Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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METHODS OF REGULATING THE CONDITION
OF MAMMALIA.~1' KERATINOUS TISSUE
Cross Reference To Related Application
This application claims the benefit of U.S. Provisional Application No.
60/134,660, filed
May 18, 1999.
Technical Field
The present invention relates to methods of regulating the condition of
mammalian
keratinous tissue using select xanthine compounds wherein the methods include:
a) regulating
visible and/or tactile discontinuities in the texture of mammalian skin, b)
preventing and/or
retarding the appearance of spider vessels and/or red blotchiness on mammalian
skin, c)
preventing and/or retarding the appearance of dark circles under the eye of a
mammal as well as
puffy eyes, d) preventing and/or retarding sallowness of mammalian skin, e)
preventing and/or
retarding sagging of mammalian skin, f) desquamating mammalian skin, g)
softening and/or
smoothing lips, hair and nails of a mammal, and h) preventing and/or relieving
itch of
mammalian skin. These methods are accomplished via the topical application of
compositions
containing select xanthine compounds to the keratinous tissue of a mammal in
need of such
treatments.
Background of the Invention
Currently, there are a number of personal care products which are available to
consumers
which are directed to the improving the health and physical appearance of the
skin. The majority
of these products are directed to delaying, minimizing or even eliminating
skin wrinkling and
other histological changes typically associated with the aging of skin or
environmental damage to
human skin.
Mammalian keratinous tissue, particularly human skin, is subjected to a
variety of insults
by both extrinsic and intrinsic factors. Such extrinsic factors include
ultraviolet radiation,
environmental pollution, wind, heat, infrared radiation, low humidity, harsh
surfactants,
abrasives, etc.. Intrinsic factors, on the other hand, include chronological
aging and other
biochemical changes from within the skin. Whether extrinsic or intrinsic,
these factors result in
visible signs of skin damage. Typical skin damage includes uneven texture,
spider vessels or red
blotchiness, under eye circles, puffy eyes, sallowess, sagging, dead skin.
rough skin, hair, and,%or
nails, and skin irritation which results in an itch.
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Therefore, there is a need for products and methods that seek to remedy these
keratinous
tissue conditions such that the condition of the keratinous tissues like skin,
hair, and nails are
regulated.
Applicants have found that topical compositions that contain certain xanthine
compounds
may be used to provide prophylactic as well as therapeutic treatments for
these keratinous tissue
conditions. For instance, Applicants have found that such compositions may be
useful for
treating uneven skin texture, spider vessels or red blotchiness. under eye
circles, puffy eyes,
sallowmess, skin sagging, dead skin, rough keratinous tissue including, but
not limited to, skin,
hair, and/or nails, and skin irritation which results in an itch.
Summary of the Invention
The present invention relates to methods for regulating the condition of
mammalian
keratinous tissue wherein the methods comprise the step of topically applying
to the keratinous
tissue of a mammal in need of such treatment a safe and effective amount of a
composition
comprising:
a) a safe and effective amount of a repair agent consisting essentially of a
xanthine
compound selected from the group consisting of theophylline, theobromine, and
combinations thereof; and
b) a dermatologically acceptable earner for the repair agent.
In particular embodiments, such compositions or modified versions thereof are
suitable
for regulating visible and/or tactile discontinuities in the texture of
mammalian skin, preventing
and/or retarding the appearance of spider vessels and/or red blotchiness on
mammalian skin,
preventing and/or retarding the appearance of dark circles under the eye of a
mammal as well as
their puffy eyes, desquamating mammalian skin, preventing and/or retarding
sallowness of
mammalian skin, preventing and/or retarding sagging of mammalian skin,
softening and/or
smoothing lips, hair and nails of a mammal, and preventing and/or relieving
itch of mammalian
skin.
Detailed Description of the Invention
All percentages and ratios used herein are by weight of the total composition
and all
measurements made are at 25~C, unless otherwise designated.
The compositions of the present invention can comprise, consist essentially
of, or consist
of, the essential as well as optional ingredients and components described
herein. As used
herein, "consisting essentially of means that the composition or component may
include
additional ingredients, but only if the additional ingredients do not
materially alter the basic and
novel characteristics of the claimed compositions or methods.
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All publications cited herein are hereby incorporated by reference in their
entirey.
The term "keratinous tissue," as used herein, refers to keratin-containing
layers disposed
as the outermost protective covering of mammals which includes, but is not
limited to, skin, hair,
and nails (e.g., toenails, fingernails, hooves, cuticles, etc.).
The term "topical application", as used herein, means to apply or spread the
compositions
of the present invention onto the surface of mammalian keratinous tissue.
The term "dermatologically acceptable," as used herein, means that the
compositions or
components thereof so described are suitable for use in contact with human
keratinous tissue
without undue toxicity, incompatibility, instability, allergic response, and
the like.
