Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND METHODS FOR TREATING SKIN CONDITIONS
1. Field of the Invention
This invention is related to methods and compositions for
treating and ameliorating skin conditions including acne and post
inflammatory hyperpigmentation.
More particularly, this invention
relates to compositions containing salicylic acid, certain natural
extracts and natural or synthetic retinoids.
2. Background of the Invention
Acne is an inflammatory dermatological disorder, which occurs
frequently in adolescence and with some regularity in older adults
of the human species. The
condition of acne can include skin
lesions
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severe comedo-inflammatory symptoms such as pustules, papules, cysts
and nodules. The
condition is not only uncomfortable for the
scarring.
The pathology of acne vulgaris is believed to involve a number
of factors: the first of which is the formation of comedones more
commonly referred to as whiteheads (closed comedones) and blackheads
(open comedones). These are solid horny masses that plug follicles
and are associated with increased production of sebum. They are made
up of tightly packed keratinized cells and sebum. As
the comedo
enlarges through continued accumulation of keratinized cells,
pressure builds up within the follicles which eventually rupture,
dumping the contents consisting of horny material, sebum and bacteria
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into the skin. This provokes inflammatory responses which take the
form of pustules (pimples) when the rupture is small and cystic-
nodules with complete rupture.
Many different approaches to ameliorating this disorder have
been attempted in the past, with some treatments more effective than
others.
Attacks ranging from simple washing and cleansing to
pharmaceuticals have been employed. Agents known and utilized in
acne treatment include salicylic acid, the retinoids and retinols.
While these agents can significantly improve acne, their undesirable
side effects range from mild to severe irritation, redness, peeling,
and itching and burning sensation. Thus, it is desired to have a
single topical treatment that could prevent or reverse acne with
minimal or no undesired side effects.
Aging of the skin is a complex phenomenon resulting from the
interaction of several intrinsic and extrinsic factors. Skin
changes associated with aging often manifest as cosmetic
disabilities. Due to its psychological impact, aging of the skin has
become an issue of great social significance and concern. With baby
boomers aging, the era of cosmetic care, cosmetic maintenance and
rejuvenation gains increased awareness. Methods for preventing and
treating skin aging are highly desired.
Intrinsic aging is an
inevitable, genetically programmed process. Among extrinsic
influences (wind, heat, cigarette smoke, chemicals, etc.),
ultraviolet radiation appears to be the single most important factor
associated with aging of the skin. Photoaging is
induced by
cumulative exposure to ultraviolet radiation (UVR). Increased
recreational sun exposure, including excessive sunbathing, the
depletion of stratospheric ozone, and the use of UVR in the
treatment of various skin diseases, have led to increased prevalence
of photoaging during the last decades. Photodamage can be prevented
by sun avoidance and proper sun protection, and could be reversed by
the use of topical retinoids, which could be irritating and
expensive. Overexposure to ultraviolet and visible radiation also
causes sunburn. The use of aspirin and other nonsteroidal anti-
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inflammatory drugs, cool baths and topical steroids offer only
mild relief.
Post inflammatory hyperpigmentation ("PIH") results
from healed acne lesions in darkly pigmented individuals.
After the acne heals, hyperpigmented spots appear in the area
affected by acne lesions. There is a need for a composition
that alleviates acne and either prevents or ameliorates PIH.
Various approaches to treating acne, photodamage and
other skin conditions have been attempted in the past,
including treatment with Vitamin A acid (also known as
"tretinoin") and natural retinoids or retinoid precursors such
as Vitamin A alcohol (also known as "retinol"). (See U.S.
Patent No. 4,877,805 and U.S. Patent No. 4,355,028, for
example.) However, topical treatment with retinoids can be
very irritating to the skin and uncomfortable for the patient.
It can cause redness, which may be embarrassing to the patient,
particularly those suffering from acne in their teenage years.
Oral treatment with retinoids has been found to have
teratogenic effects. Thus, it would be desirable to find a
topical treatment for acne and PIH.
