solvents include, but are not
limited to, petroleum ether, cyclohexane, toluene, carbon
tetrachloride, dichloromethane, chloroform, diethyl ether,
diisopropyl ether, ethyl acetate, butanol, n-propanol, ethanol,
methanol, polyethylene glycol, propylene glycol, and pyridine. In
some instances, the solvent is a glycol. In some instances, the
solvent is butylene glycol. In some instances, the solvent is
caprylyl glycol. In some instances, the solvent is propanediol
(propylene glycol).
[0066] The solvent may be used at various percentages. In some
instances, the solvent is provided at least or about 0.001%,
0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%,
1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%,
6.5%, 7.0%, 8%, 9%, 10%, or more than 10%. The solvent may be
propanediol, butylene glycol, or caprylyl glycol.
[0067] Methods as described herein, in some embodiments, comprises
combining the peptide and a solvent to form a mixture; and
contacting the mixture with an aqueous solution comprising
liposomes, wherein the aqueous solution comprises a percentage of
water and a percentage of liposomes. In some instances, the aqueous
solution comprises at least or about 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, or more than 90% water. In some instances, the aqueous
solution comprises water in a range of about 10% to about 95%,
about 20% to about 90%, about 30% to about 85%, about 40% to about
80%, or about 50% to about 60%. In some instances, the aqueous
solution comprises at least or about 20%, 30%, 40%, 50%, 60%, or
more than 60% liposomes. In some instances, the aqueous solution
comprises liposomes in a range of about 10% to about 80%, about 20%
to about 70%, or about 30% to about 60%. A ratio of liposomes to
water may be in a range of about 1:9 to about 3:7. In some
instances, the ratio of liposomes to water may be at least or about
1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2.
[0068] Methods for generation of liposomal compositions as
described herein may result in an entrapment efficacy of no more
than 100%. In some instances, the entrapment efficacy is no more
than 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5%.
[0069] Described herein are liposomal compositions, wherein the
peptide comprises a percentage of the composition. In some
embodiments, the peptide is provided at least or about 0.0001%,
0.0005%, 0.00055%, 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%,
0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%,
4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or more than
10% of the composition. In some embodiments, the peptide is
provided at least or about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,
18%, 19%, 20%, 22%, 24%, 26%, 28%, 30% or more than 30% of the
composition. In some embodiments, the peptide is provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 5%, or about 0.02% to about 2% by weight. In some
embodiments, the peptide is provided at about 0.03% of the
composition.
[0070] Described herein are liposomal compositions, wherein the
liposomes comprise a percentage of the composition. In some
embodiments, the liposomes are provided at least or about 10%, 11%,
12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%,
30% or more than 30% of the composition. In some embodiments, the
liposomes are provided in a range of about 5% to about 90%, about
10% to about 80%, about 20% to about 70%, about 30% to about 60%,
about 10% to about 30%, or about 20% to about 40%. In some
embodiments, the liposomes are provided at about 30%. In some
embodiments, the liposomes are provided at 27%.
[0071] Liposomal compositions as described herein, in some
embodiments, comprise an average particle size of at most 220
nanometers (nm). In some instances, the average particle size is at
most 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135
nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm,
180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220
nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm,
320 nm, 340 nm, 360 nm, 380 nm, or 400 nm. In some instances, the
average particle size is about 100 nm, 105 nm, 110 nm, 115 nm, 120
nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm,
165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205
nm, 210 nm, 215 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm,
280 nm, 290 nm, 300 nm, 320 nm, 340 nm, 360 nm, 380 nm, or 400 nm.
In some instances, the average particle size is in a range of about
50 nm to about 500 nm, about 100 nm to about 400 nm, about 150 nm
to about 220 nm, about 180 nm to about 220 nm, or about 190 nm to
about 210 nm.
[0072] In some instances, the liposomal compositions comprise an
active agent that has a molecular weight of no more than about 600
Daltons (Da). In some instances, the active agent has a molecular
weight of at least or about 50, 75, 100, 125, 150, 175, 200, 225,
250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550,
575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875,
900, 925, 950, 975, 1000, or more than 1000 Daltons (Da). In some
instances, the active agent has a molecular weight of at least or
about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900,
2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000,
4000, 5000, 6000, or more than 6000 Daltons (Da). In some
instances, the active agent has a molecular weight in a range of
about 50 to about 1000, about 100 to about 900, about 200 to about
800, about 300 to about 700, or about 400 to about 600 Daltons
(Da). In some instances, the active agent is a peptide. In some
instances, the active agent is a peptide encapsulated in a
liposome.
[0073] A polydispersity index (PdI) of a liposomal composition as
described herein, in some embodiments, is in a range of 0 to about
0.2. In some instances, the polydispersity index is about 0.01,
0.025, 0.05, 0.1, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,
0.7, 0.75, or 0.8. In some instances, the polydispersity index is
in a range of about 0.01 to about 0.8, about 0.025 to about 0.75,
about 0.05 to about 0.6, or about 0.1 to about 0.3.
[0074] In some instances, an intercept of a liposomal composition
as described herein is in a range of about 0.85 to about 0.95. In
some instances, the intercept is the amplitude. In some instances,
the intercept is at least or about 0.65, 0.70, 0.75, 0.80, 0.85,
0.90, or 0.95.
[0075] In some embodiments, the liposomes comprise propanediol,
lecithin, or a combination thereof. In some embodiments, the
propanediol is provided at least or about 0.001%, 0.005%, 0.01%,
0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%,
2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%,
10%, or more than 10% by weight (wt. %). In some embodiments, the
propanediol is provided in a range of about 0.001% to about 6%,
about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02%
to about 2% by weight. In some embodiments, the lecithin is
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or
more than 10% by weight (wt. %). In some embodiments, the lecithin
is provided in a range of about 0.001% to about 6%, about 0.002% to
about 4%, about 0.01% to about 3%, or about 0.02% to about 2% by
weight. In some embodiments, the liposomes comprise propanediol and
lecithin. In some embodiments, the propanediol and lecithin are
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or
more than 10% by weight (wt. %). In some embodiments, the
propanediol and lecithin are provided in a range of about 0.0010%
to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or
about 0.02% to about 2% by weight. In some embodiments, the
propanediol and lecithin are provided at about 0.90% by weight
[0076] Described herein are liposomal compositions comprising
improved distribution, efficacy, bioavailability, and/or activity.
The liposomal compositions may comprise improved distribution,
efficacy, bioavailability, and/or activity as compared to
compositions not comprising liposomes. In some instances, the
distribution is improved by at least or about 0.5.times.,
1.0.times., 1.5.times., 2.0.times., 2.5.times., 3.0.times.,
4.0.times., 4.5.times., 5.times., or more than 5.times. as compared
to compositions not comprising liposomes. In some instances, the
efficacy is improved by at least or about 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 4.0.times.,
4.5.times., 5.times., or more than 5.times. as compared to
compositions not comprising liposomes. In some instances, the
bioavailability is improved by at least or about 0.5.times.,
1.0.times., 1.5.times., 2.0.times., 2.5.times., 3.0.times.,
4.0.times., 4.5.times., 5.times., or more than 5.times. as compared
to compositions not comprising liposomes. In some instances, the
activity is improved by at least or about 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 4.0.times.,
4.5.times., 5.times., or more than 5.times. as compared to
compositions not comprising liposomes. The distribution, efficacy,
bioavailability, and/or activity may be improved by at least or
about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, or more than 90% as compared to
compositions not comprising liposomes.
[0077] Liposomal compositions and methods as described herein, in
some embodiments, are topical compositions. In some instances, the
liposomal compositions are oil free. In some instances, the
liposomal compositions are preservative free. In some embodiments,
the liposomal formulation is an aqueous formulation. In some
embodiments, the liposomal formulation is an anhydrous formulation.
In some instances, the liposomal composition comprises a pH in a
range of about 5 to about 8. In some instances, the liposomal
composition comprises a pH of at least or about 2, 3, 4, 5, 6, 7,
8, 9, or 10.
[0078] Methods and compositions as described herein may result in
improved follicular penetration. In some instances, the follicular
penetration is improved by at least or about 0.5.times.,
1.0.times., 1.5.times., 2.0.times., 2.5.times., 3.0.times.,
4.0.times., 4.5.times., 5.times., or more than 5.times.. The
follicular penetration may be improved by at least or about 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, 90%, or more than 90%. In some instances, compositions
result in follicular penetration of a depth of at least or about
0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8,
9, 10, or more than 10 millimeters.
[0079] Peptides
[0080] Peptides as described herein, in some embodiments, improve
bruising, elastin and/or collagen simulation, hyaluronic acid
stimulation, adipocyte stimulation, reduce inflammation, or
combinations thereof. In some embodiments, peptides as described
herein improve macrophage function. In some embodiments,
tripeptide-1 results in elastin and/or collagen stimulation,
extracellular matrix (ECM) recycling, anti-inflammatory effects, or
combinations thereof. In some embodiments, hexapeptide-12 draws in
newly produced elastin. In some embodiments, acetyl tetrapeptide-2
stimulates fibroblasts to produce elastin.
[0081] Peptides as described herein, in some embodiments, in
combination improve bruising, elastin and/or collagen simulation,
hyaluronic acid stimulation, adipocyte stimulation, reduce
inflammation, or combinations thereof. For example, tripeptide-1
and hexapeptide-12 improve macrophage function. In some
embodiments, tripeptide-1 and hexapeptide-11 improve macrophage
function. In some embodiments, tripeptide-1, hexapeptide-11, and
hexapeptide-12 improve macrophage function. For example,
hexapeptide-11 in combination with one or more different peptides
such as tripeptide-1, hexapeptide-12, or a combination thereof is a
potent stimulator of autophagy and macrophage clustering and can
improve removal of hemosiderin pigment associated with bruising and
bleeding.
[0082] Compositions as described herein comprise a varying
concentration of peptide. In some instances, a peptide is present
at about 50 ppm or less to 1000, 5000, 10000, 50000, 100000, 500000
ppm or more, e.g., 100 ppm of the peptide. In some instances, a
peptide is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,
25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or
more than 1000 ppm. In some instances, a peptide is present in a
range of about 1 to about 100, about 1 to about 50, about 1 to
about 40, about 1 to about 30, about 1 to about 20, about 1 to
about 10, about 5 to about 90, about 10 to about 80, about 20 to
about 60, or about 30 to about 50 ppm. In some instances, a peptide
is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50,
75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more than
1000 microgram per milliliter (ug/mL). In some instances, a peptide
is present in a range of about 1 to about 100, about 1 to about 50,
about 1 to about 40, about 1 to about 30, about 1 to about 20,
about 1 to about 10, about 5 to about 90, about 10 to about 80,
about 20 to about 60, or about 30 to about 50 microgram per
milliliter. In some instances, a peptide is present from about
0.01% to about 10%, about 0.01% to about 0.02%, about 0.01% to
about 0.03%, about 0.01% to about 0.04%, about 0.01% to about
0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1%
to about 10% by weight (wt. %).
[0083] Compositions as described herein, in some embodiments,
comprise a plurality of peptides. In some instances, a peptide of
the plurality of peptides is present at about 50 ppm or less to
1000, 5000, 10000, 50000, 100000, 500000 ppm or more, e.g., 100 ppm
of the peptide, or any other suitable amount. In some instances, a
peptide of the plurality of peptides is present at about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500,
600, 700, 800, 900, 1000, or more than 1000 ppm. In some instances,
a peptide of the plurality of peptides is present in a range of
about 1 to about 100, about 1 to about 50, about 1 to about 40,
about 1 to about 30, about 1 to about 20, about 1 to about 10,
about 5 to about 90, about 10 to about 80, about 20 to about 60, or
about 30 to about 50 ppm. In some instances, a peptide of the
plurality of peptides is present at about 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800,
900, 1000, or more than 1000 microgram per milliliter (ug/mL). In
some instances, a peptide of the plurality of peptides is present
in a range of about 1 to about 100, about 1 to about 50, about 1 to
about 40, about 1 to about 30, about 1 to about 20, about 1 to
about 10, about 5 to about 90, about 10 to about 80, about 20 to
about 60, or about 30 to about 50 microgram per milliliter. In some
instances, a peptide of the plurality of peptides is present from
about 0.01% to about 10%, about 0.01% to about 0.02%, about 0.01%
to about 0.03%, about 0.01% to about 0.04%, about 0.01% to about
0.05%, about 0.01% to about 0.1%, about 1% to about 5%, or about 1%
to about 10% by weight (wt. %). In some embodiments, a peptide of
the plurality of peptides is provided at least or about 0.00001%,
0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%, 0.0055%, 0.01%, 0.02%,
0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or
more than 10% by weight (wt. %). In some embodiments, a peptide of
the plurality of peptides is provided in a range of about 0.25% to
about 10%, about 0.5% to about 8%, about 0.75% to about 6%, or
about 10% to about 4% by weight. In some embodiments, each peptide
of the plurality of peptides is provided in a range of about 0.001%
to about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or
about 0.02% to about 2% by weight.
[0084] In some embodiments, the peptide is tripeptide-1,
hexapeptide-12, hexapeptide-11, hexapeptide-38, tetrapeptide-2, or
combinations thereof.
[0085] In some embodiments, the tripeptide-1 is provided at least
or about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%,
0.0055%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%,
or more than 10% by weight (wt. %). In some embodiments, the
tripeptide-1 is provided in a range of about 0.25% to about 10%,
about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to
about 4% by weight. In some embodiments, the tripeptide-1 is
provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5,
4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25 ppm. In some
embodiments, the tripeptide-1 is provided in a range of about 0.25
to about 10, about 0.5 to about 8, about 1 to about 6, or about 2
to about 4 ppm. In some embodiments, the tripeptide-1 is provided
in a range of about 1 to about 10 ppm. In some embodiments, the
tripeptide-1 is provided at least or about 0.25, 0.5, 0.75, 1, 1.5,
2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25
microgram per milliliter (ug/mL). In some embodiments, the
tripeptide-1 is provided in a range of about 0.25 to about 10,
about 0.5 to about 8, about 1 to about 6, or about 2 to about 4
microgram per milliliter.
[0086] In some embodiments, the hexapeptide-12 is provided at least
or about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%,
0.0055%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%,
or more than 10% by weight (wt. %). In some embodiments, the
hexapeptide-12 is provided in a range of about 0.25% to about 10%,
about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to
about 4% by weight. In some embodiments, the hexapeptide-12 is
provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5,
4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25 ppm. In some
embodiments, the hexapeptide-12 is provided in a range of about 1
to about 10 ppm. In some embodiments, the hexapeptide-12 is
provided in a range of about 0.25 to about 10, about 0.5 to about
8, about 1 to about 6, or about 2 to about 4 ppm. In some
embodiments, the hexapeptide-12 is provided at least or about 0.25,
0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 15, 20,
25, or more than 25 microgram per milliliter (ug/mL). In some
embodiments, the hexapeptide-12 is provided in a range of about
0.25 to about 10, about 0.5 to about 8, about 1 to about 6, or
about 2 to about 4 microgram per milliliter.
[0087] In some embodiments, the hexapeptide-11 is provided at least
or about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%,
0.0055%, 0.01%, 0.02%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%,
1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%,
7.0%, 8%, 9% 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more
than 90% by weight (wt. %). In some embodiments, the hexapeptide-11
is provided in a range of about 0.25% to about 10%, about 0.5% to
about 8%, about 0.75% to about 6%, or about 1% to about 4% by
weight. In some embodiments, the hexapeptide-11 is provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 3%, or about 0.02% to about 2%. In some embodiments,
the hexapeptide-11 is provided in a range of about 0.005% to about
0.02% by weight. In some embodiments, the hexapeptide-11 is
provided at least or about 5, 10, 20, 25, 50, 75, 100, 150, 200,
250, or more than 250 ppm. In some embodiments, the hexapeptide-11
is provided in a range of about 25 to about 250, about 50 to about
200, or about 75 to about 150 ppm. In some embodiments, the
hexapeptide-11 is provided in a range of about 10 to about 100 ppm.
In some embodiments, the hexapeptide-11 is provided at least or
about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, or more than 250
microgram per milliliter (ug/mL). In some embodiments, the
hexapeptide-11 is provided in a range of about 25 to about 250,
about 50 to about 200, or about 75 to about 150 microgram per
milliliter.
[0088] In some embodiments, the hexapeptide-38 is provided at least
or about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%,
0.0055%, 0.01%, 0.02%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%,
1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%,
7.0%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more
than 90% by weight (wt. %). In some embodiments, the hexapeptide-38
is provided in a range of about 0.25% to about 10%, about 0.5% to
about 8%, about 0.75% to about 6%, or about 1% to about 4% by
weight. In some embodiments, the hexapeptide-38 is provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 3%, or about 0.02% to about 2%. In some embodiments,
the hexapeptide-38 is provided in a range of about 0.005% to about
0.02% by weight. In some embodiments, the hexapeptide-38 is
provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5,
4, 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, or more than 250 ppm.
In some embodiments, the hexapeptide-38 is provided in a range of
about 25 to about 250, about 50 to about 200, or about 75 to about
150 ppm. In some embodiments, the hexapeptide-38 is provided at
least or about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, or more
than 250 microgram per milliliter (ug/mL). In some embodiments, the
hexapeptide-38 is provided in a range of about 25 to about 250,
about 50 to about 200, or about 75 to about 150 microgram per
milliliter. In some embodiments, the hexapeptide-38 is acetyl
hexapeptide-38.
[0089] In some embodiments, the tetrapeptide-2 is provided at least
or about 0.00001%, 0.0003%, 0.0005%, 0.001%, 0.001%, 0.005%,
0.0055%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%,
or more than 10% by weight (wt. %). In some embodiments, the
tetrapeptide-2 is provided in a range of about 0.25% to about 10%,
about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to
about 4% by weight. In some embodiments, the tetrapeptide-2 is
provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5,
4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25 ppm. In some
embodiments, the tetrapeptide-2 is provided in a range of about
0.25 to about 10, about 0.5 to about 8, about 1 to about 6, or
about 2 to about 4 ppm. In some embodiments, the tetrapeptide-2 is
provided at least or about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5,
4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more than 25 microgram per
milliliter (ug/mL). In some embodiments, the tetrapeptide-2 is
provided in a range of about 0.25 to about 10, about 0.5 to about
8, about 1 to about 6, or about 2 to about 4 microgram per
milliliter.
[0090] In example embodiments, a weight ratio for the first peptide
to the second peptide in a topical composition is 1 part first
peptide to 0.2 to 10 parts second peptide, 1 to 10 parts second
peptide, 1 to 8 parts second peptide, or 1 to 5.5 parts second
peptide. The following nomenclature is employed herein to refer to
various amino acids: Alanine (also referred to herein as "Ala" or
"A"), Arginine (also referred to herein as "Arg" or "R"),
Asparagine (also referred to herein as "Asn" or "N"), Aspartic acid
(also referred to herein as "Asp" or "D"), Cysteine (also referred
to herein as "Cys" or "C"), Glutamic acid (also referred to herein
as "Glu" or "E"), Glutamine (also referred to herein as "Gln" or
"Q"), Glycine (also referred to herein as "Gly" or "G"), Histidine
(also referred to herein as "His" or "H"), Isoleucine (also
referred to herein as "Ile" or "I"), Leucine (also referred to
herein as "Leu" or "L"), Lysine (also referred to herein as "Lys"
or "K"), Methionine (also referred to herein as "Met" or "M"),
Phenylalanine (also referred to herein as "Phe" or "F"), Proline
(also referred to herein as "Pro" or "P"), Serine (also referred to
herein as "Ser" or "S"), Threonine (also referred to herein as
"Thr" or "T"), Tryptophan (also referred to herein as "Trp" or
"W"), Tyrosine (also referred to herein as "Tyr" or "Y"), Valine
(also referred to herein as "Val" or "V").
[0091] In some embodiments, the first peptide is a dipeptide.
Suitable dipeptides include but are not limited to those having the
following sequence of amino acids: KK, KP, CK, KC, KT, DF, NF, VW,
YR, or TT. In some embodiments, the dipeptide has the following
amino acid sequence: KV. In other embodiments, the first peptide is
a tripeptide. Suitable tripeptides include but are not limited to
those having the following sequence of amino acids: HGG, RKR, GHK,
GKH, GGH, GHG, KFK, or KPK. In some embodiments, the tripeptide has
the following amino acid sequence: KVK. In some embodiments, the
first peptide is a tetrapeptide. Suitable tetrapeptides include but
are not limited to those having the following sequence of amino
acids: GQPR, KTFK, AQTR, or RSRK. In some embodiments, the
tetrapeptide has the following sequence of amino acids: KDVY. In
some embodiments, the second peptide is a pentapeptide. Suitable
pentapeptides include but are not limited to those having the
following sequence of amino acids: KTTKS, YGGFX, or KLAAK. In some
embodiments, the second peptide is a hexapeptide. Suitable
hexapeptides include but are not limited to those having the
following sequence of amino acids: VGVAPG or GKTTKS. In some
embodiments, the hexapeptide has the following sequence of amino
acids: FVAPFP. In some embodiments, the second peptide is a
heptapeptide. Suitable heptapeptides include but are not limited to
one having an amino acid sequence RGYYLLE, or Heptapeptide-6 (a
pro-sirtuin peptide). The compositions may include two or more
peptides, e.g., two dipeptides and one pentapeptide; one tripeptide
and one hexapeptide; one dipeptide, one tripeptide, and one
heptapeptide, or the like, provided that the composition contains
at least one dipeptide, tripeptide, or tetrapeptide and at least
one pentapeptide, hexapeptide, or heptapeptide. In some
embodiments, the compositions comprise a tripeptide and one or more
hexapeptides. In some embodiments, the compositions comprise a
tripeptide, one or more hexapeptides, and a tetrapeptide. In some
embodiments, the tripeptide is tripeptide-1. In some embodiments,
the one or more hexapeptide is hexapeptide-12. In some embodiments,
the one or more hexapeptide is hexapeptide-11. In some embodiments,
the one or more hexapeptide is hexapeptide-38. In some embodiments,
the compositions comprise tripeptide-1, hexapeptide-12,
hexapeptide-11, and hexapeptide-38. In some embodiments, the
tetrapeptide is tetrapeptide-2.