The term "safe and effective amount" as used herein means an amount of a
compound or
composition sufficient to significantly induce a positive benefit, preferably
a positive keratinous
tissue appearance or feel benefit, including independently the benefits
disclosed herein, but low
enough to avoid serious side effects, i.e., to provide a reasonable benefit to
risk ratio, within the
scope of sound judgment of the skilled artisan.
The terms "desquamation, exfoliation, and/or increasing turnover" as used
herein mean
the removal of the upper layers of the stratum corneum (comprising the horny
and granular
layers). Without intending to be limited by theory, it is believed that these
benefits may be
accomplished via chemical and physical means that remove these layers from the
top down.
Additionally, it is possible to elicit exfoliation via a biological means that
drives the turnover of
the epidermal layers from the basal layers upwards. It is believed that this
involves the process
of keratinocyte proliferation as well as induction of differentiation. The
latter leads to an
elevation in keratinization levels as well, which ultimately lead to a
reorganization of the upper
epidermal layers that comprise the stratum corneum and stratum granular
layers.
The term "sagging" as used herein refers to the laxity, slackness, or the like
condition of
skin that occurs as a result of loss of, damage to, alterations to, and /or
abnormalities in dermal
elastin.
The terms "smoothing" and "softening" as used herein means altering the
surface of the
keratinous tissue such that its tactile feel is improved.
The compositions of the present invention are useful for topical application
and for
regulating keratinous tissue condition. Regulation of keratinous tissue
condition is often required
due to conditions that may be induced or caused by internal and/or external
factors. In particular,
"regulating skin condition" includes prophylactically regulating and/or
therapeutically regulating
skin condition, including preventing loss of skin elasticity (loss and/or
inactivation of functional
skin elastin) such as elastosis, sagging, loss of skin recoil from
deformation; non-melanin skin
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discoloration such as under eye circles, blotching (e.g., uneven red
coloration due to, e.g.,
rosacea), sallowness (pale color), discoloration caused by telangiectasia or
spider vessels. As
used herein, prophylactically regulating skin condition includes delaying,
minimizing and/or
preventing visible and/or tactile discontinuities in skin. As used herein,
therapeutically
regulating skin condition includes ameliorating, e.g., diminishing, minimizing
andJor effacing,
discontinuities in skin. Regulating skin condition involves improving skin
appearance and/or
feel, especially facial skin (i. e., regulating visible and/or tactile
discontinuities in the texture of
mammalian skin).
As used herein, "regulating skin condition" is intended to include regulation
of such
signs irrespective of the mechanism of origin.
The compositions of the present invention, including the essential and
optional
components thereof, are described in detail hereinafter.
Xanthine Compound
The topical compositions of the present invention comprise a safe and
effective amount
of various repair agents that consist essentially of a xanthine compound
selected from the group
consisting of theophylline, theobromine, and combinations thereof.
Theophylline (also referred to as 7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione
or 1,3-
dimethylxanthine) and theobromine (also referred to as 3,7-Dihydro-3,7-
dimethyl-1H-purine-2,6-
dione ) are commercially available from Sigma Chemical Company (St. Louis,
MO); Aldrich
Chemical Company (Milwaukee, WI), and Fluka Chemika-USA (Ronkonkonma, NY).
In the compositions of the present invention, the xanthine compound preferably
comprises from about 0.01% to about 50%, by weight of the composition, more
preferably from
about 0.1 % to about 20%, even more preferably from about 1 % to about 10%,
even still more
preferably from about 2% to about 8%, and most preferably from about 4% to
about 6%.
Without being limited by theory, it is believed that these xanthine compounds
increase
the turnover rate of the epidermis, which in turn leads to an ultimate
improvement in the texture
appearance of skin, especially facial skin. It is believed that the mechanism
of action for such
xanthine compounds involves an increase in cellular cyclic adenosine
monophosphate (CAMP)
levels which leads to induction of secondary signaling pathways such as
increases in intracellular
calcium and inositol phosphate formation. Ultimately, this leads to
alterations in gene expression
patterns that impact the homeostasis of cells.
Dermatologcally Acceptable Carrier
The topical compositions of the present invention also comprise a
dermatologically
acceptable carrier for the xanthine compound. The phrase "dermatologically
acceptable carrier",
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as used herein, means that the carrier is suitable for topical application to
mammalian keratinous
tissue, has good aesthetic properties, is compatible with the actives of the
present invention and
any other components, and will not cause any untoward safety or toxicity
concerns. A safe and
effective amount of carrier is from about 50% to about 99.99%, preferably from
about 80% to
about 99.9%, more preferably from about 90°~'o to about 98%, and most
preferably from about
90% to about 95% of the composition.