Summary of the Invention
In accordance with this invention, we have found
compositions and methods for treating and ameliorating acne and
PIH containing salicylic acid, nondenatured plant extracts
including legume and vegetable extracts having trypsin
inhibitory activity and at least one natural or synthetic
retinoid or retinol compound.
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In an embodiment, the invention relates to a topical
composition for use in the treatment of post-inflammatory
hyperpigmentation in a mammal in need of treatment therefore, the
composition comprising: (a) from about 0.5 to about 2% by weight
of salicylic acid, (b) from about 0.01 to about 1% by weight of a
compound selected from the group consisting of synthetic
retinoids, natural retinoids, and retinol, and (c) from about
0.01 to about 50% by weight of a nondenatured aqueous soybean
extract having trypsin-inhibiting activity effective for the
treatment of post-inflammatory hyperpigmentation.
In another embodiment, the invention relates to a
topical composition for use in the treatment of post-inflammatory
hyperpigmentation comprising: an effective amount of a topical
composition comprising: (a) from about 0.01 to about 1% by weight
of a compound selected from the group consisting of synthetic
retinoids, natural retinoids, and retinol, (b) from about 0.5 to
about 2% by weight of salicylic acid, and (c) from about 0.01 to
about 50% by weight of a nondenatured aqueous soybean extract
having trypsin-inhibiting activity.
Detailed Description of the Preferred Embodiments
The compositions of the present invention contain
salicylic acid. The amount of salicylic acid may range from
about 0.5 percent to about 2 percent by weight, based on the
total weight of the composition. The amount of salicylic acid
should be high enough to be effective in combating acne disease
but not higher than a dose which would irritate a patient's skin.
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Preferably, the compositions of this invention contain
nondenatured legume or vegetable extracts containing compounds that
inhibit trypsin, such as serine protease inhibitors. In particular,
nondenatured legume extracts will also be useful in methods of this
invention. More preferably, nondenatured soybean, limabean and
blackbean extracts, and other natural products made from these beans,
such as, but not limited to, bean milk, bean paste, and the like,
also serve to reduce pigmentation by this mechanism. Serine protease
inhibitors isolated from vegetables or legumes are also useful in
this invention, such as, but not limited to, the soybean-derived
proteins soybean trypsin inhibitor, "STI" and Bowman-Birk Inhibitor,
"BBI".
The novel compositions of this invention preferably contain
legume products, and more preferably, soy products, that may be in
the form of a fluid (e.g., soymilk) or a solid (e.g., a soybean
powder or soymilk powder).
What is meant by "soy product" is a
substance derived from the soybean, containing the ingredients
naturally found in soybeans, at the relative concentrations as found
in the beans. What is meant
by a "Soy Product" is a substance
derived from the soybean. The soy product may contain only a portion
of the soybean (e.g., an extract of the soybean such as a lipid
reduced soybean powder or filtered soymilk) or may contain the entire
soybean (e.g., a ground powder of the legume). The soy product may
be in the form of a fluid (e.g., soymilk) or a solid (e.g., a soybean
powder or soymilk powder). When in the form of a fluid, the term
"soy product" refers to the solid constituents of the fluid that are
derived from the soybean.
The soy product may be soybean powder. Soybean powder may be
made by grinding dry soybeans. The soybean
powder may be
lyophilized.
Soymilk and soymilk powder are also useful soy
products. Soymilk is a combination of solids derived from soybeans
and water, the mixture of which has some or all of the insoluble
constituents filtered off.
Soymilk powder is evaporated soymilk,
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which in one embodiment, is in a lyophilized or spray-dried form.
Procedures for manufacturing soymilk include, but are not
limited to, the following three procedures. First, soymilk may be
made by placing soybeans into water to allow them to absorb the
water. The swelled beans are then ground and additional water is
then added. The mixture may then be filtered to remove any insoluble
residue. Second, soymilk may also be prepared from soybean powder.
Soybean powder is thoroughly mixed with water (e.g., for at least one
hour), which may then be followed by a filtration process to remove
insoluble residues. Third, soymilk can also be reconstituted from
soymilk powder by adding water.