[0092] The peptide can be functionalized. For example, the peptide
can be functionalized with a fatty acid, e.g., myristoleic acid,
palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic
acid, linoleic acid, linoelaidic acid, .alpha.-linolenic acid,
arachidonic acid, eicosapentaenoic acid, erucic acid,
docosahexaenoic acid, caprylic acid, capric acid, lauric acid,
palmitic acid, stearic acid, arachidic acid, behenic acid,
lignoceric acid, cerotic acid, or the like. Examples include
palmitoyl hexapeptide-12 (Pal-VGVAPG), palmitoyl tripeptide-1
(Pal-GHK), myristoyl hexapeptide-12 (Myr-VGVAPG), and myristoyl
tripeptide-1 (Myr-GHK). Palmitoyl or myristoyl functionalization
can be desirable in certain embodiments as it exhibits enhanced
penetration when compared to other fatty acids. In some
embodiments, the peptide is functionalized with a chemical group.
For example, the peptide is functionalized with acetyl. Examples
include acetyl hexapeptide-38 and acetyl tetrapeptide-2. In some
instances, the peptide is functionalized with a functional group
comprising no more than 14 carbons. In some instances, the peptide
is functionalized with a functional group comprising no more than
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or
more than 20 carbons. In some instances, the peptide is
non-palmitoylated. Without wishing to be limited to a particular
theory, incorporation of the peptide in a liposome, in some
embodiments, increases the lipophilicity of a peptide that is
functionalized or is not functionalized.
[0093] Some embodiments of the methods and compositions provided
herein include as a first peptide gly cine-histidine-lysine (GHK).
GHK is a peptide sequence that is rarely found in the class of
proteins in general, but is frequently found in extracellular
matrix proteins. The small size of GHK permits it to approach
membrane receptors far more easily than larger peptides. Further,
its unique, copper-binding structure enhances copper transport into
and out of cells and promotes wound healing through several
different but related pathways. Due to its strong copper binding
structure, GHK can be provided in the form of GHK-Cu (copper-bound
GHK form).
[0094] In compositions, the tripeptide is typically present in an
amount of from about 50 ppm or less to about 100, 200, 300, 400, or
500 ppm or more, e.g., 50 ppm to 150 ppm.
[0095] In compositions, the hexapeptide is typically present in an
amount of from about 50 ppm or less to about 100, 200, 300, 400, or
500 ppm or more, e.g., 50 ppm to 150 ppm.
[0096] In compositions, the tetrapeptide is typically present in an
amount of from about 50 ppm or less to about 100, 200, 300, 400, or
500 ppm or more, e.g., 50 ppm to 150 ppm.
[0097] The peptides can advantageously be provided in a base for
suitable for combining with other components of a liposomal
composition. The base can include one or more components such as a
thickener/binding agent (e.g., pentaerythrityl tetraisostearate),
an emollient/dispersing agent (e.g., caprylic/capric triglyceride),
a solvent (e.g., propylene carbonate), and/or a rheology
modifier/antisettling agent (e.g., disteardimonium hectorite).
[0098] Phosphatidylserine
[0099] Compositions as described herein, in some embodiments,
comprise phosphatidylserine. Exposure of phosphatidylserine from
the inner cell membrane of red blood cells can induce phagocytosis
of red blood cells. See Chang C F, Goods B A, Askenase M H, et al.
Erythrocyte efferocytosis modulates macrophages towards recovery
after intracerebral hemorrhage. The Journal of clinical
investigation. 2018; 128(2):607-624.
[0100] In some embodiments, phosphatidylserine is provided at least
or about 0.0010%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%,
0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or more
than 4% by weight (wt. %). In some embodiments, the
phosphatidylserine is provided in a range of about 0.25% to about
10%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1%
to about 4% by weight. In some embodiments, the phosphatidylserine
is provided in a range of about 0.001% to about 6%, about 0.002% to
about 4%, about 0.005% to about 0.1%. about 0.01% to about 3%, or
about 0.02% to about 2% by weight. In some embodiments, the
phosphatidylserine is provided in a range of about 0.005% to about
0.02% by weight. In some embodiments, the phosphatidylserine is
provided at about 0.05% by weight. In some embodiments, the
phosphatidylserine is provided at about 0.25% by weight. In some
embodiments, the phosphatidylserine is provided at about 1% by
weight. In some embodiments, the phosphatidylserine is provided at
least or about 5, 10, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350,
400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 or
more than 1000 microgram per milliliter (ug/mL). In some
embodiments, the phosphatidylserine is provided in a range of about
5 to about 1000, about 10 to about 900, about 30 to about 800,
about 50 to about 700, about 60 to about 600, or about 100 to about
500 microgram per milliliter (ug/mL).
[0101] Arnica Montana Extract
[0102] Compositions as described herein, in some embodiments,
comprise an anti-inflammatory agent. Exemplary anti-inflammatory
agents include, but are not limited to, Amica montana extract.
Arnica montana extract includes components such as essential oils,
fatty acids, thymol, pseudoguaianolide sesquiterpene lactones,
flavanone glycosides, flavonoids, and coumarins. It can exhibit an
anti-inflammatory effect. In some instances, Arnica montana extract
accelerates healing, reduces bruising potential, modulates
inflammation, and stimulates granular tissue and accelerates
healing, or combinations thereof. See Rajasingh J, Marzotto M,
Bonafini C, et al. Arnica montana Stimulates Extracellular Matrix
Gene Expression in a Macrophage Cell Line Differentiated to
Wound-Healing Phenotype. PloS one. 2016; 11(11). In some instances,
Arnica montana improves bruising by decreasing the inflammation
associated with blood products. In some instances, Arnica montana
stimulates the function of M2 macrophages and improves wound
healing. See Rajasingh J, Marzotto M, Bonafini C, et al. Arnica
montana Stimulates Extracellular Matrix Gene Expression in a
Macrophage Cell Line Differentiated to Wound-Healing Phenotype.
PloS one. 2016; 11(11).
[0103] In some embodiments, Arnica montana extract is provided at
least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%,
0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 5%,
6%, 7%, 8%, 9%, 10%, or more than 10% by weight (wt. %). In some
embodiments, the Arnica montana extract is provided in a range of
about 0.25% to about 10%, about 0.5% to about 8%, about 0.75% to
about 6%, or about 1% to about 4% by weight. In some embodiments,
the Arnica montana extract is provided in a range of about 0.001%
to about 6%, about 0.002% to about 4%, about 0.01% to about 3%,
about 0.02% to about 2% by weight, or about 0.1% to about 2.5%.
[0104] Ledum Palustre
[0105] Compositions as described herein, in some embodiments,
comprise Ledum palustre extract. Ledum palustre is also known as
marsh tea, wild rosemary, or labrador tea. Ledum palustre has been
used for insect bites, puncture wounds, and cold swellings or
bruises. See Kang J Y, Tran K D, Seiff S R, Mack W P, Lee W W.
Assessing the Effectiveness of Arnica montana and Rhododendron
tomentosum (Ledum palustre) in the Reduction of Ecchymosis and
Edema After Oculofacial Surgery: Preliminary Results. Ophthalmic
Plast Reconstr Surg. 2017; 33(1):47-52.
[0106] In some embodiments, Ledum palustre extract is provided at
least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%,
0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or
more than 4% by weight (wt. %). In some embodiments, the Ledum
palustre extract is provided in a range of about 0.25% to about
10%, about 0.5% to about 8%, about 0.75% to about 6%, or about 1%
to about 4% by weight. In some embodiments, the Ledum palustre
extract is provided in a range of about 0.001% to about 6%, about
0.002% to about 4%, about 0.01% to about 3%, about 0.02% to about
2% by weight, or about 0.1% to about 2.5%. In some embodiments, the
Ledum palustre extract is provided at about 0.25%. In some
embodiments, the Ledum palustre extract is provided at about 0.5%.
In some embodiments, the Ledum palustre extract is provided at
about 1.0%.
[0107] Leuconostoc Radish Root Ferment Filtrate
[0108] Compositions as described herein, in some embodiments,
comprise Leuconostoc/radish root ferment filtrate. In some
embodiments, the Leuconostoc/radish root ferment filtrate is
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, or more than 4% by weight (wt. %). In some embodiments,
the Leuconostoc/radish root ferment filtrate is provided in a range
of about 0.25% to about 10%, about 0.5% to about 8%, about 0.75% to
about 6%, or about 1% to about 4% by weight. In some embodiments,
the Leuconostoc/radish root ferment filtrate is provided in a range
of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01%
to about 3%, about 0.02% to about 2% by weight, or about 0.1% to
about 2.5%. In some embodiments, the Leuconostoc/radish root
ferment filtrate is provided at about 0.25%. In some embodiments,
the Leuconostoc/radish root ferment filtrate is provided at about
0.5%. In some embodiments, the Leuconostoc/radish root ferment
filtrate is provided at about 1.0%.
[0109] Lactoferrin
[0110] Compositions as described herein, in some embodiments,
comprise a transferrin. In some embodiments, the transferrin is a
lactoferrin. In some embodiments, lactoferrin is encapsulated in a
liposome. Lactoferrin has wound healing attributes, promotes
proliferation of fibroblasts and increases HA secretion. See Saito
S, Takayama Y, Mizumachi K, Suzuki C. Lactoferrin promotes
hyaluronan synthesis in human dermal fibroblasts. Biotechnology
letters. 2011; 33(1):33-39; Takayama Y. Effects of Lactoferrin on
Skin Wound Healing. In: Lactoferrin and its Role in Wound Healing.
2012:87-100.
[0111] In some instances, the lactoferrin has antimicrobial
activity. In some instances, the lactoferrin has antimicrobial
activity against bacteria, fungi, yeasts, viruses, parasites, or
combinations thereof. Lactoferrin, in some instances, comprises
antibiofilm activity. In some instances, lactoferrin interacts with
the bacterial surface and destabilizes the microbial membrane. In
some instances, lactoferrin chelates iron to disrupt the microbial
membrane.
[0112] In some embodiments, lactoferrin is provided at least or
about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%,
0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or more
than 4% by weight (wt. %). In some embodiments, the lactoferrin is
provided in a range of about 0.005% to about 0.1%, about 0.25% to
about 10%, about 0.5% to about 8%, about 0.75% to about 6%, or
about 1% to about 4% by weight. In some embodiments, the
lactoferrin is provided in a range of about 0.001% to about 6%,
about 0.002% to about 4%, about 0.01% to about 2.5%, or about 0.02%
to about 2% by weight. In some embodiments, the lactoferrin is
provided at about 0.025%. In some embodiments, the lactoferrin is
provided at about 0.05%. In some embodiments, the lactoferrin is
provided at about 0.10%. In some embodiments, the lactoferrin is
provided at least or about 5, 10, 20, 25, 50, 75, 100, 150, 200,
250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850,
900, 950, 1000 or more than 1000 microgram per milliliter (ug/mL).
In some embodiments, the lactoferrin is provided in a range of
about 5 to about 1000, about 10 to about 900, about 30 to about
800, about 50 to about 700, about 60 to about 600, or about 100 to
about 500 microgram per milliliter (ug/mL).
[0113] Dill Extract
[0114] Compositions as described herein, in some embodiments,
comprise dill extract. The dill extract, in some embodiments,
stimulates LOXL reinduction and elastin formation. In some
embodiments, the dill extract is Anethum graveolens extract. In
some embodiments, the dill extract is Peucedanum graveolens
extract.
[0115] In some embodiments, the dill extract is provided at least
or about 0.01%, 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%,
2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%,
8%, 9%, 10%, or more than 10% by weight (wt. %). In some
embodiments, the dill extract is provided in a range of about 0.25%
to about 10%, about 0.025% to about 4%, about 0.5% to about 8%,
about 0.75% to about 6%, or about 1% to about 4% by weight. In some
embodiments, the dill extract is provided at about 1.0% by
weight.
[0116] Hydroxymethoxyphenyl Decanone
[0117] Compositions as described herein, in some embodiments,
comprise hydroxymethoxyphenyl decanone. In some embodiments, the
hydroxymethoxyphenyl decanone is a potent intrinsic hyaluronic acid
booster, antioxidant, anti-irritant, or a combination thereof.
[0118] In some embodiments, hydroxymethoxyphenyl decanone is
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, or more than 4% by weight (wt. %). In some embodiments,
the hydroxymethoxyphenyl decanone is provided in a range of about
0.25% to about 10%, about 0.1% to about 2.5%, about 0.5% to about
8%, about 0.75% to about 6%, or about 1% to about 4% by weight. In
some embodiments, the hydroxymethoxyphenyl decanone is provided in
a range of about 0.001% to about 6%, about 0.002% to about 4%,
about 0.01% to about 3%, or about 0.02% to about 2% by weight.
[0119] Tremella fuciformis
[0120] Compositions as described herein, in some embodiments,
comprise Tremella fuciformis extract. In some embodiments, the
Tremella fuciformis extract is derived from an edible mushroom. In
some embodiments, Tremella fuciformis extract provides moisture and
antioxidant properties.
[0121] In some embodiments, Tremella fuciformis extract is provided
at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%,
0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%,
4.0%, or more than 4% by weight (wt. %). In some embodiments, the
Tremella fuciformis extract is provided in a range of about 0.25%
to about 10%, about 0.1% to about 2.5%, about 0.5% to about 8%,
about 0.75% to about 6%, or about 1% to about 4% by weight. In some
embodiments, the Tremella fuciformis extract is provided in a range
of about 0.001% to about 6%, about 0.002% to about 4%, about 0.01%
to about 3%, or about 0.02% to about 2% by weight.
[0122] Sodium Hyaluronate Crosspolymer
[0123] Compositions as described herein, in some embodiments,
comprise sodium hyaluronate crosspolymer. Sodium hyaluronate
crosspolymer is a high molecular weight synthetic hyaluronic acid
with high water-binding capacity and moisturizing abilities.
[0124] In some embodiments, the sodium hyaluronate crosspolymer is
provided at least or about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%,
0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%,
2.5%, 3.0%, 3.5%, 4.0%, or more than 4.0% by weight (wt. %). In
some embodiments, the sodium hyaluronate crosspolymer is provided
at about 0.5% by weight. In some embodiments, the sodium
hyaluronate crosspolymer is provided in a range of about 0.0001% to
about 4.0%, about 0.001% to about 4.0%, about 0.01% to about 3.0%,
about 0.1% to about 2.5%, or about 0.50% to about 1.5% by
weight.
[0125] Phytoene and Phytofluene
[0126] Compositions as described herein, in some embodiments,
comprise phytoene, phytofluene, or combinations thereof. Phytoene
and phytofluene are colorless carotenoids derived from saltwater
microalgae that modulate Prostaglandin E-2 (PGE-2).
[0127] In some embodiments, the phytoene, phytofluene, or
combinations thereof is provided at least or about 0.001%, 0.005%,
0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%,
2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or more than 4% by weight (wt. %). In
some embodiments, the phytoene, phytofluene, or combinations
thereof is provided in a range of about 0.25% to about 10%, about
0.1% to about 2.5%, about 0.5% to about 8%, about 0.75% to about
6%, or about 1% to about 4% by weight. In some embodiments, the
phytoene, phytofluene, or combinations thereof is provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 3%, or about 0.02% to about 2% by weight.
[0128] Xylitol
[0129] Compositions as described herein, in some embodiments,
comprise xylitylglucoside, anhydroxylitol, xylitol, or combinations
thereof. Xylitol is a sugar alcohol and comprises anti-biofilm and
anti-inflammatory effects. In some embodiments, xylitol and
lactoferrin in combination comprise anti-biofilm effects. In some
embodiments, xylitol and lactoferrin act synergistically. For
example, lactoferrin destabilizes the bacterial membrane and allows
xylitol to cross the bacterial membrane to inhibit biofilm
development and growth.
[0130] In some embodiments, the xylitylglucoside, anhydroxylitol,
xylitol, or combinations thereof is provided at least or about
0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%,
0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or more than 4% by
weight (wt. %). In some embodiments, the xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof is provided in a
range of about 0.25% to about 10%, about 0.1% to about 2.5%, about
0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4%
by weight. In some embodiments, the xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof is provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 3%, or about 0.02% to about 2% by weight.
[0131] Sorbitan Isostearate
[0132] Compositions as described herein, in some embodiments,
comprise sorbitan isostearate. In some embodiments, the sorbitan
isostearate is provided at least or about 0.001%, 0.005%, 0.01%,
0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%,
2.5%, 3.0%, 3.5%, 4.0%, or more than 4% by weight (wt. %). In some
embodiments, the sorbitan isostearate is provided in a range of
about 0.25% to about 10%, about 0.1% to about 2.5%, about 0.5% to
about 8%, about 0.75% to about 6%, or about 1% to about 4% by
weight. In some embodiments, the sorbitan isostearate is provided
in a range of about 0.001% to about 6%, about 0.002% to about 4%,
about 0.01% to about 3%, or about 0.02% to about 2% by weight. In
some embodiments, the sorbitan isostearate is provided at about
0.10% by weight.
[0133] Glucose
[0134] In some embodiments, compositions as described herein
comprise glucose. In some embodiments, the glucose is provided at
least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%,
0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or
more than 4% by weight (wt. %). In some embodiments, the glucose is
provided in a range of about 0.25% to about 10%, about 0.1% to
about 2.5%, about 0.5% to about 8%, about 0.75% to about 6%, or
about 1% to about 4% by weight. In some embodiments, the glucose is
provided in a range of about 0.001% to about 6%, about 0.002% to
about 4%, about 0.01% to about 3%, or about 0.02% to about 2% by
weight. In some embodiments, the glucose is provided at about 0.01%
by weight.
[0135] Compositions as described herein, in some embodiments,
comprise seed oil. In some embodiments, the seed oil is Helianthus
annuus (sunflower) seed oil. In some embodiments, the seed oil is
provided at least or about 0.001%, 0.003%, 0.005%, 0.01%, 0.02%,
0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, or more than 4% by weight (wt. %). In some
embodiments, the seed oil is provided in a range of about 0.25% to
about 10%, about 0.1% to about 2.5%, about 0.5% to about 8%, about
0.75% to about 6%, or about T % to about 4% by weight. In some
embodiments, the seed oil is provided in a range of about 0.001% to
about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or
about 0.02% to about 2% by weight. In some embodiments, the seed
oil is provided at about 0.003% by weight.
[0136] Other Components
[0137] Other components can include anti-inflammatory agents,
antioxidants, and solubility enhancers. Exemplary anti-irritation
agents include, but are not limited to, panthenyl triacetate and
naringenin. Panthenyl triacetate and naringenin are natural plant
extracts that reduce redness and water loss through the skin.
Typical amounts for anti-irritation agents when employed in
compositions are from 1% by weight to 4% by weight (wt. %).
[0138] Exemplary antioxidant agents include, but are not limited
to, Dunaliella salina extract and squalane. Dunaliella salina
extract includes components such as beta carotenes. It can exhibit
an antioxidant effect. Typical amounts for anti-inflammatory agents
when employed in compositions are from 0.1% by weight to 2.5% by
weight (wt. %). In some embodiments, the Dunaliella salina extract
is provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, or more than 4% by weight. In some embodiments, the
Dunaliella salina extract is provided in a range of about 0.001% to
about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or
about 0.50% to about 1.5%. In some embodiments, the squalane is
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, or more than 4% by weight. In some embodiments, the
squalane is provided in a range of about 0.0010% to about 4.0%,
about 0.010% to about 3.0%, about 0.1% to about 2.5%, or about
0.50% to about 1.5%. In some embodiments, the Dunaliella salina
extract and the squalane is provided at least or about 0.001%,
0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%,
1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or more than 4% by
weight. In some embodiments, the Dunaliella salina and the squalane
extract is provided in a range of about 0.001% to about 4.0%, about
0.01% to about 3.0%, about 0.1% to about 2.5%, or about 0.50% to
about 1.5%.
[0139] In some embodiments, the composition comprises a siloxane
polymer. In some embodiments, the siloxane polymer is caprylyl
methicone. In some embodiments, caprylyl methicone is provided at
least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%,
0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or
more than 4.0% by weight (wt. %). In some embodiments, the caprylyl
methicone is provided at about 0.5% by weight. In some embodiments,
the caprylyl methicone is provided in a range of about 0.001% to
about 4.0%, about 0.01% to about 3.0%, about 0.1% to about 2.5%, or
about 0.50% to about 1.5% by weight. In some embodiments, the
caprylyl methicone is provided at about 0.25% by weight. In some
embodiments, the caprylyl methicone is provided at about 1% by
weight.
