U.S. patent application number 14/794462 was filed with the patent office on 2016-02-04 for calcium sequestration compositions and methods of treating skin pigmentation disorders and conditions.
The applicant listed for this patent is Neocuitis S.A.. Invention is credited to Frank Dreher.
Application Number | 20160030321 14/794462 |
Document ID | / |
Family ID | 42340297 |
Filed Date | 2016-02-04 |
United States Patent
Application |
20160030321 |
Kind Code |
A1 |
Dreher; Frank |
February 4, 2016 |
CALCIUM SEQUESTRATION COMPOSITIONS AND METHODS OF TREATING SKIN
PIGMENTATION DISORDERS AND CONDITIONS
Abstract
The present invention provides compositions containing one or
more calcium sequestration agents and methods for topical
application of such compositions to the skin to treat skin
pigmentation disorders, such as melasma, post-inflammatory
hyperpigmentation, pigmentation changes due to skin aging, or any
other skin conditions related with normal such as skin of color or
abnormal pigmentation such as hypo- or hyper-pigmentation in
humans.
Inventors: |
Dreher; Frank; (San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neocuitis S.A. |
Pully |
|
CH |
|
|
Family ID: |
42340297 |
Appl. No.: |
14/794462 |
Filed: |
July 8, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12688107 |
Jan 15, 2010 |
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14794462 |
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61145325 |
Jan 16, 2009 |
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Current U.S.
Class: |
424/62 ;
558/177 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 8/55 20130101; A61Q 19/02 20130101 |
International
Class: |
A61K 8/55 20060101
A61K008/55; A61Q 19/02 20060101 A61Q019/02 |
Claims
1. A composition for treating or ameliorating at least one symptom
of a skin pigmentation disorder or condition comprising at least
one calcium sequestering or calcium binding agent.
2. The composition of claim 1, wherein the at least one calcium
sequestering or calcium binding agent is a phosphate free of
calcium.
3. The composition of claim 2, wherein the phosphate is
glycerophosphoric acid or a non-calcium salt thereof.
4. The composition of claim 3, wherein the phosphate is sodium
glycerophosphate.
5. The composition of claim 1, wherein the at least one calcium
sequestering or calcium binding agent is present in an amount of
about 0.1% to about 25% by weight.
6. The composition of claim 2, wherein the phosphate free of
calcium is present in an amount of about 1% to about 5% by
weight.
7. The composition of claim 1, wherein the composition further
comprises at least one additional agent that modulates or regulates
at least one step of melanogenesis.
8. The composition of claim 7, wherein the at least one additional
agent is selected from the group consisting of L-alanine, glycine,
L-isoleucine, L-leucine, hydroquinone, 4-(1-phenylethyl)
1,3-benzenediol, arbutin, bearberry leaf extract, kojic acid,
oxyresveratrol, gnetol, a melanosome transfer inhibitor, and an
.alpha.-MSH antagonist.
9. The composition of claim 1, wherein the composition further
comprises at least one skin moisturization and skin rejuvenation
agent.
10. The composition of claim 9, wherein the skin moisturization and
skin rejuvenation agent is selected from the group consisting of
ascorbic acid, vitamin E, jojoba oil, shea butter, human fibroblast
lysate, retinoic acid, retinol, and any derivatives thereof.
11. The composition of claim 1, wherein said composition is
suitable for topical administration to a subject in need
thereof.
12. The composition of claim 1, wherein said composition is in the
form of a solution, an oil-in-water emulsion, a water-in-oil
emulsion, a gel, an ointment, a patch, a paste, a liquid, a foam, a
mousse, a spray, an aerosol, a triple emulsion, a nanoemulsion, a
microemulsion, a hydrogel, a jelly, a dispersion, a suspension, and
a tape.
13. The composition of claim 1, wherein said composition is
substantially free of calcium.
14. The composition of claim 1, wherein said composition is stable,
does not cause an acnegenic or comedogenic response, and produces
minimal skin irritation in said subject.
15. A method of treating or ameliorating a skin pigmentation
disorder comprising administering an effective amount of the
composition of claim 1 to a patient suffering therefrom.
16. The method of claim 15, wherein the skin pigmentation disorder
is selected from the group consisting of melasma, post-inflammatory
hyper-pigmentation, pigmentation changes due to skin aging, age or
liver spots, freckles, hypo-pigmentation, and
hyper-pigmentation.
17. The method of claim 15, wherein the patient is a human.
18. The method of claim 15, wherein the composition is administered
to the patient topically.
19. The method of claim 15, wherein, following administration, the
composition reduced skin pigmentation in the patient.
20. A pharmaceutical formulation comprising the composition of
claim 1 and at least one pharmaceutically acceptable carrier.
21-32. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/688,107, filed Jan. 15, 2010 which claims
priority to U.S. Ser. No. 61/145,325, filed Jan. 16, 2009, both of
which are herein incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates generally to compositions containing
one or more calcium sequestration agents and methods for topical
application to the skin to treat skin pigmentation disorders, such
as melasma, post-inflammatory hyperpigmentation, pigmentation
changes due to skin aging, or any other skin conditions related
with normal such as skin of color or abnormal pigmentation such as
hypo- or hyper-pigmentation in humans.
BACKGROUND OF THE INVENTION
[0003] In humans, skin color arises from a complex series of
cellular processes that are carried out within a group of cells
known as melanocytes. Melanocytes are located in the lower part of
the epidermis and their function is to synthesize a pigment,
melanin, which protects the body from the damaging effects of
ultraviolet radiation. Melanin is a biopolymer originating from
conversions of the amino acids phenylalanine or tyrosine.
[0004] The mechanism by which the skin pigment melanin is formed
(melanin formation=melanogenesis) and skin ultimately gets its
color (skin color=skin pigmentation) is a multi-step process and
involves the following main steps: [0005] 1) Uptake (active
transport via transporter) of amino acid precursors (L-tyrosine,
L-phenylalanine) into melanocytes promoted by active transport
mechanism [0006] 2) Conversion (turnover) of phenylalanine into
tyrosine catalyzed by enzyme phenylalanine hydroxylase in
melanocytes [0007] 3) Uptake (active transport via transporter) of
amino acid precursors L-tyrosine into melanosmes located in
melanocytes promoted by active transport mechanism [0008] 4)
Conversion (turnover) of L-tyrosine into L-Dopa by enzyme
tyrosinase in melanosme [0009] 5) Conversion (turnover) of L-Dopa
into dopaquinone by enzyme tyrosinase in melanosme [0010] 6)
Conversion (turnover) of dopaquinone into two different types of
melanin called eumelanin (i.e., darker melanin) and phaeomelanin
(i.e., lighter melanin) by various biochemical pathways in
melanosme. The amount of each type of melanin determines the color
and degree of pigmentation in a person's skin [0011] 7) Once
melanin is produced, transfer of melanosme with melanin from
melanocytes to keratinocytes (which are found in the upper layers
of the epidermis) via the melanocyte dendrites.
[0012] In spite of the fact that the chemical and enzymatic basis
of melanogenesis and skin pigmentation are rather well-documented,
their regulation at the cellular and biochemical level is only
partially understood. For instance, it is well known that the
activity of tyrosinase is promoted by the action of
alpha-melanocyte stimulating hormone (.alpha.-MSH) and UV rays.
However, the processes of melanosome maturation and melanosome
transfer into the keratinocyte are currently far less studied and
not yet understood.
[0013] Typically, the more melanin is formed, the darker (or more
tanned) the skin. However, melanogenesis and skin pigmentation can
be disturbed or disorder, which may lead to undesirable
pigmentation patterns. Examples of pigmentation disorders (i.e.,
disorders where pigmentation is disturbed or disordered) include
age spots, liver spots, melasma, hyperpigmentation, etc. This has
lead to research to find compounds that will inhibit melanogenesis
and reduce skin pigmentation. One of the targets of this research
is tyrosinase, the enzyme which catalyses the initial steps in the
generation of melanin.
[0014] Skin pigmentation has been of concern to human beings for
many years. In particular, the ability to remove hyperpigmentation
(i.e., areas of darker skin color than the surrounding or adjacent,
normal pigmented skin), such as found in age spots, freckles or
aging skin generally, is of interest to individuals desiring a
uniform skin color, skin complexion, or skin tone. In certain areas
of the world, general body whitening is desirable.
[0015] There are also hypopigmentation (i.e., areas of less dark
skin color than the surrounding or adjacent, normal pigmented skin)
and hyperpigmentation disorders that are desirable to treat.
Likewise, the ability to generate a tanned appearance without
incurring photodamage due to solar radiation is important to many
individuals.
[0016] Many methods proposed to accomplish depigmentation (i.e.,
reduction or limitation of skin pigmentation or skin color). For
example, arbutin, kojic acid, hydroquinone, retinoids, and other
chemical compounds have been used for depigmentation. Chemicals
that allow depigmentation of skin are also called skin lighteners,
skin brighteners, skin whiteners, skin bleachers or actives with
skin lightening, skin brightening, skin whitening or skin bleaching
properties.
[0017] Many of these previous examples were not acceptable or were
of limited efficacy in treating skin pigmentation. Most of these
compounds have been described to address only a few steps of the
multiple steps leading to melanin formation and ultimately skin
pigmentation, which may result their limited efficacy. For
instance, most chemicals used for depigmentation are described as
inhibitors of tyrosinase. Although tyrosinase production and
activity is a key factor in melanin formation, melanogenesis is a
multi-step process and involves other important and rate-limiting
steps than tyrosinase catalyzed conversion of L-tyrosine and L-Dopa
and Dopa-quinone. In addition, many of these compounds have been
found to be irritating to the skin and, therefore, undesirable for
use. Also, precise application of all these compounds may be
necessary in order to achieve the desired result and to avoid
distinct line of demarcation between the areas of skin to which
such previous compositions have been applied.
[0018] Accordingly, there is a need for compositions which inhibit
melanogenesis and reduce skin pigmentation by modulating one or
more of the multiple steps involved in melanogenesis and skin
pigmentation. At the same time, there is also a need for
compositions that allow skin depigmentation without irritation. The
compositions and methods of the present invention address these
long felt needs in the art.
SUMMARY OF THE INVENTION
[0019] The present invention provides compositions containing at
least one calcium sequestering or calcium binding agent for
treating or ameliorating at least one symptom of a skin
pigmentation disorder or condition, in a subject in need thereof.
Preferably, the calcium sequestering or binding agent is a
phosphate. More preferably, the phosphate is glycerophosphoric acid
or a, non-calcium, salt thereof. Most preferably, the phosphate is
sodium glycerophosphate. The calcium sequestering or binding agent
is present in the composition in the amount of about 0.1% to about
25%. When the calcium sequestering or binding agent is phosphate it
is preferably present in the composition in the amount of about 1%
to about 5% by weight.
[0020] The compositions for treating or ameliorating at least one
symptom of a skin pigmentation disorder or condition in a subject
in need thereof can contain a calcium sequestering or binding agent
and can further contain one or more of the following agents, which
modulate or regulate at least one step of melanogenesis: L-alanine,
glycine, L-isoleucine, L-leucine, hydroquinone,
4-(1-phenylethyl)1,3-benzenediol, arbutin, bearberry leaf extract,
kojic acid, oxyresveratrol, gnetol, retinoic acid or retinol,
melanosome transfer inhibitor, or .alpha.-MSH antagonist.
[0021] Also provided are compositions that include at least one
additional agent selected from the group consisting of skin
moisturization or skin rejuvenation agents. For example, the skin
moisturization or skin rejuvenation agents may be ascorbic acid,
vitamin E, jojoba oil, shea butter, human fibroblast lysate,
retinoic acid, retinol, and/or any derivatives thereof.
[0022] The compositions for treating, or ameliorating at least one
symptom of, a skin pigmentation disorder or condition, in a subject
in need thereof, are formulated for topical administration. By way
of non-limiting example, the compositions of the invention can be
in the form of a solution, an oil-in-water emulsion, a water-in-oil
emulsion, a gel, an ointment, a patch, a paste, a liquid, a foam, a
mousse, a spray, an aerosol, a triple emulsion, a nanoemulsion, a
microemulsion, a hydrogel, a jelly, a dispersion, a suspension,
and/or a tape. The compositions are stable, substantially free of
calcium, do not cause an acnegenic/comedogenic response, and/or
produce only minor skin irritation upon administration.
[0023] Also provided herein are methods of treating or ameliorating
a skin pigmentation disorder comprising administering an effective
amount of any of the compositions of the invention to a patient
suffering therefrom. For example, the skin pigmentation disorder
can include, but is not limited to, melasma, post-inflammatory
hyperpigmentation, pigmentation changes due to skin aging, age or
liver spots, freckles, or any other skin conditions related with
normal such as skin of color or abnormal pigmentation such as hypo-
or hyper-pigmentation. Preferably, administration of the compound
reduces skin pigmentation. The subject can be any mammal,
preferably a human.
[0024] The invention also provides pharmaceutical formulations
containing any of the compositions described herein and at least
one pharmaceutically acceptable carrier. Similarly, the invention
also provides cosmetic formulations containing any of the
compositions described herein an at least one cosmetically
acceptable carrier. In other embodiments, the invention provides
kits including, in one or more containers, these pharmaceutical or
cosmetic formulations. Those skilled in the art will recognize that
such kits may optionally contain instructions for use of the
pharmaceutical or cosmetic formulations in the treatment or
amelioration of said skin pigmentation disorder or condition.
[0025] The invention also includes unit dosage forms containing
therapeutically effective amounts of any of the compositions and/or
pharmaceutical formulations described herein.
[0026] Any of the compositions or formulations described herein can
be used in methods of reducing skin pigmentation in a patient by
administering an effective amount of the composition and/or
formulation to the patient. In such methods, the effective amount
of the composition is administered topically to the patient.
[0027] Also provided are compositions for treating or ameliorating
at least one symptom of a skin pigmentation disorder or condition
that include 59.68% (by weight) water, 0.1% (by weight) disodium
EDTA, 0.3% (by weight) xanthan gum, 0.3% (by weight)
chlorphenesisn, 0.6% (by weight) phenoxyethanol, 0.5% (by weight)
undecylenoyl phenylalanine, 3.00% (by weight) sodium
glycerophosphate, 1.00% (by weight) leucine, 6.00% (by weight)
cetearyl alcohol/ceteareth-20, 6.00% (by weight) glyceryl stearate,
3.00% (by weight) diisopropyl adipate, 3.00% (by weight) caprylyl
methicone, 1.00% (by weight) dimethicone, 1.00% (by weight)
simmondsia chinensis (jojoba) seed oil, 1.00% (by weight)
butryospermum parkii shea butter), 0.2% (by weight) DL-alpha
tocopheryl acetate, 1.92% (by weight) citric acid 50% solution,
4.00% (by weight) hydroquinone, 0.4% (by weight) sodium
metabisulfite, 2.00% (by weight) glycerin, 0.5% (by weight)
phenylethyl resorcinol, 0.5% (by weight) aminopropyl ascorbyl
phosphate, and 4.00% (by weight) hydroxyethyl acrylate/sodium
acryloyldimethyl taurate copolymer isohexadecane polysorbate 60.
For example, such a composition can be formulated as a water-in-oil
emulsion.