The carrier can be in a wide variety of forms. For example, emulsion carriers,
including,
but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-
in-water-in-silicone
emulsions, are useful herein.
Preferred carriers comprise an emulsion such as oil-in-water emulsions or
water-in-oil
emulsions (e.g., silicone-in-water or water-in-silicone). As will be
understood by the skilled
artisan, a given component will distribute primarily into either the water or
oil phase, depending
on the water solubility/dispersibility of the component in the composition.
The xanthine
compounds distribute primarily into the water phase. Oil-in-water emulsions
are especially
preferred.
Emulsions according to the present invention generally contain a solution as
described
above and a lipid or oil. Lipids and oils may be derived from animals, plants,
or petroleum and
may be natural or synthetic (i.e., man-made). Preferred emulsions also contain
a humectant, such
as glycerin. Emulsions will preferably further contain from about 1% to about
10%, more
preferably from about 2% to about 5%, of an emulsifier, based on the weight of
the carrier.
Emulsifiers may be nonionic, anionic or cationic. Suitable emulsifiers are
disclosed in, for
example, U.S. Patent No. 3,755,560, issued August 28, 1973, Dickert et al.;
U.S. Patent No.
4,421,769, issued December 20, 1983, Dixon et al.; and McCutcheon's Detergents
and
Emulsifiers, North American Edition, pages 317-324 (1986).
The emulsion may also contain an anti-foaming agent to minimize foaming upon
application to the skin. Anti-foaming agents include high molecular weight
silicones and other
materials well known in the art for such use.
Preferred water-in-silicone and oil-in-water emulsions are described in
greater detail
below.
a) Water-in-silicone emulsion
Water-in-silicone emulsions contain a continuous silicone phase and a
dispersed aqueous
phase.
Vii) Continuous silicone phase
Preferred water-in-silicone emulsions of the present invention comprise from
about 1%
to about 60%, preferably from about 5% to about 40%, more preferably from
about 10% to about
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20%, by weight of a continuous silicone phase. The continuous silicone phase
exists as an
external phase that contains or surrounds the discontinuous aqueous phase
described hereinafter.
The continuous silicone phase contains a polyorganosiloxane oil. A preferred
water-in
silicone emulsion system is formulated to provide an oxidatively stable
vehicle for the optional
retinoid. The continuous silicone phase of these preferred emulsions comprises
between about
50% and about 99.9% by weight of organopolysiloxane oil and less than about
50% by weight of
a non-silicone oil. In an especially preferred embodiment, the continuous
silicone phase
comprises at least about 50%, preferably from about 60% to about
99.9°,%, more preferably from
about 70% to about 99.9%, and even more preferably from about 80% to about
99.9%,
polyorganosiloxane oil by weight of the continuous silicone phase, and up to
about 50% non-
silicone oils, preferably less about 40%, more preferably less than about 30%,
even more
preferably less than about 10%, and most preferably less than about 2%, by
weight of the
continuous silicone phase. These preferred emulsion systems provide more
oxidative stability to
the retinoid over extended periods of time than comparable water-in-oil
emulsions containing
lower concentrations of the polyorganosiloxane oil. Concentrations of non-
silicone oils in the
continuous silicone phase are minimized or avoided altogether so as to further
enhance oxidative
stability of the selected retinoid in the compositions. Water-in-silicone
emulsions of this type are
described in copending U.S. Patent Application Serial No. 08/570,275, filed
December 11, 1995,
in the names of Joseph Michael Zukowski, Brent William Mason, Larry Richard
Robinson and
Greg George Hillebrand.
The organopolysiloxane oil for use in the composition may be volatile, non-
volatile, or a
mixture of volatile and non-volatile silicones. The term "nonvolatile" as used
in this context
refers to those silicones that are liquid under ambient conditions and have a
flash point (under
one atmospheric of pressure) of or greater than about 100°C. The term
"volatile" as used in this
context refers to all other silicone oils. Suitable organopolysiloxanes can be
selected from a wide
variety of silicones spanning a broad range of volatilities and viscosities.
Examples of suitable
organopolysiloxane oils include polyalkylsiloxanes, cyclic polyalkylsiloxanes,
and
polyalkylarylsiloxanes.
Polyalkylsiloxanes useful in the composition herein include polyalkylsiloxanes
with
viscosities of from about 0.5 to about 1,000,000 centistokes at 25°C.