The soymilk may comprise from
between about 1% to about 50%, by weight (e.g., from about 5% to
about 20%, by weight) of solids from the soybean.
The surface of legume fruits often contain high levels of
microorganisms. Thus, prior to use by humans, the legume product
needs to be treated to reduce or eliminate such microorganisms.
The legume products utilized in the present invention may have
a total microbial content of less than about 10,000 colony-forming
units ("cfu") per gram. Preferably, the soy products utilized in the
present invention have a microbial content of less than about 1,000
cfu per gram (such as less than about 100 cfu per gram) of the
legume product.
The legume products utilized in the present invention may have
a total objectionable microbial content of less than 300 cfu per
gram such as less than 150 cfu per gram. Preferably,
the legume
products utilized in the present invention have an undetectable
amount of any objectionable microbials for at least one gram (e.g.,
at least ten grams) of legume product.
The legume product may be exposed to gamma irradiation. The
legume product may be exposed to between about 2 to about 30 kGy of
gamma irradiation, such as between about 5 and about 10 kGy of gamma
irradiation. Such treatment reduces the microbial content of the
legume product, while maintaining its biological activity (e.g.,
serine protease inhibitory activity).
The treatment of legume
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products with gamma irradiation maintains the cosmetic elegance of
the legume product, such as maintained natural colors and does not
induce significant malodors.
Other anti-microbial processes that also maintain the protease
inhibitory activity of the legume product that can be practiced alone
or in combination with gamma irradiation, include, but are not
limited to, exposure to x-rays, high energy electron or proton beams,
ultraviolet radiation, hydrostatic pressure, and addition of chemical
agents possessing antimicrobial activity, and combinations thereof.
In one embodiment, the soy product is a non-denatured soy
product. "Denaturation" is defined in the Bantam Medical Dictionary
(1990 edition) as "the change in the physical and the physiological
properties of a protein, that are brought about by heat, X-rays or
chemicals. These changes include loss of activity (in the case of
enzymes) and loss (or alteration) of antigenicity (in the case of
antigens)".
What is meant by "non-denatured plant extract" is a
product extracted or derived from a plant in which the processing for
the derivation of such plant extract (e.g., the temperature,
extraction media) did not eliminate its protease inhibitory activity.
One such protease is trypsin. In one embodiment, the non-denatured
state of the soy product of this invention is measured by the
presence of an intact soybean trypsin inhibitor (STI) protein, or by
its trypsin inhibitory activity.
The compositions of this invention also contain at least one
retinoid (i.e., compounds that bind to any members of the family of
retinoid receptors) or retinoid precursor such as retinol,
including, for example, tretinoin, retinol, esters of tretinoin
and/or retinol, synthetic retinoids such as those set forth in U.S.
Patent No. 4,877,805, for example, and the like.
The amount of
retinoid in the compositions of the present invention may range from
about 0.01 percent to about 1 percent, preferably from about 0.01%
percent (the commercial formula has 0.04% retinol)to about 0.5
percent by weight, based on the total weight of the composition.
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The compositions of the present invention may contain
additional sources of serine protease inhibitors. Additional sources
of serine protease inhibitors may be extracted from the species
belonging to the following plant families: Solanaceae (e.g., potato,
tomato, tomatilla, and the like); Gramineae (e.g., rice, buckwheat,
sorghum, wheat, barley, oats and the like); Cucurbitaceae (e.g.,
cucumbers, squash, gourd, luffa and the like); and, preferably,
Leguminosae (e.g., beans, peas, lentils, peanuts, and the like).
Ingredients in soy, such as isoflavones, or soy trypsin inhibitor, or
non-denatured soy have not previously been known or utilized for
reducing retinoid-induced irritation or redness.
Surprisingly, we
have found that compositions containing such elements are capable of
reducing retinoid-induced irritation or redness without affecting
retinoid activity.
The compounds which are active in the compositions and methods
of this invention may be delivered topically by any means known to
those of skill in the art. If
the delivery parameters of the
topically active pharmaceutical or cosmetic agent so require, the
topically active composition of this invention may preferably be
further composed of a pharmaceutically or cosmetically acceptable
vehicle capable of functioning as a delivery system to enable the
penetration of the topically active agent into the skin.