[0028] Finally, the invention further provides a composition for
treating or ameliorating at least one symptom of a skin
pigmentation disorder or condition containing 63.41% (by weight)
water, 0.1% (by weight) disodium EDTA, 0.3% (by weight) xanthan
gum, 0.3% (by weight) chlorphenesisn, 0.6% (by weight)
phenoxyethanol, 0.5% (by weight) undecylenoyl phenylalanine, 3.00%
(by weight) sodium glycerophosphate, 1.00% (by weight) leucine,
1.92% (by weight) citric acid 50% solution, 8.25% (by weight)
cetearyl alcohol/ceteareth-20, 6.00% (by weight) glyceryl stearate,
5.00% (by weight) diisopropyl adipate, 3.00% (by weight) caprylyl
methicone, 1.00% (by weight) dimethicone, 1.00% (by weight)
simmondsia chinensis (jojoba) seed oil, 1.00% (by weight)
butryospermum parkii shea butter), 0.2% (by weight) DL-alpha
tocopheryl acetate, 2.00% (by weight) glycerin, 0.5% (by weight)
phenylethyl resorcinol, 0.5% (by weight) aminopropyl ascorbyl
phosphate, and 0.42% (by weight) hydroxyethyl acrylate/sodium
acryloyldimethyl taurate copolymer/isohexadecane/polysorbate 60.
For example, such a composition can be formulated as a water-in-oil
emulsion.
[0029] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, suitable methods and materials are described below. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In the case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0030] Other features and advantages of the invention will be
apparent from the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 is a graph showing skin irritation of a composition
of the present invention (see Example 3, infra) as compared to
other known compositions (e.g.: Compositions A to D), which are not
part of this invention. This graph, which represents a "survival"
type curve, shows the percentage of subjects who did not show any
irritancy reaction reaching an evaluation score of "3" or higher as
a function of time (i.e., observation) during the repetitive human
irritancy patch test of three weeks (21 days) duration. As judged
during this test (by providing "exaggerated" irritation data), the
composition of the present invention was better tolerated (i.e.,
fewer subjects reached an evaluation score of "3" or higher with
continued, prolonged application of patch with test material) as
compared to Compositions A to D).
[0032] FIG. 2 shows the color stability of a composition of the
present invention (Composition A) as compared to other, control
compositions (e.g.: Compositions B, C and D), which are not part of
this invention.
[0033] FIG. 3 is a photograph showing the reduction of pigmentation
in the skin of a patient using the compounds of the present
invention (i.e., the composition described in Example 3, infra).
Panel A shows the hyperpigmentation of the patient's skin prior to
administration of a compound of the present invention. Panel B
shows the reduction in skin pigmentation following 12 weeks of
treatment with a composition of the present invention.
DETAILED DESCRIPTION
[0034] The present invention is directed to modulating (increasing
or decreasing) various steps of melanogenesis (melanin formation)
and to reduce skin pigmentation (skin color). More specifically,
the present invention provides compositions for treating or
ameliorating a symptom of a pigmentation disorder or condition
involving a single active agent which modulates more than one step
in the multi-step process of melanin formation and skin
pigmentation. The present invention also provides compositions
which contain at least two active agents (e.g., 2, 3, 4, 5, or
more), where each active agent can target at least one step in the
multi-step process of melanin formation. These multiple agents
decrease melanin formation and skin pigmentation. By targeting
multiple steps of melanogenesis and skin pigmentation, the
compositions of present invention provide superior properties as
compared to hypopigmentation products currently known in the
art.
Calcium Sequestration or Binding Agents
[0035] Calcium (Ca.sup.2+) may be an important regulator of some
steps in melanogenesis and skin pigmentation. For instance,
increase in calcium is believed to promote active transport of
L-phenylalanine and its turnover via phenylalanine hydroxylase to
L-tyrosine to significantly increase the pool of this substrate for
melanogenesis. (See Dermatol Clin 25, 2007, pp. 283-291). Further,
there is some evidence from in vitro studies that calcium impacts
the melanosome transfer. (See Pigment Cell Res 20, 2007, pp.
380-384). This study, which used melanocyte-keratinocyte
co-cultures, implied that melanin transfer was inhibited when
intracellular calcium in keratinocytes was bound (chelated) with
calcium chelator
1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid
tetra-acetoxymethyl ester (BAPTA-AM).
[0036] Thus, the present invention provides compositions and
methods for skin depigmentation which interferes one or more steps
in the melanogenesis and skin pigmentation process where calcium is
involved by administering a composition suitable for topical
application containing at least one calcium sequestration or
binding agent.
[0037] Examples of calcium sequestering or binding agents include
either inorganic, organic (or a combination thereof, or
organo-metallics) derived molecules. Preferably, the agents are
calcium-free oxoanions of any or all possible oxidation states,
achiral or chiral, selected from phosphates, phosphate esters,
phosphonates, phosphonate esters, phosphoramidites, sulfates,
sulfate esters, sulfonates, sulfonate esters, sulfites, siloxanes,
carbonates, boronates, borinates, borinate esters, siloxanes,
siloxane esters, polysiloxanes, sulfoxides, sulfonamides, sulfinic
acids, sulfinimides, thiol esters, thioureas, and tosylates.
Preferably the organic agents would possess calcium free anionic or
neutral Lewis Base donors, achiral or chiral selected from
carboxylic acids, polycarboxylates, carboxylic esters, nitriles,
isocyanates, hydrazines, hydrazones, ureas, carboxylic esters,
oximes, amides, amidines, thioethers, ethers, amines, alcohols,
alkoxides, thiols, thiolates.
[0038] Table 1 recites non-limiting, representative, examples of
carboxylic acids, boronic acids, amines, sulfates suitable to be
utilized as calcium sequestration or binding agents
TABLE-US-00001 TABLE 1 Product Code & Pack Size Product Name
CAS Structure MF MW AC10430DA AC10430EA 1 GR 10 GR 25.00 USD 189.00
USD Amino- phenylboronic acid 0.5 ulfate 66472- 86-4 ##STR00001##
C6H8BNO2.cndot.0.5 H2O4S 185.98176 (136.94502) ##STR00002##
AC10702EA AC10702EE 10 GR 50 GR 19.00 USD 42.00 USD 5-bromo-
2-furoic acid 585- 70-6 ##STR00003## C5H3BrO3 190.98102 AC10728DA
AC10728EA 1 GR 10 GR 19.00 USD 102.00 USD 4-bromo- phenylboronic
acid 5467- 74-3 ##STR00004## C6H6BBrO2 200.82644 AC11546EA
AC11546EE 10 GR 50 GR 21.00 USD 33.00 USD 3,5- dimethoxy- benzoic
acid 1132- 21-4 ##STR00005## C9H10O4 182.176 AC11968DA 1 GR 59.00
USD 2-amino- 3-(5-fluoro- 1H-indol-3- yl)propanoic acid 154-08- 5
##STR00006## C11H11FN2O2 222.218943 SEW01633CB SEW01633DA
SEW01633DE 250 MG 1 GR 5 GR 93.00 USD 270.00 USD 761.00 USD
Thieno[2,3- b]thiophene- 2-carboxylic acid 14756- 75-3 ##STR00007##
C7H4O2S2 184.22756 AC12788DA AC12788EA 1 GR 10 GR 48.00 USD 155.00
USD 5-methyl-2- thiophene- carboxylic acid 1918- 79-2 ##STR00008##
C6H6O25 142.17244 AC13036EA AC13036EE 10 GR 50 GR 29.00 USD 117.00
USD Phenyl- boronic acid 98-80- 6 ##STR00009## C6H7BO2 121.93038
AC13196EA 10 GR 74.00 USD Pyridine- 3-ylacetic acid hydro- chloride
6419- 36-9 ##STR00010## C7H7NO2.cndot.HCl 173.59902 (137.13808)
AC13366DA AC13366EA 1 GR 10 GR 33.00 USD 65.00 USD 2- piperazine-
carboxylic acid dihydro- chloride 3022-15- 9 ##STR00011##
C5H10N2O2.cndot.2 HCl 203.06848 (130.1466) AC14674CB AC14674DA 250
MG 1 GR 179.00 USD 522.00 USD 2-Amino- 3-(6-fluoro- 1H-indol-3-
yl)-propanoic acid 7730- 20-3 ##STR00012## C11H11FN2O2
222.218943
Table 2 recites non-limiting, representative, examples of
phosphates suitable to be utilized as calcium sequestration or
binding agents.
TABLE-US-00002 TABLE 2 ##STR00013## 1-Naphthyl phosphate
##STR00014## 1-Naphthyl phosphate calcium salt trihydrate
##STR00015## 2,4-Diamino-6,7- diisopropylpteridine phosphate salt
##STR00016## 2-Cyanoethyl phosphate barium salt dihydrate
##STR00017## 2-Naphthyl phosphate disodium salt ##STR00018##
3,9-Bis(2,4- dicumylphenoxy)- 2,4,8,10-tetraoxa-3,9-
diphosphasphiro[5.5] undecane ##STR00019## 6-Benzoyl-2-naphthyl
phosphate disodium salt ##STR00020## Anilinium hypophosphite
Table 3 recites non-limiting, representative, examples of
phosphonates or phosphinates suitable to be utilized as calcium
sequestration or binding agents.
TABLE-US-00003 TABLE 3 ##STR00021## Dimethyl thiophosphonate
##STR00022## Ethyl methylphosphonate ##STR00023## Dimethyl
vinylphosphonate ##STR00024## Trimethyl phosphonoformate
##STR00025## Diethyl (trichloromethyl) phosphonate ##STR00026##
Diethyl cyanophosphonate ##STR00027## O,O'-Diethyl
methylphosphonothioate ##STR00028## Diethyl vinylphosphonate
##STR00029## Triethyl phosphonoformate
Table 4 recites non-limiting, representative, examples of
phosphonic/phosphoric acids suitable to be utilized as calcium
sequestration or binding agents.
TABLE-US-00004 TABLE 4 ##STR00030## Methylphosphonic acid
##STR00031## (Aminomethyl)phosphonic acid ##STR00032##
Methylenediphosphonic acid ##STR00033## Vinylphosphonic acid
##STR00034## Phosphonoacetic acid ##STR00035## Dimethylphosphinic
acid ##STR00036## Ethylphosphonic acid ##STR00037##
2-Aminoethylphosphonic acid
Table 5 recites non-limiting, representative, examples of amidines
suitable to be utilized as calcium sequestration or binding
agents.
TABLE-US-00005 TABLE 5 Product Code & Pack Size Product Name
CAS Structure MF MW CC12331DA CC12331EA 1 GR 10 GR 121.00 USD
443.00 USD 1-benzothiophene-3- carboxamidamidine hydrochloride
465515-36-0 ##STR00038## C9H8N2S.cndot.HCl 212.69686 (176.23592)
MO07267DA MO07267EA 1 GR 10 GR 70.00 USD 270.00 USD N-Hydroxy-
butyramidine 27620-10-6 ##STR00039## C4H10N2O 102.1362 RF00749DA
RF00749EA 1 GR 10 GR 42.00 USD 328.0 USD 3,5- Bis(trifluoromethyl)
benzamidine hydrochloride 97603-94-6 ##STR00040##
C9H6F6N2.cndot.HCl 292.611398 (256.150458) RF01501DA RF10501EA
RF01501EB 1 GR 10 GR 25 GR 25.00 USD 225.00 USD 358.00 USD
2,2-dimethyl- propanimidamide 18202-73-8 ##STR00041##
C5H12N2.cndot.HCl 136.62452 (100.16368) MO07766D MO07766EA
MO07766EB 1 GR 10 GR 25 GR 33.00 USD 270.00 USD 490.00 USD
Pyridine-3- carboxamidine hydrochloride 0.5 hydrate 7356-60-7
##STR00042## C6H7N3.cndot.HCl.cndot.0.5 H2O 166.61026 (121.14168)
CC39931CB CC29931DA 250 MG 1 GR 104.00 USD 260.00 USD
Tetrahydropyran-4- carboxamidine hydrochloride 426828-34-4
##STR00043## C6H12N2O.cndot.ClH 164.63502 (128.17408)
Table 6 recites non-limiting, representative, examples of boronic
acids suitable to be utilized as calcium sequestration or binding
agents.
TABLE-US-00006 TABLE 6 Product Code & Pack Size Product Name
CAS Structure MF MW AC10430DA AC10430EA 1 GR 10 GR 25.00 USD 189.00
USD 3-amino- phenyl boronic acid 0.5 sulfate 66472- 86-4
##STR00044## C6H8BN02.cndot.0.5 H2O4S 185.98176 (136.94502)
AC10728DA AC10728EA 1 GR 10 GR 19.00 USD 102.00 USD 4- bromophenyl-
boronic acid 5467- 74-3 ##STR00045## C6H6BBrO2 200.82644 AC13036EA
AC13036EE 10 GR 50 GR 29.00 USD 117.00 USD Phenylboronic acid
98-80-6 ##STR00046## C6H7BO2 121.93038 AC30926DA AC30926EA 1 GR 10
GR 19.00 USD 157.00 USD 2- methylphenyl- boronic acid 16419- 60-6
##STR00047## C7H9BO2 135.95726 AC30948DA AC30948EA 1 GR 10 GR 81.00
USD 430.00 USD 4-methoxy- phenylboronic 5720- 07-0 ##STR00048##
C9H9BO3 151.95666 AC34441DA AC3RRR1E AC34441EE 1 GR 10 GR 50 GR
48.00 USD 155.00 USD 577.00 USD 4-chlorophenyl- boronic acid 1679-
18-1 ##STR00049## C6H6BClO2 156.37544 AC34443DA 1 GR 25.00 USD
4-methylphenyl- boronic acid 5720- 05-8 ##STR00050## C7H9BO2
135.95726 AC34465DA AC34465EA 1 GR 10 GR 33.00 USD 187.00 USD
Hexylboronic acid 16343- 08-1 ##STR00051## C6H15BO2 129.9939
AC34468DA AC34468EA 1 GR 10 GR 19.00 USD 117.00 USD 4-
(methylsulfanyl) phenylboronic acid 98546- 51-1 ##STR00052##
C7H9BO2S 168.01726 AC34469DA AC34469E 1 GR 10 GR 19.00 USD 151.00
USD 1-naphthyl- boronic acid 13922- 41-3 ##STR00053## C10H9BO2
171.99026 AC35883DA AC35883EA 1 GR 10 GR 19.00 USD 151.00 USD
3-acetylphenyl- boronic acid 204841- 19-0 ##STR00054## C8H9BO3
163.96766
Table 7 recites non-limiting, representative, examples of esters or
alcohols suitable to be utilized as calcium sequestration or
binding agents.