[0140] Bentonite clays can be employed in conjunction with the
peptides to provide impart penetration and adsorption properties to
the compositions, and can aid in stabilizing emulsions. Other
clays, such as hectorite and magnesium aluminum silicate can also
be employed. Bentonite or other clays can be modified to yield an
organic modified clay compound. Salts (e.g., quaternary ammonium
salts) of fatty acids (e.g., hydrogenated fatty acids) can be
reacted with hectorite or other clays. As provided herein, fatty
acids are referred to and described using conventional nomenclature
as is employed by one of skill in the art. A saturated fatty acid
includes no carbon-carbon double bonds. An unsaturated fatty acid
includes at least one carbon-carbon double bond. A monounsaturated
fatty acid includes only one carbon-carbon double bond. A
polyunsaturated fatty acid includes two or more carbon-carbon
double bonds. Double bonds in fatty acids are generally cis;
however, trans double bonds are also possible. The position of
double bonds can be indicated by .DELTA.n, where n indicates the
lower numbered carbon of each pair of double-bonded carbon atoms. A
shorthand notation specifying total # carbons: # double bonds,
.DELTA..sub.double bond positions can be employed. For example,
20:4.DELTA..sub.5,8,11,14 refers to a fatty acid having 20 carbon
atoms and four double bonds, with the double bonds situated between
the 5 and 6 carbon atom, the 8 and 9 carbon atom, the 11 and 12
carbon atom, and the 14 and 15 carbon atom, with carbon atom 1
being the carbon of the carboxylic acid group. Stearate
(octadecanoate) is a saturated fatty acid. Oleate
(cis-.DELTA.9-octadecenoate) is a monounsaturated fatty acid,
linolenate (all-cis-.DELTA.9,12,15-octadecatrienoate) is a
polyunsaturated fatty acid. Fatty acids suitable for use can
comprise from 5 to 30 carbon atoms, e.g., 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, or 30 carbon atoms. The fatty acid can be fully saturated, or
can include as many double bonds as are feasible for the chain
length. Fatty acids suitable for functionalizing hectorite or other
clays include palmitic acid and stearic acid. Dialkyl quaternary
cationic modifiers include dipalmoyldimonium chloride and
distearyldimonium chloride. Amidoamine quaternary cationic
modifiers include palmitamidopropyltrimonium chloride cetearyl
alcohol and palmitamidopropyltrimonium chloride.
[0141] In some embodiments, the peptides can be in admixture with a
suitable carrier, diluent, or excipient, and can contain auxiliary
substances such as wetting or emulsifying agents, pH buffering
agents, gelling or viscosity enhancing additives, preservatives,
scenting agents, colors, and the like, depending upon the route of
administration and the preparation desired. See, e.g., "Remington:
The Science and Practice of Pharmacy", Lippincott Williams &
Wilkins; 20th edition (Jun. 1, 2003) and "Remington's
Pharmaceutical Sciences," Mack Pub. Co.; 18th and 19th editions
(December 1985, and June 1990, respectively). Such preparations can
include complexing agents, metal ions, polymeric compounds such as
polyacetic acid, polyglycolic acid, hydrogels, dextran, and the
like, liposomes, microemulsions, micelles, unilamellar or
multilamellar vesicles, erythrocyte ghosts or spheroblasts.
Suitable lipids for compositions include, without limitation,
monoglycerides, diglycerides, sulfatides, lysolecithin,
phospholipids, saponin, bile acids, and the like. In some
embodiments, compositions described herein comprise,
phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate,
or combinations thereof. In some embodiments, phosphatidylserine,
phospholipids, tocopherol, ascorbyl palmitate, or combinations
thereof is provided at 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%,
0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%,
4.0%, or more than 4% by weight (wt. %). In some embodiments, the
phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate,
or combinations thereof is provided in a range of about 0.25% to
about 10%, about 0.5% to about 8%, about 0.75% to about 6%, or
about 1% to about 4% by weight. In some embodiments, the
phosphatidylserine, phospholipids, tocopherol, ascorbyl palmitate,
or combinations thereof is provided in a range of about 0.001% to
about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or
about 0.02% to about 5% by weight. In some embodiments, the
additive is betaine. Betaine, in some embodiments, is provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 3%, or about 0.02% to about 5% by weight. In some
embodiments, the compositions as described herein comprise caprylyl
glycol. In some embodiments, the caprylyl glycol provided in a
range of about 0.001% to about 6%, about 0.002% to about 4%, about
0.01% to about 3%, or about 0.02% to about 5% by weight. In some
embodiments, the compositions as described herein comprise
caprylhydroxamic acid. In some embodiments, the caprylhydroxamic
acid provided in a range of about 0.001% to about 6%, about 0.002%
to about 4%, about 0.01% to about 3%, or about 0.02% to about 5% by
weight. The presence of such additional components can influence
the physical state, solubility, stability, rate of release, rate of
clearance, and penetration of active ingredients.
[0142] The compositions for topical administration comprise the
peptide compositions as described herein and a dermatologically
acceptable vehicle. The vehicle may be aqueous or nonaqueous. The
dermatologically acceptable vehicle used in the topical composition
may be in the form of a lotion, a gel, an ointment, a liquid, a
cream, or an emulsion. If the vehicle is an emulsion, the emulsion
may have a continuous aqueous phase and a discontinuous nonaqueous
or oil phase (oil-in-water emulsion), or a continuous nonaqueous or
oil phase and a discontinuous aqueous phase (water-in-oil
emulsion). When administered topically in liquid or gel form, a
liquid carrier such as water, petroleum, oils of animal or plant
origin such as peanut oil, mineral oil, soybean oil, or sesame oil,
or synthetic oils can be added to the active ingredient(s).
Physiological saline solution, dextrose, or other saccharide
solution, or glycols such as ethylene glycol, propylene glycol, or
polyethylene glycol are also suitable liquid carriers. The
pharmaceutical compositions can also be in the form of oil-in-water
emulsions. The oily phase can be a vegetable oil, such as olive or
arachis oil, a mineral oil such as liquid paraffin, or a mixture
thereof. Suitable emulsifying agents include naturally-occurring
gums such as gum acacia and gum tragacanth, naturally occurring
phosphatides, such as soybean lecithin, esters or partial esters
derived from fatty acids and hexitol anhydrides, such as sorbitan
mono-oleate, and condensation products of these partial esters with
ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The
emulsions can also contain coloring and scenting agents.
[0143] In certain embodiments, a silicone elastomer (e.g.,
dimethicone crosspolymer) is employed to increase delivery and
penetration of the peptides into the skin. An alternative to
increasing molecular weight (as with silicone gums) or adding
filler (as with silicone compounds) is to partially crosslink
siloxane polymers and disperse this material in an appropriate
silicone carrier fluid. The resulting dimethicone crosspolymers
(also known as silicone elastomers in the personal care industry)
differ from basic polydimethylsiloxane (PDMS) because of the
cross-linking between the linear polymers. These materials can be
employed in peptide compositions, and also offer benefits in scar
treatment, periwound protection and enzyme delivery. In skin care
applications, the aesthetics of silicone elastomers (including
those with functional groups) and their ability to absorb various
oils (e.g., with a dimethicone/vinyl dimethicone crosspolymer such
as Dow Corning.RTM. 9506 Elastomer Powder) are two of the
elastomer's desirable properties. Silicone elastomers have a skin
feel different from any of the silicone fluids, described as
"smooth," "velvety," and "powdery." It can be modified by
controlling the amount of liquid phase in the formula, and
therefore the degree of swelling. Due to their film-forming
properties, dimethicone crosspolymers can be used as delivery
systems for active ingredients such as the peptides described
herein, or other composition components such as oil-soluble
vitamins and sunscreens. Sunscreens such as octyl methoxycinnamate
can be more efficiently delivered from a composition containing a
silicone elastomer, producing a higher sun protection factor (SPF).
Silicone elastomer blends can be used to enhance SPF in
oil-in-water compositions containing organic sunscreens. For
example, in testing conducted regarding SPF, the addition of 4%
silicone elastomer blend to a sun care composition containing
organic sunscreens increased the SPF from 5.7 to 18. This property
of the silicone elastomer allows the effectiveness of sunscreen
agents in a composition to be maximized while reducing the amount
needed to achieve a desired SPF. As a result, composition costs can
be reduced along with potential irritation caused by sunscreen
actives. Accordingly, a higher SPF can be achieved with the same
amount of UV absorber, resulting in enhanced performance with no
added composition cost. Silicone elastomers can be produced from
linear silicone polymers by a variety of crosslinking reactions,
e.g., by a hydrosilylation reaction in which a vinyl group reacts
with a silicon hydride. The general process involves linear
silicone polymers with reactive sites along the polymer chain
reacting with a cross-linker. The dimethicone crosspolymer can be
produced either as a gel made of a suspension of elastomer
particles swollen in a carrier fluid (e.g., a mixture of high
molecular weight silicone elastomer in cyclopentasiloxane such as
Dow Corning.RTM. 9040 Silicone Elastomer Blend), or as a
spray-dried powder (a dimethicone/vinyl dimethicone crosspolymer
such as Dow Corning.RTM. 9506 Elastomer Powder). The gel form
having desirable attributes is cyclomethicone, but low viscosity
dimethicones and organic fluids can also be used. Examples of
dimethicone crosspolymers in the suspension or gel form are high
molecular weight silicone elastomer (12%) in
decamethylcyclopentasiloxane (e.g., Dow Corning.RTM. ST-Elastomer
10) and a mixture of high molecular weight silicone elastomer in
cyclopentasiloxane (e.g., Dow Corning.RTM. 9040 Silicone Elastomer
Blend), which typically have an elastomer content ranging from 10
to 20% by weight.
[0144] The pharmaceutical excipients used in the topical
preparations of the peptide compositions may be selected from the
group consisting of solvents, emollients and/or emulsifiers, oil
bases, preservatives, antioxidants, tonicity adjusters, penetration
enhancers and solubilizers, chelating agents, buffering agents,
surfactants, one or more polymers, and combinations thereof.
[0145] Suitable solvents for an aqueous or hydrophilic liposomal
composition include water; ethyl alcohol; isopropyl alcohol;
mixtures of water and ethyl and/or isopropyl alcohols; glycerin;
ethylene, propylene or butylene glycols; DMSO; pentylene glycol;
and mixtures thereof. In some embodiments, glycerin is provided at
least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
or more than 12% by weight (wt. %). In some embodiments, glycerin
is provided at least or about 7%. In some embodiments, glycerin is
provided in a range of about 1% to about 12%, about 2% to about
11%, or about 3% to about 10% by weight. In some embodiments,
butylene glycol is provided at least or about 0.0025%, 0.005%,
0.075%, 0.01%, 0.025%, 0.05%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%,
8%, 9%, 10%, 11%, 12%, or more than 12% by weight. In some
embodiments, butylene glycol is provided in a range of about 0.01%
to about 10%, about 0.025% to about 5%, or about 0.05% to about
1.25% by weight. In some embodiments, pentylene glycol is provided
at least or about 0.0025%, 0.005%, 0.075%, 0.01%, 0.025%, 0.05%,
0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more
than 12% by weight. In some embodiments, pentylene glycol is
provided in a range of about 0.010% to about 10%, about 0.025% to
about 5%, or about 0.05% to about 1.25% by weight. Suitable
solvents for hydrophobic compositions include mineral oils,
vegetable oils, and silicone oils. If desired, the peptide
compositions as described herein may be dissolved or dispersed in a
hydrophobic oil phase, and the oil phase may then be emulsified in
an aqueous phase comprising water, alone or in combination with
lower alcohols, glycerin, and/or glycols. In some embodiments, an
anhydrous composition is applied as the presence of water can
result in stinging upon administration to skin tissues subject to
laser treatment, chemical peel, dermabrasion, or the like.
Anhydrous compositions may also act to prevent the development of
water-based irritant contact dermatitis in damaged or sensitive
skin, which may produce rashes and skin irritation that may retard
wound healing and improvement in skin quality. Tsai, T. F.,
Maibach, H. I. How irritant is water? An overview. Contact
Dermatitis 41(6) (1999): 311-314 (describing contact dermatitis
caused by water as an irritant). However, in certain embodiments it
may be acceptable to provide water based compositions, or to permit
a limited amount of water to be present. For example, water may be
present, but at amounts below the threshold at which a stinging
sensation when applied to damaged skin may result. Osmotic shock or
osmotic stress is a sudden change in the solute concentration
around a cell, causing a rapid change in the movement of water
across its cell membrane. Under conditions of high concentrations
of either salts, substrates or any solute in the supernatant, water
is drawn out of the cells through osmosis. This also inhibits the
transport of substrates and cofactors into the cell thus "shocking"
the cell. Alternatively, at low concentrations of solutes, water
enters the cell in large amounts, causing it to swell and either
burst or undergo apoptosis. Certain of the compositions as
described herein can be advantageously employed where it is
desirable to minimize osmotic shock.
[0146] Compositions as described herein may comprise varying
amounts of solvent. In some embodiments, the solvent is water. In
some embodiments, the solvent is at least or about 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, or more than 95% by weight (wt. %). In some embodiments,
the solvent is in a range of about 10% to about 95%, about 20% to
about 90%, about 30% to about 85%, about 40% to about 80%, or about
50% to about 75% by weight.
[0147] Viscosity of the compositions can be maintained at the
selected level using a pharmaceutically acceptable thickening
agent. Suitable viscosity enhancers or thickeners which may be used
to prepare a viscous gel or cream with an aqueous base include
sodium polyacrylate, xanthan gum, polyvinyl pyrrolidone, acrylic
acid polymer, carrageenans, hydroxyethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, ethyl cellulose, propyl cellulose,
hydroxypropyl methyl cellulose, polyethoxylated polyacrylamides,
polyethoxylated acrylates, and polyethoxylated alkane thiols.
Methylcellulose is preferred because it is readily and economically
available and is easy to work with. Other suitable thickening
agents include, for example, xanthan gum, carboxymethyl cellulose,
hydroxypropyl cellulose, carbomer, and the like. The preferred
concentration of the thickener will depend upon the thickening
agent selected. An amount is preferably used that will achieve the
selected viscosity. Viscous compositions are normally prepared from
solutions by the addition of such thickening agents, or by
employing a base that has an acceptable level of viscosity.
[0148] The viscosity of the compositions as described herein, in
some embodiments, are in a range of about 8,000 centipoise (cps) to
about 30,000 cps. In some embodiments, the viscosity is at least or
about 4,000; 5,000; 6,000; 7,000; 8,000; 9,000; 10,000; 11,000;
12,000; 13,000; 14,000; 15,000; 16,000; 17,000; 18,000; 19,000;
20,000; 21,000; 22,000; 23,000; 24,000; 25,000; 26,000; 27,000;
28,000; 29,000; 30,000; 31,000; 32,000; 33,000; 34,000, 35,000;
36,000; 37,000; 38,000; 39,000; 40,000; or more than 40,000 cps. In
some embodiments, the composition comprises a viscosity in a range
of about 4,000 to about 40,000, about 6,000 to about 38,000, about
8,000 to about 36,000, about 10,000 to about 34,000 cps, about
12,000 to about 32,000 cps, or about 14,000 to about 30,000
cps.
[0149] Suitable emollients include hydrocarbon oils and waxes such
as mineral oil, petrolatum, paraffin, ceresin, ozokerite,
microcrystalline wax, polyethylene, squalene, perhydrosqualene,
silicone oils, triglyceride esters, acetoglyceride esters, such as
acetylated monoglycerides; ethoxylated glycerides, such as
ethoxylated glyceryl monostearate; alkyl esters of fatty acids or
dicarboxylic acids. In some embodiments, the emollient is
caprylic/capric triglyceride.
[0150] In some embodiments, the emollient is provided at least or
about 0.0025%, 0.005%, 0.075%, 0.01%, 0.025%, 0.05%, 0.75%, 1%, 2%,
3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more than 12% by
weight. In some embodiments, the emollient is provided in a range
of about 0.01% to about 10%, about 0.01% to about 2.5%, about
0.025% to about 5%, or about 0.05% to about 1.25% by weight. In
some embodiments, the caprylic/capric triglyceride is provided at
least or about 0.0025%, 0.005%, 0.075%, 0.01%, 0.025%, 0.05%,
0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or more
than 12% by weight. In some embodiments, the caprylic/capric
triglyceride is provided in a range of about 0.010% to about 10%,
about 0.01% to about 2.5%, about 0.025% to about 5%, or about 0.05%
to about 1.25% by weight.
[0151] Suitable silicone oils for use as emollients include
dimethyl polysiloxanes, methyl(phenyl) polysiloxanes, and
water-soluble and alcohol-soluble silicone glycol copolymers.
Suitable triglyceride esters for use as emollients include
vegetable and animal fats and oils including castor oil, safflower
oil, cotton seed oil, corn oil, olive oil, cod liver oil, almond
oil, avocado oil, palm oil, sesame oil, and soybean oil.
[0152] Suitable esters of carboxylic acids or diacids for use as
emollients include methyl, isopropyl, and butyl esters of fatty
acids. Specific examples of alkyl esters including hexyl laurate,
isohexyl laurate, iso-hexyl palmitate, isopropyl palmitate, decyl
oleate, isodecyl oleate, hexadecyl stearate, decyl stearate,
isopropyl isostearate, dilauryl lactate, myristyl lactate, and
cetyl lactate; and alkenyl esters of fatty acids such as oleyl
myristate, oleyl stearate, and oleyl oleate. Specific examples of
alkyl esters of diacids include diisopropyl adipate, diisohexyl
adipate, bis(hexyldecyl) adipate, and diisopropyl sebacate.
[0153] Other suitable classes of emollients or emulsifiers which
may be used in the compositions include fatty acids, fatty
alcohols, fatty alcohol ethers, ethoxylated fatty alcohols, fatty
acid esters of ethoxylated fatty alcohols, and waxes.
[0154] Specific examples of fatty acids for use as emollients
include pelargonic, lauric, myristic, palmitic, stearic,
isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic,
behenic, and erucic acids. Specific examples of fatty alcohols for
use as emollients include lauryl, myristyl, cetyl, hexadecyl,
stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl,
and erucyl alcohols, as well as 2-octyl dodecanol.
[0155] Specific examples of waxes suitable for use as emollients
include lanolin and derivatives thereof including lanolin oil,
lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl
lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols,
ethoxolated cholesterol, propoxylated lanolin alcohols, acetylated
lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate,
lanolin alcohols recinoleate, acetate of lanolin alcohols
recinoleate, acetate of lanolin alcohols recinoleate, acetate of
ethoxylated alcohols esters, hydrogenolysates of lanolin,
hydrogenated lanolin, ethoxylated hydrogenated lanolin, ethoxylated
sorbitol lanolin, and liquid and semisolid lanolin. Also usable as
waxes include hydrocarbon waxes, ester waxes, and amide waxes.
Useful waxes include wax esters such as beeswax, spermaceti,
myristyl myristate and stearyl stearate; beeswax derivatives, e.g.,
polyoxyethylene sorbitol beeswax; and vegetable waxes including
carnauba and candelilla waxes.
[0156] Polyhydric alcohols and polyether derivatives may be used as
solvents and/or surfactants in the compositions. Suitable
polyhydric alcohols and polyethers include propylene glycol,
dipropylene glycol, polypropylene glycols 2000 and 4000,
poly(oxyethylene-co-oxypropylene) glycols, glycerol, sorbitol,
ethoxylated sorbitol, hydroxypropylsorbitol, polyethylene glycols
200-6000, methoxy polyethylene glycols 350, 550, 750, 2000 and
5000, poly[ethylene oxide] homopolymers (100,000-5,000,000),
polyalkylene glycols and derivatives, hexylene glycol,
2-methyl-2,4-pentanediol, 1,3-butylene glycol, 1,2,6-hexanetriol,
2-ethyl-1,3-hexanediol, vicinal glycols having 15 to 18 carbon
atoms, and polyoxypropylene derivatives of trimethylolpropane.
[0157] Polyhydric alcohol esters may be used as emulsifiers or
emollients. Suitable polyhydric alcohol esters include ethylene
glycol mono- and di-fatty acid esters, diethylene glycol mono- and
di-fatty acid esters, polyethylene glycol (200-6000) mono- and
di-fatty acid esters, propylene glycol mono- and di-fatty esters,
polypropylene glycol 2000 monooleate, polypropylene glycol 2000
monostearate, ethoxylated propylene glycol monostearate, glyceryl
mono- and di-fatty acid esters, polyglycerol poly-fatty acid
esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol
monostearate, 1,3-butylene glycol distearate, polyoxyethylene
polyol fatty acid ester, sorbitan fatty acid esters, and
polyoxyethylene sorbitan fatty acid esters.
[0158] Suitable emulsifiers for use in compositions include
anionic, cationic, nonionic, and zwitterionic surfactants.
Preferred ionic emulsifiers include phospholipids, such as lecithin
and derivatives.
[0159] Sterols including, for example, cholesterol and cholesterol
fatty acid esters; amides such as fatty acid amides, ethoxylated
fatty acid amides, and fatty acid alkanolamides may also be used as
emollients and/or penetration enhancers.
[0160] A pharmaceutically acceptable preservative can be employed
to increase the shelf life of the composition. Other suitable
preservatives and/or antioxidants for use in compositions include
benzalkonium chloride, benzyl alcohol, phenol, urea, parabens,
butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),
tocopherol, thimerosal, chlorobutanol, or the like, and mixtures
thereof, can be employed. If a preservative, such as an
antioxidant, is employed, the concentration is typically from about
0.02% to about 2% based on the total weight of the composition,
although larger or smaller amounts can be desirable depending upon
the agent selected. Reducing agents, as described herein, can be
advantageously used to maintain good shelf life of the composition.
It is generally observed that the anhydrous compositions of the
embodiments exhibit satisfactory stability, such that a
preservative can be omitted from the composition.
[0161] Suitable chelating agents for use in compositions include
ethylene diamine tetraacetic acid, alkali metal salts thereof
alkaline earth metal salts thereof, ammonium salts thereof, and
tetraalkyl ammonium salts thereof. In some embodiments, the
chelating agent is disodium ethylenediaminetetraacetic acid (EDTA).