Such polyalkylsiloxanes
can be represented by the general chemical formula R3Si0[R2Si0]xSiR3 wherein R
is an alkyl
group having from one to about 30 carbon atoms (preferably R is methyl or
ethyl, more
preferably methyl; also mixed alkyl groups can be used in the same molecule),
and x is an integer
from 0 to about 10,000, chosen to achieve the desired molecular weight which
can range to over
about 10,000,000. Commercially available polyalkylsiloxanes include the
polydimethylsiloxanes, which are also known as dimethicones, examples of which
include the
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Vicasil~ series sold by General Electric Company and the Dow Corning~ 200
series sold by
Dow Corning Corporation. Specific examples of suitable polydimethylsiloxanes
include Dow
Corning~ 200 fluid having a viscosity of 0.65 centistokes and a boiling point
of 100°C. Dow
Corning~ 225 fluid having a viscosity of 10 centistokes and a boiling point
greater than 200°C,
and Dow Corning~ 200 fluids having viscosities of 50, 350, and 12,500
centistokes,
respectively, and boiling points greater than 200°C. Suitable
dimethicones include those
represented by the chemical formula (CH3)3Si0[(CH3)2Si0]x[CH3RSi0]vSi(CH3)3
wherein R
is straight or branched chain alkyl having from two to about 30 carbon atoms
and x and y are
each integers of 1 or greater selected to achieve the desired molecular weight
which can range to
over about 10,000,000. Examples of these alkyl-substituted dimethicones
include cetyl
dimethicone and lauryl dimethicone.
Cyclic polyalkylsiloxanes suitable for use in the composition include those
represented
by the chemical formula [SiR2-O]n wherein R is an alkyl group (preferably R is
methyl or ethyl,
more preferably methyl) and n is an integer from about 3 to about 8, more
preferably n is an
integer from about 3 to about 7, and most preferably n is an integer from
about 4 to about 6.
When R is methyl, these materials are typically referred to as
cyclomethicones. Commercially
available cyclomethicones include Dow Corning~ 244 fluid having a viscosity of
2.5
centistokes, and a boiling point of 172°C, which primarily contains the
cyclomethicone tetramer
(i.e. n=4), Dow Corning~ 344 fluid having a viscosity of 2.5 centistokes and a
boiling point of
178°C, which primarily contains the cyclomethicone pentamer (i.e. n=5),
Dow Corning 245
fluid having a viscosity of 4.2 centistokes and a boiling point of
205°C, which primarily contains
a mixture of the cyclomethicone tetramer and pentamer (i.e. n=4 and 5), and
Dow Corning~ 345
fluid having a viscosity of 4.5 centistokes and a boiling point of
217°, which primarily contains a
mixture of the cyclomethicone tetramer, pentamer, and hexamer (i.e. n=4, ~,
and 6).
Also useful are materials such as trimethylsiloxysilicate, which is a
polymeric material
corresponding to the general chemical formula [(CH2)3Si01/2]x[Si02]y, wherein
x is an integer
from about 1 to about 500 and y is an integer from about 1 to about 500. A
commercially
available trimethylsiloxysilicate is sold as a mixture with dimethicone as Dow
Corning 593
fluid.
Dimethiconols are also suitable for use in the composition. These compounds
can be
represented by the chemical formulas R3Si0[R2Si0]xSiR20H and
HOR2Si0[R2Si0]xSiR20H
wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably
methyl) and x is an
integer from 0 to about 500, chosen to achieve the desired molecular weight.
Commercially
available dimethiconols are typically sold as mixtures with dimethicone or
cyclomethicone (e.g.
Dow Corning~ 1401, 1402, and 1403 fluids).
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Polyalkylaryl siloxanes are also suitable for use in the composition.
Polymethylphenyl
siloxanes having viscosities from about 15 to about 65 centistokes at
25°C are especially useful.
Preferred for use herein are organopolysiloxanes selected from the group
consisting of
polyalkylsiloxanes, alkyl substituted dimethicones, cyclomethicones,
trimethylsiloxysilicates,
dimethiconols, polyalkylaryl siloxanes, and mixtures thereof. More preferred
for use herein are
polyalkylsiloxanes and cyclomethicones. Preferred among the polyalkylsiloxanes
are
dimethicones.
As stated above, the continuous silicone phase may contain one or more non-
silicone
oils. Concentrations of non-silicone oils in the continuous silicone phase are
preferably
minimized or avoided altogether so as to further enhance oxidative stability
of the selected
retinoid in the compositions. Suitable non-silicone oils have a melting point
of about 25°C or
less under about one atmosphere of pressure. Examples of non-silicone oils
suitable for use in
the continuous silicone phase are those well known in the chemical arts in
topical personal care
products in the form of water-in-oil emulsions, e.g., mineral oil, vegetable
oils, synthetic oils,
semisynthetic oils, etc..