TABLE-US-00007 TABLE 7 Product Code & Pack Size Product Name
CAS Structure MF MW CC03622DA CC03622EA 1 GR 10 GR 102.00 USD
537.00 USD 1-Methyl-1H- imidazole-4- carboxylic acid methyl ester
17289- 19-9 ##STR00055## C6H8N2O2 140.14172 CC04940DA 1 GR 106.00
USD Isoquinoline-4- boronic acid 2,2- dimethyl- propanedial-
1,3-cyclic ester 844891- -01-6 ##STR00056## C14H16BN02 241.09654
CC19422DA 1 GR 159.00 USD 3-(2-Methyl- thiazol-4-yl)- benzoic acid
methyl ester 850375- -07-4 ##STR00057## C12H11NO2S 233.28484
MO07248CD MO07248DA 250 MG 1 GR 78.00 USD 161.00 USD 3-(5-Bromo-
pyridin-3-yl)- [1,2,4] oxadiazole- 5-carboxylic acid ethyl ester
850375- 34-7 ##STR00058## C10H8BrN3O3 298.09582 MO07285DA MO07285EA
1 GR 471.00 GR 66.00 USD 471.00 USD (4-Hydroxy- emethyl- benzyl)-
carbamic acid tert-butyl ester 123986- 64-1 ##STR00059## C13H19NO3
237.29876 MO07286CB MO07286DA MO07286DE 250 MG 1 GR 5 GR 78.00 USD
200.00 USD 546.00 USD (3-Hydroxy- methyl- benzyl)- carbamic acid
tert- butyl ester 226070- 69-5 ##STR00060## C13H19NO3 237.29876
MO07352CB MO07352DA MO07352EA 250 MG 1 GR 10 GR 48.00 USD 95.00 USD
706.00 USD 3-Amino- methyl- benzoic acid methyl ester hydrochloride
17841- 68-8 ##STR00061## C9H11NO2.cndot.HCl 201.65278 (165.19184)
RDP00077DA RDP00077EA RPD00077EB 1 GR 10 GR 25 GR 42.00 USD 65.00
USD 115.00 USD (S)-tryptophan ethyl ester hydrochloride 7479- 05-2
##STR00062## C13H16N2O2.cndot.ClH 268.74318 (232.28224) BTB06937EE
BTB06937FA 50 GR 100 GR 36.00 USD 65.00 USD 4-methoxy-4-
oxobutanoic acid 3878- 55-5 ##STR00063## C5H8O4 132.11612 SB01817EA
SB01817EB 10 GR 25 GR 55.00 USD 83.00 USD Methyl propiolate 922-
67-8 ##STR00064## C4H4O2 84.07456
Table 8 recites non-limiting, representative, examples of
isocyanates suitable to be utilized as calcium sequestration or
binding agents.
TABLE-US-00008 TABLE 8 Product Code & Pack Size Product Name
CAS Structure MF MW AC29669EA AC29669EB 10 GR 25 GR 31.00 USD 59.00
USD 2-nitrophenyl isocyanante 3320-86-3 ##STR00065## C7H4N2O3
164.12036 AC29670EA AC29670EB 10 GR 25 GR 65.00 USD 70.00 USD
4-nitrophenyl isocyanate 100-28-7 ##STR00066## C7H4N2O3 164.12036
AC30815DA 1 GR 31.00 USD 2,6-difluorophenyl isocyanate 65295-69-4
##STR00067## C7H3F2NO 155.10372 AC30913DA 1 GR 19.00 USD
4-chloro-3- (trifluoromethyl)phenyl isocyanate 327-78-6
##STR00068## C8H3ClF3NO 221.566129 AC30914DA AC30914EA 1 GR 10 GR
27.00 USD 217.00 USD 2,5-difluorophenyl isocyanate 39718-32-6
##STR00069## C7H3H2NO 155.103726 AC31411DA AC31411EA 1 GR 10 GR
19.00 USD 155.00 USD [1,1'-biphenyl]-2-yl isocyanate 17337-13-2
##STR00070## Cl3H9NO 195.22056 AC31419DA AC31419E AC31419EB 1 GR 10
GR 25 GR 19.00 USD 74.00 177.00 USD 4-(methylsulfanyl)phenyl
isocyanate 1632-84-4 ##STR00071## C8H7NOS 165.20968 AC31420DA 1 GR
19.00 USD 2-ethylphenyl isocyanate 40411-25-4 ##STR00072## C9H9NO
147.17656 AC31427EA AC31427EB 10 GR 25 GR 81.00 USD 181.00 USD
4-methyl-3- nitrophenyl isocyanate 13471-69-7 ##STR00073## C8H6N2O3
178.14724 AC31429DA AC31429EA AC31429EB 1 GR 10 GR 25 GR 19.00 USD
95.00 USD 177.00 USD 2,4-dimethoxyphenyl isocyanate 84370-87-6
##STR00074## C9H9NO3 179.17536 AC31435DA AC31435EA 1 GR 10 GR 25.00
USD 198.00 USD 4- (chloromethyl)phenyl isocyanate 29173-65-7
##STR00075## C8H6ClNO 167.59474 AC31931CB 250 MG 55.00 2-fluoro-5-
methylphenyl isocyanate 190774-50-6 ##STR00076## C8H6FNO
151.140143
Table 9 recites non-limiting, representative, examples of oximes
suitable to be utilized as calcium sequestration or binding
agents.
TABLE-US-00009 TABLE 9 Product Code & Pack Size Product Name
CAS Structure MF MF CD11194DA CD11194EA 1 GR 10 GR 81.00 USD 432.00
USD Azepan-2- one axime 19214-08-5 ##STR00077## C6H12N2O 128.17408
SPB04865DA SPB04865EA SPB04865EB 1 GR 10 GR 25 GR 51.00 USD 76.00
USD 142.00 USD 2,4- dichloro- benzaldehyde oxime 56843-28-8
##STR00078## C7H5C12NO 190.0288 SPB04935EA SPB04935FA 10 GR 100 GR
321.00 USD 801.00 USD 3,4- dichloro- benzaldehyde oxime 5331-92-0
##STR00079## C7H5C12NO 190.0288 CD00359DA CD00359EA CD00359EE 1 GR
10 GR 50 GR 42.00 USD 65.00 USD 232.00 USD 2-furaldehyde oxime
1121-47-7 ##STR00080## C5H5NO2 111.1002 SPB05555DA SPB05555EA 1 GR
10 GR 55.00 USD 332.00 USD 4- (trifluoro- methoxy) benzaldehyde
oxime 150162- 39-3 ##STR00081## C8H6F3NO2 205.136349 SPB05820DA
SPB05820EA SPB05820EE 1 GR 10 GR 50 GR 42.00 USD 65.00 232.00 USD
2,6-dichloro- benzaldehyde oxime 25185-95-9 ##STR00082## C7H5Cl2NO
190.0288 END00218DA 1 GR 53.00 USD 4-phenylbut- 3-en-2-one oxime
2887-98-1 ##STR00083## C10H11NO 161.20344 SPB08294DA SPB08294EA
SPB08294EB 1 GR 10 GR 25 GR 19.00 USD 147.00 USD 275.00 USD
2-chloro-5- fluoro- benzaldehyde oxime 443-33-4 ##STR00084##
C7H5ClFNO 173.574203 SPB08414DA SPB08414EA 1 GR 10 GR 53.00 USD
321.00 USD 3,5-dibromo-4- hydroxy- benzaldehyde oxime 25952-74-3
##STR00085## C7H5Br2NO2 294.9302 MO00284CB MO00284DA 250 MG 1 GR
68.00 134.00 USD 2-bromo- 1-phenyl-1- ethanone oxime 14181-72-7
##STR00086## C8H8BrNO 214.06162 KM08088DA 1 GR 53.00 USD
4-(3-hydroxy-3- methylbut-1-yn- yl)benzaldehyde oxime 175203-57-3
##STR00087## Cl2H13NO2 203.24072 TL00712DA TL00712EA TL00712EB 1 GR
10 GR 25 GR 57.00 USD 337.00 USD 426.00 USD (1E)-1-(5,6,7,8-
tetrahydro- napthalen-2- yl)ethanone oxime 7357-12- 2 ##STR00088##
C12H15NO 189.2572 BTB09548DA BTB09548EA BTB09548EB 1 GR 10 GR 25 GR
29.00 USD 65.00 USD 81.00 USD 3-phenyl- acrylaldehyde oxime
13372-81-1 ##STR00089## C9H9NO 147.17656
Table 10 recites non-limiting, representative, examples of sulfites
suitable to be utilized as calcium sequestration or binding
agents.
TABLE-US-00010 TABLE 10 Product Code & Pack Size Product Name
CAS Structure MF MF AC27651DA 1 GR 70.00 USD 1-methyl-1H-
benzimidazole- 2- sulfonic acid 5533- 38-0 ##STR00090## C8H9N2O3S
212.223312 AC40114CA AC40114CB 100 MG 250 MG 74.00 USD 255.00 USD
Ammonium 7-chloro- 2,1,3- benzoxa- diazole- 4-sulfonate 81377- 14-2
##STR00091## C6H2ClN2O4S.cndot.H4N 251.64434 (233.60588) MO000766DA
MO00766DE 1 GR 5 GR 142.00 USD 403.00 USD 6-chloro- imidazo[2,1-
b]thiazole- 5-sulfonic acid amide 112582- 89-5 ##STR00092##
C5H4ClN3O2S2 237.67866 BTB06262DA BTB06262EA BTB06262EB 1 GR 10 GR
25 GR 23.00 USD 65.00 USD 115.00 USD 8-chloro- naphthalene-
1-sulfonic acid 145-74- 4 ##STR00093## C10H7ClO3S 242.67678
BTB09138DA 1 GR 55.00 USD 2- {[amino(imino) methyl]amino}-
ethane-1- sulfonic acid 543-18- 0 ##STR00094## C3H9N3O3S 167.18276
BTB13613DA BTB13613EA 1 GR 10 GR 53.00 USD 321.00 USD 2-(4-
aminophenyl)- 6-methyl-1,3- benzothiazole- 7- sulfonic acid 130-17-
6 ##STR00095## C14H12N2O3S2 320.38088 RJC04098DA RJC04098EA 1 GR 10
GR 53.00 USD 321.00 USD 2,5-dichloro- 4-(5- hydroxy-3- methyl-1H-
pyrazol-1-yl) benzenesulfonic acid dihydrate 306935- 68-2
##STR00096## C10H8Cl2NO204S.cndot.2H2O 359.18108 (323.15052)
SB01747DA SB01747EA SB01747EB 1 GR 10 GR 25 GR 42.00 USD 65.00 USD
115.00 USD 3-amino-4- hydroxy-5- nitobenzene-1- sulfonic acid
hydrate 175278- 60-1 ##STR00097## C6H6N2O6S.cndot.H2O 252.19872
(234.18344)
Table 11 recites non-limiting, representative, examples of sulfates
suitable to be utilized as calcium sequestration or binding
agents.
TABLE-US-00011 TABLE 11 Product Product Code & Pack Size Name
CAS Structure MF MF AC10430DA AC10430EA 1 GR 10 GR 25.00 USD 189.00
USD 3-amino- phenyl- boronic acid 0.5 sulfate 66472-86-4
##STR00098## C6H8BNO2.cndot.0.5 H2O4S 185.98176 (136.94502)
AC33706CB 250 MG 27.00 USD Potassium 1H- indol-3-yl sulfate
2642-37-7 ##STR00099## C8H6NO4S.cndot.K 251.29824 (212.19994)
Table 12 recites non-limiting, representative, examples of
hydrazines suitable to be utilized as calcium sequestration or
binding agents.
TABLE-US-00012 TABLE 12 ##STR00100## 3-Fluorophenyl- hydrazine
hydrochloride ##STR00101## 4-Fluorophenyl- hydrazine hydrochloride
##STR00102## 4-Iodophenyl- hydrazine ##STR00103## 2-Nitrophenyl-
hydrazine ##STR00104## 3-Nitrophenyl- hydrazine hydrochloride
##STR00105## 4-Nitrophenyl- hydrazine ##STR00106## Phenylhydrazine
##STR00107## Phenylhydrazine hydrochloride ##STR00108## Diethyl
1,2- hydrazine- dicarboxylate
[0039] Table 13 recites non-limiting, representative, examples of
carboxylic acids suitable to be utilized as calcium sequestration
or binding agents.
TABLE-US-00013 TABLE 13 ##STR00109## ##STR00110## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH 2355 85.59 ALDRICH 2461
86.11 ##STR00111## ##STR00112## ##STR00113## ##STR00114## Catalog
Catalog Brand Number MW Brand Number MW ALDRICH 36838 100.12
ALDRICH 277827 136.95 ##STR00115## ##STR00116## indicates data
missing or illegible when filed
[0040] Table 14 recites non-limiting, representative, examples of
aryl carboxylic acids suitable to be utilized as calcium
sequestration or binding agents.
TABLE-US-00014 TABLE 14 ##STR00117## ##STR00118## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH 132.42 ALDRICH 25.11
##STR00119## ##STR00120## ##STR00121## ##STR00122## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH 122.11 ALDRICH 120.10
##STR00123## ##STR00124## ##STR00125## ##STR00126## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH P06609 120.10 ALDRICH
P13823 526.33 ##STR00127## ##STR00128## ##STR00129## ##STR00130##
Catalog Catalog Brand Number MW Brand Number MW ALDRICH P3404
196.18 ALDRICH A2244 149.12 ##STR00131## ##STR00132## ##STR00133##
##STR00134## Catalog Catalog Brand Number MW Brand Number MW
ALDRICH 41894 540.10 ALDRICH 182780 149.98 ##STR00135##
##STR00136## ##STR00137## ##STR00138## Catalog Catalog Brand Number
MW Brand Number MW ALDRICH 813886 159.14 ALDRICH 182.43
##STR00139## ##STR00140## indicates data missing or illegible when
filed
[0041] Table 15 recites non-limiting, representative, examples of
cycloalkyl carboxylic acids suitable to be utilized as calcium
sequestration or binding agents.
TABLE-US-00015 TABLE 15 ##STR00141## ##STR00142## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH 924.94 ALDRICH P24606 10839
##STR00143## ##STR00144## ##STR00145## ##STR00146## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH O1493 124.95 ALDRICH 158.52
##STR00147## ##STR00148## ##STR00149## ##STR00150## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH 34847 115.12 ALDRICH 725803
126.23 ##STR00151## ##STR00152## ##STR00153## ##STR00154## Catalog
Catalog Brand Number MW Brand Number MW ALDRICH 56.034 126.17
ALDRICH 28085 129.12 ##STR00155## ##STR00156## ##STR00157##
##STR00158## Catalog Catalog Brand Number MW Brand Number MW
ALDRICH 81533 122.49 ALDRICH 12802 125.16 ##STR00159## ##STR00160##
##STR00161## ##STR00162## Catalog Catalog Brand Number MW Brand
Number MW ALDRICH 104950 129.18 ALDRICH 29055 148.39 ##STR00163##
##STR00164## indicates data missing or illegible when filed
[0042] Table 16 recites non-limiting, representative, examples of
heteroaryl and biaryl acids suitable to be utilized as calcium
sequestration or binding agents.
TABLE-US-00016 TABLE 16 ##STR00165## ##STR00166## Catalog Catalog
Brand Number MW Brand Number MW ALDRICH 814654 186.58 ALDRICH
831588 158.19 ##STR00167## ##STR00168## ##STR00169## ##STR00170##
Catalog Catalog Brand Number MW Brand Number MW ALDRICH 813483
588.47 ALDRICH 834152 100.22 ##STR00171## ##STR00172## ##STR00173##
##STR00174## Catalog Catalog Brand Number MW Brand Number MW
ALDRICH 054829 188.72 ALDRICH 10847 279.96 ##STR00175##
##STR00176## ##STR00177## ##STR00178## Catalog Catalog Brand Number
MW Brand Number MW ALDRICH 107926 258.25 ALDRICH 109337 258.25
##STR00179## ##STR00180##
[0043] Table 17 recites non-limiting, representative, examples of
ureas suitable to be utilized as calcium sequestration or binding
agents.