One acceptable vehicle for topical delivery of some of the
compositions of this invention, particularly proteins such as
trypsin and STI, may contain liposomes. The liposomes
are more
preferably non-ionic and contain a) glycerol dilaurate (preferably
in an amount of between about 5% and about 70% by weight); b)
compounds having the steroid backbone found in cholesterol
(preferably in an amount of between about 5% and about 45% by
weight); and c) one or more fatty acid ethers having from about 12
to about 18 carbon atoms (preferably in an amount of between about
5% and about 70% by weight collectively), wherein the constituent
compounds of the liposomes are preferably in a ratio of about
37.5:12.5:33.3:16.7.
Liposomes comprised of glycerol dilaurate /
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cholesterol/ polyoxyethylene -10-stearyl ether/polyoxyethylene-9-
lauryl ether (GDL liposomes) are most preferred.
Preferably the
liposomes are present in an amount, based upon the total volume of
the composition, of from about 10 mg/mL to about 100 mg/mL, and more
preferably from about 20 mg/mL to about 50 mg/mL. A ratio of about
37.5:12.5:33.3:16.7 is most preferred.
Suitable liposomes may
preferably be prepared in accordance with the protocol set forth in
Example 1 of parent application U.S. Serial No. 09/110,409, though
other methods commonly used in the art are also acceptable. The
above described composition may be prepared by combining the desired
components in a suitable container and mixing them under ambient
conditions in any conventional high shear mixing means well known in
the art for non-ionic liposomes preparations, such as those disclosed
in Niemiec et al., "Influence of Nonionic Liposomal Composition On
Topical Delivery of Peptide Drugs Into Pilosebacious Units: An In
Vivo Study Using the Hamster Ear Model," 12 Pharm. Res. 1184-88
(1995) ("Niemiec").
We have found that the presence of these liposomes in the
compositions of this invention may enhance the therapeutic
capabilities of some of the compositions of this invention.
Other preferable formulations may contain, for example, soybean
milk or other liquid formulations derived directly from legumes or
other suitable plant. For example, such a formulation may contain a
large proportion of soybean milk, an emulsifier that maintains the
physical stability of the soybean milk, and, optionally a chelating
agent, preservatives, emollients, humectants and/or thickeners or
gelling agents.
Oil-in-water emulsions, water-in-oil emulsions, solvent-based
formulations and aqueous gels known to those of skill in the art may
also be utilized as vehicles for the delivery of the compositions of
this invention.
The topical compositions useful in the present invention
involve formulations suitable for topical application to skin. The
composition may comprise the soy product and a cosmetically-
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acceptable topical carrier.
The cosmetically-acceptable topical
carrier may comprise from about 50% to about 99.99%, by weight, of
the composition (e.g., from about 80% to about 95%, by weight, of
the composition).
The compositions may be made into a wide variety of product
types that include but are not limited to solid and liquid
compositions such as lotions, creams, gels, sticks, sprays, shaving
creams, ointments, cleansing liquid washes and solid bars, shampoos,
pastes, powders, mousses, adhesive strips, and wipes. These product
types may comprise several types of cosmetically acceptable topical
carriers including, but not limited to solutions, emulsions (e.g.,
microemulsions and nanoemulsions), gels, solids and liposomes. The
following are non-limitative examples of such carriers. Other
carriers can be formulated by those of ordinary skill in the art.
The topical compositions useful in the present invention can
be formulated as solutions. Solutions typically include an aqueous
solvent (e.g., from about 50% to about 99.99% or from about 90% to
about 99% of a cosmetically acceptable aqueous solvent).
Topical compositions useful in the subject invention may be
formulated as a solution comprising an emollient. Such compositions
preferably contain from about 2% to about 50% of an emollient(s).