(ii) Dispersed aqueous phase
The topical compositions of the present invention comprise from about 30% to
about 90%,
more preferably from about 50% to about 85%, and most preferably from about
70% to about
80% of a dispersed aqueous phase. In emulsion technology, the term "dispersed
phase" is a term
well-known to one skilled in the art which means that the phase exists as
small particles or
droplets that are suspended in and surrounded by a continuous phase. The
dispersed phase is also
known as the internal or discontinuous phase. The dispersed aqueous phase is a
dispersion of
small aqueous particles or droplets suspended in and surrounded by the
continuous silicone phase
described hereinbefore.
The aqueous phase can be water, or a combination of water and one or more
water soluble
or dispersible ingredients. Nonlimiting examples of such optional ingredients
include thickeners,
acids, bases, salts, chelants, gums, water-soluble or dispersible alcohols and
polyols, buffers,
presen~atives, sunscreening agents, colorings, and the like.
The topical compositions of the present invention will typically comprise from
about 25%
to about 90%, preferably from about 40% to about 80%, more preferably from
about 60% to
about 80%, water in the dispersed aqueous phase by weight of the composition.
(iii) Emulsifier for dispersing the agueous phase
The water-in-silicone emulsions of the present invention preferably comprise
an
emulsifier. In a preferred embodiment, the composition contains from about
0.1% to about 10%
emulsifier, more preferably from about 0.5% to about 7.5%, most preferably
from about 1% to
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about 5%, emulsifier by weight of the composition. The emulsifier helps
disperse and suspend
the aqueous phase within the continuous silicone phase.
A wide variety of emulsifying agents can be employed herein to form the
preferred water-
in-silicone emulsion. Knovvn or conventional emulsifying agents can be used in
the composition,
provided that the selected emulsifying agent is chemically and physically
compatible with
essential components of the composition, and provides the desired dispersion
characteristics.
Suitable emulsifiers include silicone emulsifiers, non-silicon-containing
emulsifiers, and
mixtures thereof, known by those skilled in the art for use in topical
personal care products.
Preferably these emulsifiers have an HLB value of or less than about 14, more
preferably from
about 2 to about 14, and most preferably from about 4 to about 14. Emulsifiers
having an HLB
value outside of these ranges can be used in combination with other
emulsifiers to achieve an
effective weighted average HLB for the combination that falls within these
ranges.
Silicone emulsifiers are preferred. A wide variety of silicone emulsifiers are
useful herein.
These silicone emulsifiers are typically organically modified
organopolysiloxanes, also known to
those skilled in the art as silicone surfactants. Useful silicone emulsifiers
include dimethicone
copolyols. These materials are polydimethyl siloxanes which have been modified
to include
polyether side chains such as polyethylene oxide chains, polypropylene oxide
chains, mixtures of
these chains, and polyether chains containing moieties derived from both
ethylene oxide and
propylene oxide. Other examples include alkyl-modified dimethicone copolyols,
i.e., compounds
which contain C2-C30 pendant side chains. Still other useful dimethicone
copolyols include
materials having various cationic, anionic, amphoteric, and zwitterionic
pendant moieties.
The dimethicone copolyol emulsifiers useful herein can be described by the
following
general structure:
~ H3 CH3 ~ H3 ~ H3 ~ H3
CH3- i i-O Si O i i O i i O i i-CH3
CH3 CH3 ~ R ~ R2 CH3
x Y
wherein R is C1-C30 straight, branched, or cyclic alkyl and R2 is selected
from the group
consisting of
_-(CH2)n__O__(CH2CHR30)m--H,
and
__(CH2)n__O__(CH2CHR30)m--(CH2CHR40)o--H,
wherein n is an integer from 3 to about 10; R3 and R4 are selected from the
group consisting of
H and C1-C6 straight or branched chain alkyl such that R3 and R4 are not
simultaneously the
same; and m, o, x, and y are selected such that the molecule has an overall
molecular weight
from about 200 to about 10,000,000, with m, o, x, and y being independently
selected from
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integers of zero or greater such that m and o are not both simultaneously
zero, and z being
independently selected from integers of 1 or greater. It is recognized that
positional isomers of
these copolyols can be achieved. The chemical representations depicted above
for the R2
moieties containing the R3 and R4 groups are not meant to be limiting but are
shown as such for
convenience.
Also useful herein, although not strictly classified as dimethicone copolyols,
are silicone
surfactants as depicted in the structures in the previous paragraph wherein R2
is:
__(CH2)n_-O__RS
wherein RS is a cationic, anionic, amphoteric, or zwitterionic moiety.