TABLE-US-00017 TABLE 17 ##STR00181## Urea ##STR00182## Hydroxyurea
##STR00183## Semicarbazide hydrochloride ##STR00184##
1-Cyanoisourea sodium salt ##STR00185## Biuret ##STR00186##
N-Methylurea ##STR00187## o-Methylisourea bisulfate
[0044] Table 18 recites non-limiting, representative, examples of
hydrazones suitable to be utilized as calcium sequestration or
binding agents.
TABLE-US-00018 TABLE 18 ##STR00188## Glyoxal mono- dimethyl-
hydrazone ##STR00189## Benz- aldehyde semi- carbazone ##STR00190##
Benz- aldehyde p- nitrophenyl- hydrazone ##STR00191## Benzo-
phenone hydrazone ##STR00192## 2-Hydroxy- benz- aldehyde phenyl-
hydrazone ##STR00193## Benzil mono- hydrazone ##STR00194## 2-Nitro-
benz- aldehyde tosyl- hydrazone ##STR00195## 2'- Amino- aceto-
phenone phenyl- hydrazone ##STR00196## Valero- phenone tosyl-
hydrazone
[0045] The "calcium sequestration agent" or "calcium binding agent"
of the present invention is any agent capable of binding or
sequestering calcium ion (Ca.sup.II) such that the bound or
sequestered calcium ion is prevented or inhibited (i.e., reduced)
from interacting with other binding agents. In the context of the
present invention, the calcium sequestration or binding agent, when
administered to the skin of a patient in need of such treatment,
binds or sequesters calcium ion in the local area of topical
administration and regulates or modulates (i.e., prevents, limits,
or inhibits) calcium from acting as a regulator in several (i.e.,
at least two) steps of melanogenesis and skin pigmentation.
[0046] The present composition contain a calcium sequestration or
binding agent in an amount effective to reduce pigmentation. For
example, the calcium sequestration or binding agent is present in
the composition in an amount from about 0.1% to the solubility
limit of the calcium sequestration or binding agent in the
composition. Preferably, the calcium sequestration or binding agent
is present in the composition in the amount of about 0.1% to about
25%, more preferably about 0.2% to about 10%, most preferably about
1% to about 5% by weight.
[0047] The pH range of any of the compositions containing a calcium
sequestration or binding agent described herein is about 2.5 to
about 9.0, preferably about 3.0 to about 7.0, more preferably about
4.0 to about 5.0. Solutions for adjusting pH to appropriate value,
e.g., sodium hydroxide (NaOH), may be added to the composition of
the present invention, as required.
[0048] Preferably, the agent capable of binding or sequestering
calcium ion is a phosphate agent. A phosphate is defined as a form
of phosphoric acid. The phosphate can contain one or more of
phosphorus (P) atoms as follows: [0049] i) one phosphorus atom
(i.e., orthophosphates) such as H.sub.3PO.sub.4, any possible salts
of H.sub.3PO.sub.4, or esters of H.sub.3PO.sub.4 as shown in FIG. 1
[0050] ii) two phosphorus atoms (i.e., pyrophosphates) such as
H.sub.4P.sub.2O.sub.7, any possible salts of H.sub.4P.sub.2O.sub.7,
or esters of H.sub.4P.sub.2O.sub.7 [0051] iii) three phosphorus
atoms (i.e., tripolyphosphates) such H.sub.5P.sub.3O.sub.10, any
possible salts of H.sub.5P.sub.3O.sub.10, or esters of
H.sub.5P.sub.3O.sub.10 [0052] iv) more than three phosphorus atoms
(i.e., polyphosphates) such as H.sub.(n+4)(PO.sub.3).sub.(n+2), any
possible salts of H.sub.(n+4)(PO.sub.3).sub.(n+2), or esters of
H.sub.(n+4)(PO.sub.3).sub.(n+2)
[0053] The structural formula of orthophosphate esters is shown in
Formula I, where R1, R2 and R3 are each chosen from branched or
unbranched alkyl or alkenyl groups having one or more carbon
atoms.
##STR00197##
[0054] As used herein, the terms "phosphate" or "phosphates" does
not include phosphate derivatives of ascorbic acid, such as sodium
or magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate and
other known phosphate derivatives of ascorbic acid with antioxidant
properties.
[0055] Preferably, the composition can be prepared contains a
phosphate form substantially free of calciums such as the
phosphoric acid glycerophosphoric acid (C.sub.3H.sub.9O.sub.6P).
Glycerophosphoric acid can be present in two different chemical
structures, including: [0056] i) alpha-glycerophosphoric acid (also
known as 3-glycerophosphate, 1-glycerophosphate, 3-phosphoglycerol,
alpha-phosphoglycerol, glycerol-3-phosphate, glycerol 1-phosphate,
glycerol-3-P, glycerophosphoric acid, 1-glycerophosphoric acid,
alpha-glycerophosphate), and [0057] ii) beta-glycerophosphoric acid
(also known as glycerol 2-phosphate, beta-glycerol phosphate,
beta-GP, 2-glycerophosphoric acid, glycerophosphoric acid II).
[0058] More preferably, the compositions of the present invention
contain the sodium salts of glycerophosphoric acid. The term
"glycerophosphoric acid" includes alpha-glycerophosphoric acid,
beta-glycerophosphoric acid, or any mixture thereof. Sodium salts
of glycerophosphoric can further include the monosodium sodium salt
of glycerophosphoric acid (C.sub.3H.sub.8NaO.sub.6P), the disodium
sodium salt of glycerophosphoric acid
(C.sub.3H.sub.7Na.sub.2O.sub.6P), and/or any mixture of the mono-
and disodium salts. Sodium salts of glycerophosphoric acid are
herein referred as "sodium glycerophosphate".
[0059] The sodium glycerophosphate may further contain some bound
water and may be in its hydrated form. The bound water is present
in an amount of about 20 to about 40%; preferably between about 25
to about 35% per weight. For the present invention, the sodium
glycerophosphate in accordance to the descriptions provided in
European Pharmacopoeia 6.sup.th Ed. (2007) represents one of the
preferred forms and qualities of sodium glycerophosphate.
[0060] Excluding any calcium salts of glycerophosphoric acid, the
composition may be prepared with other possible salts of
glycerophosphoric acid such as the potassium salts of
glycerophosphoric acid, the magnesium salts of glycerophosphoric
acid, the manganese salts of glycerophosphoric acid, and/or any
possible combination thereof including the sodium salts of
glycerophosphoric acid. Those skilled in the art will recognize
that calcium glycerophosphate or any other calcium salts of
phosphoric acid are not phosphates free of calcium and, therefore,
are not used in the present invention.
[0061] The compositions of the invention contain phosphate(s) in an
amount effective to reduce pigmentation. For example, phosphate is
present in the composition in an amount from about 0.1% to the
solubility limit of the phosphate in the composition. Preferably,
the phosphate is present in the composition in the amount of about
0.1% to about 25%, more preferably about 0.2% to about 10%, most
preferably about 1% to about 5% by weight.
[0062] Preferably, the composition is prepared with sodium
glycerophosphate (C.sub.3H.sub.7Na.sub.2O.sub.6P.times.H.sub.2O
according to specifications provided in European Pharmacopoeia
6.sup.th Ed. (2007)) between about 1% to about 5% by weight.
[0063] The present invention also provides a skin lightening
composition, which is well tolerated. Preferably, such skin
lightening compositions provide less skin irritation than is
commonly observed with several of the skin lightening products
containing hydroquinone; in particular those skin lightening
products with additionally contain chemicals with known human skin
irritant properties such as retinoic acid, tretinoin, retinol,
alpha hydroxy acids such as glycolic or lactic acid, beta hydroxyl
acids such as salicylic acid, azelaic acid, free short chain fatty
acids, free short chain fatty acid esters, ionic surfactants such
as SLS or SLES. Examples of skin lightening products containing
hydroquinone along with chemicals with known human skin irritant
properties, include, but are not limited to, Tri-Luma.RTM. (from
Galderma), EpiQuin.RTM. Micro (from SkinMedica), Obagi Nu-Derm.RTM.
Clear and Obagi Nu-Derm.RTM. Blender (both from OMP, Inc.) and
Lustra.RTM. Hydroquinone USP 4% (from TaroPharma).
[0064] Specifically, the compositions of the present invention are
well tolerated and do not (or only minimally) lead to visibly
noticeable skin redness (i.e., erythema, contact dermatitis) or
rash (i.e., edema, contact allergy, uticaria) when used once to
twice daily for a prolonged period of time (i.e., more than two
weeks) under normal in use conditions typical of a skincare or
dermatological product. More specifically, the compositions of the
present invention provide less skin irritation as compared to skin
lightening products containing hydroquinone as observed in
repetitive skin irritancy patch tests in humans or animals realized
according to the art-recognized models described in J.
Toxicol.--Ot. & Ocular Toxicol., 1(2); 109-115. 1982; Contact
Dermatitis, 20(1); 3-9. 1989; Lanman, B. M., E. B. Elvers, and C.
J. Howard, 1968, "The Role of Human Patch Testing in a Product
Development Program," Joint Conference on Cosmetic Sciences, The
Toilet Goods Association (currently, the Cosmetic, Toiletry and
Fragrance Association), Washington, D.C., Apr. 21-23, 1968 and
Patel, S. M., E. Patrick, and H. I. Maibach, 1976, "Animal, Human,
and In Vitro Test Methods for Predicting Skin Irritation,"
Dermatotoxicology, Chpt. 33, 5th Ed., Eds. F. N. Marzulli, H. I.
Maibach, Taylor, and Frances) (each of which are incorporated
herein by reference).
[0065] Preferably, the present invention provides methods and
compositions for skin depigmentation which are effective in
concentrations not resulting in significant skin irritancy as
determined by the art-recognized models described herein.
Preferably, the present invention provides compositions which are
substantially free of calcium, steroids, parabens, anti-microbial
preservatives and/or formaldehyde releasers The term "substantially
free" as used herein means that the composition of interest (e.g.,
calcium) is present in the composition in an amount less than 0.1%
per weight, preferably less than 0.5% by weight and most preferably
less than 0.01% per weight. Preferably, the present invention
provides compositions which are suitable for topical application,
cosmetically elegant and fast absorbing. That is, the compositions
of the present invention do not provide sticky, oily, greasy or
otherwise unpleasant feeling when applied onto skin after about one
to maximum of about two minutes of application; in case applied as
dose per skin area typical for skincare or dermatological products
(typically less than 1 mg of composition per cm.sup.2).
Additional Active Agents
[0066] The present invention also provides stable skin lightening
composition, which contain at least one calcium sequestration or
binding agent, as described above, and which may further contain at
least one additional active agent capable or modulating or reducing
(as assessed in vitro and/or in vivo) at least one of the following
steps in melanogenesis:
[0067] i) uptake of L-tyrosine into melanocytes, and/or
[0068] ii) uptake of L-phenylalanine into melanocytes, and/or
[0069] iii) turnover of phenylalanine into tyrosine by
phenylalanine hydroxylase, and/or
[0070] iv) uptake of L-tyrosine into melanosmes, and/or
[0071] v) turnover of L-tyrosine into L-Dopa by tyrosinase or
tyrosine hydroxylase, and/or
[0072] vi) turnover of L-Dopa into dopaquinone by tyrosinase,
and/or
[0073] vii) transfer of melanosme from melanocytes to
keratinocytes.
[0074] Several compounds can be described as compounds capable of
competing with the transport (active uptake into cell or cell
organelle) of L-tyrosine into melanocytes and/or into melanosmes,
what may result in a reducing or limiting pool of L-tyrosine for
melanogenesis.
Amino Acids
[0075] Several amino acids are known competitively inhibit the
uptake of L-tyrosine into melanocytes and/or melanosmes. Amino
acids L-alanine, glycine, L-isoleucine, L-leucine, but not their
D-forms, were described to have hypopigmenting effects in an in
vitro assay using B16F0 melanoma cells as cell model for studying
melanogenesis. (See Biol Pharm Bull 30, 2007, pp. 677-681). These
amino acids were shown not to function as inhibitors of
tyrosinase.
[0076] Another compound potentially inhibiting tyrosine transport
is the sulfur homologue of tyrosine 4-S-cysteinylphenol. (See
Biochem J 280, 1991, pp. 721-725). 4-S-cysteinylphenol may also act
as substrate of tyrosinase and can therefore be also regarded as
inhibitor of tyrosinase. There is some evidence that amino acids
L-phenylalanine and L-tryptophan also compete for tyrosine
transport. (See Biochem J 280, 1991, pp. 721-725; J Biol Chem 271,
1996, pp. 4002-4008). However, phenylalanine is a precursor of
melanin and is therefore excluded in the present invention.
L-Tyrosine is formed from L-phenylalanine in the presence of enzyme
phenylalanine hydroxylase in melanocytes. Similarly, tryptophan is
excluded in the present invention.
[0077] Thus, the compositions of the present invention can contain
at least one calcium sequestration or binding agent and can further
contain L-alanine, glycine, L-isoleucine, L-leucine or a
combination thereof. L-alanine, glycine, L-isoleucine, L-leucine
can also include esters (e.g. R--COOR' with R=from amino acid and
R'=branched or not branched alky/aryl side chain consisting of up
to 18 carbons), amides (R--NH(C.dbd.O)--R'), with R=from amino acid
and R'=branched or not branched alky/aryl side chain consisting of
up to 18 carbons) or both to increase their skin bioavailability.
These amino acids also include zwitterions with a sodium or
potassium as positive ion (cation).
[0078] The present composition can also contain amino acids or
their respective derivatives (esters, amides, etc.) in an amount
effective to reduce pigmentation or reduce the transport of
L-tyrosine either into the melanocyte and/or into the melanosome.
For example, the amino acid is present in the composition in an
amount from about 0.001% to the solubility limit of the amino acid
in the composition. Preferably, the amino acid is present in the
composition in the amount of about 0.01% to about 10%, more
preferably about 0.05% to about 5%, most preferably about 0.1% to
about 2% by weight.
[0079] In one embodiment, the invention provides a composition
containing one or more phosphates, substantially free of calcium,
and further containing L-leucine in an amount of about 0.1% to
about 2% by weight. Preferably, the present invention provides a
composition containing sodium glycerophosphate
(C.sub.3H.sub.7Na.sub.2O.sub.6P.times.H.sub.2O; according to
specifications provided in Ph. Eur. 6.sup.th Ed.) in an amount of
about 1% to 5% by weight and further contains L-leucine in an
amount of about 0.1% to 2% by weight.
Tyrosinase Inhibitors
[0080] The compositions of the present invention can contain at
least one calcium sequestration or binding agent and may further
contain one or more compounds capable of reducing (as assessed in
vitro and/or in vivo) the turnover of L-tyrosine into L-Dopa by
tyrosinase or tyrosine hydroxylase, and/or the turnover of L-Dopa
into dopaquinone by tyrosinase. Compounds which reduce the turnover
of L-tyrosine into L-Dopa and/or reduce the turnover of L-Dopa into
dopaquinone are generally referred as tyrosinase inhibitors meaning
that they inhibit of tyrosinase activity, tyrosinase gene
expression, and/or tyrosine protein formation and/or
maturation.