In some embodiments, the disodium EDTA is provided at least or
about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%,
0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or more
than 4% by weight (wt. %). In some embodiments, the disodium EDTA
is provided in a range of about 0.25% to about 10%, about 0.1% to
about 2.5%, about 0.5% to about 8%, about 0.75% to about 6%, or
about 1% to about 4% by weight. In some embodiments, the disodium
EDTA is provided in a range of about 0.001% to about 6%, about
0.002% to about 4%, about 0.01% to about 3%, or about 0.02% to
about 2% by weight.
[0162] The carrier preferably has a pH of between about 4.0 and
10.0, more preferably between about 4.8 and about 7.8, more
preferably between about 5.0 to about 6.5. The pH may be controlled
using buffer solutions or other pH modifying agents. Suitable pH
modifying agents include phosphoric acid and/or phosphate salts,
citric acid and/or citrate salts, hydroxide salts (i.e., calcium
hydroxide, sodium hydroxide, potassium hydroxide) and amines, such
as triethanolamine. Suitable buffer solutions include a buffer
comprising a solution of monopotassium phosphate and dipotassium
phosphate, maintaining a pH of between 5.8 and 8; and a buffer
comprising a solution of monosodium phosphate and disodium
phosphate, maintaining a pH of between 6 and 7.5. Other buffers
include citric acid/sodium citrate, and dibasic sodium
phosphate/citric acid. The peptide compositions of the embodiments
are preferably isotonic with the blood or other body fluid of the
recipient. The isotonicity of the compositions can be attained
using sodium tartrate, propylene glycol or other inorganic or
organic solutes. Sodium chloride is particularly preferred.
Buffering agents can be employed, such as acetic acid and salts,
citric acid and salts, boric acid and salts, and phosphoric acid
and salts. It can be desirable to include a reducing agent in the
composition, such as vitamin C, vitamin E, or other reducing agents
as are known in the pharmaceutical arts.
[0163] Surfactants can also be employed as excipients, for example,
anionic detergents such as sodium lauryl sulfate, dioctyl sodium
sulfosuccinate and dioctyl sodium sulfonate, cationic such as
benzalkonium chloride or benzethonium chloride, or nonionic
detergents such as polyoxyethylene hydrogenated castor oil,
glycerol monostearate, polysorbates, sucrose fatty acid ester,
methyl cellulose, or carboxymethyl cellulose.
[0164] In certain embodiments, it can be advantageous to include
additional agents having pharmacological activity. Anti-infective
agents include, but are not limited to, anthelmintic (mebendazole),
antibiotics including aminoglycosides (gentamicin, neomycin,
tobramycin), antifungal antibiotics (amphotericin b, fluconazole,
griseofulvin, itraconazole, ketoconazole, nystatin, micatin,
tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime,
ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam
antibiotics (cefotetan, meropenem), chloramphenicol, macrolides
(azithromycin, clarithromycin, erythromycin), penicillins
(penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin,
nafcillin, piperacillin, ticarcillin), tetracyclines (doxycycline,
minocycline, tetracycline), bacitracin, clindamycin, colistimethate
sodium, polymyxin b sulfate, vancomycin, antivirals including
acyclovir, amantadine, didanosine, efavirenz, foscarnet,
ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir,
saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine,
quinolones (ciprofloxacin, levofloxacin), sulfonamides
(sulfadiazine, sulfisoxazole), sulfones (dapsone), furazolidone,
metronidazole, pentamidine, sulfanilamidum crystallinum,
gatifloxacin, and sulfamethoxazole/trimethoprim. Anesthetics can
include, but are not limited to, ethanol, bupivacaine,
chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine,
ropivacaine, tetracaine, desflurane, isoflurane, ketamine,
propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine,
meperidine, methadone, morphine, oxycodone, remifentanil,
sufentanil, butorphanol, nalbuphine, tramadol, benzocaine,
dibucaine, ethyl chloride, xylocaine, and phenazopyridine.
Anti-inflammatory agents include but are not limited to,
nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin,
celecoxib, choline magnesium trisalicylate, diclofenac potassium,
diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid,
nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam,
rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids
such as cortisone, hydrocortisone, methylprednisolone, prednisone,
prednisolone, betamethesone, beclomethasone dipropionate,
budesonide, dexamethasone sodium phosphate, flunisolide,
fluticasone propionate, triamcinolone acetonide, betamethasone,
fluocinonide, betamethasone dipropionate, betamethasone valerate,
desonide, desoximetasone, fluocinolone, triamcinolone, clobetasol
propionate, and dexamethasone.
[0165] In certain embodiments, the addition of emollients, emulsion
stabilizers, moisturizers, excipients, and other compounds may be
modified to enhance the sensory properties of the topical
compositions, including but not limited to: skin feel (silkiness,
lightness, creaminess, etc.), absorbency (required time at which
product loses wet feel and is no longer perceived on skin),
consistency, firmness, spreadability (e.g. viscosity, flow onset,
shear rates), stickiness, integrity of shape, glossiness,
hydrophilicity or hydrophobicity, and others. Preferably,
compositions will have high spreadability and low viscosity
properties. Compositions with such properties have been
demonstrated to have an enhanced "silky" or "light" skin feel
rating (see e.g. Bekker, M. Webber, G., Louw, N. Relating
rheological measurements to primary and secondary skin feeling when
mineral-based and Fischer-Tropsch wax-based cosmetic emulsions and
jellies are applied to the skin, International Journal of Cosmetic
Science 2013, 35(4), pp. 354-61).
[0166] In some embodiments, compositions comprise phenoxyethanol,
ethylhexylglycerin, or combinations thereof. In some embodiments,
phenoxyethanol is provided at least or about 0.05%, 0.10%, 0.25%,
0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%,
5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or more than 10% by weight
(wt. %). In some embodiments, phenoxyethanol is provided in a range
of about 0.25% to about 10%, about 0.5% to about 8%, about 0.75% to
about 6%, or about 1% to about 4% by weight. In some embodiments,
ethylhexylglycerin is provided at least or about 0.05%, 0.10%,
0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%,
4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or more than 10%
by weight (wt. %). In some embodiments, ethylhexylglycerin is
provided in a range of about 0.25% to about 10%, about 0.5% to
about 8%, about 0.75% to about 6%, or about 1% to about 4% by
weight. In some embodiments, phenoxyethanol and ethylhexylglycerin
are provided at least or about 0.05%, 0.10%, 0.25%, 0.50%, 0.75%,
1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%,
6.5%, 7.0%, 8%, 9%, 10%, or more than 10% by weight (wt. %). In
some embodiments, phenoxyethanol and ethylhexylglycerin are
provided in a range of about 0.25% to about 10%, about 0.1% to
about 4%, about 0.5% to about 8%, about 0.75% to about 6%, or about
1% to about 4% by weight.
[0167] In some embodiments, compositions comprise polyacrylate-13,
polyisobutene, polysorbate 20, or combinations thereof. In some
embodiments, polyacrylate-13 is provided at least or about 0.05%,
0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%,
4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or more than
10% by weight (wt. %). In some embodiments, polyacrylate-13 is
provided in a range of about 0.25% to about 10%, about 0.5% to
about 8%, about 0.75% to about 6%, or about 1% to about 4% by
weight. In some embodiments, polyisobutene is provided at least or
about 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%,
or more than 10% by weight (wt. %). In some embodiments,
polyisobutene is provided in a range of about 0.25% to about 10%,
about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to
about 4% by weight. In some embodiments, polyacrylate-13 is
provided in a range of about 0.25% to about 10%, about 0.5% to
about 8%, about 0.75% to about 6%, or about 1% to about 4% by
weight. In some embodiments, polysorbate 20 is provided at least or
about 0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%,
or more than 10% by weight (wt. %). In some embodiments,
polysorbate 20 is provided in a range of about 0.25% to about 10%,
about 0.5% to about 8%, about 0.75% to about 6%, or about 1% to
about 4% by weight. In some embodiments, polyacrylate-13,
polyisobutene, and polysorbate 20 are provided at least or about
0.05%, 0.10%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or
more than 10% by weight (wt. %). In some embodiments,
polyacrylate-13, polyisobutene, and polysorbate 20 are provided in
a range of about 0.25% to about 10%, about 0.1% to about 4%, about
0.5% to about 8%, about 0.75% to about 6%, or about 1% to about 4%
by weight (wt. %).
[0168] In some embodiments, compositions as described herein
comprise potassium sorbate. In some embodiments, the potassium
sorbate is provided at least or about 0.001%, 0.00175%, 0.0025%,
0.005%, 0.01%, 0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%,
1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%,
6.5%, 7.0%, 8%, 9%, 10%, or more than 10% by weight (wt. %). In
some embodiments, the potassium sorbate is provided in a range of
about 0.001% to about 6%, about 0.002% to about 4%, about 0.01% to
about 3%, or about 0.02% to about 2% by weight.
[0169] In some embodiments, the liposomes comprise propanediol,
lecithin, or a combination thereof. In some embodiments, the
propanediol is provided at least or about 0.001%, 0.005%, 0.01%,
0.02%, 0.05%, 0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%,
2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%,
10%, or more than 10% by weight (wt. %). In some embodiments, the
propanediol is provided in a range of about 0.001% to about 6%,
about 0.002% to about 4%, about 0.01% to about 3%, or about 0.02%
to about 2% by weight. In some embodiments, the lecithin is
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or
more than 10% by weight (wt. %). In some embodiments, the lecithin
is provided in a range of about 0.001% to about 6%, about 0.002% to
about 4%, about 0.01% to about 3%, or about 0.02% to about 2% by
weight. In some embodiments, the liposomes comprise propanediol and
lecithin. In some embodiments, the propanediol and lecithin are
provided at least or about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%,
0.10%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 8%, 9%, 10%, or
more than 10% by weight (wt. %). In some embodiments, the
propanediol and lecithin are provided in a range of about 0.001% to
about 6%, about 0.002% to about 4%, about 0.01% to about 3%, or
about 0.02% to about 2% by weight. In some embodiments, the
propanediol and lecithin are provided at about 0.90% by weight.
[0170] The topical composition may contain micelles, or an
aggregate of surfactant molecules dispersed in an aqueous solution.
Micelles may be prepared by dispersing an oil solvent in an aqueous
solution comprising a surfactant, where the surfactant
concentration exceeds the critical micelle concentration. The
resulting composition contains micelles, i.e., spherical oil
droplets
[0171] Penetration Enhancers
[0172] Fatty acids and alcohols can be employed to enhance
penetration of the peptides, and to provide a silky feel to
compositions, e.g., methanoic acid, ethanoic acid, propanoic acid,
butanoic acid, isobutyric acid, pentanoic acid, hexanoic acid,
heptanoic acid, octanoic acid, nonanoic acid, decanoic acid,
myristoleic acid, isovaleric acid, palmitoleic acid, sapienic acid,
oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic
acid, .alpha.-linolenic acid, arachidonic acid, eicosapentaenoic
acid, erucic acid, docosahexaenoic acid, caprylic acid, capric
acid, lauric acid, palmitic acid, stearic acid, arachidic acid,
behenic acid, lignoceric acid, cerotic acid, medium chain fatty
acids, e.g., C6-12 fatty acids, or the like. Typical amounts when
employed in compositions are from 1% by weight to 4% by weight.
[0173] Antimicrobial Efficacy
[0174] Described herein, in some embodiments, are chemically and
physically stable compositions at physiological pH. In some
embodiments, the compositions are sterile and safe for human
administration. In some embodiments, the compositions comply with
or pass the required antimicrobial efficacy tests such as the
Antimicrobial Effectiveness Test. In some embodiments, the
compositions result in complete or substantially complete
eradication of bacteria, yeast, mold, or combinations thereof.
Therapeutic Uses
[0175] Described herein are compositions and methods for improving
bruising. Bruising can be caused by a variety of sources. In some
embodiments, bruising is a result of surgery, laser treatment, or
trauma. In some embodiments, bruising is a result of a cosmetic
procedure. In some embodiments, bruising is a result of a medical
procedure. In some embodiments, the compositions and methods
described herein improve bruising prior to or after a cosmetic
procedure, a medical procedure, or a trauma.
[0176] Also described herein are compositions and methods for
stimulation of increased collagen, elastin, fat, or hyaluronic
acid. In some embodiments, the stimulation is adjunct to an
injection of a soft tissue filler.
[0177] In some embodiments, the cosmetic procedure comprises a
cosmetic surgery. Exemplary cosmetic surgeries include, but are not
limited to, forehead lift, cheek enhancement, otoplasty,
rhytidectomy, lower rhytidectomy, cheek reduction, mentoplasty,
blepharoplasty, facial implant, nose surgery, skin excision, skin
biopsy, invasive cellulite treatment, injection of a filler, and
injection of an injectable such as Botox.RTM., Dysport.RTM., or
Xeomin.RTM..
[0178] In some embodiments, the cosmetic procedure comprises
injection of a filler. In some embodiments, the filler is a soft
tissue filler product. For example, the soft tissue filler is an
injectable dermal or subdermal filler. In some embodiments, the
filler is a breast augmentation or reconstruction filler, a lip
filler, or filler suitable for other soft tissue restoration or
augmentation. In some embodiments, the filler is dermal filler. In
some instances, the dermal filler is administered through injection
into or beneath the skin of a subject.
[0179] In some embodiments, the cosmetic procedure comprises
injection of an injectable such as Botox.RTM., Dysport.RTM., or
Xeomin.RTM..
[0180] In some embodiments, the cosmetic procedure is
microneedling. In some instances, the cosmetic procedure is
radiofrequency microneedling. In some instances, the cosmetic
procedure is a chemical peel. In some instances, the cosmetic
procedure is microdermabrasion.
[0181] In some embodiments, the cosmetic procedure comprises
cellulite reduction or enzymatic (collagenase) or mechanical
disruption of fascial bands.
[0182] Bruising, in some instances, is caused by an invasive
procedure. In some instances, the invasive procedure comprises use
of an invasive laser or surgery. In some instances, bruising is
caused by a non-invasive procedure. In some instances, the
non-invasive procedure comprises non-surgical skin tightening,
non-surgical fat reduction, or use of a non-invasive laser. In some
instances, the procedure is a body-shaping or body-contouring
procedure. Exemplary body-shaping or body-contouring procedures
include, but are not limited to, high frequency focused ultrasound,
pulsed focus ultrasound, cryolipolysis, radiofrequency induced
electroporation, injectable lipolytic agents, and liposuction. In
some embodiments, the procedure is a fat reduction procedure. The
fat reduction procedure may be low level laser therapy, infrared
light, ultrasound, radiofrequency, or cryolipolysis. In some
instances, the procedure comprises an energy source. In some
instances, the energy source is electromagnetic energy. In some
instances, the procedure is high intensity focused electro-magnetic
technology (HIFEM).
[0183] In some embodiments, the medical procedure comprises
therapeutic injections, placement of intravenous (IV) lines, or
invasive surgery.
[0184] In some embodiments, the medical procedure comprises
procedures to reduce visibility of veins. In some embodiments, the
visible vein is a varicose vein. Exemplary procedures to reduce
visibility of veins include, but are not limited to, post vein
sclerotherapy, laser treatment, endovenous laser therapy (EVLT),
radiofrequency ablation (RFA), catheter-assisted procedures using
radiofrequency or laser energy, high ligation and vein stripping,
ambulatory phlebectomy, and endoscopic vein surgery.
[0185] Bruising may be caused by various factors. In some
embodiments, bruising is caused by trauma. In some instances,
bruising is caused by an injury, contusion, strain, sprain,
dislocation, broken bone, tom tendon, or muscle swelling resulting
in bruising. In some instances, bruising is caused by a medication,
herb, or supplement. In some instances, bruising is caused by a
vitamin deficiency. In some cases, bruising is caused by
malnutrition. In some embodiments, bruising is a result of an
underlying disease or disorder. Exemplary diseases or disorders
that can result in bruising include, but are not limited to,
Cushing's syndrome, thrombocytopenia, leukemia, Von Willebrand
disease, hemophilia A, hemophilia B, Factor VII deficiency, Factor
X deficiency, Factor V deficiency, Factor II deficiency, varicose
veins, and deep vein thrombosis.
[0186] In some embodiments, bruising resulting from a trauma occurs
in a subject more prone to bruising. In some embodiments, the
subject more prone to bruising is an elderly individual having
capillary fragility. In some embodiments, the subject more prone to
bruising is taking a medication having a side effect of increasing
the propensity to bruise.
[0187] Described herein are methods and compositions for improving
various types of bruises. In some embodiments, the bruise is a
nonpalpable (macular) purpura. In some embodiments, the bruise is a
palpable (papular) purpura. In some embodiments, the bruise is a
nonthrombocytopenic purpura. In some embodiments, the bruise is a
thrombocytopenic purpura. In some embodiments, the bruise is senile
purpura.
[0188] Described herein are methods and compositions for improving
various types of bruises in an elderly individual. In some
embodiments, the elderly individual has chronic skin fragility. In
some embodiments, the elderly individual has dermatoporosis. In
some embodiments, the elderly individual has a nonpalpable
(macular) purpura, a palpable (papular) purpura, a
nonthrombocytopenic purpura, a thrombocytopenic purpura, or a
senile purpura. In some embodiments, the elderly individual has a
senile purpura.
[0189] Methods and compositions as described herein may improve
bruising following a cosmetic procedure. In some embodiments,
methods and compositions improve bruising prior to a cosmetic
procedure. In some instances, bruising is caused by red blood
cells. Generally, red blood cells efficiently bind oxygen from the
atmosphere, deliver it to the tissues, and help remove carbon
dioxide. In some instances, red blood cells are involved in
pathophysiologic problems with hemorrhage and extravasation of
these cells into the tissue. Once outside the vascular system, red
blood cells can quickly burst releasing free hemoglobin (Hb). That
Hb may be prone to spontaneous oxidation and may be converted to
higher oxidation states such as ferrylHb which have potent
pro-inflammatory and pro-oxidant effects. See Jeney V, Eaton J W,
Balla G, Balla J. Natural history of the bruise: formation,
elimination, and biological effects of oxidized hemoglobin.
Oxidative medicine and cellular longevity. 2013; 2013:703571. The
heme that is released may be phagocytosed by macrophages. Following
internalization by the macrophage, heme is cleaved into biliverdin,
carbon monoxide, and iron. This mechanism can provide effective
elimination of Hb, but it also assures iron recycling for new
erythropoiesis (new red blood cell formation) under normal
circumstances. See Jeney V, Eaton J W, Balla G, Balla J. Natural
history of the bruise: formation, elimination, and biological
effects of oxidized hemoglobin. Oxidative medicine and cellular
longevity. 2013; 2013:703571. In some instances, leaving the
byproducts of bleeding around for too long runs the risk of the
pro-inflammatory effects. In some instances, these effects
interfere with wound healing, promote pigmentation, or are
unsightly. In some instances, delayed bruising results. See
Sadeghpour M, Dover J S. Understanding Delayed Bruising After
Hyaluronic Acid Injections: Why the Molecule and Not Just the
Injection Matters--letters and communications. Dermatol Surg. 2019;
45(3):471-473. Compositions and methods as described herein, in
some embodiments, improve bruising by removing by-products of red
blood cell extravasation more efficiently. In some embodiments,
compositions described herein result in improving function of
macrophages.
[0190] Compositions as described herein comprising lactoferrin,
phosphatidylserine, tripeptide-1, hexapeptide-12, hexapeptide-11,
Arnica montana extract, Ledum palustre, or combinations thereof, in
some embodiments, improve bruising. Lactoferrin is a plasmin
inhibitor with high iron binding capacity and can aid in clearing
lysed red blood cells and their constituents. Lactoferrin can block
plasminogen activation on the cell surface by direct binding to
human plasminogen, decreasing conversion to plasmin. Lactoferrin
also has anti-microbial activity. See Zwirzitz A, Reiter M,
Skrabana R, et al. Lactoferrin is a natural inhibitor of
plasminogen activation. Journal of Biological Chemistry. 2018;
293(22):8600-8613.
[0191] Compositions as described herein, in some embodiments,
improve bruising by improving healing or appearance of the bruise.
In some embodiments, the compositions improve bruising by
accelerating resolution of the bruise. For example, the
compositions accelerate the transition of blue coloration to red
coloration of the bruise. In some embodiments, improved appearance
of the bruise comprises reduced size of the bruise. In some
embodiments, improved appearance of the bruise comprises reduced
discoloration of the skin. In some embodiments, improved appearance
of the bruise comprises reduced swelling. In some embodiments, the
compositions as described herein improve bruising by at least or
about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, 95%, or more than 95%. In some
embodiments, the compositions as described herein improve bruising
by at least or about 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times..
[0192] Compositions described herein may improve bruising by
improving macrophage function. In some embodiments, macrophage
function comprises phagocytosis. In some embodiments, compositions
as described herein improve macrophage phagocytosis by at least or
about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, 95%, or more than 95%. In some
embodiments, compositions as described herein improve macrophage
phagocytosis by at least or about 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 3.5.times.,
4.0.times., 5.0.times., 6.0.times., 7.0.times., 8.0.times.,
9.0.times., 10.times., or more than 10.times..
[0193] Compositions and methods as described herein may result in
elastin and/or collagen stimulation. Elastin is an assembly of
microfibrils and tropoelastin (or soluble elastin). Elastin fibers
are formed first by the synthesis of fibrillin microfibers which
intertwine and then associate with tropoelastin (TE) protein
molecules. TE molecules are bound together and cross linked
together with fibrillin fibers by lysyl oxidase like enzyme 1
(LOXL1). The generated complex is then presented to the fibroblast
by Fibulin 5 (FBLN5) which connects the complex to integrins that
connect to the fibroblast. See Ashcroft, G. et al. Age-related
Changes in the Temporal and Spatial Distributions of Fibrillin and
Elastin mRNAs and Protein in Acute Cutaneous Wounds of Healthy
Humans, Journal of Pathology. 1997; 183:80-89; Cenizo V,
Andre{acute over ( )} V, Reymermier C, Sommer P, Damour O, E. P.