As used herein, "emollients" refer to materials used for the
prevention or relief of dryness, as well as for the protection of
the skin. A wide variety of suitable emollients are known and may
be used herein. See International Cosmetic Ingredient Dictionary and
Handbook, eds. Wenninger and McEwen, pp. 1656-61, 1626, and 1654-55
(The Cosmetic, Toiletry, and Fragrance Assoc., Washington, D.C., 7th
Edition, 1997) (hereinafter "INCI Handbook") contains numerous
examples of suitable materials.
A lotion can be made from such a solution. Lotions typically
comprise from about 1% to about 20% (e.g., from about 5% to about
10%) of an emollient(s) and from about 50% to about 90% (e.g., from
about 60% to about 80%) of water.
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Another type of product that may be formulated from a solution
is a cream. A cream typically comprises from about 5% to about 50%
(e.g., from about 10% to about 20%) of an emollient(s) and from
about 45% to about 85% (e.g., from about 50% to about 75%) of water.
Yet another type of product that may be formulated from a
solution is an ointment. An ointment may comprise a simple base of
animal or vegetable oils or semi-solid hydrocarbons. An ointment
may comprise from about 2% to about 10% of an emollient(s) plus from
about 0.1% to about 2% of a thickening agent(s). A more complete
disclosure of thickening agents or viscosity increasing agents
useful herein can be found in the INCI Handbook pp. 1693-1697.
The topical compositions useful in the present invention may
be formulated as emulsions. If the carrier is an emulsion, from
about 1% to about 10% (e.g., from about 2% to about 5%) of the
carrier comprises an emulsifier(s). Emulsifiers
may be nonionic,
anionic or cationic.
Suitable emulsifiers are disclosed in, for
example, INCI Handbook, pp.1673-1686.
Lotions and creams can be formulated as emulsions. Typically
such lotions comprise from 0.5% to about 5% of an emulsifier(s).
Such creams would typically comprise from about 1% to about 20%
(e.g., from about 5% to about 10%) of an emollient(s); from about
20% to about 80% (e.g., from 30% to about 70%) of water; and from
about 1% to about 10% (e.g., from about 2% to about 5%) of an
emulsifier(s).
Single emulsion skin care preparations, such as lotions and
creams, of the oil-in-water type and water-in-oil type are well-
known in the cosmetic art and are useful in the subject invention.
Multiphase emulsion compositions, such as the water-in-oil-in-water
type are also useful in the subject invention. In
general, such
single or multiphase emulsions contain water, emollients, and
emulsifiers as essential ingredients.
The topical compositions of this invention can also be
formulated as a gel (e.g., an aqueous gel using a suitable gelling
agent(s)).
Suitable gelling agents for aqueous gels include, but
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are not limited to, natural gums, acrylic acid and acrylate polymers
and copolymers, and cellulose derivatives (e.g., hydroxymethyl
cellulose and hydroxypropyl cellulose). Suitable gelling agents for
oils (such as mineral oil) include, but are not limited to,
hydrogenated butylene/ethylene/styrene copolymer and hydrogenated
ethylene/propylene/styrene copolymer. Such gels typically comprise
between about 0.1% and 5%, by weight, of such gelling agents.
The topical compositions of the present invention can also be
formulated into a solid formulation (e.g., a wax-based stick, soap
bar composition, powder, or a wipe containing powder).
The topical compositions useful in the subject invention may
contain, in addition to the aforementioned components, a wide
variety of additional oil-soluble materials and/or water-soluble
materials conventionally used in compositions for use on skin, hair,
and nails at their art-established levels.
The source of active compound to be formulated will generally
depend upon the particular form of the compound.
Small organic
molecules and peptidyl fragments can be chemically synthesized and
provided in a pure form suitable for pharmaceutical/cosmetic usage.
Products of natural extracts can be purified according to techniques
known in the art.
Recombinant sources of compounds are also
available to those of ordinary skill in the art.
In alternative embodiments, the topically active
pharmaceutical or cosmetic composition may be optionally combined
with other ingredients such as moisturizers, cosmetic adjuvants,
anti-oxidants, bleaching agents, tyrosinase inhibitors and other
known depigmentation agents, surfactants, foaming agents,
conditioners, humectants, fragrances, viscosifiers, buffering
agents, preservatives, sunscreens and the like.