[0081] For example, the following compounds have been described to
act as tyrosinase inhibitors as assessed in diverse in vitro
enzymatic and cellular assays (see Journal of Medicinal Chemistry
42 (2007) 1370-1381 [including supporting information mentioned
under Appendix A]; Pigment Cell Res 19, 2006, pp. 550-571)
(incorporated herein by reference) and are therefore suitable to be
incorporated, either alone or in combination, into the compositions
described herein: hydroquinone (1,4-benzenediol); diphenylmethane
derivatives (see WO 2004/105736; incorporated herein by reference)
including but not limited to 4-(1-phenylethyl)1,3-benzenediol
(phenylethyl resorcinol); kojic acid; alpha-arbutin; beta-arbutin;
deoxyarbutin, L-mimosine; monobenzyl ether of hydroquinone;
hydroquinone fatty esters; L-tropolone; ascorbic acid; benzoic
acid; oxyresveratrol (i.e., 2,4,3',5'-tetrahydroxystilbene);
quercetin; benzaldehyde; aloesin; trans-resveratrol; anisaldehyde;
cinnamic acid; gnetol; dihydrognetol;
3,3',4-hydroxy-trans-stilbene; 3,3',4,4'-hydroxy-trans-stilbene;
3-amino-L-tyrosine, 2-aminophenol; isoliquiritigenin;
4-hydroxychalcone; butein; 4'-hydroxychalcone;
2',4'-dihydroxychalcone; 2',4-dihydroxychalcone; trans-4-azobenzene
carboxylic acid; cis-4-azobenzene carboxylic acid;
trans-4,4'-azobenzene dicarboxylic acid; cis-4,4'-azobenzene
dicarboxylic acid; castanospermine; deosynojirimycin; Ko-YGC;
Ko-YGV; Ko-YGE; Ko-YGT; Ko-YGL; Ko-YGW; Ko-YGF; Ko-YGH; Ko-YGN;
Ko-YGD; Ko-YGG; Ko-YIG; Ko-YYG; Ko-YSG; Ko-YMG; Ko-YQG; Ko-YRG;
Ko-YHG; Ko-YNG; Ko-YDG; Ko-FIY; Ko-FRY; Ko-FYY; Ko-FWY; Ko-FFY;
Ko-KWY; Ko-KRY; Ko-KKY; Ko-KIY; Ko-FWW; Ko-FWF; Ko-FWI; Ko-FWD;
Ko-WWY; glabridin; N-cyclopenthyl-N-nitrosohydroxyl-amine;
N-benzyl-N-nitrosohydroxylamine; N-benzyl-N-nitrosohydroxylamine;
N-cyclopenthyl-N-nitrosohydroxyl-amine;
3,5-dihydroxy-4'-methoxystilbene; 3,4'-dimethoxy-5-hydroxystilbene;
piceid; rhapontigenin; rhaponticin; kurarinone; kushnol F;
4-hydroxyanisol; 2-hydroxy-4-methoxy benzaldehyde; cuminaldehyde;
artocarbene; norartocarpanone; 4-propylresorcinol;
3,4-dihydroxybenzonitrile; 3,4,2,4-trans-stilbene; artogomezianol;
andalasin; crocusatins H; crocin-1; crocin-3; 3,4-dihydroxycinnamic
acid; 4-hydroxy-3-methoxycinnamic acid; anisic acid;
2-methoxycinnamic acid; 3-methoxycinnamic acid; 4-methoxycinnamic
acid; kaempferol; glabrene; pyridoxine; Pyridoxamine; Pyridoxal;
Pyridoxamine 5'-phosphate; Protocatechuic acid methyl ester;
Protocatechuic acid; m-coumaric acid; 3-caffeoylquinic acid;
4-caffeoylquinic acid; 5-caffeoylquinic acid; 3,4-dicaffeoylquinic
acid; Caffeic acid; Fisetin; 3,7,4'-trihydroxyflavone; Morin;
Luteolin; Apigenin; Galangin; Diethyldithiocarbamate;
Phenylthiourea; Phloroglucinol; Eckstolonol; Eckol;
Phlorofucofuroeckol; Dieckol; HPABS; Gluthatione;
B-Mercaptoethanol; Protocatechualdehyde; 8'-epi-cleomiscosin A;
3,4-Dihydroxybenzaldoxime; 3-Hydroxy-4-methoxybenzaldoxime;
3,4,5-Trihydroxybenzaldoxime; 4-Hydroxy-3-methoxy benzaldoxime;
3-Ethoxy-4-hydroxy benzaldoxime; 4-Hydroxybenzaldoxime;
3,4-Dihydroxy-benzaldehyde-O-ethyloxime;
3,4-Dihydroxybenzaldehyde-O-(4-methylbenzyl)-oxime;
3-Hydroxy-4-methoxy benzaldehyde-O-ethyloxime;
3,4,5-Trihydroxybenzaldehyde-O-ethyloxime;
4-Hydroxy-3-methoxybenzaldehyde-O-ethyloxime;
3-Ethoxy-4-hydroxybenzaldehyde-O-ethyloxime;
4-Hydroxybenzaldehyde-O-ethyloxime;
4-Hydroxy-3-methylbenzaldehyde-O-ethyloxime;
3,5-Dimethyl-4-hydroxybenzaldehyde-O-ethyloxime;
(+)-Androst-4-ene-3,17-dione; Androsta-1,4-diene-3,17-dione;
17.beta.-Hydroxyandrosta-1,4-dien-3-one;
11.alpha.-Hydroxyandrost-4-ene-3,17-dione; 17.beta.,
11.alpha.-Dihydroxyandrost-4-en-3-one; Esculetin; Lappaconitine;
Stigmast-5-ene-3.beta.,26-diol; Stigmast-5-ene-3.beta.-ol;
Campesterol; arctostaphylos uva ursi (bearberry) leaf extract;
glycyrrhiza glabra (licorice) extract; sanguisorba officinalis
(burnet) extract; scutellaria baicalensis root (skull cap) extract;
and morus alba (mulberry) extract; pinosylvin, dihydropinosylvin;
gallic acid; gentisic acid; methyl gentisate;
epigallocatechin-3-O-gallate; epigallocatechin; green tea leave
extract; ellagic acid; pyognol; myrica rubra leave extract; and/or
octadecenedioic acid.
[0082] In addition to these recited tyrosinase inhibitors, any
biological precursors (pro-forms) of above chemicals can also be
included in the present invention. Biological precursors can be
simple esters (i.e. methyl-, ethyl-, propyl-, or butyl-esters) of
inhibitors with carboxy group. Also included are derivatives of
ascorbic acid, such as aminopropyl ascorbyl phosphate, magnesium
ascorbyl phosphate, alkyl esters of L-ascorbic acid such as
L-ascorbyl palmitrate, L-ascorbyl isopalmitate, L-ascorbyl
dipalmitate, L-ascorbyl isostearate, L-ascorbyl distearate,
L-ascorbyl diisostearate, L-ascorbyl myristate, L-ascorbyl
isomyristate, L-ascorbyl 2-ethylhexanoate, L-ascorbyl
di-2-ethylhexanoate, L-ascorbyl oleate and L-ascorbyl dioleate;
phosphates of L-ascorbic acid such as L-ascorbyl-2-phosphate and
L-ascorbyl-3-phosphate; sulfates of L-ascorbic acid such as
L-ascorbyl-2-sulfate and L-acorbyl-3-sulfate; as well as their
sodium, potassium, magnesium and/or manganese salts.
[0083] The present composition may contain at least one tyrosinase
inhibitor in an amount effective to reduce pigmentation or reduce
the turnover of L-tyrosine into L-Dopa by tyrosinase or tyrosine
hydroxylase, and/or the turnover of L-Dopa into dopaquinone by
tyrosinase. For example, the tyrosinase inhibitor can be present in
the composition in an amount from about 0.001% to the solubility
limit of the tyrosinase inhibitor in the composition. Preferably,
the tyrosinase inhibitor is present in the composition in the
amount of about 0.01% to about 15%, more preferably about 0.05% to
about 10%, most preferably about 0.1% to about 5% by weight. The
present invention provides a composition containing one or more
phosphates, substantially free of calcium, and further containing:
a) hydroquinone (1,4-benzenediol) in an amount of about 0.1% to
about 10% by weight, b) 4-(1-phenylethyl)1,3-benzenediol
(phenylethyl resorcinol) in an amount of about 0.1% to about 5% by
weight, c) arbutin in an amount of about 0.1% to about 10% by
weight, d) bearberry leaf extract in an amount of about 0.1% to
about 10% by weight, e) kojic acid in an amount of about 0.1% to
about 5% by weight, f) oxyresveratrol in an amount of about 0.1% to
about 5% by weight, and/or g) gnetol in an amount of about 0.1% to
about 5% by weight.
[0084] The compositions of the invention may contain, in some
embodiments, one or more phosphates, substantially free of calcium,
and may further contain hydroquinone (1,4-benzenediol) in an amount
of about 1% to about 10% by weight and/or may further contain
4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an
amount of about 0.1% to about 5% by weight
Melanosome Transfer Inhibitors
[0085] In some embodiments, the compositions of the present
invention contain at least one calcium sequestration or binding
agent and may additionally contain one or more compounds capable of
reducing (as assessed in vitro and/or in vivo) the transfer of
melanosmes from melanocytes to keratinocytes. Inhibitors of the
transfer of melanosomes from melanocytes to keratinocytes have been
described previously (see Pigment Cell Res 19, 2006, pp. 550-571)
and include, for example, niacinamide (vitamin B3); centaureidine;
lectins; neoglycoproteins and certain inhibitors of serine
proteases. In addition, N-acetyl-glucosamine may also reduce
melanosme transfer.
[0086] The present composition may contain at least one melanosme
transfer inhibitor in an amount effective to reduce pigmentation or
reduce the transfer of melanosmes from melanocytes to
keratinocytes. For example, the melanosme transfer inhibitor can be
present in the composition in an amount from about 0.001% to the
solubility limit of the melanosme transfer inhibitor in the
composition. Preferably, the melanosme transfer inhibitor is
present in the composition in the amount of about 0.01% to about
12%, more preferably about 0.05% to about 6%, most preferably about
0.1% to about 3% by weight.
[0087] The invention provides a composition containing one or more
phosphates, substantially free of calcium, and may further contain
hydroquinone in an amount of about 0.1% to about 10% by weight, and
further containing a melanosome transfer inhibitor in an amount of
about 0.1% to about 3% by weight.
[0088] For example, the present invention also provides a
composition including one or more phosphates, substantially free of
calcium, and also includes 4-(1-phenylethyl)1,3-benzenediol
(phenylethyl resorcinol) in an amount of about 0.1% to about 5% by
weight, and may also include a melanosome transfer inhibitor in an
amount of about 0.1% to about 3% by weight.
[0089] In one embodiments, the invention additionally provides a
composition containing one or more phosphates, substantially free
of calcium; hydroquinone in an amount of about 0.1% to about 10% by
weight; 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol)
in an amount of about 0.1% to about 5% by weight: and a melanosome
transfer inhibitor in an amount of about 0.1% to about 3% by
weight.
Melanocortin Receptor 1 Inhibitors
[0090] The compositions of the present invention can contain at
least one calcium sequestration or binding agent and can further
contain one or more compounds capable of decreasing (as assessed in
vitro and/or in vivo) melanocortin receptor 1 (MC1R) activity. For
instance, agouti signaling protein regulates skin pigmentation by
antagonizing the binding of .alpha.-MSH to MC1R. (See Abdel-Malek
et al., J. Cell Sci. 2001, 114 (Pt.5):1019-24; Jordan and Jackson,
Bioessays. 1998, 20(8):603-606; Voisey and Van Daal, Pigment Cell
Res. 2002; 15(1):10-18; Wolff, Pigment Cell Res. 2003, 16(1):2-15).
The signaling inhibition through the receptor results from two
effects (i) a direct competition at the binding site, and (ii) a
downregulation of the receptor signaling. (See Barsh et al.,
Pigment Cell Res., 2000, 13 Suppl. 8:48-53). As an example,
undecylenoyl phenylalanine was described to have an affinity
towards MC1R and was shown to act as antagonist of .alpha.-MSH in
vitro.
[0091] In some embodiments, the present composition contains at
least one .alpha.-MSH antagonist in an amount effective to
antagonizing the binding of .alpha.-MSH to MC1R. For example, the
.alpha.-MSH antagonist is present in the composition in an amount
from about 0.001% to the solubility limit of the .alpha.-MSH
antagonist in the composition. Preferably, the .alpha.-MSH
antagonist is present in the composition in the amount of about
0.01% to about 10%, more preferably about 0.05% to about 5%, most
preferably about 0.1% to about 4% by weight.
[0092] In one embodiment, the present invention provides a
composition containing one or more phosphates, substantially free
of calcium, and also contains hydroquinone in an amount of about
0.1% to about 10% by weight and an .alpha.-MSH antagonist in an
amount of about 0.1% to about 4% by weight. By way of non-limiting
example, the .alpha.-MSH antagonist is undecylenoyl phenylalanine
(with chemical structure:
CH.sub.2.dbd.CH--(CH.sub.2).sub.8--CO--NH--CH(--COOH)(--CH.sub.2--C.sub.6-
H.sub.5), as described in WO2003/061768].
[0093] Preferably, the present invention additionally provides a
composition containing one or more phosphates, substantially free
of calcium; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount
of about 0.1% to about 5% by weight; and an .alpha.-MSH antagonist
in an amount of about 0.1% to about 4% by weight. By way of
non-limiting example, the .alpha.-MSH antagonist is undecylenoyl
phenylalanine.
[0094] Alternatively, the present invention also provides a
composition including one or more phosphates, substantially free of
calcium; hydroquinone in an amount of about 0.1% to about 10% by
weight; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount of
about 0.1% to about 5% by weight; and an .alpha.-MSH antagonist in
an amount of about 0.1% to about 4% by weight. Preferably, the
.alpha.-MSH antagonist is undecylenoyl phenylalanine.
[0095] Also provided are compositions containing one or more
phosphates, substantially free of calcium; hydroquinone in an
amount of about 0.1% to about 10% by weight;
4-(1-phenylethyl)1,3-benzenediol by weight in an amount of about
0.1% to about 5% by weight; and an .alpha.-MSH antagonist in an
amount of about 0.1% to about 4% by weight. For example, the
.alpha.-MSH antagonist is undecylenoyl phenylalanine. These
compositions may additionally contain a melanosome transfer
inhibitor in an amount of about 0.1% to about 3% by weight.