LOXL as a target to increase the elastin content in adult skin: a
dill extract induces the LOXL gene expression. Experimental
dermatology. 2006; 15:574-581; Noblesse E, Cenizo V, Bouez C, et
al. Lysyl oxidase-like and lysyl oxidase are present in the dermis
and epidermis of a skin equivalent and in human skin and are
associated to elastic fibers. The Journal of investigative
dermatology. 2004; 122(3):621-630.
[0194] In some embodiments, elastin and/or collagen stimulation is
a result of the compositions as described herein. In some
embodiments, palmitoyl tripeptide-1 and palmitoyl hexapeptide-12
clear the extracellular matrix of aggregated fragmented collagen
and elastin and then stimulate increased new collagen and elastin
production. See Widgerow A D, Fabi S G, Palestine R F, et al.
Extracellular Matrix Modulation: Optimizing Skin Care and
Rejuvenation Procedures. journal of drugs in dermatology. 2016;
15(4s):S63-S71; Widgerow A. TOPICAL SKIN RESTORATION
TECHNOLOGY--ADVANCES IN AGE MANAGEMENT STRATEGIES. MODERN
AESTHETICS. 2016(May/June):1-8. In some embodiments, acetyl
tetrapeptide-2 increases FBLN5 and LOXL1 protein levels, resulting
in an increase in elastin synthesis. In some instances, acetyl
tetrapeptide-2 upregulates genes related to Collagen 1 synthesis.
Acetyl tetrapetide-2 can reduce parameters linked to skin
flaccidity and dermal disorganization in vivo. See Product
monograph: Uplevity.TM.. Lipotec. June 2013.
[0195] In some embodiments, Anethum graveolens (dill extract)
improves elastin and/or collagen stimulation by producing a
reinduction of LOXL synthesis. See Cenizo V, Andre{acute over ( )}
V, Reymermier C, Sommer P, Damour O, E. P. LOXL as a target to
increase the elastin content in adult skin: a dill extract induces
the LOXL gene expression. Experimental dermatology. 2006;
15:574-581. While microfibrils and soluble elastin continue to be
synthesized throughout life, LOXL dramatically decreases from the
age of 18. Increased levels of LOXL in the skin cause the assembly
of microfibrils and tropoelastin, leading to improved mechanical
properties of the skin. Id. Elastogenesis mainly occurs until the
end of the second decade of the life, although the global content
of skin elastin can increase after that, the nature of this elastin
protein is often suboptimal and dysfunctional. See Ashcroft, G. et
al. Age-related Changes in the Temporal and Spatial Distributions
of Fibrillin and Elastin mRNAs and Protein in Acute Cutaneous
Wounds of Healthy Humans, Journal of Pathology. 1997; 183:80-89.
After this period, the elastin gene and fibrillin-1 gene are still
active throughout the life although elastogenesis becomes low or
inefficient. See Cenizo V, Andre{acute over ( )} V, Reymermier C,
Sommer P, Damour O, E. P. LOXL as a target to increase the elastin
content in adult skin: a dill extract induces the LOXL gene
expression. Experimental dermatology. 2006; 15:574-581. LOXL, which
declines after the first decades of life, has been shown to
stimulate elastogenesis and maintain elastic fibers homeostasis.
Id.; Noblesse E, Cenizo V, Bouez C, et al. Lysyl oxidase-like and
lysyl oxidase are present in the dermis and epidermis of a skin
equivalent and in human skin and are associated to elastic fibers.
The Journal of investigative dermatology. 2004; 122(3):621-630; Liu
X, Zhao Y, Gao J, et al. Elastic fiber homeostasis requires lysyl
oxidase-like 1 protein. Nat Genet. 2004; 36(2):178-182. In some
instances, dill extract increases the expression of LOXL in
fibroblasts and in the skin engineering models and to de novo
elastogenesis in vivo. See Cenizo V, Andre{acute over ( )} V,
Reymermier C, Sommer P, Damour O, E. P. LOXL as a target to
increase the elastin content in adult skin: a dill extract induces
the LOXL gene expression. Experimental dermatology. 2006;
15:574-581.
[0196] In some embodiments, the compositions as described herein
stimulate elastin production by at least or about 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, or more than 95%. In some embodiments, the compositions
as described herein stimulate elastin production by at least or
about 0.5.times., 1.0.times., 1.5.times., 2.0.times., 2.5.times.,
3.0.times., 3.5.times., 4.0.times., 5.0.times., 6.0.times.,
7.0.times., 8.0.times., 9.0.times., 10.times., or more than
10.times.. In some embodiments, the compositions as described
herein stimulate collagen production by at least or about 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,
85%, 90%, 95%, or more than 95%. In some embodiments, the
compositions as described herein stimulate collagen production by
at least or about 0.5.times., 1.0.times., 1.5.times., 2.0.times.,
2.5.times., 3.0.times., 3.5.times., 4.0.times., 5.0.times.,
6.0.times., 7.0.times., 8.0.times., 9.0.times., 10.times., or more
than 10.times..
[0197] Compositions and methods as described herein, in some
embodiments, simulate intrinsic hyaluronic acid (HA) production.
Compositions and methods as described herein can improve high
molecular weight HA penetration of the skin to the dermis. In some
embodiments, compositions comprising hydroxymethoxyphenyl decanone,
Tremella fuciformis extract, lactoferrin, sodium hyaluronate
crosspolymer, phosphatidylserine, or combinations thereof stimulate
intrinsic hyaluronic acid production.
[0198] In some embodiments, hydroxymethoxyphenyl decanone
stimulates intrinsic hyaluronic acid production.
Hydroxymethoxyphenyl decanone is a potent hyaluronic acid booster,
antioxidant and anti-irritant and has been demonstrated to
stimulate the dermal and epidermal hyaluronic acid level by 259%
and 198% versus placebo, respectively in ex vivo human skin model.
See Product monograph: Symdecanox, Symrise June 2015.
[0199] In some embodiments, Tremella fuciformis extract stimulates
intrinsic hyaluronic acid production. In some embodiments, Tremella
fuciformis provides high levels of moisture and anti-oxidant
properties. See Li H, Lee H S, Kim S H, Moon B, Lee C. Antioxidant
and anti-inflammatory activities of methanol extracts of Tremella
fuciformis and its major phenolic acids. J Food Sci. 2014;
79(4):C460-468; Liao W C, Hsueh C Y, Chan C F. Antioxidative
activity, moisture retention, film formation, and viscosity
stability of Auricularia fuscosuccinea, white strain water extract.
Biosci Biotechnol Biochem. 2014; 78(6):1029-1036.
[0200] In some embodiments, sodium hyaluronate crosspolymer
stimulates intrinsic hyaluronic acid production. Sodium hyaluronate
crosspolymer is a chemically crosslinked hyaluronic acid derived
from a non-animal source with high water-binding capacity. Sodium
hyaluronate crosspolymer can function as a scavenger of damaging
free radicals. Sodium hyaluronate crosspolymer comprises a gel
structure with gel domains that hold tightly bound water, which can
form a film on the skin and delivers water over time. In some
embodiments, sodium hyaluronate crosspolymer comprises fifty (50)
times the water binding capacity of hyaluronic acid.
[0201] In some embodiments, the compositions as described herein
stimulate intrinsic hyaluronic acid production by at least or about
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 95%, or more than 95%. In some embodiments, the
compositions as described herein stimulate intrinsic hyaluronic
acid production by at least or about 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 3.5.times.,
4.0.times., 5.0.times., 6.0.times., 7.0.times., 8.0.times.,
9.0.times., 10.times., or more than 10.times..
[0202] Described herein are compositions and methods for
stimulating adipogenesis. In some embodiments, fillers stimulate
new adipose formation by mechanical stimulation of adipose stem
cells in the dermal white adipose tissue layer. See Kruglikov I L,
Wollina U. Soft tissue fillers as non-specific modulators of
adipogenesis: change of the paradigm? Experimental dermatology.
2015; 24(12):912-915. In some embodiments, compositions comprising
acetyl hexapeptide-38 stimulate adipogenesis. Hexapeptide-38 is a
PGC1a stimulator (peroxisome proliferator-activated
receptor-gamma--PPAR.gamma.--coactivator 1 alpha). PGC1a plays a
central role in adipogenic activity. See Liang H, Ward W F.
PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ.
2006; 30(4):145-151. Compositions and methods as described herein
may comprise a phospholipid delivery system to facilitate
penetration and absorption of the materials through the stratum
corneum. PGC1a strongly induces in differentiation of preadipocytes
into white adipocytes under the influence of PPAR.gamma.. The young
adipocytes formed under these conditions appear to be small and
active, and this size and activity have been seen to be synergistic
and in line with good elastin formation. See Ezure T, Amano S.
Increment of subcutaneous adipose tissue is associated with
decrease of elastic fibres in the dermal layer. Exp Dermatol. 2015;
24(12):924-929. As such, large, mature adipocytes have been
associated with diminished elastin-manifesting as aged sagging
skin--whereas younger, smaller, newly synthesized adipocytes are
accompanied by increased elastin levels.
[0203] In some embodiments, the compositions as described herein
stimulate adipogenesis by at least or about 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,
95%, or more than 95%. In some embodiments, the compositions as
described herein stimulate adipogenesis by at least or about
0.5.times., 1.0.times., 1.5.times., 2.0.times., 2.5.times.,
3.0.times., 3.5.times., 4.0.times., 5.0.times., 6.0.times.,
7.0.times., 8.0.times., 9.0.times., 10.times., or more than
10.times..
[0204] Described herein are compositions and methods resulting in
reduced inflammation. Compositions and methods, in some
embodiments, comprising phytoene, phytofluene, xylitol, or
combinations thereof comprise anti-inflammatory effects.
[0205] In some embodiments, the compositions as described herein
reduce inflammation by at least or about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or
more than 95%. In some embodiments, the compositions as described
herein reduce inflammation by at least or about 0.5.times.,
1.0.times., 1.5.times., 2.0.times., 2.5.times., 3.0.times.,
3.5.times., 4.0.times., 5.0.times., 6.0.times., 7.0.times.,
8.0.times., 9.0.times., 10.times., or more than 10.times..
[0206] Improvements in bruising, elastin and/or collagen
simulation, hyaluronic acid stimulation, adipocyte stimulation,
anti-inflammatory effects, or a combination thereof may be
determined by comparison to a control. In some embodiments, the
control is no treatment. In some embodiments, the control is
vehicle treatment. In some embodiments, improvements are measured
in a subject who received treatment with a composition described
herein on a first portion of the body and vehicle or no treatment
on a second portion of the body. For example, improvements are
compared between a right arm that is treated with a composition as
described herein and a left arm that received vehicle
treatment.
[0207] Treatment
[0208] Compositions as described herein may be used with various
treatment regimens. In some instances, the topical compositions
described herein are administered once per day, twice per day,
three times per day or more. In some instances, the topical
compositions described herein are administered twice per day. The
topical compositions described herein, in some embodiments, are
administered daily, every day, every alternate day, five days a
week, once a week, every other week, two weeks per month, three
weeks per month, once a month, twice a month, three times per
month, or more. In some embodiments, the topical compositions
described herein are administered twice daily, e.g., morning and
evening. In some embodiments, the topical compositions described
herein are administered for at least 1 day, 2 days, 3 days, 4 days,
5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3
months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months,
10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4
years, 5 years, 10 years, or more. In some embodiments, the topical
compositions described herein are administered twice daily for at
least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3
months, 4 months, 5 months, 6 months, or more. In some embodiments,
the topical compositions described herein are administered once
daily, twice daily, three times daily, four times daily, or more
than four times daily for at least or about 1 week, 2 weeks, 3
weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months,
or more.
[0209] In some embodiments, the compositions described herein are
used in conjunction with a cosmetic procedure. In some embodiments,
the cosmetic procedure comprises injection of a filler.
[0210] Compositions as described herein when administered prior to,
during, or following injection of a filler may improve bruising,
elastin and/or collagen simulation, hyaluronic acid stimulation,
adipocyte stimulation, anti-inflammatory effects, or a combination
thereof. In some instances, the compositions as described herein
improve bruising, elastin and/or collagen simulation, hyaluronic
acid stimulation, adipocyte stimulation, anti-inflammatory effects,
or a combination thereof by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95%
as compared to a control. In some embodiments, the compositions as
described herein improve bruising, elastin and/or collagen
simulation, hyaluronic acid stimulation, adipocyte stimulation,
anti-inflammatory effects, or a combination thereof by at least or
about 0.5.times., 1.0.times., 1.5.times., 2.0.times., 2.5.times.,
3.0.times., 3.5.times., 4.0.times., 5.0.times., 6.0.times.,
7.0.times., 8.0.times., 9.0.times., 10.times., or more than
10.times.. In some embodiments, the compositions as described
herein improve bruising, elastin and/or collagen simulation,
hyaluronic acid stimulation, adipocyte stimulation,
anti-inflammatory effects, or a combination thereof following 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3
weeks, 1 month, 2 months, or more than 2 months following use of
the compositions.
[0211] Compositions as described herein used in conjunction with
injection of a filler, in some embodiments, improve bruising,
elastin and/or collagen simulation, hyaluronic acid stimulation,
adipocyte stimulation, anti-inflammatory effects, or a combination
thereof following the injection of the filler. In some embodiments,
the compositions as described herein improve bruising, elastin
and/or collagen simulation, hyaluronic acid stimulation, adipocyte
stimulation, anti-inflammatory effects, or a combination thereof by
at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95%. In some
embodiments, the compositions as described herein improve bruising,
elastin and/or collagen simulation, hyaluronic acid stimulation,
adipocyte stimulation, anti-inflammatory effects, or a combination
thereof by at least or about 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times..
[0212] In some instances, the compositions described herein are
administered up to 1 day, up to 2 days, up to 3 days, up to 5 days,
up to 6 days, up to 1 week, up to 2 weeks, up to 3 weeks, or more
than 3 weeks prior to injection of a filler. In some instances, the
compositions described herein are administered immediately prior to
injection of a filler, up to 1 hour, up to 2 hours, up to 3 hours,
up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to
12 hours, up to 16 hours, up to 20 hours, or up to 24 hours prior
to injection of a filler. Sometimes the compositions described
herein are administered singly, or over a time course, such as
daily, multiple times weekly, weekly, biweekly, monthly or less
frequently prior to injection of a filler. In some instances, the
compositions described herein are administered singly, or over a
time course, such as daily, multiple times weekly, weekly,
biweekly, monthly or more frequently prior to injection of a
filler. In some embodiments, the compositions are topical
compositions. In some instances, the topical compositions are
administered twice daily for at least or about 1 week, 2 weeks, 3
weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months,
or more prior to injection of a filler. In some embodiments, the
topical compositions described herein are administered once daily,
twice daily, three times daily, four times daily, or more than four
times daily for at least or about 1 week, 2 weeks, 3 weeks, 1
month, 2 months, 3 months, 4 months, 5 months, 6 months, or more
prior to injection of a filler.
[0213] In some instances, the compositions described herein are
administered up to 1 day, up to 2 days, up to 3 days, up to 5 days,
up to 6 days, up to 1 week, up to 2 weeks, up to 3 weeks, or more
than 3 weeks prior to a medical or cosmetic procedure described
herein or a trauma. In some instances, the compositions described
herein are administered immediately prior to the procedure or
trauma, up to 1 hour, up to 2 hours, up to 3 hours, up to 5 hours,
up to 6 hours, up to 7 hours, up to 8 hours, up to 12 hours, up to
16 hours, up to 20 hours, or up to 24 hours prior to the procedure
or trauma. Sometimes the compositions described herein are
administered singly, or over a time course, such as daily, multiple
times weekly, weekly, biweekly, monthly or less frequently prior to
the procedure or trauma. In some instances, the compositions
described herein are administered singly, or over a time course,
such as daily, multiple times weekly, weekly, biweekly, monthly or
more frequently prior to the procedure or trauma. In some
embodiments, the compositions are topical compositions. In some
instances, the topical compositions are administered twice daily
for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months,
3 months, 4 months, 5 months, 6 months, or more the procedure or
trauma. In some embodiments, the topical compositions described
herein are administered once daily, twice daily, three times daily,
four times daily, or more than four times daily for at least or
about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4
months, 5 months, 6 months, or more prior to the procedure or
trauma.
[0214] In some instances, the compositions described herein are
administered up to 1 day, up to 2 days, up to 3 days, up to 5 days,
up to 6 days, up to 1 week, up to 2 weeks, up to 3 weeks, or more
than 3 weeks following injection of a filler. In some instances,
the compositions described herein are administered immediately
following injection of a filler, up to 1 hour, up to 2 hours, up to
3 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8
hours, up to 12 hours, up to 16 hours, up to 20 hours, or up to 24
hours following injection of a filler. Sometimes the compositions
described herein are administered singly, or over a time course,
such as daily, multiple times weekly, weekly, biweekly, monthly or
less frequently following injection of a filler. In some instances,
the compositions described herein are administered singly, or over
a time course, such as daily, multiple times weekly, weekly,
biweekly, monthly or more frequently following injection of a
filler. In some embodiments, the compositions are topical
compositions. In some instances, the topical compositions are
administered twice daily for at least or about 1 week, 2 weeks, 3
weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months,
or more following injection of a filler. In some embodiments, the
topical compositions described herein are administered once daily,
twice daily, three times daily, four times daily, or more than four
times daily for at least or about 1 week, 2 weeks, 3 weeks, 1
month, 2 months, 3 months, 4 months, 5 months, 6 months, or more
following injection of a filler.
[0215] In some instances, the compositions described herein are
administered up to 1 day, up to 2 days, up to 3 days, up to 5 days,
up to 6 days, up to 1 week, up to 2 weeks, up to 3 weeks, or more
than 3 weeks following a medical or cosmetic procedure described
herein or a trauma. In some instances, the compositions described
herein are administered immediately following the procedure or
trauma, up to 1 hour, up to 2 hours, up to 3 hours, up to 5 hours,
up to 6 hours, up to 7 hours, up to 8 hours, up to 12 hours, up to
16 hours, up to 20 hours, or up to 24 hours following the procedure
or trauma. Sometimes the compositions described herein are
administered singly, or over a time course, such as daily, multiple
times weekly, weekly, biweekly, monthly or less frequently
following the procedure or trauma. In some instances, the
compositions described herein are administered singly, or over a
time course, such as daily, multiple times weekly, weekly,
biweekly, monthly or more frequently following the procedure or
trauma. In some embodiments, the compositions are topical
compositions. In some instances, the topical compositions are
administered twice daily for at least or about 1 week, 2 weeks, 3
weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months,
or more the procedure or trauma. In some embodiments, the topical
compositions described herein are administered once daily, twice
daily, three times daily, four times daily, or more than four times
daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, or more following
the procedure or trauma.
Stability Testing
[0216] Stability testing of the compositions can be conducted as
follows.
[0217] High temperature testing is now commonly used as a predictor
of long-term stability. High temperature testing can be conducted
at 37.degree. C. (98.degree. F.) and 45.degree. C. (113.degree.
F.). If a product is stored at 45.degree. C. for three months (and
exhibits acceptable stability) then it should be stable at room
temperature for two years. A good control temperature is 4.degree.
C. (39.degree. F.) where most products will exhibit excellent
stability. Sometime, the product is also be subjected to
-10.degree. C. (14.degree. F.) for three months.
[0218] In some instances, stability of the product is assessed by
passing three cycles of temperature testing from -10.degree. C.
(14.degree. F.) to 25.degree. C. (77.degree. F.). In such cases,
the product is placed at -10.degree. C. for 24 hours and then
placed at room temperature (25.degree. C.) for 24 hours. This
completes one cycle. An even more rigorous test is a -10.degree. C.
to 45.degree. C. five-cycle test. This puts emulsions under a
tremendous stress.
[0219] The dispersed phase (of an oil-in-water emulsion) has a
tendency to separate and rise to the top of the emulsion forming a
layer of oil droplets. This phenomenon is called creaming. Creaming
is one of the first signs of impending emulsion instability. A test
method to predict creaming is centrifugation. Heat the emulsion to
50.degree. C. (122.degree. F.) and centrifuge it for thirty minutes
at 3000 rpm. Then inspect the resultant product for signs of
creaming.
[0220] Both formulas and packaging can be sensitive to the UV
radiation. The product is placed in glass and the actual package in
a light box that has a broad-spectrum output. Another glass jar
completely covered with aluminum foil serves as a control.
Discoloration of the product may be observed.
[0221] For all the above mentioned tests the color, odor/fragrance,
viscosity, pH value, and, if available, particle size uniformity
and/or particle agglomeration under the microscope can be
observed.
Kits for Non-Invasive Use and Use with Invasive Procedures
[0222] Some embodiments of the methods and compositions provided
herein include kits comprising peptides provided herein. In some
embodiments, kits can be provided to an administering physician,
other health care professional, a patient, or a caregiver. In some
embodiments, a kit comprises a container which contains the peptide
compositions in a suitable topical composition, and instructions
for administering the peptide composition to a subject. The kit can
optionally also contain one or more additional therapeutic or other
agents. For example, a kit containing a peptide composition in
topical form can be provided along with other skin care agents,
such as, cleansers, occlusive moisturizers, penetrating
moisturizers, sunscreens, sunblocks, and the like. The kit may
contain the peptide composition in bulk form, or can contain
separate doses of the peptide composition for serial or sequential
administration. The kit can optionally contain one or more
diagnostic tools, administration tools, and/or instructions for
use. The kit can contain suitable delivery devices, such as,
syringes, pump dispensers, single dose packets, and the like, along
with instructions for administering the peptide compositions and
any other therapeutic or beneficial agents. The kit can optionally
contain instructions for storage, reconstitution (if applicable),
and administration of any or all therapeutic or beneficial agents
included. The kits can include a plurality of containers reflecting
the number of administrations to be given to a subject, or the
different products to be administered to the subject.