Nonlimiting examples of dimethicone copolyols and other silicone surfactants
useful as
emulsifiers herein include polydimethylsiloxane polyether copolymers with
pendant
polyethylene oxide sidechains, polydimethylsiloxane polyether copolymers with
pendant
polypropylene oxide sidechains, polydimethylsiloxane polyether copolymers with
pendant mixed
polyethylene oxide and polypropylene oxide sidechains, polydimethylsiloxane
polyether
copolymers with pendant mixed poly(ethylene)(propylene)oxide sidechains,
polydimethylsiloxane polyether copolymers with pendant organobetaine
sidechains,
polydimethylsiloxane polyether copolymers with pendant carboxylate sidechains,
polydimethylsiloxane polyether copolymers with pendant quaternary ammonium
sidechains; and
also further modifications of the preceding copolymers containing pendant C2-
C30 straight,
branched, or cyclic alkyl moieties. Examples of commercially available
dimethicone copolyols
useful herein sold by Dow Corning Corporation are Dow Corning~ 190, 193, Q2-
5220, 2501
Wax, 2-5324 fluid, and 3225C (this later material being sold as a mixture
~~ith cyclomethicone).
Cetyl dimethicone copolyol is commercially available as a mixture with
polyglyceryl-4
isostearate (and) hexyl laurate and is sold under the tradename ABILD WE-09
(available from
Goldschmidt). Cetyl dimethicone copolyol is also commercially available as a
mixture with
hexyl laurate (and) polyglyceryl-3 oleate (and) cetyl dimethicone and is sold
under the tradename
ABIL~ WS-08 (also available from Goldschmidt). Other nonlimiting examples of
dimethicone
copolyols also include lauryl dimethicone copolyol, dimethicone copolyol
acetate, diemethicone
copolyol adipate, dimethicone copolyolamine, dimethicone copolyol behenate,
dimethicone
copolyol butyl ether, dimethicone copolyol hydroxy stearate, dimethicone
copolyol isostearate,
dimethicone copolyol laurate, dimethicone copolyol methyl ether, dimethicone
copolyol
phosphate, and dimethicone copolyol stearate. See International Cosmetic
Ingredient Dictionary,
Fifth Edition, 1993.
Dimethicone copolyol emulsifiers useful herein are described, for example, in
U.S. Patent
No. 4,960,764, to Figueroa, Jr. et al., issued October 2, 1990; European
Patent No. EP 330,369,
to SanoGueira, published August 30, 1989; G.H. Dahms, et al., "New Formulation
Possibilities
CA 02373194 2001-11-05
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Offered by Silicone Copolyols," Cosmetics ~ Toiletries, vol. 110, pp. 91-100,
March 1995; M.E.
Carlotti et al., "Optimization of W/O-S Emulsions And Study Of The
Quantitative Relationships
Between Ester Structure And Emulsion Properties," J. Dispersion Science And
Technology,
13(3), 315-336 (1992); P. Hameyer, "Comparative Technological Investigations
of Organic and
Organosilicone Emulsifiers in Cosmetic Water-in-Oil Emulsion Preparations,"
HAPPI 28(4), pp.
88-128 (1991); J. Smid-Korbar et al., "Efficiency and usability of silicone
surfactants in
emulsions," Provisional Communication, International Journal of Cosmetic
Science, 12, 135-139
(1990); and D.G. Krzysik et al., "A New Silicone Emulsifier For Water-in-Oil
Systems." Drus
and Cosmetic Industry, vol. 146(4) pp. 28-81 (April 1990).
Among the non-silicone-containing emulsifiers useful herein are various non-
ionic and
anionic emulsifying agents such as sugar esters and polyesters, alkoxylated
sugar esters and
polyesters, C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated
derivatives of C1-C30
fatty acid esters of C1-C30 fatty alcohols, alkoxylated ethers of C1-C30 fatty
alcohols,
polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters of polyols, C1-C30
ethers of polyols,
alkyl phosphates, polyoxyalkylene fatty ether phosphates, fatty acid amides,
acyl lactylates,
soaps, and mixtures thereof. Other suitable emulsifiers are described, for
example, in
McCutcheon's, Detergents and Emulsifiers, North American Edition (1986),
published by
Allured Publishing Corporation; U.S. Patent No. 5,011,681 to Ciotti et al.,
issued April 30, 1991;
U.S. Patent No. 4,421,769 to Dixon et al., issued December 20, 1983; and U.S.
Patent No.
3,755,560 to Dickert et al., issued August 28, 1973.
Nonlimiting examples of these non-silicon-containing emulsifiers include:
polyethylene
glycol 20 sorbitan monolaurate (Polysorbate 20), polyethylene glycol 5 Soya
sterol, Steareth-20,
Ceteareth-20, PPG-2 methyl glucose ether distearate, Ceteth-10, Polysorbate
80, cetyl phosphate,
potassium cetyl phosphate, diethanolamine cetyl phosphate, Polysorbate 60,
glyceryl stearate,
PEG-100 stearate, polyoxyethylene 20 sorbitan trioleate (Polysorbate 85),
sorbitan monolaurate,
polyoxyethylene 4 lauryl ether sodium stearate, polyglyceryl-4 isostearate,
hexyl laurate,
steareth-20, ceteareth-20, PPG-2 methyl glucose ether distearate, ceteth-10,
diethanolamine cetyl
phosphate, glyceryl stearate, PEG-100 stearate, and mixtures thereof.
b~ Oil-in-Water Emulsions
Other preferred topical carriers include oil-in-water emulsions, having a
continuous
aqueous phase and a hydrophobic, water-insoluble phase ("oil phase") dispersed
therein.