One of the problems encountered by many individuals who
utilize retinoic acid-containing products is increased erythema
caused by irritation, a common side effect of retinoid usage. We
have found that, surprisingly, the combination of tretinoin and
soybean extracts with trypsin inhibitory activity products, such as
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nondenatured soymilk powder, result in decreased skin redness when
applied in combination with or simultaneously with retinoic acid.
Preferably, the soy products are utilized in a topical composition
containing from about 0.01 to about 50% soybean powder or soymilk
powder, more preferably about 0.05 to about 20% soybean powder or
soymilk powder and most preferably about 0.5 to about 5% soybean
powder or soymilk powder.
The topically active pharmaceutical or cosmetic composition
should be applied in an amount effective to reduce retinoid-induced
irritation of mammalian skin. As used herein
"amount effective"
shall mean an amount sufficient to cover the region of skin surface
where reduce retinoid-induced irritation is desired.
Preferably,
the composition is liberally applied to the skin surface such that,
based upon a square cm of skin surface, from about 2 1 /cm2 to
about 200 1 /cm2 of topically active agent is present when a
reduction in irritation or redness is desired.
Natural extracts made directly from plants or botanical
sources may be employed in the compositions of this invention in a
concentration (w/v) from about 1 to about 99%. Fractions of natural
extracts and naturally-derived protease inhibitors such as STI or
BBI may have a different preferred range, from about 0.01% to about
20% and, more preferably, from about 0.5% to about 10% of the
composition, and most preferably from 0.1% to about 2.5%. Of
course, mixtures of the active agents of this invention may be
combined and used together in the same formulation, or in serial
applications of different formulations.
We have unexpectedly found that when topically active agents
are topically applied to an animal's skin, a significant change in
skin condition was achieved.
Preferably, active agents of this
invention are applied to the skin of a mammal at a relatively high
concentration and dose (from about 0.005% to about 1% for compounds
having high therapeutic indices such as natural and synthetic
retinoids and related compounds; from about 20% to about 99% for
liquid derivatives and extracts of botanical materials; and from
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about 0.1% to about 20% for dried extracts or fractions of natural
extracts and naturally-derived protease inhibitors such as STI or
mixtures thereof) between one and two times daily for a period of
time until the skin evidences a change in skin condition. This may
be for from about four to about ten weeks or more. Thereafter, once
the change in skin condition has been achieved, a lower
concentration and dose (from about 0.00001% to about 0.005% for
compounds having high therapeutic indices such as natural and
synthetic retinoids and related compounds; from about 10% to about
90% for liquid derivatives and extracts of botanical materials; and
from about 0.01% to about 5% for fractions of natural extracts and
naturally-derived protease inhibitors such as STI or mixtures
thereof), of active ingredient may be applied on a less frequent
time schedule, e.g., about once per day to about twice per week.
The effects of the active agents of this invention are reversible,
therefore, in order to maintain these effects, continuous
application or administration should be performed. The invention
illustratively disclosed herein suitably may be practiced in the
absence of any component, ingredient, or step which is not
specifically disclosed herein.
Several examples are set forth below to further illustrate the
nature of the invention and the manner of carrying it out, but do not
serve to limit the scope of the methods and compositions of this
invention.
Example 1:
A composition of the present invention was prepared by
combining the ingredients listed in Table 1 below by the process
described below Table 1.