[0223] In some embodiments, the composition is configured to
support the skin before, during and after cosmetic procedures, and
also works with the skin's own natural regenerating process and
assists in improving the skin's appearance, and skin tightness. The
topical composition can be applied immediately post-procedure for
faster recovery, or generally for healthier looking skin. The
composition can increase natural levels of elastin in the skin,
improves the quality of existing elastin, stimulates increase in
collagen production, and exhibits high antioxidant activity to
reduce inflammation, redness and irritation. The topical
composition is suitable for all skin types and post-procedure skin.
The topical compositions can be provided to the patient in bulk
form, to permit a suitable amount of the peptides to be
self-administered by the patient. For example, the patient can
apply an amount of the composition sufficient to provide an even
coating over the affected area or as otherwise instructed by the
physician. In certain embodiments it can desirable to incorporate
additional therapeutic or active agents into the topical
composition. Alternatively, adjunct therapies or agents can be
administered separately. For example, a cleanser, a sunblock, a
sunscreen, a penetrating moisturizer, and/or an occlusive
moisturizer can be provided for administration before or after the
topical composition of the embodiments.
[0224] In one embodiment, a kit is provided for use in connection
with a cosmetic skin procedure, as described herein. The kit may
include a topical peptide composition, an occlusive moisturizer, a
gentle cleanser, a penetrating moisturizer, and a broad spectrum
SPF 30+ sunscreen.
[0225] The various examples of creams, ointments, lotions,
solutions, gels, sprays and patches may incorporate the peptide
compositions as described herein as the active ingredient, in
combination with penetration enhancing agents and other active
agents acting synergistically on the skin for the promotion of
wound healing or wound closure or the treatment of chronic
cutaneous wound.
Numbered Embodiments
[0226] Numbered embodiment 1 comprises a topical composition for
improving bruising following injection of a filler comprising: one
or more ingredients encapsulated in a liposome a tripeptide-1; and
a hexapeptide-12, wherein the topical composition improves healing
or appearance of a bruise following injection of the filler.
Numbered embodiment 2 comprises the topical composition of numbered
embodiment 1, wherein the tripeptide-1 is present at 1-10 ppm.
Numbered embodiment 3 comprises the topical composition of numbered
embodiments 1-2, wherein the tripeptide-1 comprises palmitoyl
tripeptide-1, myristoyl tripeptide-1, or a combination thereof.
Numbered embodiment 4 comprises the topical composition of numbered
embodiments 1-3, wherein the hexapeptide-12 comprises palmitoyl
hexapeptide-12, myristoyl hexapeptide-12, or a combination thereof.
Numbered embodiment 5 comprises the topical composition of numbered
embodiments 1-4, wherein the hexapeptide-12 is present at 1-10 ppm.
Numbered embodiment 6 comprises the topical composition of numbered
embodiments 1-5, wherein a first ingredient of the one or more
ingredients encapsulated in the liposome is hexapeptide-11.
Numbered embodiment 7 comprises the topical composition of numbered
embodiments 1-6, wherein the hexapeptide-11 is present at 50-150
ppm. Numbered embodiment 8 comprises the topical composition of
numbered embodiments 1-7, wherein a second ingredient of the one or
more ingredients encapsulated in the liposome is hexapeptide-38.
Numbered embodiment 9 comprises the topical composition of numbered
embodiments 1-8, wherein the hexapeptide-38 is acetyl
hexapeptide-38. Numbered embodiment 10 comprises the topical
composition of numbered embodiments 1-9, further comprising a
tetrapeptide. Numbered embodiment 11 comprises the topical
composition of numbered embodiments 1-10, wherein the tetrapeptide
is tetrapeptide-2. Numbered embodiment 12 comprises the topical
composition of numbered embodiments 1-11, wherein the
tetrapeptide-2 is acetyl tetrapeptide-2. Numbered embodiment 13
comprises the topical composition of numbered embodiments 1-12,
further comprising phosphatidylserine. Numbered embodiment 14
comprises the topical composition of numbered embodiments 1-13,
wherein the phosphatidylserine is present at no more than 0.050% by
weight (wt. %). Numbered embodiment 15 comprises the topical
composition of numbered embodiments 1-14, wherein the
phosphatidylserine is present in a range of about 0.005 wt. % to
about 0.1 wt. %. Numbered embodiment 16 comprises the topical
composition of numbered embodiments 1-15, wherein the
phosphatidylserine is present at no more than 5.0 wt %. Numbered
embodiment 17 comprises the topical composition of numbered
embodiments 1-16, wherein the phosphatidylserine is present at 0.1
wt %. Numbered embodiment 18 comprises the topical composition of
numbered embodiments 1-17, wherein a third ingredient of the one or
more ingredients encapsulated in the liposome is lactoferrin.
Numbered embodiment 19 comprises the topical composition of
numbered embodiments 1-18, wherein the lactoferrin is present at no
more than 0.050 wt. %. Numbered embodiment 20 comprises the topical
composition of numbered embodiments 1-19 wherein the lactoferrin is
present in a range of about 0.005 wt. % to about 0.1 wt. %.
Numbered embodiment 21 comprises the topical composition of
numbered embodiments 1-20, wherein the lactoferrin is present at no
more than 5.0 wt %. Numbered embodiment 22 comprises the topical
composition of numbered embodiments 1-21, further comprising Ledum
palustre extract. Numbered embodiment 23 comprises the topical
composition of numbered embodiments 1-22, wherein the Ledum
palustre extract is present in a range of about 0.1 wt. % to about
2.5 wt. %. Numbered embodiment 24 comprises the topical composition
of numbered embodiments 1-23, further comprising dill extract.
Numbered embodiment 25 comprises the topical composition of
numbered embodiments 1-24, wherein the dill extract is present in a
range of about 0.01 wt. % to about 2.5 wt. %. Numbered embodiment
26 comprises the topical composition of numbered embodiments 1-25,
further comprising hydroxymethoxyphenyl decanone. Numbered
embodiment 27 comprises the topical composition of numbered
embodiments 1-26 wherein the hydroxymethoxyphenyl decanone is
present in a range of about 0.001 wt. % to about 2.5 wt. %.
Numbered embodiment 28 comprises the topical composition of
numbered embodiments 1-27, further comprising Tremella fuciformis
extract. Numbered embodiment 29 comprises the topical composition
of numbered embodiments 1-28, wherein the Tremella fuciformis
extract is present in a range of about 0.001 wt. % to about 2.5 wt.
%. Numbered embodiment 30 comprises the topical composition of
numbered embodiments 1-29, further comprising sodium hyaluronate
crosspolymer. Numbered embodiment 31 comprises the topical
composition of numbered embodiments 1-30, wherein the sodium
hyaluronate crosspolymer is present in a range of about 0.0001 wt.
% to about 2.5 wt. %. Numbered embodiment 32 comprises the topical
composition of numbered embodiments 1-31, further comprising
xylitylglucoside, anhydroxylitol, xylitol, or combinations thereof.
Numbered embodiment 33 comprises the topical composition of
numbered embodiments 1-32, wherein the xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof is present in a
range of about 0.25 wt. % to about 5 wt. %. Numbered embodiment 34
comprises the topical composition of numbered embodiments 1-33,
further comprising butylene glycol, glycerin, squalane, Dunaliella
salina extract, phospholipids, tocopherol, ascorbyl palmitate,
xanthan gum, betaine, propanediol, lecithin, caprylic/capric
triglyceride, caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, or
combinations thereof. Numbered embodiment 35 comprises the topical
composition of numbered embodiments 1-34, wherein the topical
composition is aqueous. Numbered embodiment 36 comprises the
topical composition of numbered embodiments 1-35, wherein a
viscosity of the topical composition is in a range of about 8,000
centipoise (cps) to about 30,000 cps. Numbered embodiment 37
comprises the topical composition of numbered embodiments 1-36,
wherein the filler is a soft tissue filler. Numbered embodiment 38
comprises the topical composition of numbered embodiments 1-37,
wherein the filler is a dermal filler. Numbered embodiment 39
comprises a topical composition for improving bruising comprising:
one or more ingredients encapsulated in a liposome, wherein a first
ingredient of the one or more ingredients encapsulated in the
liposome is hexapeptide-11; a tripeptide-1; and a hexapeptide-12,
wherein the topical composition improves healing or appearance of a
bruise. Numbered embodiment 40 comprises the topical composition of
numbered embodiments 1-39, wherein the tripeptide-1 is present at
1-10 ppm. Numbered embodiment 41 comprises the topical composition
of numbered embodiments 1-40, wherein the tripeptide-1 comprises
palmitoyl tripeptide-1, myristoyl tripeptide-1, or a combination
thereof. Numbered embodiment 42 comprises the topical composition
of numbered embodiments 1-41, wherein the hexapeptide-12 comprises
palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a
combination thereof. Numbered embodiment 43 comprises the topical
composition of numbered embodiments 1-42, wherein the
hexapeptide-12 is present at 1-10 ppm. Numbered embodiment 44
comprises the topical composition of numbered embodiments 1-43,
wherein the hexapeptide-11 is present at 50-150 ppm. Numbered
embodiment 45 comprises the topical composition of numbered
embodiments 1-44, wherein a second ingredient of the one or more
ingredients encapsulated in the liposome is hexapeptide-38.
Numbered embodiment 46 comprises the topical composition of
numbered embodiments 1-45, wherein the hexapeptide-38 is acetyl
hexapeptide-38. Numbered embodiment 47 comprises the topical
composition of numbered embodiments 1-46, further comprising a
tetrapeptide. Numbered embodiment 49 comprises the topical
composition of numbered embodiments 1-48, wherein the tetrapeptide
is tetrapeptide-2. Numbered embodiment 50 comprises the topical
composition of numbered embodiments 1-49, wherein the
tetrapeptide-2 is acetyl tetrapeptide-2. Numbered embodiment 51
comprises the topical composition of numbered embodiments 1-50,
further comprising phosphatidylserine. Numbered embodiment 52
comprises the topical composition of numbered embodiments 1-51,
wherein the phosphatidylserine is present at no more than 0.050% by
weight (wt. %). Numbered embodiment 53 comprises the topical
composition of numbered embodiments 1-52, wherein the
phosphatidylserine is present in a range of about 0.005 wt. % to
about 0.1 wt. %. Numbered embodiment 54 comprises the topical
composition of numbered embodiments 1-53, wherein the
phosphatidylserine is present at no more than 5.0 wt %. Numbered
embodiment 55 comprises the topical composition of numbered
embodiments 1-54, wherein the phosphatidylserine is present at 0.1
wt %. Numbered embodiment 56 comprises the topical composition of
numbered embodiments 1-55, wherein a third ingredient of the one or
more ingredients encapsulated in the liposome is lactoferrin.
Numbered embodiment 57 comprises the topical composition of
numbered embodiments 1-56, wherein the lactoferrin is present at no
more than 0.050 wt. %. Numbered embodiment 58 comprises the topical
composition of numbered embodiments 1-57, wherein the lactoferrin
is present in a range of about 0.005 wt. % to about 0.1 wt. %.
Numbered embodiment 59 comprises the topical composition of
numbered embodiments 1-58, wherein the lactoferrin is present at no
more than 5.0 wt %. Numbered embodiment 60 comprises the topical
composition of numbered embodiments 1-59, further comprising Ledum
palustre extract. Numbered embodiment 61 comprises the topical
composition of numbered embodiments 1-60, wherein the Ledum
palustre extract is present in a range of about 0.1 wt. % to about
2.5 wt. %. Numbered embodiment 62 comprises the topical composition
of numbered embodiments 1-61, further comprising dill extract.
Numbered embodiment 63 comprises the topical composition of
numbered embodiments 1-62, wherein the dill extract is present in a
range of about 0.01 wt. % to about 2.5 wt. %. Numbered embodiment
64 comprises the topical composition of numbered embodiments 1-63,
further comprising hydroxymethoxyphenyl decanone. Numbered
embodiment 65 comprises the topical composition of numbered
embodiments 1-64, wherein the hydroxymethoxyphenyl decanone is
present in a range of about 0.001 wt. % to about 2.5 wt. %.
Numbered embodiment 66 comprises the topical composition of
numbered embodiments 1-65, further comprising Tremella fuciformis
extract. Numbered embodiment 67 comprises the topical composition
of numbered embodiments 1-66, wherein the Tremella fuciformis
extract is present in a range of about 0.001 wt. % to about 2.5 wt.
%. Numbered embodiment 68 comprises the topical composition of
numbered embodiments 1-67, further comprising sodium hyaluronate
crosspolymer. Numbered embodiment 69 comprises the topical
composition of numbered embodiments 1-68, wherein the sodium
hyaluronate crosspolymer is present in a range of about 0.0001 wt.
% to about 2.5 wt. %. Numbered embodiment 70 comprises the topical
composition of numbered embodiments 1-69, further comprising
xylitylglucoside, anhydroxylitol, xylitol, or combinations thereof.
Numbered embodiment 71 comprises the topical composition of
numbered embodiments 1-70, wherein the xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof is present in a
range of about 0.25 wt. % to about 5 wt. %. Numbered embodiment 72
comprises the topical composition of numbered embodiments 1-71,
further comprising butylene glycol, glycerin, squalane, Dunaliella
salina extract, phospholipids, tocopherol, ascorbyl palmitate,
xanthan gum, betaine, propanediol, lecithin, caprylic/capric
triglyceride, caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, or
combinations thereof. Numbered embodiment 73 comprises the topical
composition of numbered embodiments 1-72, wherein the topical
composition is aqueous. Numbered embodiment 74 comprises the
topical composition of numbered embodiments 1-73, wherein a
viscosity of the topical composition is in a range of about 8,000
centipoise (cps) to about 30,000 cps. Numbered embodiment 75
comprises the topical composition of numbered embodiments 1-74,
wherein the bruise appears following a cosmetic procedure. Numbered
embodiment 76 comprises the topical composition of numbered
embodiments 1-75, wherein the cosmetic procedure is an injection of
a filler. Numbered embodiment 77 comprises the topical composition
of numbered embodiments 1-76, wherein the cosmetic procedure is an
injection of a neurotoxin. Numbered embodiment 781 comprises the
topical composition of numbered embodiments 1-77, wherein the
cosmetic procedure is an invasive surgery. Numbered embodiment 79
comprises the topical composition of numbered embodiments 1-78,
wherein the bruise appears following a medical procedure. Numbered
embodiment 80 comprises the topical composition of numbered
embodiments 1-79, wherein the medical procedure is a therapeutic
injection. Numbered embodiment 81 comprises the topical composition
of numbered embodiments 1-80, wherein the medical procedure is an
intravenous injection. Numbered embodiment 82 comprises the topical
composition of numbered embodiments 1-81, wherein the medical
procedure is an invasive surgery. Numbered embodiment 83 comprises
the topical composition of numbered embodiments 1-82, wherein the
bruise appears following a trauma. Numbered embodiments 84
comprises a topical composition for rejuvenating skin comprising a
liposome encapsulating: one or more peptides; and lactoferrin,
wherein the topical composition rejuvenates skin. Numbered
embodiment 85 comprises the topical composition of numbered
embodiments 1-84, further comprising tripeptide-1. Numbered
embodiment 86 comprises the topical composition of numbered
embodiments 1-85, wherein the tripeptide is tripeptide-1. Numbered
embodiment 87 comprises the topical composition of numbered
embodiments 1-86, wherein the tripeptide-1 is present at 1-10 ppm.
Numbered embodiment 88 comprises the topical composition of
numbered embodiments 1-87, wherein the tripeptide-1 comprises
palmitoyl tripeptide-1, myristoyl tripeptide-1, or a combination
thereof. Numbered embodiment 89 comprises the topical composition
of numbered embodiments 1-88, further comprising hexapeptide-12.
Numbered embodiment 90 comprises the topical composition of
numbered embodiments 1-89, wherein the hexapeptide-12 comprises
palmitoyl hexapeptide-12, myristoyl hexapeptide-12, or a
combination thereof. Numbered embodiment 91 comprises the topical
composition of numbered embodiments 1-90, wherein the
hexapeptide-12 is present at 1-10 ppm. Numbered embodiment 92
comprises the topical composition of numbered embodiments 1-91,
wherein a first peptide of the one or more peptides comprises
hexapeptide-11. Numbered embodiment 93 comprises the topical
composition of numbered embodiments 1-92, wherein the
hexapeptide-11 is present at 50-150 ppm. Numbered embodiment 94
comprises the topical composition of numbered embodiments 1-93,
wherein a second peptide of the one or more peptides comprises
hexapeptide-38. Numbered embodiment 95 comprises the topical
composition of numbered embodiments 1-94, wherein the
hexapeptide-38 is acetyl hexapeptide-38. Numbered embodiment 96
comprises the topical composition of numbered embodiments 1-95,
further comprising a tetrapeptide. Numbered embodiment 97 comprises
the topical composition of numbered embodiments 1-96, wherein the
tetrapeptide is tetrapeptide-2. Numbered embodiment 948 comprises
the topical composition of numbered embodiments 1-97, wherein the
tetrapeptide-2 is acetyl tetrapeptide-2. Numbered embodiment 99
comprises the topical composition of numbered embodiments 1-98,
further comprising phosphatidylserine. Numbered embodiment 100
comprises the topical composition of numbered embodiments 1-99,
wherein the phosphatidylserine is present at no more than 0.050% by
weight (wt. %). Numbered embodiment 101 comprises the topical
composition of numbered embodiments 1-100, wherein the
phosphatidylserine is present in a range of about 0.005 wt. % to
about 0.1 wt. %. Numbered embodiment 102 comprises the topical
composition of numbered embodiments 1-101, wherein the
phosphatidylserine is present at no more than 5.0 wt %. Numbered
embodiment 103 comprises the topical composition of numbered
embodiments 1-102, wherein the phosphatidylserine is present at 0.1
wt %. Numbered embodiment 104 comprises the topical composition of
numbered embodiments 1-103, wherein the lactoferrin is present at
no more than 0.050 wt. %. Numbered embodiment 105 comprises the
topical composition of numbered embodiments 1-104, wherein the
lactoferrin is present in a range
of about 0.005 wt. % to about 0.1 wt. %. Numbered embodiment 106
comprises the topical composition of numbered embodiments 1-105,
wherein the lactoferrin is present at no more than 5.0 wt %.
Numbered embodiment 107 comprises the topical composition of
numbered embodiments 1-106, further comprising
Ledum palustre extract. Numbered embodiment 108 comprises the
topical composition of numbered embodiments 1-107, wherein the
Ledum palustre extract is present in a range of about 0.1 wt. % to
about 2.5 wt. %. Numbered embodiment 109 comprises the topical
composition of numbered embodiments 1-108, further comprising dill
extract. Numbered embodiment 110 comprises the topical composition
of numbered embodiments 1-109, wherein the dill extract is present
in a range of about 0.01 wt. % to about 2.5 wt. %. Numbered
embodiment 111 comprises the topical composition of numbered
embodiments 1-110, further comprising hydroxymethoxyphenyl
decanone. Numbered embodiment 112 comprises the topical composition
of numbered embodiments 1-111, wherein the hydroxymethoxyphenyl
decanone is present in a range of about 0.001 wt. % to about 2.5
wt. %. Numbered embodiment 113 comprises the topical composition of
numbered embodiments 1-112, further comprising Tremella fuciformis
extract. Numbered embodiment 114 comprises the topical composition
of numbered embodiments 1-113, wherein the Tremella fuciformis
extract is present in a range of about 0.001 wt. % to about 2.5 wt.
%. Numbered embodiment 115 comprises the topical composition of
numbered embodiments 1-114, further comprising sodium hyaluronate
crosspolymer. Numbered embodiment 116 comprises the topical
composition of numbered embodiments 1-114, wherein the sodium
hyaluronate crosspolymer is present in a range of about 0.0001 wt.
% to about 2.5 wt. %. Numbered embodiment 116 comprises the topical
composition of numbered embodiments 1-115, further comprising
xylitylglucoside, anhydroxylitol, xylitol, or combinations thereof.