Dermatological Drugs, Biologics and Skin Care Additives
[0096] Any of the compositions of the present invention can include
at least one calcium sequestration or binding agent and can further
include one or more compounds, skincare actives or dermatology
drugs and/or biologics other than calcium containing chemicals
known in the arts of the treatment of skin pigmentation; general
dermatology; cosmetic dermatology; skincare such as, for example
skin moisturization; or rejuvenation, including but not limiting
to, transforming growth factor (including TGF-beta1, TGF-beta2,
TGF-beta3); collagen stimulators such as certain growth factors
(e.g. PDGFs, FGFs, etc.) and/or certain peptides (e.g.,
Matrixyl-3000); stimulators of keratinocyte proliferation such as
(e.g. EGF, KGFs, etc.); inhibitors of collagen degrading enzymes
(e.g., natural or synthetic inhibitors of MMPs); inhibitors of
elastin degrading enzymes (e.g., natural or synthetic inhibitors of
elastase); appropriate antioxidants (such as vitamin C, vitamin E,
ferulic acid, lipoic acid, polyphenols, ergothioneine, etc.) and
their derivatives; appropriate sunscreens and/or solar UV
reflectors (e.g., spheres and/or microparticles made of polymers,
etc.); anti-inflammatory agents (e.g., steroids, non-steroidal
anti-inflammatory agents, anti-inflammatory interleukins, IL-1ra,
etc.); emollients; humectants (e.g., glycerin, urea, hyaluronic
acid, natural moisturizing factors, etc.); inhibitors of
neurotransmitter release; skin penetration agents (e.g., oleic
acid, propylene glycol, etc.); skin protectants (e.g., allantoin,
calamine, coca butter, cod liver oil, colloidal oatmeal,
dimethicone, glycerin, hard fat, kaolin, lanolin, mineral oil,
petrolatum, topical starch, white petrolatum, etc.); vitamins
(e.g., vitamin B3, vitamin B5, vitamin B6, vitamin D, vitamin F,
etc.) and derivatives thereof; keratolytic agents (e.g., urea,
alpha-hydroxyl acids (e.g., lactic acid, glycolic acid, citric
acid, etc.), beta-hydroxyl acids (e.g., salicylic acid, etc.), and
polyhydroxyacids, etc.)); external analgesic agents (e.g.,
benzocaine, butamben picrate, dibuccaine, diemethisoquin,
dyclonine, lidocaine, pramoxine, tetracaine, etc.) and their
respective salts; antipruritic agents; cell metabolism stimulants
(e.g., pantothenic acid, niacin, nicotinic acid esters, etc.);
appropriate anti-acne agents; astringents; counter irritants;
antihistamine agents; azelaic acid; retinoic acid, retinol and/or
derivatives; natural oils (e.g., jojoba oil, shea butter, etc.);
appropriate biological components (e.g., cell lysate, human dermal
fibroblast lysate, conditioned cell culture medium, stem cell
components, etc.); mixtures of growth factors (e.g., PSP.RTM. from
Neocutis Inc, Nouricel-MD.RTM. from SkinMedica Inc., etc.); and/or
wound healing agents.
Formulations and Modes of Administration
[0097] Those skilled in the art will recognize that any of the
compositions of the present invention can contain at least one
calcium sequestration or binding agent and can further contain one
or more compounds capable of chemically stabilizing any of the
ingredients present in the composition. Compounds that help to
chemically stabilize any of the ingredients may include, but are
not limited to, sodium metabisulfite; sodium bisulfate; BHT; BHA;
propyl gallate; disodium EDTA; lemon extract; antioxidants,
including ascorbic acid (vitamin C) and its derivatives such as
phosphate derivatives of ascorbic acid including sodium or
magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate, and
other known phosphate derivatives of ascorbic acid having
antioxidant properties; and tocopherol and derivatives of
tocopherol such as, sodium vitamin E phosphate (VEP), lauryl imino
dipropionic acid tocopheryl phosphate, tocopheryl glucoside,
tocopheryl succinate, tocophersolan (tocopheryl polyethylene glycol
1000 succinate), disodium lauriminodipropionate tocopheryl
phosphates, tocophereth-5,10,12,18, and 50 (polyethylene glycol
(PEG) tocopheryl ethers. Sulfites such as sodium metabisulfite,
and/or sodium bisulfate are particularly useful to stabilize
hydroquinone or other chemically labile (i.e., easily being
oxidized) compounds present in the said composition. In general,
the compositions may contain between about 0.05 to 0.5% sulfites by
weight.
[0098] The compounds, compositions and formulations of the instant
invention can be administered by any means known in the art.
Preferably, the compositions of the present invention are
formulated as a topical preparation or dosage form. Topical
preparations are ointments, creams, gels and lotions. The
definition of these topical dosage forms is given by Bhuse L. et
al. (Int J Pharm 295: 2005, 101-112) (incorporated by reference).
The carrier can also be a liquid, a foam, a mousse, a spray, an
aerosol, an oil-in-water emulsion, a water-in-oil emulsion, a
triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a
solution, a paste, a jelly, a patch, a wipe, a cloth, and/or a
dispersion or suspension. The carrier may contain niosomes,
liposomes, nanospheres, microspheres, nanoparticles,
microparticles, lipid droplets, solid particles, pigments and/or
water droplets.
[0099] In one preferred embodiment, the carrier is a cream. In
various embodiments, the cream may be either an oil-in-water
mixture, or a water-in-oil based carrier. In another preferred
embodiment, the carrier is a gel or hydrogel.
[0100] Those skilled in the art will recognize that any reference
herein to a composition of the invention includes any composition
containing one or more phosphates free of calcium in conjunction
with a carrier.
[0101] Those skilled in the art will also recognize that additional
agents can be added in any of the methods and compositions of the
invention. These agents may include, but are not limited to, e.g.,
antimicrobial agents (e.g., parabens, phenoxyethanol,
chlorophenesin, propylene glycol, butylene glycol,
ethylhexylglycerin, imidazolidinyl urea,
methylchloroisothiazolinone, potassium benzoate, DMDM hydantoin,
etc.), etc.), color additives, fragrances, sensory stimulating
agents, polymers, surfactants, water, oils, etc. Information
regarding the preparation of compositions, can be found, e.g., in
Volume 3: Liquid Products, Volume 4: Semisolid Products and Volume
5: Over-the-Counter Products, of the `Handbook of Pharmaceutical
Manufacturing Formulations` (edited by S. K. Niazi, CRC Press, Boca
Raton, 2004). Moreover, information regarding the preparation of
cosmetic or cosmeceutical compositions may be found in the
formulary archive of the Happy Magazine (see
http://www.happi.com/formulary). In addition, formulary information
for cosmetic or cosmeceutical compositions can be also obtained
from diverse ingredient suppliers such as Croda, Ciba, BASF, Dow
Chemicals, etc.
[0102] The present invention provides stable and none to little
irritating (i.e., no or only limited and acceptable skin irritancy)
compositions for topical application to the skin to treat skin
pigmentation disorders, such as melasma, post-inflammatory
hyperpigmentation, pigmentation changes due to skin aging, or any
other skin conditions related with normal such as skin of color or
abnormal pigmentation such as hypo- or hyper-pigmentation in
humans.
[0103] Stable compositions can be obtained by (1) selecting
appropriate calcium sequestration or binding agent
concentration(s), (2) selecting appropriate salt form(s) of the
agent other than calcium salt(s), (3) adjusting the pH of the
composition, (4) selecting appropriate type of formulation (e.g.,
liquid, a foam, a mousse, a spray, an aerosol, an oil-in-water
emulsion, a water-in-oil emulsion, a triple emulsion, a
nanoemulsion, a microemulsion, a hydrogel, a solution, a paste, a
jelly, a patch, a wipe, a cloth, and/or a dispersion or suspension)
for the composition, (5) selecting appropriate ingredients allowing
to stabilize the composition, (6) selecting and appropriate
container for composition suitable for topical administration
(e.g., tube, airless pump, jar, vial, monodose, etc.), and/or (7)
selecting conditions allowing the preparation of a stable
preparation (e.g., preparation of composition under inert gas,
etc.).
[0104] The term "stable" when applied to the compositions of the
instant invention is defined as having a comparable color when the
composition is placed on a flat and inert surface (i.e., removed
from its container) under normal ambient air and light conditions
(i.e., air and light conditions as normally exist in the living
room at home) when kept for at least one month at room temperature
(about 25.degree. C.).
[0105] Other than the above-defined color stability, stability of
the composition may further include physical stability (e.g.,
viscosity, odor, appearance, texture, etc.) and chemical stability
of the selected active(s) such as a drug active (e.g., calcium
sequestration agent, hydroquinone, etc.). Chemical stability can be
assessed using HPLC or other appropriate analytical methods. When
the composition is placed (e.g., filled) into a suitable container
(e.g., a tube, pump, jar, etc.), the composition should be
chemically stable (i.e., less than a .+-.10% change in the content
as compared to the baseline value) for at least a year under normal
storage condition (i.e., room temperature; or common temperature
fluctuations occurring in house/living room/bath room due to
changes in season or geographical region). Stability may also be
tested under accelerated conditions at elevated temperatures (e.g.,
40.degree. C. or higher) in order to predict stability of the
composition at room temperature (about 25.degree. C.).
[0106] The compositions of the present invention may be applied to
the entire body, including the face. These compositions may be
applied as needed or alternatively, as part of a skin care routine.
Preferably, the composition is applied weekly. More preferably, the
composition is applied once daily at night at least half an hour
before bedtime. However, it can be also applied twice daily, with
the preferred mode being once in the morning and once in the
evening. When compositions are applied twice daily, the
compositions may be the same or different for each application. For
example, the same composition may be applied twice daily or
alternately, one composition may be applied in the morning and a
second, different composition, may be applied in the evening. The
compositions can be applied to any mammal (e.g., a primate, rodent,
feline, canine, domestic livestock (such as cattle, sheep, goats,
horses, and pigs). Preferably, the compositions are applied to
humans.
[0107] In some embodiments, a sunscreen formulation offering a SPF
15 or higher is used in addition during day time in order to
protect skin from sun exposure or damage. Additionally, the
compositions of the present invention may further contain one or
more sunscreen active agents, such as those that provide a UV-B
filter and, in some embodiments, additionally a UV-A filter.
Examples of suitable UV-A and UV-B filters include those described
in U.S. Pat. No. 7,078,022 (incorporated herein by reference).
[0108] Preferably, the compositions of the invention dry quickly
and cleanly (without visible residue or significant stickiness)
after application of a normal amount (i.e., 0.2 to 2 mg composition
per cm.sup.2) on the skin.
[0109] The examples as set forth herein are meant to exemplify the
various aspects of carrying out the invention and are not intended
to limit the invention in any way. Unless otherwise specified, it
is to be understood that the concentrations of the component
ingredients in the compositions of the invention are in %, w/w,
based on the total weight of the composition.
Example 1
[0110] Exemplary compositions formulated in accordance with the
present invention are presented in Table 19. These compositions
serve as illustrative formulations which provide several of the
advantageous features of the invention, namely, mildness to the
skin after application with no or only limited skin irritancy;
clearness and non-greasiness upon application (transparent) to face
and other skin areas other than the palms and the soles; and
quick-drying, particularly when the compositions are preferably
formulated as water-in-oil formulations.
TABLE-US-00019 TABLE 19 INGREDIENT % BY NO. PHASE (TRADE NAME) INCI
DESIGNATION SUPPLIER WEIGHT 1 A DEIONIZED WATER WATER (AQUA) 63.310
2 A NA.sub.2EDTA DISODIUM EDTA AKZO/DEWOLF 0.100 3 A KELTROL CG-T
XANTHAN GUM CP KELCO/ 0.300 UNIVAR 4 B LIPOWAX D CETEARYL ALCOHOL
LIPO 8.250 CETEARETH-20 5 B LIPO GMS 450 GLYCERYL STEARATE LIPO
6.000 6 B CERAPHYL 230 DIISOPROPYL ADIPATE ISP SUTTON 5.000 7 B DC
TORAY FZ-3196 CAPRYLYL METHICONE DOW CORNING/ 3.000 UNIVAR 8 B DC
200 FLUID 100 CST DIMETHICONE DOW CORNING/ 1.000 UNIVAR 9 B LIPOVOL
J SIMMONDSIA LIPO 1.000 CHINENSIS (JOJOBA) SEED OIL 10 B SHEA
BUTTER HMP BUTYROSPERMUM EARTH SUPPLIED 1.000 PARKII (SHEA BUTTER)
PRODUCTS 11 B VITAMIN E ACETATE OIL DL-ALPHA BASF/ 0.200 (USP, FCC)
TOCOPHERYL ACETATE CHEMCENTRAL 12 C DEIONIZED WATER WATER (AQUA)
0.100 13 C ELESTAB CPN ULTRA PURE CHLORPHENESIN COGNIS 0.300 14 C
PHENOXETOL PHENOXYETHANOL CLARIANT 0.600 15 C SEPIWHITE MSH
UNDECYLENOYL SEPPIC 0.500 PHENYLALANINE 16 C SODIUM
GLYCEROPHOSPHATE SODIUM DR. PAUL 3.000 (Ph. Eur. 6 Ed, Item#
500012045500) GLYCEROPHOSPHATE LOHMANN 17 C L-LEUCINE LEUCINE
AJINOMOTO 1.000 18 C1 CITRIC ACID 50% SOLUTION CITRIC ACID PCI
1.920 (TO pH 4.5-5.0) 19 C2 GLYCERIN 99.7% (USP) GLYCERIN
ACME-HARDESTY 2.000 20 C2 SYMWHITE 377 PHENYLETHYL KAH/SYMRISE
0.500 RESORCINOL 21 C2 VITAGEN AMINOPROPYL BASF 0.500 ASCORBYL
PHOSPHATE 22 D SIMULGEL INS 100 HYDROXYETHYL SEPPIC 0.420
ACRYLATE/SODIUM ACRYLOYLDIMETHYL TAURATE COPOLYMER ISOHEXADECANE
POLYSORBATE 60 TOTAL 100.00
[0111] Such compositions (e.g., Table 19) were generally prepared
in a clean and sanitized stainless steel vessel, which was suitable
for blending products containing hydroquinone, as described herein
below: [0112] PHASE A: DISPERSE KELTROL IN WATER, MIX UNTIL ALL
HYDRATES; [0113] ADD REMAINING PHASE A INGREDIENTS, HEAT TO ABOUT
75.degree. C. WHILE MIX UNTIL ALL DISSOLVES. [0114] PHASE B:
COMBINE PHASE B INGREDIENTS IN A SEPARATE VESSEL AND MIX WHILE
HEATING TO 75.degree. C.; ONCE ALL WAXES MELT AND PHASE IS AT TEMP
AND UNIFORM, SLOWLY ADD TO PHASE A; COOL TO 35.degree. C. [0115]
PHASE C: COMBINE PHASE C INGREDIENTS WITH MECHANICAL STIRRING UNIT
AND MIX WITH MODERATE AGITATION [0116] PHASE C1: USE PHASE C1 TO
ADJUST pH OF PHASE C TO 4.0-4.5 [0117] PHASE C2: COMBINE PHASE C2
AND MIX WHILE HEATING SLIGHTLY TO 40.degree. C.; CONTINUE MIXING
UNTIL POWDERS DISSOLVE THEN ADD TO PHASE C; ADD PHASE C TO BATCH
WITH MODERATE AGITATION [0118] PHASE D: ADD PHASE D TO BATCH, MIX
UNTIL UNIFORM; [0119] HOMOGENIZE THE BATCH AT 3500 RPM FOR 5
MINUTES; SWITCH TO IMPELLER MIXING; COOL TO ROOM TEMPERATURE.