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Table 1
INCI 'Name' Function
%wiry
Water Phase DI Water Vehicle
51.588
Methyl Gluceth 20 Humectant
2.000
Disodium EDTA Chelating
Agent 0.100
Glycerin Humectant
1.000
Ammonium Hydroxide pH Adjuster
0Ø46
Oil Phase C12-C15 Alkyl Benzoate Emollient
7.000
Isoceteth 20 Solubilizing Agent
1.375
PPG 10 Cetyl Ether Skin Conditioning Agent
2.200
Salicylic Acid Anti-acne
Agent 1.000
Dimethicone Skin Conditioning Agent
2.750
Phenyl Trimethicone Skin Conditioning Agent
0.750
BHT Anti-oxidant
0.100
Arachidyl Alcohol (and)
Behenyl Alcohol (and)
Arachidylglucoside Emulsifier
3.850
Cetearyl Alcohol (and)
Cetearyl Glucoside Emulsifier
4.400
Cetearyl Alcohol Emulsifier
1.400
Polyacrylamide (and) C13-
14 Isoparaffin (and)
Post Phase Laureth-7
Viscosity Increasing Agent 2.700
Soy Premix 1 Water Vehicle ,
12.000
Glycine soja (soybean)
Seeds Extracts Natural
Ingredient 2.000
Ethylene/Acrylic Acid
Copolymer Skin Conditioning Agent
0.500
Glycine soja (soybean)
Soy Premix 2 Seeds Extracts Skin Conditioning Agent
0.025
Benzyl Alcohol Preservative
0.500
Methylparaben,
Propylparaben,
Butylparaben,
Ethylparaben &
Phenoxyethanol Preservative
1.000
Fragrance Cosmetic
Appeal 0.300
Benzalkonium Chloride Preservative
0.050
Retinol Active 0.092
100.000
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Soy premix 1 was prepared by adding 12 g of deionized water to
a glass beaker. Glycine soja (soybean) Seeds Extracts (2 g) and
Ethylene/Acrylic Acid Copolymer (0.5 g) were added with stirring in
between additions.
Soy premix 2 was prepared by combining 0.025 g Glycine soja
(soybean) Seeds Extracts with 0.5 g benzyl alcohol in a glass beaker
and stirring for thirty minutes.
The water phase was prepared in an ESCO VESSEL. To the vessel
was added 51.588 g water. Mixing was turned on and the following
materials were added: 2 g Methyl Gluceth 20, 0.1 g Disodium EDTA,
1 g Glycerin, and 0.46 g ammonium hydroxide. The solution was
heated to 70 - 75 C.
The oil phase was prepared in a glass beaker by combining the
following ingredients while mixing at 75 - 80 C: 7 g C12-C15 Alkyl
Benzoate, 1.375 g Isoceteth 20, 2.2 g PPG 10 Cetyl Ether, 1 g
salicylic acid, 2.75 g DIMETHICONE , 0.75 g phenyl Trimethicone,
0.1 g BHT, 3.85 g Arachidyl Alcohol (and) Behenyl Alcohol (and)
Arachidylglucoside, 4.4 g Cetearyl Alcohol (and) Cetearyl
Glucoside, and 1.4 g Cetearyl Alcohol. The solution was mixed for
5 minutes, then cooled to 70 - 75 C with continued mixing.
The oil phase was slowly added to the water phase with slow to
moderate sweep mixing at 70 C. Polyacrylamide (and) C13-14
Isoparaf fin (and) Laureth-7 (2.7 g) was added to the solution. The
solution was cooled to 45 C and the soy premix 1 and soy premix 2
were added with stirring. The soy premix vessels were washed with
0.8 g water and the water was added to the solution. The solution
was mixed for 10 minutes. The benzalkonium chloride, preservative,
and fragrance were added to the solution with 10 minutes stirring
between additions. RETINOL (0.092 g) was added to the solution and
stirred for 10 minutes.
Example 2:
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A placebo control was prepared by making a second sample based
on the ingredients in Table 1 without the soy derivatives, retinol,
and salicylic acid.
Clinical Study
A double-blind, placebo controlled, randomized study was
conducted to evaluate the efficacy of a topical formulation of the
present invention in improving the appearance of acne and post acne
PIH in male and female Asian, African-American and Hispanic subjects
with Fitzpatrick Skin Type III-V.
Forty-one Asian, African-American and Hispanic male and female
subjects with Skin Type III-V and mild acne vulgaris (10 - 50 total
facial acne lesions), 12 to 45 years of age, completed the double-
blind, placebo controlled, randomized, full face, four month long
study. Subjects had physically distinct, recent, facial PIH acne
marks. Exclusion criteria included subjects using systemic
medication within 30 days or topical medication within 14 days
before study entry and those who exhibited skin conditions that
could interfere with the outcome of the study.