Examples of suitable carriers comprising oil-in-water emulsions are described
in U.S. Pat. No.
5,073,371, to Turner, D.J. et al., issued Dec. 17, 1991, and U.S. Pat. No.
5,073,372, to Turner,
D.J. et al., issued Dec. 17, 1991. An especially preferred oil-in-water
emulsion, containing a
structuring agent, hydrophilic surfactant and water, is described in detail
hereinafter.
ail Structuring Agent
CA 02373194 2001-11-05
WO 00/69408 PCT/US00/13647
A preferred oil-in-water emulsion comprises a structuring agent to assist in
the formation
of a liquid crystalline gel network structure. Without being limited by
theory, it is believed that
the structuring agent assists in providing rheological characteristics to the
composition which
contribute to the stability of the composition. The structuring agent may also
function as an
emulsifier or surfactant. Preferred compositions of this invention comprise
from about 0.5% to
about 20%, more preferably from about 1% to about 10%, most preferably from
about 1% to
about 5%, by weight of the composition, of a structuring agent.
The preferred structuring agents of the present invention are selected from
the group
consisting of stearic acid, palmitic acid, stearyl alcohol, cetyl alcohol,
behenyl alcohol, stearic
acid, palmitic acid, the polyethylene glycol ether of stearyl alcohol having
an average of about 1
to about 21 ethylene oxide units, the polyethylene glycol ether of cetyl
alcohol having an average
of about 1 to about 5 ethylene oxide units, and mixtures thereof. More
preferred structuring
agents of the present invention are selected from the group consisting of
stearyl alcohol, cetyl
alcohol, behenyl alcohol, the polyethylene glycol ether of stearyl alcohol
having an average of
about 2 ethylene oxide units (steareth-2), the polyethylene glycol ether of
stearyl alcohol having
an average of about 21 ethylene oxide units (steareth-21), the polyethylene
glycol ether of cetyl
alcohol having an average of about 2 ethylene oxide units, and mixtures
thereof. Even more
preferred structuring agents are selected from the group consisting of stearic
acid, palmitic acid,
stearyl alcohol, cetyl alcohol, behenyl alcohol, steareth-2, steareth-21, and
mixtures thereof.
(ii) Hydrophilic surfactant
The preferred oil-in-water emulsions comprise from about 0.05 ~o to about 10%,
preferably
from about 1 % to about 6%, and more preferably from about 1 °~o to
about 3% of at least one
hydrophilic surfactant which can disperse the hydrophobic materials in the
water phase
(percentages by weight of the topical carrier). The surfactant, at a minimum,
must be hydrophilic
enough to disperse in water.
Suitable surfactants include any of a wide variety of known cationic, anionic,
zwitterionic,
and amphoteric surfactants. See, McCutcheon's. Detergents and Emulsifiers,
North American
Edition (1986), published by Allured Publishing Corporation; U.S. Patent No.
5,011,681; U.S.
Patent No. 4,421,769; and U.S. Patent No. 3,755,560.
The exact surfactant chosen will depend upon the pH of the composition and the
other
components present.
Preferred are cationic surfactants, especially dialkyl quaternary ammonium
compounds,
examples of which are described in U.S. Patent No. 5,151,209; U.S. Patent No.
5,151,210; U.S.
Patent No. 5,120,532; U.S. Patent No. 4,387,090; U.S. Patent No. 3,155,591;
U.S. Patent No.
3,929,678; U.S. Patent No. 3,959,461; McCutcheon's, Detergents & Emulsifiers,
(North
American edition 1979) M.C. Publishing Co.; and Schwartz, et al., Surface
Active A ents, Their
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WO 00/69408 PCT/US00/13647
Chemistry and Technolo~y, New York: Interscience Publishers, 1949; which
descriptions are
incorporated herein by reference. The cationic surfactants useful herein
include cationic
ammonium salts such as those having the formula:
R~
RZ-- i -R3 X
wherein R1, is an alkyl group having from about 12 to about 30 carbon atoms,
or an aromatic,
aryl or alkaryl group having from about 12 to about 30 carbon atoms; R2, R3,
and R4 are
independently selected from hydrogen, an alkyl group having from about 1 to
about 22 carbon
atoms, or aromatic, aryl or alkaryl groups having from about 12 to about 22
carbon atoms; and X
is any compatible anion, preferably selected from the group consisting of
chloride, bromide,
iodide, acetate, phosphate, nitrate, sulfate, methyl sulfate, ethyl sulfate,
tosylate, lactate, citrate,
glycolate, and mixtures thereof. Additionally, the alkyl groups of R1, R2, R3,
and R4 can also
contain ester and/or ether linkages, or hydroxy or amino group substituents
(e.g., the alkyl groups
can contain polyethylene glycol and polypropylene glycol moieties).