[0120] The composition obtained as described in Example 1 was then
filled into an airless pump container (e.g., 30 ml TopFill airless
pump from MegaPlast--Mega Pumps) and then tested for physical
stability (color, odor, viscosity, pH, appearance, etc.) under
accelerated conditions (40 to 50.degree. C.) for up to three
months. During this period of time, the composition filled into the
airless pump was stable (i.e., color, odor, viscosity, pH and
appearance did not change or only changed to a limited and
acceptable extent (.+-.10% from baseline)).
[0121] The composition obtained as described in Example 1 does not
leave greasy or oily residues on the skin and dries quickly and
cleanly (without visible residue or significant stickiness) within
one to two minutes after application on the skin.
Example 2
[0122] Additional compositions formulated in accordance with the
present invention are presented in Table 20. Again, these
compositions serve as illustrative formulations which provides the
advantageous features of the invention, namely, mildness to the
skin after application with no or only limited skin irritancy;
clearness and non-greasiness upon application (transparent) to face
and other skin areas other than the palms and the soles; and
quick-drying, particularly when the compositions are preferably
formulated as water-in-oil formulations.
TABLE-US-00020 TABLE 20 INGREDIENT % BY NO. PHASE (TRADE NAME) INCI
DESIGNATION SUPPLIER WEIGHT 1 A DEIONIZED WATER WATER (AQUA) 59.680
2 A NA.sub.2EDTA DISODIUM EDTA AKZO 0.100 3 A KELTROL CG-T XANTHAN
GUM CP KELCO 0.300 4 A ELESTAB CPN ULTRA PURE CHLORPHENESIN COGNIS
0.300 5 A PHENOXETOL PHENOXYETHANOL CLARIANT 0.600 6 A SEPIWHITE
MSH UNDECYLENOYL SEPPIC 0.500 PHENYLALANINE 7 A SODIUM
GLYCEROPHOSPHATE SODIUM DR. PAUL 3.000 (Ph. Eur. 6 Ed, Item#
500012045500) GLYCEROPHOSPHATE LOHMANN 8 A L-LEUCINE LEUCINE
AJINOMOTO 1.000 9 B LIPOWAX D CETEARYL ALCOHOL LIPO 6.000
CETEARETH-20 10 B LIPO GMS 450 GLYCERYL STEARATE LIPO 6.000 11 B
CERAPHYL 230 DIISOPROPYL ADIPATE ISP SUTTON 3.000 12 B DC TORAY
FZ-3196 CAPRYLYL METHICONE DOW CORNING 3.000 13 B DC 200 FLUID 100
CST DIMETHICONE DOW CORNING/ 1.000 UNIVAR 14 B LIPOVOL J SIMMONDSIA
LIPO 1.000 CHINENSIS (JOJOBA) SEED OIL 15 B SHEA BUTTER HMP
BUTYROSPERMUM EARTH SUPPLIED 1.000 PARKII (SHEA BUTTER) PRODUCTS 16
B VITAMIN E ACETATE OIL DL-ALPHA BASF/ 0.200 (USP, FCC) TOCOPHERYL
ACETATE CHEMCENTRAL 17 C CITRIC ACID 50% SOLUTION CITRIC ACID PCI
1.920 (TO pH 4.5-5.0) 18 D EASTMAN .TM. HYDROQUINONE HYDROQUINONE
EASTMAN/ 4.000 (USP GRADE) CHEMPOINT 19 E SODIUM METABISULFITE
SODIUM UPI 0.400 (NF/FCC) METABISULFITE 20 F GLYCERIN 99.7% (USP)
GLYCERIN ACME-HARDESTY 2.000 21 F SYMWHITE 377 PHENYLETHYL
KAH/SYMRISE 0.500 RESORCINOL 22 F VITAGEN AMINOPROPYL BASF 0.500
ASCORBYL PHOSPHATE 23 G SIMULGEL INS 100 HYDROXYETHYL SEPPIC 4.000
ACRYLATE/SODIUM ACRYLOYLDIMETHYL TAURATE COPOLYMER ISOHEXADECANE
POLYSORBATE 60 TOTAL 100.00
[0123] Such compositions (e.g., Table 20) were generally prepared
in a clean and sanitized stainless steel vessel, which was suitable
for blending products containing hydroquinone, as described herein
below: [0124] PHASE A: DISPERSE KELTROL IN WATER, MIX UNTIL ALL
HYDRATES; ADD EDTA, MIX UNTIL ALL DISSOLOVES; [0125] ADD REMAINING
PHASE A INGREDIENTS, HEAT TO 75.degree. C. WHILE MIX UNTIL ALL
DISSOLVES. [0126] PHASE B: COMBINE PHASE B INGREDIENTS, HEAT TO
75.degree. C., MIX UNTIL ALL MELTED AND UNIFORM; [0127] WHEN BOTH
PHASE A AND PHASE B AT 75.degree. C., ADD PHASE B INTO PHASE A WITH
AGITATION MIX FOR 10 MINUTES, START COOLING TO 50.degree. C. [0128]
PHASE C: ADJUST pH WITH PHASE C TO pH 4.5-5.0, COOL TO 45.degree.
C. [0129] PHASE D: ADD PHASE D TO BATCH WITH MIX, MIX UNTIL ALL
DISSOLVES AND UNIFORM. [0130] PHASE E: ADD PHASE E TO BATCH WITH
MIXING, MIX UNTIL ALL DISSOLVES. [0131] PHASE F: COMBINE PHASE F
INGREDIENTS, SLIGHTLY HEAT AND MIX UNTIL ALL DISSOLVES, ADD TO THE
BATCH. [0132] PHASE G: ADD PHASE G TO BATCH, MIX UNTIL UNIFORM;
[0133] HOMOGENIZE THE BATCH AT 3500 RPM FOR 5 MINUTES, SWITCH TO
IMPELLER MIXER, MIX; [0134] ADJUST pH WITH PHASE C TO pH 4.5-5.0 IF
NECESSARY.
[0135] The composition obtained as described in Example 2 was then
filled into aluminum tubes (or aluminum coated plastic tubes) and
then tested for physical stability (color, odor, viscosity, pH,
appearance) and chemical stability (by HPLC) of hydroquinone under
accelerated conditions (40 to 50.degree. C.) for up to three
months. During this period of time, the composition filled into
aluminum tubes was stable (i.e., color, odor, viscosity, pH and
appearance did not change or only changed to a limited and
acceptable extent (.+-.10% from baseline) and the hydroquinone
content remained between 3.84% to 4.24% (weight %).
[0136] The composition obtained as described in Example 2 does not
leave greasy or oily residues on the skin and dries quickly and
cleanly (without visible residue or significant stickiness) within
one to two minutes after application on the skin.
Example 3
[0137] Additional compositions formulated in accordance with the
present invention are presented in Table 21. These compositions
serve as illustrative formulations, which provide the advantageous
features of the invention, namely, stability of the composition,
mildness to the skin after application with no or only limited and
acceptable skin irritancy; clearness and non-greasiness upon
application (transparent) to face and other skin areas other than
the palms and the soles; and quick-drying, particularly when the
compositions are preferably formulated as water-in-oil
formulations.
TABLE-US-00021 TABLE 21 INGREDIENT % BY NO. PHASE (TRADE NAME) INCI
DESIGNATION WEIGHT 1 A DEIONIZED WATER WATER (AQUA) 59.680 2 A
NA.sub.2EDTA DISODIUM EDTA 0.100 3 A KELTROL CG-T XANTHAN GUM 0.300
4 A ELESTAB CPN ULTRA PURE CHLORPHENESIN 0.300 5 A PHENOXETOL
PHENOXYETHANOL 0.600 6 A SEPIWHITE MSH UNDECYLENOYL PHENYLALANINE
0.500 7 A SODIUM GLYCEROPHOSPHATE (Ph. SODIUM GLYCEROPHOSPHATE
3.000 Eur. 6 Ed, Item# 500012045500) 8 A L-LEUCINE LEUCINE 1.000 9
B CITRIC ACID 50% SOLUTION CITRIC ACID 1.920 (TO pH 4.5-5.0) 10 C
LIPOWAX D CETEARYL ALCOHOL CETEARETH-20 6.000 11 C LIPO GMS 450
GLYCERYL STEARATE 6.000 12 C CERAPHYL 230 DIISOPROPYL ADIPATE 3.000
13 C DC TORAY FZ-3196 CAPRYLYL METHICONE 3.000 14 C DC 200 FLUID
100 CST DIMETHICONE 1.000 15 C LIPOVOL J SIMMONDSIA CHINENSIS
(JOJOBA) SEED OIL 1.000 16 C SHEA BUTTER HMP BUTYROSPERMUM PARKII
(SHEA BUTTER) 1.000 17 C VITAMIN E ACETATE OIL DL-ALPHA TOCOPHERYL
ACETATE 0.200 (USP, FCC) 18 D EASTMAN .TM. HYDROQUINONE (USP
HYDROQUINONE 4.000 GRADE) 19 E SODIUM METABISULFITE (NF/FCC) SODIUM
METABISULFITE 0.400 20 F GLYCERIN 99.7% (USP) GLYCERIN 2.000 21 F
SYMWHITE 377 PHENYLETHYL RESORCINOL 0.500 22 F VITAGEN AMINOPROPYL
ASCORBYL PHOSPHATE 0.500 23 G SIMULGEL INS 100 HYDROXYETHYL
ACRYLATE/SODIUM 4.000 ACRYLOYLDIMETHYL TAURATE COPOLYMER
ISOHEXADECANE POLYSORBATE 60 TOTAL 100.00
[0138] Such compositions (e.g., Table 21) were generally prepared
in a clean and sanitized stainless steel vessel, which was suitable
for blending products containing hydroquinone, as described herein
below: [0139] PHASE A: WEIGHT WATER AND HEAT TO 70.degree. C.
[0140] DISPERSE KELTROL IN WATER, MIX UNTIL ALL HYDRATES; ADD EDTA,
MIX UNTIL ALL DISSOLOVES; [0141] THEN ADD REMAINING PHASE A
INGREDIENTS ONE BY ONE; MIX UNTIL ALL DISSOLVES. [0142] PHASE B:
ADD CITRIC ACID 50% SOLUTION TO PHASE A; MIX WELL; CHECK pH OF
BATCH; pH SHOULD BE BETWEEN 4.5-5.0 [0143] PHASE C: COMBINE PHASE C
INGREDIENTS; [0144] HEAT TO 60.degree. C., MIX UNTIL ALL MELTED AND
UNIFORM; [0145] WHEN BOTH, COMBINED PHASES A & B AND PHASE C
ARE AT 60.degree. C., ADD PHASE C INTO COMBINED PHASES A & B
WITH AGITATION MIX FOR 10 MINUTES; START COOLING TO 45.degree. C.
[0146] PHASE D: ADD PHASE D TO BATCH WITH MIX, MIX UNTIL ALL
DISSOLVES AND UNIFORM. [0147] PHASE E: ADD PHASE E TO BATCH WITH
MIXING, MIX UNTIL ALL DISSOLVES. [0148] PHASE F: COMBINE PHASE F
INGREDIENTS, SLIGHTLY HEAT AND MIX UNTIL ALL DISSOLVES, ADD TO THE
BATCH. [0149] PHASE G: ADD PHASE G TO BATCH, MIX UNTIL UNIFORM;
[0150] HOMOGENIZE THE BATCH AT 3500 RPM FOR 5 MINUTES, SWITCH TO
IMPELLER MIXER, MIX FOR 5 to 10 MINUTES; [0151] CHECK FINAL pH;
[0152] ADJUST pH WITH PHASE B TO pH 4.5-5.0 IF NECESSARY.
[0153] Compositions obtained as described in Example 3 were then
filled into aluminum tubes (or aluminum coated plastic tubes) and
then tested for physical stability (color, odor, viscosity, pH,
appearance) and chemical stability (by HPLC; following USP protocol
for hydroquinone analysis) of hydroquinone under accelerated
conditions (40 to 50.degree. C.) for up to three months. During
this period of time, the composition was stable and the
hydroquinone content remained between 3.84% to 4.24% (weight
%).
[0154] These compositions do not leave greasy or oily residues on
the skin and dries quickly and cleanly (without visible residue or
significant stickiness) within one to two minutes following
application on the skin.
Example 4
[0155] The results of skin tolerability testing (e.g., no or only
limited and acceptable skin irritancy) of the compositions
formulated in accordance with the present invention are presented
below.
[0156] The compositions of the present invention can be evaluated
by acute (1 day) or repetitive (more than one day) human irritancy
patch test to assess the skin irritation potential. The repetitive
human irritancy patch test provides "exaggerated" irritation data
since the test material is applied repetitively at a rather large
dose (i.e., >20 mg per cm.sup.2) under occlusive (i.e., allowing
no water diffusion from skin surface to air) or semi-occlusive
conditions (i.e., allowing limited water diffusion from skin
surface to air). Therefore, the repetitive human irritancy patch
test allows easily distinguishing skin irritation (i.e., skin
irritation potential) of different compositions.
[0157] The composition obtained as described in Example 3 was
evaluated by repetitive human irritancy patch test over a period of
three weeks (with 15 observations (i.e., evaluation of patch
application sites for severity of skin irritation); one observation
before patch application at beginning of study followed by 14
additional observations; see below for more details) on the back of
25 subjects. The test was performed according to standard irritancy
patch testing by an independent contract organization specialized
in consumer product testing. Several currently commercialized skin
lightening prescription products with 4% hydroquinone were also
evaluated under identical conditions for comparison. The repetitive
human irritancy patch test demonstrated that the composition
obtained as described in Example 3 was equally or better tolerated
than a series of currently commercialized skin lightening
prescription products with 4% hydroquinone. (See FIG. 1)
[0158] As shown in FIG. 1, the following compositions were
evaluated: [0159] i) Composition described in Example 3 [0160] ii)
Composition A: composition with 4% hydroquinone and further
containing sodium lauryl sulfate and lactic acid (OBAGI
NU-DERM.RTM. Blender.RTM. (PM 5) by OMP Inc., Long Beach, CA 90802;
Lots: 6K2423 and 8E1677) [0161] iii) Composition B: composition
with 4% hydroquinone and further containing sodium lauryl sulfate
and lactic acid (OBAGI-C RX SYSTEM.TM. C-Therapy Night Cream (PM)
by OMP Inc., Long Beach, CA 908020; Lot: 8E1440) [0162] iv)
Composition C: composition with 4% hydroquinone and further
containing glycolic acid (LUSTRA.RTM. Hydroquinone USP 4% by Taro
Pharmaceuticals U.S.A, Hawthorne, NY 10532; Lot: H8114) [0163] v)
Composition D: composition with 4% hydroquinone and further
containing sodium lauryl sulfate (GLYTONE Skin Bleaching/Clarifying
Cream Hydroquinone USP 4% by Pierre Fabre/Genesis Pharmaceutical
Inc., Parsippany N.J. 07054; Lot: 1058/01) The following standard
method was used to assess skin irritation:
[0164] The upper back between the scapulae served as treatment
area. Approximately 0.2 grams of each test material was applied to
the 1 inch.times.1 inch absorbent pad portion of an adhesive strip.