Numbered embodiment 117 comprises the topical composition of
numbered embodiments 1-116, wherein the xylitylglucoside,
anhydroxylitol, xylitol, or combinations thereof is present in a
range of about 0.25 wt. % to about 5 wt. %. Numbered embodiment 118
comprises the topical composition of numbered embodiments 1-117,
further comprising butylene glycol, glycerin, squalane, Dunaliella
salina extract, phospholipids, tocopherol, ascorbyl palmitate,
xanthan gum, betaine, propanediol, lecithin, caprylic/capric
triglyceride, caprylyl glycol, caprylyl methicone, phenoxyethanol,
ethylhexylglycerin, polyacrylate-13, polyisobutene, polysorbate 20,
caprylhydroxamic acid, disodium EDTA, Arnica Montana extract,
sorbitan isostearate, pentylene glycol, glucose, sunflower seed
oil, radish root ferment filtrate, potassium sorbate, or
combinations thereof. Numbered embodiment 119 comprises the topical
composition of numbered embodiments 1-118, wherein the topical
composition is aqueous. Numbered embodiment 120 comprises the
topical composition of numbered embodiments 1-119, wherein a
viscosity of the topical composition is in a range of about 8,000
centipoise (cps) to about 30,000 cps. Numbered embodiment 121
comprises a method for improving bruising in an individual,
comprising administering a topical composition of the numbered
embodiments 1-120. Numbered embodiment 122 comprises the method of
numbered embodiments 1-121, wherein the bruising is improved by at
least 5%, 10, 1%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
more than 90%. Numbered embodiment 123 comprises the method of
numbered embodiments 1-122, wherein the bruising is improved by at
least 0.5.times., 1.0.times., 1.5.times., 2.0.times., 2.5.times.,
3.0.times., 3.5.times., 4.0.times., 5.0.times., 6.0.times.,
7.0.times., 8.0.times., 9.0.times., 10.times., or more than
10.times.. Numbered embodiment 124 comprises the method of numbered
embodiments 1-123, wherein the bruising is improved at least 1 day
after administering the topical composition. Numbered embodiment
125 comprises the method of numbered embodiments 1-124, wherein the
bruising is improved at least 2 days after administering the
topical composition. Numbered embodiment 126 comprises the method
of numbered embodiments 1-125, wherein improvements in bruising
comprises accelerated resolution of a bruise, reduced size of a
bruise, reduced discoloration of skin, reduced swelling, or
combinations thereof. Numbered embodiment 127 comprises a method
for improving macrophage function in an individual, comprising
administering a topical composition of any one of numbered
embodiments 1-126. Numbered embodiment 128 comprises the method of
numbered embodiments 1-127, wherein the improved macrophage
function comprises improved phagocytosis. Numbered embodiment 129
comprises the method of numbered embodiments 1-128, wherein the
improved macrophage function comprises improved hemosiderin
clearance. Numbered embodiment 130 comprises the method of numbered
embodiments 1-129, wherein the macrophage function is improved by
at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
or more than 90%. Numbered embodiment 131 comprises the method of
numbered embodiments 1-130, wherein the macrophage function is
improved by at least 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times.. Numbered embodiment 132
comprises a method for stimulating production of elastin, collagen,
or a combination thereof in an individual, comprising administering
a topical composition of the numbered embodiments 1-131. Numbered
embodiment 133 comprises the method of numbered embodiments 1-132,
wherein the production of elastin, collagen, or a combination
thereof is stimulated by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, or more than 90%. Numbered embodiment 134
comprises the method of numbered embodiments 1-133, wherein the
production of elastin, collagen, or a combination thereof is
stimulated by at least 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times.. Numbered embodiment 135
comprises a method for stimulating intrinsic hyaluronic acid
production in an individual, comprising administering a topical
composition of the numbered embodiments 1-134. Numbered embodiment
136 comprises the method of numbered embodiments 1-135, wherein the
intrinsic hyaluronic acid production is stimulated by at least 5%,
10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than
90%. Numbered embodiment 137 comprises the method of numbered
embodiments 1-136, wherein the intrinsic hyaluronic acid production
is stimulated by at least 0.5.times., 1.0.times., 1.5.times.,
2.0.times., 2.5.times., 3.0.times., 3.5.times., 4.0.times.,
5.0.times., 6.0.times., 7.0.times., 8.0.times., 9.0.times.,
10.times., or more than 10.times.. Numbered embodiment 138
comprises a method for increasing adipogenesis in an individual,
comprising administering a topical composition of the numbered
embodiments 1-137. Numbered embodiment 139 comprises the method of
numbered embodiments 1-138, wherein adipogenesis is increased by at
least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
more than 90%. Numbered embodiment 140 comprises the method of
numbered embodiments 1-139, wherein adipogenesis is increased by at
least 0.5.times., 1.0.times., 1.5.times., 2.0.times., 2.5.times.,
3.0.times., 3.5.times., 4.0.times., 5.0.times., 6.0.times.,
7.0.times., 8.0.times., 9.0.times., 10.times., or more than
10.times.. Numbered embodiment 141 comprises a method for reducing
inflammation in an individual, comprising administering a topical
composition of the numbered embodiments 1-140. Numbered embodiment
142 comprises the method of numbered embodiments 1-141, wherein
inflammation is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or more than 90%. Numbered embodiment
143 comprises the method of numbered embodiments 1-142, wherein
inflammation is reduced by at least 0.5.times., 1.0.times.,
1.5.times., 2.0.times., 2.5.times., 3.0.times., 3.5.times.,
4.0.times., 5.0.times., 6.0.times., 7.0.times., 8.0.times.,
9.0.times., 10.times., or more than 10.times.. Numbered embodiment
144 comprises the method of numbered embodiments 1-143, wherein the
topical composition is administered following a cosmetic procedure.
Numbered embodiment 145 comprises the method of numbered
embodiments 1-144, wherein the topical composition is administered
prior to a cosmetic procedure. Numbered embodiment 146 comprises
the method of numbered embodiments 1-145, wherein the cosmetic
procedure comprises injection of a filler. Numbered embodiment 147
comprises the method of numbered embodiments 1-146, wherein the
filler is a soft tissue filler. Numbered embodiment 148 comprises
the method of numbered embodiments 1-147, wherein the filler is a
dermal filler. Numbered embodiment 149 comprises the method of
numbered embodiments 1-148, wherein the cosmetic procedure is a
microneedling procedure. Numbered embodiment 150 comprises the
method of numbered embodiments 1-149, wherein the microneedling
procedure is a radiofrequency microneedling procedure. Numbered
embodiment 151 comprises the method of numbered embodiments 1-150,
wherein the topical composition is administered at least 1 day
prior to the microneedling procedure. Numbered embodiment 152
comprises the method of numbered embodiments 1-151, wherein the
topical composition is administered at least 1 week prior to the
microneedling procedure. Numbered embodiment 153 comprises the
method of numbered embodiments 1-152, wherein the topical
composition is administered at least 2 weeks prior to the
microneedling procedure. Numbered embodiment 154 comprises the
method of numbered embodiments 1-153, wherein the topical
composition is administered at least 1 day following the
microneedling procedure. Numbered embodiment 155 comprises the
method of numbered embodiments 1-154, wherein the topical
composition is administered at least 1 week following the
microneedling procedure. Numbered embodiment 156 comprises the
method of numbered embodiments 1-155, wherein the topical
composition is administered at least 2 weeks following the
microneedling procedure. Numbered embodiment 157 comprises the
method of numbered embodiments 1-156, wherein the topical
composition is administered immediately prior to the injection of
the filler. Numbered embodiment 158 comprises the method of
numbered embodiments 1-157, wherein the topical composition is
administered at least 1 day prior to the injection of the filler.
Numbered embodiment 159 comprises the method of numbered
embodiments 1-158, wherein the topical composition is administered
at least 1 week prior to the injection of the filler. Numbered
embodiment 160 comprises the method of numbered embodiments 1-159,
wherein the topical composition is administered at least 2 weeks
prior to the injection of the filler. Numbered embodiment 161
comprises the method of numbered embodiments 1-160, wherein the
topical composition is administered immediately following the
injection of the filler. Numbered embodiment 162 comprises the
method of numbered embodiments 1-161, wherein the topical
composition is administered at least 1 day following the injection
of the filler. Numbered embodiment 163 comprises the method of
numbered embodiments 1-162, wherein the topical composition is
administered at least 1 week following the injection of the filler.
Numbered embodiment 164 comprises the method of numbered
embodiments 1-163, wherein the topical composition is administered
at least 2 weeks following the injection of the filler. Numbered
embodiment 165 comprises the method of numbered embodiments 1-164,
wherein the cosmetic procedure is an injection of a neurotoxin.
Numbered embodiment 166 comprises the method of numbered
embodiments 1-165, wherein the cosmetic procedure is an invasive
surgery. Numbered embodiment 167 comprises the method of numbered
embodiments 1-166, wherein the topical composition is administered
following a medical procedure. Numbered embodiment 168 comprises
the method of numbered embodiments 1-167, wherein the topical
composition is administered prior to a medical procedure. Numbered
embodiment 169 comprises the method of numbered embodiments 1-168,
wherein the medical procedure is a therapeutic injection. Numbered
embodiment 170 comprises the method of numbered embodiments 1-169,
wherein the medical procedure is an intravenous injection. Numbered
embodiment 171 comprises the method of numbered embodiments 1-170,
wherein the medical procedure is an invasive surgery. Numbered
embodiment 172 comprises the method of numbered embodiments 1-171,
wherein the topical composition is administered following a trauma.
Numbered embodiment 173 comprises the method of numbered
embodiments 1-172, wherein the topical composition is administered
prior to a trauma. Numbered embodiment 174 comprises the method of
numbered embodiments 1-173, wherein the topical composition is
administered 1, 2, 3, 4, 5, 6, 7, or 8 times a day. Numbered
embodiment 175 comprises the method of numbered embodiments 1-174,
wherein the topical composition is administered 4 times a day.
Numbered embodiment 176 comprises the method of numbered
embodiments 1-175, wherein the individual is a human.
EXAMPLES
[0227] The following examples are given for the purpose of
illustrating various embodiments of the disclosure and are not
meant to limit the present disclosure in any fashion. The present
examples, along with the methods described herein are presently
representative of preferred embodiments, are exemplary, and are not
intended as limitations on the scope of the disclosure. Changes
therein and other uses which are encompassed within the spirit of
the disclosure as defined by the scope of the claims will occur to
those skilled in the art.
Example 1: Exemplary Compositions
[0228] An exemplary composition is seen in Table 1.
TABLE-US-00001 TABLE 1 Ingredient % by wt. Butylene Glycol, Aqua,
Acetyl 0.05-1.25 Hexapeptide-38 Xylitylglucoside, Anhydroxylitol,
0.2-5 Xylitol Water, Butylene Glycol, Arnica 0.1-2.5 Montana Flower
Extract Glycerin, Palmitoyl Tripeptide-1 0.5-15 Glycerin, Palmitoyl
Hexapeptide-12 0.5-15 Hexapeptide-11 0.001-0.025 Sodium Hyaluronate
Crosspolymer 0.1-2.5 Squalane, Dunaliella Salina Extract 0.1-2.5
Ledum Palustre (Labrador Tea) Extract, 0.1-2.5 Radish Root Ferment
Filtrate Lactoferrin 0.01-0.25 Phosphatidylserine, Phospholipids,
0.02-0.5 Tocopherol, Ascorbyl Palmitate Aqua, Butylene Glycol,
Peucedanum 0.1-2.5 Graveolens (Dill) Extract, Xanthan Gum Water,
Tremella Fuciformis Sporocarp 0.1-2.5 (Silver Ear Mushroom)
Extract, Betaine, Glycerin Propanediol, Lecithin 0.4-10
Caprylic/Capric Triglyceride, 0.1-2.5 Hydroxymethoxyphenyl Decanone
Water, Acetyl Tetrapeptide-2, 0.2-5 Caprylyl Glycol Caprylic/Capric
Triglyceride 0.4-10 Caprylyl Methicone 0.1-2.5 Water/Aqua/Eau 40-90
Phenoxyethanol, Ethylhexylglycerin 0.17-4.25 Polyacrylate-13,
Polyisobutene, 0.5-12.5 Polysorbate 20 Caprylyl Glycol,
Caprylhydroxamic 0.1-2.5 Acid, Glycerin Disodium EDTA 0.02-0.5
Propanediol 0.04-1
Example 2: Macrophage Phagocytosis of Red Blood Cells
[0229] Macrophage phagocytosis of red blood cells was measured to
determine the effects of peptides and various reagents in
hemosiderin clearance.
[0230] FIG. 1A shows a schematic of the macrophage phagocytosis
assay. The assay was performed according to manufacturer's
instructions (Cell BioLabs, Inc.). Macrophages used were RAW-Difluo
mLC3 autophagy reporter cells. Human red blood cells (RBCs) were
obtained from ZenBio (catalog number SER-10MLRBC). Briefly, 24
hours before the assay, macrophages were plated on 96-well plates.
One plate was plated with 12,500 macrophages and a second plate
with 25,000 macrophages. The day of the assay, human red blood
cells (RBCs) were opsonized with human RBC antibody. As a negative
control, sheep RBCs were opsonized with human RBC antibody. The
media was then replaced with either peptide or no peptide. Blood
was added to the plates at a 200:1 RBC to macrophage ratio.
Phagocytosis was measured beginning at 2 hours after blood was
added. The media and blood were removed from the wells of the
plate. The plate was washed once with RBC lysis buffer to remove
non-phagocytosed RBCs followed by two washes with PBS. Macrophage
lysis buffer was then added to the plate and the lysed solution was
transferred to a 96-well plate. The substrate solution to detect
heme was added to the 96-well plate and absorbance was recorded at
1 minute, 5 minutes, 10, minutes, and 20 minutes. FIGS. 1B-1C show
images of macrophage phagocytosis prior to red blood cell (RBC)
washout (FIG. 1B) and after RBC washout (FIG. 1C). Arrows indicate
macrophages with RBCs (hollow circles). Macrophages without RBCs
are seen as dark central nuclei.
[0231] The assay was validated and data is seen in FIG. 2. FIG. 2
shows the following groups: no treatment positive control, no
treatment negative control, hexapeptide-11 (Hex11-Peptide),
hexapeptide-12 (Hex12-peptide), tripeptide-1 (Tri-peptide),
Oct-peptide, and blood only. The no treatment positive control
comprised macrophages and human blood (human antibody). The no
treatment negative control comprised macrophages and human blood
(sheep antibody). The peptide treatments (hexapeptide-11,
hexapeptide-12, tripeptide-1, and Oct-peptide) were done with
macrophages and human blood (human antibody). Blood only treatment
was performed with no macrophages and to assess the efficiency of
washing out RBCs. Absorbance was recorded 2 hours after RBC
addition. As seen in FIG. 2, the no treatment negative control was
half of the no treatment positive control. Further as seen in FIG.
2, the RBC wash steps removed almost all non-phagocytosed
blood.
[0232] A red blood cell (RBC) curve was performed to quantitate the
number of RBCs that are phagocytosed in an assay, which was used to
extrapolate number of RBCs from an absorbance value (FIGS. 3A-3B).
FIG. 3A shows a graph of a RBC standard curve with absorbance on
the y-axis and number of RBCs on the x-axis. FIG. 3B shows a graph
of RBC standard curve (log 2) with absorbance (log 2) on the y-axis
and number of RBCs (log 2) on the x-axis.
[0233] A time course was performed to determine at which time to
study phagocytosis. FIG. 4 shows a graph of absorbance for no
treatment control samples with absorbance on the y-axis and time
(24 hours, 48 hours, and 72 hours) on the x-axis. At 24 hours, most
red blood cells (RBCs) were phagocytosed. At 48 hours, almost all
RBCs were phagocytosed and were starting to be degraded. At 72
hours, all RBCs were phagocytosed and degraded. Therefore, 24 hours
was chosen for subsequent experiments.
[0234] Phagocytosis Following Various Treatments
[0235] Phagocytosis of red blood cells (RBCs) was performed after
various treatments. Briefly, 24 hours before the phagocytosis
assay, 25,000 macrophages were plated onto a 96-well plate. On the
day of the assay, the media was replaced with the various peptide
or compound treatments. RBCs were then added to macrophages at a
100:1 RBC to macrophage ratio. The cells were then incubated at
37.degree. C. and 5% CO.sub.2. After 24 hours the non-phagocytosed
RBCs were washed away, macrophages lysed, and heme assay substrate
added to detect absorbed RBCs/heme 15 minutes later. Concentrations
of the peptides included the following: 2.9 ug/mL of tripeptide-1,
100 ug/mL of hexapeptide-11, and 2.9 ug/mL of hexapeptide-12.
Comparisons of lactoferrin and phosphatidylserine were relative to
no treatment (NT) PBS control. Each 0.1 increment on the y-axis
demonstrates a 10% increase in efficacy of macrophage function
representing significant increase in RBC phagocytosis.
[0236] FIG. 5 shows a time course of phagocytosis following various
treatments. The treatments included the following: no treatment
(NT), tripeptide-1 (Tri), hexapeptide-11 (Hex11), hexapeptide-12
(Hex12), tripeptide-1 and hexapeptide-11 (Tri+Hex11), and
tripeptide-1, hexapeptide-11, and hexapeptide-12 (Tri+Hex11+Hex12)
A time course was performed over 24 hours (1d, black bars), 48
hours (2d, white bars), and 72 hours (3d, horizontal bars). At 24
hours, the peptide-combination treatments showed the highest
increase in phagocytosis. The 24 hour time point was used for the
experiments described below.
[0237] Effects of various peptide treatments on phagocytosis were
then determined. FIG. 6 shows the various peptide treatments on
phagocytosis including: No treatment (NT, white bars), tripeptide-1
(Tri, black bar), hexapeptide-11 (Hex11, black bar), hexapeptide-12
(Hex12, black bar), tripeptide-1 and hexapeptide-11 (Tri+Hex11,
horizontal bar), and tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12, horizontal bar). As seen in FIG.
6, peptide treatment alone (tripeptide-1, hexapeptide-11, and
hexapeptide-12) showed a decrease or no change in phagocytosis
relative to NT control. Tripeptide-1 and hexapeptide-11 treatment
as well as tripeptide-1, hexapeptide-11, and hexapeptide-12
treatment resulted in an increase in efficacy around 15%
(3.times.-4.times. change) as compared to peptide treatment alone,
demonstrating synergy of combining peptides in macrophage
phagocytosis of red blood cells and dissolution of bruising.
[0238] The effect of phosphatidylserine was also determined. FIG. 7
shows effects of No treatment (NT), tripeptide-1 (Tri),
hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1 and
hexapeptide-11 (Tri+Hex11), tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12), phosphatidylserine at 10 ug/mL
(PS_10 ug/mL), phosphatidylserine at 50 ug/mL (PS_50 ug/mL),
tripeptide-1, hexapeptide-11, hexapeptide-12, and
phosphatidylserine at 10 ug/mL (Pep_PS_10 ug/mL), tripeptide-1,
hexapeptide-11, hexapeptide-12, and phosphatidylserine at 50 ug/mL
(Pep_PS_50 ug/mL), tripeptide-1, hexapeptide-11, hexapeptide-12,
and phosphatidylserine at 100 ug/mL (Pep_PS_100 ug/mL), and
tripeptide-1, hexapeptide-11, hexapeptide-12, and
phosphatidylserine at 500 ug/mL (Pep_PS_500 ug/mL). As seen in FIG.
7, tripeptide-1, hexapeptide-11, hexapeptide-12, and
phosphatidylserine at 50 ug/mL treatment and tripeptide-1,
hexapeptide-11, hexapeptide-12, and phosphatidylserine at 500 ug/mL
treatment showed a significant increase over peptide treatment
alone. The increase of tripeptide-1, hexapeptide-11, and
hexapeptide-12 treatment was 1.15. The increase of tripeptide-1,
hexapeptide-11, hexapeptide-12, and phosphatidylserine at 50 ug/mL
treatment was 1.30. The increase of tripeptide-1, hexapeptide-11,
hexapeptide-12, and phosphatidylserine at 500 ug/mL treatment was
1.40. Tripeptide-1, hexapeptide-11, hexapeptide-12, and
phosphatidylserine at 50 ug/mL treatment as well as tripeptide-1,
hexapeptide-11, hexapeptide-12, and phosphatidylserine at 500 ug/mL
treatment resulted in a 2.times.-3.times. efficacy over peptide
treatment alone and a 4.times. efficacy over NT control.
[0239] The effects of lactoferrin were determined. FIG. 8 shows
effects of No treatment (NT), tripeptide-1 (Tri), hexapeptide-11
(Hex11), hexapeptide-12 (Hex12), tripeptide-1 and hexapeptide-11
(Tri+Hex11), tripeptide-1, hexapeptide-11, and hexapeptide-12
(Tri+Hex11+Hex12), tripeptide-1, hexapeptide-11, hexapeptide-12,
and lactoferrin at 10 ug/mL (Pep_Lac_10 ug/mL), tripeptide-1,
hexapeptide-11, hexapeptide-12, and lactoferrin at 50 ug/mL
(Pep_Lac_50 ug/mL), tripeptide-1, hexapeptide-11, hexapeptide-12,
and lactoferrin at 100 ug/mL (Pep+Lac 100 ug/mL), tripeptide-1,
hexapeptide-11, hexapeptide-12, and lactoferrin at 500 ug/mL
(Pep_Lac_500 ug/mL), tripeptide-1, hexapeptide-11, hexapeptide-12,
phosphatidylserine at 500 ug/mL and lactoferrin at 50 ug/mL
(Pep+PS+Lac50 ug/mL), tripeptide-1, hexapeptide-11, hexapeptide-12,
phosphatidylserine at 500 ug/mL and lactoferrin at 100 ug/mL
(Pep+PS+Lac100 ug/mL), and tripeptide-1, hexapeptide-11,
hexapeptide-12, phosphatidylserine at 500 ug/mL and lactoferrin at
500 ug/mL (Pep+PS+Lac500 ug/mL). As seen in FIG. 8, tripeptide-1,
hexapeptide-11, hexapeptide-12, and lactoferrin at 50 ug/mL
resulted in about 30% increase in phagocytosis relative to
tripeptide-1, hexapeptide-11, and hexapeptide-12 treatment and
45-50% (4.5-5.times. efficacy) increase over NT control. Treatment
with tripeptide-1, hexapeptide-11, hexapeptide-12, and lactoferrin
at 500 ug/mL resulted in about 20% increase in efficacy as compared
to NT control. Treatment with tripeptide-1, hexapeptide-11,
hexapeptide-12, phosphatidylserine at 500 ug/mL, and lactoferrin at
500 ug/mL also resulted in about 45% increase in efficacy as
compared to NT control.