Subjects were provided a composition of the present invention
or its placebo based on a randomization scheme. They were asked to
apply the test preparation twice on the face, once in the morning
and once at night. Subjects were instructed to use a provided
facial cleanser and an SPF 15 facial moisturizer throughout the
study.
An expert clinical grader assessed global facial acne lesions
and target inflammatory lesions as well as skin improvements in
facial skin tone and texture. Specific PIH marks were evaluated for
darkness, roughness and erythema. Assessments were made at baseline
and at various time points throughout the study. The color of the
PIH marks was rated on a scale of -1 = slightly lighter than pigment
of surrounding skin, 0 = equal with pigment of surrounding skin, 1 =
slightly darker than pigment of surrounding skin, 2 = moderately
darker than pigment of surrounding skin, and 3 = extremely darker
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than pigment of surrounding skin. Post study clinical grading of
photos (full face and targeted PIH marks) was carried out to
evaluate change in PIH darkness, erythema and size. Additionally,
the relative size of the marks was also graded. Each mark was
assigned a score of 4 at baseline and graded at subsequent visits
using the following scale: 0 = PIH mark is not readily visible; 1 -
PIE mark is 25% of the size of the mark at baseline; 2 = PIH mark is
50% of the size of the mark at baseline; 3 = PIH mark is 75% of the
size of the mark at baseline; and 4 = PIH mark is 100% of the size
of the mark at baseline.
Subjects were asked to assess various skin attributes at
baseline and at various time points throughout the study.
Visible digital photography and Diffuse Reflectance
Spectrometer (DRS) measurements were obtained at a wavelength
suitable for monitoring melanin concentration. Measurements were
taken at baseline and various time points throughout the study. The
mark to be monitored was scanned 3 times. Normal skin was also
scanned 3 times. The spectra were overlaid and subtracted. Digital
Image quantification was carried out for quantification of variables
'L' and 'a'. Variable 'L' refers to luminosity and is measured by
the brightness of the measured skin. Variable 'a' measures the
redness of the measured skin.
Results
The scores from the clinical grading were averaged and
reported as net improvements from baseline. The composition of the
present invention showed a significant decrease in darkness,
roughness and erythema compared to baseline at week 4 and continued
at week 8, 12 and 16 with reduction in darkness seen as early as
week 1. Clinical expert
grading of photos showed that this
composition showed an average % improvements in PIH size of 41% at
week 4, 68% at week 8, 82% at week 12 and 92% at week 16. This was
statistically significantly more effective than the placebo
composition at weeks 4, 8, 12 and 16. This composition was effective
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on 91% of subjects at week 4 and on 100% of subjects at weeks 8, 12
and 16.
Expert clinical grading showed an average % improvements in
PIH darkness of 41% at week 4, 63% at week 8, 80% at week 12 and 92%
at week 16. This was statistically significantly more effective than
the placebo composition at weeks 8 and 12. This composition was
effective on 95% of subjects at week 4 and on 100% of subjects at
weeks 8, 12 and 16.
Further statistical analysis of the data also showed that the
active composition worked faster than the placebo in reducing the
size and darkness of PIH marks.
At one week, target acne lesions exhibited a significant
decrease in both erythema and elevation compared to baseline.
Significant improvements were also observed in facial skin
tone, texture and global acne assessments compared to baseline.
Digital Image quantification for variable 'L' showed that at
weeks 4, 8 and 12, the mean for this composition decreased more
appreciably compared with the placebo and there was a trend in favor
of the this active composition. Additionally, for variable 'a' the
decrease from baseline for the active composition was statistically
significant at week 12 for % change in active treatment (27.46%
decrease) over the placebo treatment (6.63% increase).
Based on DRS data, the composition of the present invention
demonstrated decreases from baseline at each week and the placebo
group was equal to baseline or increased from baseline at each week.
Subsequent analysis from a subset of population based on baseline
melanin content as inclusion criterion indicated a statistically
significant decrease for the composition in this invention (0.07
decrease) versus placebo (0.01 decrease) at week 4.
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