When secured to the appropriate treatment site, these dressings
formed semi-occlusive patches. Each test material was applied to
the appropriate treatment site Monday through Friday to maintain
twenty-one (21) consecutive days of direct skin contact. Patches
applied on Friday remained n place until the following Monday.
Evaluations of the test sites were conducted prior to each patch
application. It was noted that due to inclement weather, two of the
25 subjects were unable to report, as scheduled. They were
instructed to keep their patches in place and return on the
following day. If a test site had been observed to exhibit an
evaluation score of a "3" or higher, the application of test
material to this site would have been discontinued and the observed
score of "3" (or higher) would be recorded for the remaining study
days.
[0165] The following evaluation key was used: (0) no visible skin
reaction; (+) barely perceptible or spotty erythema; (1) mild
erythema covering most of the test site; (2) moderate erythema,
possible presence of mild edema; (3) marked erythema, possible
edema; (4) severe erythema, possible edema, vesiculation, bullae
and/or ulceration.
Example 5
[0166] The results of color stability of the compositions
formulated in accordance with the present invention are presented
below. In Examples 1, 2 and 3, the color of the compositions of the
present invention is described as being stable (e.g.,
characteristic white color of compositions does not significantly
change for up to three months at elevated temperatures as evaluated
visually with the naked eye) when the composition is placed (i.e.,
filled) into an adequate container.
[0167] In this Example, the color stability was evaluated after the
composition was removed from its typical (e.g., commercialized)
container such as aluminum tube, aluminum coated plastic tube, or
airless pump. A pea size amount was placed onto a flat, inert,
white surface (e.g., porcelain dish) and left under normal
environmental conditions (i.e., temperature, light, air, etc.) of a
room (i.e., living room) in a household for at least two weeks. The
color of the composition was documented by standard, digital color
photography at beginning and at end of the observation period.
Several currently commercialized skin lightening prescription
products with 4% hydroquinone were also evaluated under identical
conditions for comparison.
[0168] As shown in FIG. 2, the following compositions were
evaluated: [0169] i) Composition A: composition described in
Example 3 [0170] ii) Composition B: composition with 4%
hydroquinone and further containing retinol (EpiQuin.RTM. Micro by
SkinMedica, Carlsbad, Calif. 92010) [0171] iii) Composition C:
composition with 4% hydroquinone and further containing 0.01%
fluocinolone acetonide and 0.05% tretinoin (Tri-Luma.RTM. Cream by
Galderma Laboratories, Fort Worth, Tex. 76177) [0172] iv)
Composition D: composition with 4% hydroquinone and further
containing sodium lauryl sulfate and lactic acid (OBAGI
NU-DERM.RTM. Blender.RTM. (PM 5) by OMP Inc., Long Beach, CA
90802)
[0173] The compositions were removed from their typical container
and placed onto porcelain dish and left under normal environmental
conditions (i.e., temperature, light, air, etc.) of a room (i.e.,
living room) in a household for 17 days. The composition of the
present invention (Composition A) did not show any significant
color change after 17 days as judged by photography or visually.
However, Compositions B, C and D showed all significant (i.e.,
clearly visible) color changes (i.e., color is changing from white
to brown or brownish, or becoming darker, more brownish, or darker
yellow) after 17 days. These color changes became more visible with
time. The color changes are mainly due to oxidation of
hydroquinone, which is a constituent of Compositions B, C and D.
While hydroquinone is also a constituent of Composition A, this
experiment thus illustrates that the hydroquinone of Composition A
is stable under the conditions of this experiment.
[0174] Although the color changes described in this Example for
Composition B, C and D generally occurs when the composition is
placed outside its typical container, these observed color changes
are not desirable, as such color changes may affect the efficacy of
the product (i.e., composition being exposed to air and light after
it is applied onto skin). Furthermore, thee color changes would
occur after short time once some composition adheres to the outside
of the container (e.g., the tube outlet or pump head) after the
first and all subsequent uses of the composition. All of these
factors make the composition less desirable to use, which
consequently affects the patient's adherence to the recommended
course of treatment (i.e., patient compliance) and therefore
reduces the likelihood for an efficient treatment outcome.
Example 6
[0175] The compositions obtained as described in Examples 1, 2, and
3 were evaluated for tolerability and efficacy in treating skin
pigmentation disorders, such as melasma, post-inflammatory
hyperpigmentation, pigmentation changes due to skin aging, or any
other skin conditions related with normal such as skin of color or
abnormal pigmentation such as hypo- or hyper-pigmentation in
humans. The compositions were generally applied to the affected
skin area(s) either once daily in the evening (at least about half
an hour before bedtime) or twice daily in the morning and in the
evening. A sunscreen offering at least a sun protection factor of
15 (SPF15) (e.g., JOURNEE Bio-restorative Day Cream by Neocutis
Inc., San Francisco, Calif. 94123) was used during daytime to
protect skin from sun. In case the compositions were also used at
daytime, the subjects were instructed to apply the sunscreen after
having applied the said compositions; preferentially at least half
an hour after having applied the compositions.
[0176] The studies lasted at least three months (i.e., 12 weeks)
and were continued over a longer period of time depending on
severity of the skin pigmentation disorder. Epidermal melasma can
be treated (i.e. skin pigmentation is visibly reduced at site of
application) within about one to three months, whereas dermal
melasma, mixed type melasma, post-inflammatory hyperpigmentation
(e.g., hyperpigmentation originating after inflammation of skin
such as related to skin burns, wounds, acne, use of certain
medications, dermatitis, etc.), pigmentation changes due to skin
aging (e.g., freckles, age or liver spots, etc.), or any other skin
conditions related with normal such as skin of color (e.g., skin of
individual with Hispanic, Asian, African or American/African
origins), or abnormal pigmentation such as hypo- or
hyper-pigmentation in humans may require generally at least a three
month treatment period to see results (i.e. skin pigmentation is
visibly reduced at site of application) when using compositions
formulated in accordance with the present invention; eventually in
combination with the use of a sunscreen product.
[0177] Results demonstrating the efficacy of the compositions
formulated in accordance with the present invention are presented
in FIG. 3.
Study with Composition Described in Example 1:
[0178] After a one month wash-out period where the subjects were
allowed to only use JOURNEE Bio-restorative Day Cream (offering
SPF30+), the subjects applied the composition described in Example
1 twice daily (morning and evening) to their entire face after
washing the face with a gentle skin cleanser (i.e., NEO-CLEANSE
Gentle Cleanser by Neocutis). In the morning, they continued to use
JOURNEE Bio-restorative Day Cream.
[0179] Assessment of global melasma severity was performed by the
investigator according to the following 4-point visual scoring
system: 0=absent (color of the melasma lesions is close to that of
surrounding skin; 1=mild (color is slightly darker than that of
normal skin); 2=moderate (color is moderately darker); and 3=severe
(color is markedly darker than surrounding normal skin). In
addition, melasma was quantified with the help of the so-called
MASI index (see Arch Dermatol 130, 1994, 727-733).
[0180] Three areas of the face were evaluated: forehead (F), malar
region (M), and chin (C) corresponding to 30%, 60% and 10% of total
face The involvement of melasma in the area of forehead, malar
region, and chin were given a numerical value (A.sub.F, A.sub.M,
A.sub.C): 0=no involvement; 1=less than 10% involvement; 2=10% to
<30%; 3=30% to <50%; 4=50% to <70%; 5=70% to <90%;
6=90% to 100%. Severity was based on two factors: darkness (D) of
melasma compared with normal skin; and homogeneity (H) of
hyperpigmentation. Patients were assessed on a scale from 0 through
to 4 as follows; the darkness (D) scale: 0=absent; 1=slight;
2=mild; 3=marked; 4=maximum; and the homogeneity (H) scale:
0=minimal; 1=slight; 2=mild; 3=marked; 4=maximum. To calculate the
MASI score, the sum of the severity rating of darkness (D) and
homogeneity (H) was multiplied by the numerical value of the
respective areas involved (A) and by the various percentages of the
three facial areas. These values were added to obtain the MASI
score as follows:
MASI=0.3(D.sub.F+H.sub.F)A.sub.F+0.6(D.sub.M+H.sub.M)A.sub.M+0.1(D.sub.C+-
H.sub.C)A.sub.C. Additionally, the number of age and liver spots
were counted in face. Those evaluations were performed at the
beginning of study (i.e., before wash-out period), after the one
month wash-out period (i.e., before starting with the treatment
with composition), and at the end of the study period (i.e., after
12 weeks of use of composition), respectively.
TABLE-US-00022 TABLE 22 Reduction in Global Reduction in Reduction
in Melasma Severity as Melasma as total Number assessed by
Investiga- assessed by of Age/Liver tor Global Assessment
MASI-Scoring Spots After one month 0 .+-. 0% 2 .+-. 3% 0 .+-. 0%
wash-out period After 12 weeks 20 .+-. 27% 56 .+-. 33% 55 .+-. 22%
of use of composition
[0181] Table 22 shows the efficacy of the composition described in
Example 1 in treating skin pigmentation disorders and diseases. The
average and standard deviation in the reduction from baseline
(i.e., data before wash-out) from five female subjects who
completed the study is shown in percentage (%) of reduction from
baseline.
[0182] This study shows that the composition leads to a reduction
in melasma severity and in the number (and intensity) of age or
liver spots in face. Thus, the composition is effective for
treating (i.e., reducing) symptoms of skin pigmentation disorders
and diseases. The composition was further well tolerated. As
further shown in this study, the use of a sunscreen (i.e., JOURNEE
Bio-restorative Day Cream) alone did not result in any significant
reduction in symptoms of skin pigmentation disorders and
diseases.
Study with Composition Described in Example 3:
[0183] The subjects applied the composition described in Example 3
once daily (evening) to either the right, or to the left side of
their face (the side was randomly assigned) after washing the face
with a gentle skin cleanser (i.e., Cetaphil by Galderma). In the
morning, they additionally used JOURNEE Bio-restorative Day
Cream.
[0184] Assessment of global melasma severity was performed by the
investigator according to the following 4-point visual scoring
system: 0=absent (color of the melasma lesions is close to that of
surrounding skin; 1=mild (color is slightly darker than that of
normal skin); 2=moderate (color is moderately darker); and 3=severe
(color is markedly darker than surrounding normal skin). In
addition, melasma was quantified with the help of the so-called
MASI index (Arch Dermatol 130, 1994, 727-733). Three areas of the
face were evaluated: forehead (F), malar region (M), and chin (C)
corresponding to 30%, 60% and 10% of total face; or 15%, 30% and 5%
of half of the face, respectively. The involvement of melasma in
the area of forehead, malar region, and chin were given a numerical
value (A.sub.F, A.sub.M, AO: 0=no involvement; 1=less than 10%
involvement; 2=10% to <30%; 3=30% to <50%; 4=50% to <70%;
5=70% to <90%; 6=90% to 100%. Severity was based on two factors:
darkness (D) of melasma compared with normal skin; and homogeneity
(H) of hyperpigmentation. Patients were assessed on a scale
from
through to 4 as follows; the darkness (D) scale: 0=absent;
1=slight; 2=mild; 3=marked; 4=maximum; and the homogeneity (H)
scale: 0=minimal; 1=slight; 2=mild; 3=marked; 4=maximum. To
calculate the MASI score for a half-face (MASI.sub.Half-Face), the
sum of the severity rating of darkness (D) and homogeneity (H) was
multiplied by the numerical value of the respective areas involved
(A) and by the various percentages of the three facial areas. These
values were added to obtain the MASI score as follows:
MASI=0.15(D.sub.F+H.sub.F)A.sub.F+0.3(D.sub.M+H.sub.M)A.sub.M+0.-
05(D.sub.C+H.sub.C)A.sub.C. Those evaluations were performed at the
beginning of study (i.e., before starting with the treatment with
composition), and at the end of the study period (i.e., after 12
weeks of use of composition), respectively.
TABLE-US-00023 TABLE 23 Reduction in Global Reduction in Melasma
Severity as Melasma as assessed by Investigator assessed by Global
Assessment MASI-Scoring After 12 weeks of 38 .+-. 37% 74 .+-. 20%
use of composition
[0185] Table 23 shows the efficacy of the composition described in
Example 3 in treating skin pigmentation disorders and diseases. The
average and standard deviation in the reduction from baseline
(i.e., data before starting with the treatment with composition)
from ten female subjects who completed the study is shown in
percentage (%) of reduction from baseline.
[0186] FIG. 3 is a photograph showing the reduction of pigmentation
in the skin of a patient using the compounds of the present
invention (e.g. the composition described in Example 3). Panel A
shows the hyperpigmentation of the patient's skin prior to
administration of a compound of the present invention. Panel B
shows the reduction in skin pigmentation following 12 weeks of
treatment with a composition of the present invention.
[0187] The results of this study show that the composition leads to
a reduction in melasma severity in treated area of face. Thus, the
composition is effective for treating (i.e., reducing) symptoms of
skin pigmentation disorders and diseases. The composition was
further well tolerated.
Study with Composition Described in Example 2:
[0188] As shown in diverse in use studies, the composition obtained
as described in Example 2 was also shown to be well tolerated and
efficient in treating skin pigmentation disorders, such as melasma,
post-inflammatory hyperpigmentation, pigmentation changes due to
skin aging, or any other skin conditions related with normal such
as skin of color or abnormal pigmentation such as hypo- or
hyper-pigmentation in humans. Female and male human subjects were
included in this study.
[0189] These studies demonstrated that the compositions obtained as
described in Examples 1, 2 and 3 are effective for treating (i.e.,
reducing) symptoms of skin pigmentation disorders and diseases and
are well tolerated under in use conditions.
Example 7
[0190] A human study showed that the composition described in
Example 3 does not cause an acnegenic/comedogenic response. Thus,
the use of this composition did not result in a significant
increase in the number and severity of comedones/acne.
[0191] Prior to initiation of the study, each subject was examined
and the facial skin condition, including counts of non-inflammatory
and inflammatory lesions, were recorded. Severity of comedones/acne
were determined by the following lesion count categories:
[0192] Grade I (mild)=Less than 10 comedones (including open:
blackheads; closed: micropapules and whiteheads and/or inflammatory
papulopustular lesions on one or both sides of the face.
[0193] Grade II (moderate)=10-25 comedones (including open:
blackheads; closed: micropapules and whiteheads) and/or
inflammatory papulopustular lesions on one or both sides of the
face.
[0194] Grade III (severe)=More than 25 comedones (including open:
blackheads; closed: micropapules and whiteheads) and/or
inflammatory papulopustular lesions on one or both sides of the
face.
[0195] Subjects were evaluated before and after four weeks of
treatment (once daily in evening) with the composition. Differences
between baseline and final dermatological evaluations were
considered statistically significant, if the probability of
obtaining the result by chance is less than or equal to 0.05 using
analysis of variance and/or appropriate t-Test statistics. All
assessments of facial skin condition and lesion counts were made by
a Board Certified Dermatologist. The study was performed by an
independent clinical research organization.
OTHER EMBODIMENTS
[0196] While the invention has been described in conjunction with
the detailed description thereof, the foregoing description is
intended to illustrate and not limit the scope of the invention,
which is defined by the scope of the appended claims. Other
aspects, advantages, and modifications are within the scope of the
following claims.
* * * * *
References