[0240] The effects of hydroxysuccinimide were determined. FIG. 9
shows the effects of No treatment (NT), tripeptide-1 (Tri),
hexapeptide-11 (Hex11), hexapeptide-12 (Hex12), tripeptide-1 and
hexapeptide-11 (Tri+Hex11), tripeptide-1, hexapeptide-11, and
hexapeptide-12 (Tri+Hex11+Hex12), hydroxysuccinimide at 1 mg/mL
(HS_1 mg/mL), hydroxysuccinimide at 2 mg/mL (HS 2 mg/mL),
tripeptide-1, hexapeptide-11, hexapeptide-12, and
hydroxysuccinimide at 1 mg/mL (Pep_HS_1 mg/mL), and tripeptide-1,
hexapeptide-11, hexapeptide-12, and hydroxysuccinimide at 2 mg/mL
(Pep_HS_2 mg/mL). As seen in FIG. 9, hydroxysuccinimide treatments
show little to no change in phagocytosis.
[0241] The effects of tripeptide-1, hexapeptide-11, hexapeptide-12,
phosphatidylserine, and lactoferrin on phagocytosis were
determined. FIG. 10 shows the effects of No treatment (NT),
tripeptide-1 (Tri), hexapeptide-11 (Hex11), hexapeptide-12 (Hex12),
tripeptide-1 and hexapeptide-11 (Tri+Hex11), tripeptide-1,
hexapeptide-11, and hexapeptide-12 (Tri+Hex11+Hex12), tripeptide-1,
hexapeptide-11, hexapeptide-12 and phosphatidylserine at 500 ug/mL
(Pep_PS_500 ug/mL), and tripeptide-1, hexapeptide-11,
hexapeptide-12, phosphatidylserine at 500 ug/mL, and lactoferrin at
500 ug/mL (Pep+PS+Lac500 ug/mL). As seen in FIG. 10, the peptide
combination (Tri+Hex11+Hex12) resulted in an increase in efficacy
(15% increase over control). The phosphatidylserine addition
(Pep_PS_500 ug/mL) demonstrated a 30% increase over control. The
tripeptide-1, hexapeptide-11, hexapeptide-12, phosphatidylserine at
500 ug/mL, and lactoferrin at 500 ug/mL treatment resulted in about
47% increase in efficacy in macrophage phagocytosis and
approximately 300% increased efficiency over peptide combination
alone.
Example 3: Clinical Trial Evaluating Improvements in Bruising
[0242] The effects of the composition of Table 1 are evaluated in
subjects following injection of a dermal filler. Twenty subjects
are chosen to participate in the trial. Exclusion and inclusion
criteria are listed in Table 2.
TABLE-US-00002 TABLE 2 Inclusion Criteria Adult females or males,
age 25 to 65 years Subjects are seeking treatment with BOTOX .RTM.
injection Subjects have one or more moderate to severe
hyperfunctional facial lines of the upper face (i.e., glabellar
lines, lateral canthal lines (crow's feet) or horizontal forehead
lines) or moderate to severe nasolabial folds based on the
physician observer assessment (0-3 scale) Women are either of
non-childbearing potential (i.e., surgically sterilized or
post-menopausal) or if of childbearing potential, are not pregnant
(as documented by a negative urine pregnancy test at the baseline
examination) or lactating and are practicing a medically acceptable
method of birth control Subjects are willing and able to provide
written informed consent Subjects are willing and able to follow
the procedures outlined in this protocol Exclusion Criteria Female
subjects who are pregnant (positive urine pregnancy test) or who
have an infant they are breast-feeding or who are of childbearing
potential and not practicing a reliable method of birth control
Previous botulinum toxin or semipermanent injectable filler therapy
within the past year or any prior history of permanent filler
therapy injection Prior cosmetic procedures (i.e., liposuction,
etc.) or visible scars that may affect evaluation of response
and/or quality of photography Known allergy or sensitivity to any
of the study medication or their components Known severe allergies
manifested by a history of anaphylaxis or history or presence of
multiple severe allergies Diagnosis of myasthenia gravis,
Eaton-Lambert syndrome, amyotrophic lateral sclerosis or any other
disease that might interfere with neuromuscular function Concurrent
use of aminoglycoside antibiotics that interfere with neuromuscular
function Subjects with profound atrophy or excessive weakness of
the muscles in the target area(s) of BOTOX .RTM. injection Subjects
with an infection at an injection site or systemic infection (in
this case, postpone study entry until one week following recovery)
Concurrent participation in an investigational drug or device study
or participation within 30 days of study start Subjects are not to
undergo any additional cosmetic procedures during the study period
Subjects are not to change use of any facial products up to 6
months prior to enrollment and during study period Subjects with a
history of poor cooperation, non-compliance with medical treatment,
or unreliability
[0243] Each subject will receive two BOTOX.RTM. Cosmetic
injections: one on a first side of an affected facial region and a
second on a second side of the affected facial region. After two
weeks, the subjects will apply the composition of Table 1 twice
daily. Assessments are taken at 3, 4, 6, 8, and 12 weeks.
Improvements in the subjects are determined using Physician Global
Aesthetic Improvement Scale (PGAIS).
Example 4. A Multi-Center, Double-Blinded Study to Evaluate the
Efficacy and Safety of a Topical Product for the Treatment of
Bruises
[0244] The objective of this study is to evaluate the efficacy and
safety of a topical product comprising a formula as described Table
1 in dissipating a bruise compared to a bland moisturizer.
[0245] The duration of the study is 3 months. Approximately 10
subjects will be enrolled per site with up to 3 sites that are
participating. Subjects include healthy male and female subjects 18
years of age or older. The inclusion criteria and exclusion
criteria are listed in Table 3.
TABLE-US-00003 TABLE 3 Inclusion and Exclusion Criteria Inclusion
Criteria Age 18-60 years old male and female subjects willing to
receive a laser induced bruise on both sides of the inner arm
Subjects are in good health Subjects are willing, have the ability
to understand and provide informed consent, and are able to
communicate with the investigator Exclusion Criteria Pregnant or
lactating Subjects who are unable to understand the protocol or
give informed consent Subjects currently under treatment with blood
thinners or any medical treatments that in the opinion of the
Investigator would deem them not suitable for this study Subjects
who have active skin disease or skin infection in the treatment
area Subjects who have a history of abnormal bleeding or bleeding
and bruising disorders
[0246] The study will consist of a screening visit, one laser
induced procedure visit and follow-up visits on post bruise Days 2,
4, 6, 8, 10 and 14. Subjects that have opted for the biopsies will
return at a designated time-point after the initial biopsies for a
second set of biopsies. Subjects may consent for the study up to 30
days before Visit 1.
[0247] Visit 1 procedures will consist of the following: Completion
of ICF, demographics, medical/dermatological history and study
criteria confirmation. If the subject is eligible for the study,
the subject will undergo a laser procedure on the right and left
inner arm in order to induce a bruise. Standard photography will be
taken pre and post bruise formation on each arm. Subjects will be
randomized to receive either topical bruise product or bland
moisturizer on the right or left arm. Subjects will use the topical
product twice daily on the designated arm. Subjects receiving a
forearm biopsy will put the randomized designated product on the
forearm twice daily.
[0248] On follow-up Days 2, 4, 6, 8, 10 and 14, the subject will
return to the clinic and be queried for any changes in health
status since the previous visit. Subject and Investigator
assessments will be completed. Standardized photography will be
completed.
[0249] At week 2, two subjects that have opted for forearm biopsies
will return to the office for the second biopsies and then return
for stitch removal as per first biopsy.
[0250] Study measurements for efficacy include standardized
photography, biopsies, and subject satisfaction questionnaire.
Standardized photos will be taken at every visit and pre-post
procedure. These photos will be used for comparable assessment of
the bruises. Biopsies will be taken of two arbitrarily patients
that consent to a biopsy of the forearms at Visit 1 and at two
weeks post use of the topical products. The specimens will be
reviewed by a blinded dermatopathologist. Subject will rate
satisfaction with the product and delivery using the subject
satisfaction questionnaire. Further safety will be determined by
recording the number of adverse events (AE) per schedule of
events.
[0251] Measurements for efficacy include co-primary efficacy
endpoints, which comprise Global Improvement in the bruises between
arms. Secondary efficacy endpoints will also be measured. The
secondary efficacy endpoints include changes from Baseline in
dermatopathology, dermal changes from skin biopsy, and Subject
Satisfaction Questionnaire at end of study. Safety endpoints will
also be measured including incidence (severity and causality) of
any local and systemic adverse events (AEs).
Example 5. Clinical Evaluation of the Efficacy of a Topical Product
for the Treatment of Bruises Post Cosmetic Injections
[0252] The objective of this study is to evaluate the efficacy of a
topical product comprising a formula as described in Table 1 in
dissipating a bruise post cosmetic injections.
[0253] The duration of the study is 3 months. Approximately 50
subjects will be enrolled. Subjects include healthy male and female
subjects 18 years of age or older. The inclusion criteria and
exclusion criteria are listed in Table 4
TABLE-US-00004 TABLE 4 Inclusion and Exclusion Criteria Inclusion
Age 18-60 years old male and female subjects Criteria electing to
receive cosmetic injectables Subjects are in good health Subjects
are willing to understand and provide informed consent Exclusion
Pregnant or lactating Criteria Subjects who in the Investigators
opinion are not suitable for cosmetic injectables
[0254] The study will consist of a Day 1 treatment visit and
follow-up visits on Days 2, 4, 6, 8, 10 and 14. Subjects may
consent for the study up to 30 days before Day 1.
[0255] The Day 1 procedures will consist of the following:
Completion of ICF, demographics, medical/dermatological history.
The subject will undergo the elected cosmetic injectables as
decided by the Investigator and subject. Standard photography will
be taken post bruise formation. Subjects will be randomized to
apply the topical bruise product on either the left or right side
of the face. Subjects will use the topical product twice daily on
the designated bruises.
[0256] Follow-up Days 2, 4, 6, 8, 10 and 14: The subject will
return to the clinic and be queried for any changes in health
status since the previous visit. Standardized photography will be
completed of the bruises.
[0257] Study measurements include efficacy and safety measurements.
Efficacy will be determined using standardized photography and the
Subject Satisfaction Questionnaire. Standardized photos will be
taken at every visit and post procedure. These photos will be used
for comparable assessment of the bruises. Using the Subject
Satisfaction Questionnaire, the subject will rate satisfaction with
the product and delivery. Safety measurements include recording
adverse events (AE) per the schedule of events.
[0258] Study efficacy is determined using primary efficacy
endpoints and secondary efficacy endpoints. Primary efficacy
endpoints include Global Improvement in the treated bruises
compared to the non-treated. Secondary efficacy endpoints include
Subject Satisfaction Questionnaire at end of study. Safety
endpoints are also measured as incidence (severity and causality)
of any local and systemic adverse events (AEs).
Example 6. Preparation of Liposomal Compositions
[0259] A liposomal preparation was prepared according to the
schematic as seen in FIG. 11A. FIG. 11A shows the various methods
for creating liposomes including hydrosoluble ingredient
entrapment, liposoluble ingredient entrapment, and a liposoluble
and hydrosoluble ingredient entrapment. FIG. 11B shows a schematic
of liposomal formation. Liposomes were observed following the
liposome suspension process manufacturing as seen in FIG. 12.
Example 7. Efficacy of Liposomal Compositions
[0260] Efficacy of liposomal compositions was tested for
bioavailability and skin penetration.
[0261] A water suspension of liposomes was prepared with 1.5% of
hydrophilic molecule A or 300 ppm (0.03%) hydrophilic molecule B,
and 27% Pro-Lipo.TM. Neo. Molecule A was caffeine and had a
molecular weight of 194.2 g/mol and a penetration ability of log
Kow of -0.07. Molecule B was a hexapeptide (hexapeptide-38) with a
molecular weight of (870 g/mol) and a penetration ability log Kow
of -1.13. A water solution with 1.5% A or 300 ppm B was used as a
control (non-entrapped molecule).
[0262] A dose of 10 mg/cm.sup.2 was applied on skin explants using
the Franz cell method. The kinetic of the molecules passed through
skin explants was measured during 24 hours. After 24 hours, the
molecule content was measured in each skin compartment including
the stratum corneum, epidermis, dermis, and receptor fluid.
[0263] FIGS. 13A-13B show graphs of diffusion of Molecule A through
the human skin (FIG. 13A) and skin distribution of Molecule A (FIG.
13B). As seen in FIG. 13A, Molecule A formulated in liposomes was
2.5.times. more effective and 1.6.times. faster than non-entrapped
molecule. As seen in FIG. 13B, Molecule A formulated in liposomes
was 2.4.times. more efficacious at total bioavailability after 24
hours. Molecule B formulated in liposomes also exhibited increased
bioavailability as seen as a 2.5.times. increase in skin
distribution of Molecule B after 24 hours (FIG. 13C).
Example 8. Particle Size of Liposomal Acetyl Hexapeptide 38
[0264] The particle size of liposomal acetyl hexapeptide 38 was
determined.
[0265] 100 uL of liposomal acetyl hexapeptide 38 was dissolved in
15 mL of water. Assay information can be seen in Table 5 for two
experiments.
TABLE-US-00005 TABLE 5 Experiment 1 Experiment 2 Material RI 1.59
1.59 Material Absorption 0.010 0.010 Dispersant Name Water Water
Dispersant RI 1.330 1.330 Viscosity (cP) 0.8872 0.8872 Temperature
(.degree. C.) 25 25 Count Rate (kcps) 149.1 149.1 Cell Description
Disposable Disposable sizing sizing cuvette cuvette Duration Used
(s) 80 80 Measurement 4.65 4.65 position (mm) Attenuator 7 7
[0266] Results from the experiments can be seen in Tables 6-8 and
FIGS. 14A-14D.
TABLE-US-00006 TABLE 6 PdI refers to polydispersity index and the
intercept refers to amplitude. Experiment 1 Experiment 2 Z-Average
(d.nm) 184.7 184.7 PdI 0.168 0.168 Intercept 0.961 0.961
TABLE-US-00007 TABLE 7 Experiment 1 Experiment 2 Diam. % In- Width
Diam. % In- Width (nm) tensity (nm) (nm) tensity (nm) Peak 211.4
99.4 88.24 205.5 98.3 100.4 1 Peak 5026 0.6 594.1 5228 1.7 752.1 2
Peak 0.000 0.0 0.000 0.000 0.0 0.000 3
TABLE-US-00008 TABLE 8 INTENSITY-WEIGHTED CUMULANT NNLS RESULTS
RESULTS PEAK OF PEAK Z-AVERAGE INTEREST WIDTH (nm) PDI (nm) (nm)
Liposomal 184.7 0.17 211.4 88.24 Acetyl Hexapeptide 38
[0267] As seen in Tables 6-8 and FIGS. 14A-14D, a liposomal acetyl
hexapeptide-38 composition was generated with a particle size of
184.7 nanometers (nm).
Example 9. Exemplary Formulations
[0268] Exemplary liposomal formulation is seen in Table 9.
TABLE-US-00009 TABLE 9 Ingredient % by wt. Water/Aqua/Eau, 50-95
Glycerin 0.5-9 Caprylic/Capric Triglyceride 1-9 Propanediol 0.01-5
Polyacrylate-13 0.5-6 Lactoferrin 0.01-1 Phosphatidylserine 0.01-1
Ledum Palustre (Labrador Tea) Extract 0.1-2.5 Arnica Montana Flower
Extract 0.0001-1 Palmitoyl Hexapeptide-12 0.0001-1 Palmitoyl
Tripeptide-1 0.0001-1 Hexapeptide-11 0.00500 Acetyl Hexapeptide-38
0.0001-1 Acetyl Tetrapeptide-2 0.0001-1 Sodium Hyaluronate
Crosspolymer 0.0001-2.5 Tremella Fuciformis Sporocarp 0.001-2.5
(Silver Ear Mushroom) Extract Peucedanum Graveolens (Dill) Extract
0.01-2.5 Hydroxymethoxyphenyl Decanone 0.001-0.1 Dunaliella Salina
Extract 0.001-0.5 Betaine 0.01-0.5 Phospholipids 0.01-1
Xylitylglucoside 0.1-2 Squalane 0.1-0.8 Caprylyl Glycol 0.1-0.5
Anhydroxylitol 0.1-1.5 Polysorbate 20 0.01-0.5 Xylitol 0.1-0.5
Butylene Glycol 0.1-2 Sorbitan Isostearate 0.1-1 Ethylhexylglycerin
0.01-1 Caprylhydroxamic Acid 0.05-0.5 Ascorbyl Palmitate 0.001-0.1
Xanthan Gum 0.01-0.8 Pentylene Glycol 0.01-0.8 Glucose 0.01-0.8
Helianthus Annuus (Sunflower) Seed Oil 0.001-0.5 Tocopherol
0.001-0.8 Leuconostoc/Radish Root Ferment Filtrate 0.01-0.8
Potassium Sorbate 0.001-0.5 Caprylyl Methicone 0.1-0.8
Polyisobutene 0.1-.8 Lecithin 0.1-1 Disodium EDTA 0.1-1
Phenoxyethanol 0.1-2
Example 10. In Vivo Testing of Bruising Resolution
[0269] Study Design
[0270] A 2-center, randomized, double-blind study was undertaken to
assess the efficacy and safety of a topical product formulated to
increase the elimination of blood products that manifest as a
bruise. This study investigated the ability of the topical product
comprising a formula as described in Table 9 to improve the
appearance of a bruise compared to a bland moisturizer. 18 subjects
were recruited the study and 16 subjects (32 bruises) completed the
study.
[0271] Eligible subjects received an induced bruise on both arms
via mechanical disruption, venipuncture, of a vessel as in a blood
draw (1 group) or via removal of blood and re-injection of 0.1 mL
subdermally in the proximal inner forearm just distal to the
antecubital fossa.
[0272] Subjects were randomized to receive the topical product and
bland moisturizer to use on the designated arm at a minimum of four
times daily. One arm received the topical product on the bruise
four times a day, and the other arm received the bland moisturizer
(Cetaphil lotion) four times a day. Subjects were screened and
underwent procedural (Day 0) visit and follow-up visits at days 1,
2, 3, 6, and 7. Two subjects consented to have a biopsy on the
forearm at Day 0, pre-treatment, and at day 12/20 post procedure.
Skin colorimetry (Skin ColorCatch) was performed in triplicate at
each visit and clinical change of bruises documented through
photography.
[0273] Assessed endpoints included global Improvement in the
appearance of bruises between arms with comparison in Skin Color
Catch measurements.
[0274] Results
[0275] 18 subjects were recruited the study, and 16 subjects (32
bruises) completed the study as two subjects were withdrawn from
analysis as they did not complete the study with sufficient data
points. Objective assessment using colorimetry (SkinColorCatch,
Delfin technologies, Kuopio, Finland) was performed. Measurement of
the intensity of the blue/yellow channel was undertaken at all time
points. This score was then compared with the baseline score prior
to bruise creation and the delta between blue intensity and
original clear skin was compared among the two groups and provided
information of bruise resolution. In order to ensure equivalence of
both groups, the scores immediately post bruising were determined
to be comparable as demonstrated in FIG. 15A.
[0276] The 2 models showed slight variation. Subdermal injection
manifested bruising slightly later; thus day 3 and 7 in this group
was equivalent to day 2 and 6 in the blood draw group. The data
demonstrated that the `tipping point` occurred at day 2/3, where
the color intensity of the experimental study product was
significantly improved over the comparator. 81% of subjects
applying the topical product had less bruising at Day 2/3 compared
to the bland moisturizer, and there was a 72% improvement in purple
intensity score, demonstrating that the topical product hastened
resolution of bruising as seen in FIGS. 15A-15G.
[0277] As seen in FIGS. 15A-15G, in many cases a transition from
blue to red was observed in the experimental group receiving the
topical product prior to resolution (e.g., day 3 of FIG. 15G of the
topical product group). The topical product encourages macrophage
efficiency (as validated in vitro) which then absorbs pigment,
leaving residual red pigment which resolves very quickly.
[0278] Swelling was also measured. Subjects underwent Profound
Radiofrequency (RF) Microneedling procedure and were administered
the topical product comprising a formula as described in Table 9 or
a bland moisturizer. Split face case studies were used to compare
the topical product and the bland moisturizer. A Quantificare 3-D
volumetric camera was used for measurements. Red color indicates
greater volume/swelling compared to baseline. Data is seen in FIGS.
16A-16B.
[0279] As seen in FIG. 16C, application of the topical product
(right side of each image) over a period of 8 days reduced bruising
and swelling in a subject treated with radiofrequency (RF)
microneedling. Application of the topical product also reduced
senile purpura as seen in FIG. 16D.
[0280] Molecular changes were also observed. As seen in FIG. 16E,
the Herovici stain (40.times. magnification) demonstrates new
mucopolysaccharide formation (denoted by blue areas in papillary
dermis). The left panel is pretreatment and the right panel is 2
weeks after use of the topical product. As seen in FIG. 16F, the
fibrillin stain (10.times. magnification) in brown shows
regeneration of elastin fibers. The left panel is pretreatment and
the right panel is 2 weeks after use of the topical product.
[0281] Conclusion
[0282] The data demonstrate improvements in bruising resolution
using the topical product.
Example 11. In Vitro Antimicrobial Effectiveness of the Topical
Product
[0283] An Antimicrobial Effectiveness Test was performed using a
topical product having a formula of Table 9. As seen in the data in
FIG. 17, there was a complete eradication of bacteria, yeast, and
mold using the topical product. The topical product was determined
to meet the USP criteria of acceptance for the Antimicrobial
Effectiveness Test for Category 2.
[0284] While preferred embodiments of the present disclosure have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
disclosure. It should be understood that various alternatives to
the embodiments of the disclosure described herein may be employed
in practicing the disclosure. It is intended that the following
claims define the scope of the disclosure and that methods and
structures within the scope of these claims and their equivalents
be covered thereby.
* * * * *