More preferably, R1 is an alkyl group having from about 12 to about 22 carbon
atoms; R2
is selected from H or an alkyl group having from about 1 to about 22 carbon
atoms; R3 and R4
are independently selected from H or an alkyl group having from about 1 to
about 3 carbon
atoms; and X is as described previously.
Most preferably, R1 is an alkyl group having from about 12 to about 22 carbon
atoms; R2,
R3, and R4 are selected from H or an alkyl group having from about 1 to about
3 carbon atoms;
and X is as described previously.
Alternatively, other useful cationic emulsifiers include amino-amides, wherein
in the
above structure R1 is alternatively RSCONH-(CH2)n, wherein RS is an alkyl
group having from
about 12 to about 22 carbon atoms, and n is an integer from about 2 to about
6, more preferably
from about 2 to about 4, and most preferably from about 2 to about 3.
Nonlimiting examples of
these cationic emulsifiers include stearamidopropyl PG-dimonium chloride
phosphate,
behenamidopropyl PG dimonium chloride, stearamidopropyl ethyldimonium
ethosulfate,
stearamidopropyl dimethyl (myristyl acetate) ammonium chloride,
stearamidopropyl dimethyl
cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride,
stearamidopropyl
dimethyl ammonium lactate, and mixtures thereof. Especially preferred is
behenamidopropyl
PG dimonium chloride.
Nonlimiting examples of quaternary ammonium salt cationic surfactants include
those
selected from the group consisting of cetyl ammonium chloride, cetyl ammonium
bromide, lauryl
ammonium chloride, lauryl ammonium bromide, stearyl ammonium chloride, stearyl
ammonium
bromide, cetyl dimethyl ammonium chloride, cetyl dimethyl ammonium bromide,
lauryl
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dimethyl ammonium chloride, lauryl dimethyl ammonium bromide, stearyl dimethyl
ammonium
chloride, stearyl dimethyl ammonium bromide, cetyl trimethyl ammonium
chloride, cetyl
trimethyl ammonium bromide, lauryl trimethyl ammonium chloride, lauryl
trimethyl ammonium
bromide, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium
bromide, lauryl
dimethyl ammonium chloride, stearyl dimethyl cetyl ditallow dimethyl ammonium
chloride,
dicetyl ammonium chloride, dicetyl ammonium bromide, dilaur~M ammonium
chloride, dilauryl
ammonium bromide, distearyl ammonium chloride, distearyl ammonium bromide,
dicetyl methyl
ammonium chloride, dicetyl methyl ammonium bromide, dilauryl methyl ammonium
chloride,
dilauryl methyl ammonium bromide, distearyl methyl ammonium chloride,
distearyl methyl
ammonium bromide, and mixtures thereof. Additional quaternary ammonium salts
include those
wherein the C12 to C3p alkyl carbon chain is derived from a tallow fatty acid
or from a coconut
fatty acid. The term "tallow" refers to an alkyl group derived from tallow
fatty acids (usually
hydrogenated tallow fatty acids), which generally have mixtures of alkyl
chains in the C16 to
Clg range. The term "coconut" refers to an alkyl group derived from a coconut
fatty acid, which
generally have mixtures of alkyl chains in the C12 to C14 range. Examples of
quaternary
ammonium salts derived from these tallow and coconut sources include ditallow
dimethyl
ammonium chloride, ditallow dimethyl ammonium methyl sulfate, di(hydrogenated
tallow)
dimethyl ammonium chloride, di(hydrogenated tallow) dimethyl ammonium acetate,
ditallow
dipropyl ammonium phosphate, ditallow dimethyl ammonium nitrate,
di(coconutalkyl)dimethyl
ammonium chloride, di(coconutalkyl)dimethyl ammonium bromide, tallow ammonium
chloride,
coconut ammonium chloride, stearamidopropyl PG-dimonium chloride phosphate,
stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl
(myristyl acetate)
ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate,
stearamidopropyl
dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and
mixtures
thereof. An example of a quaternary ammonium compound having an alkyl group
with an ester
linkage is ditallowyl oxyethyl dimethyl ammonium chloride.
More preferred cationic surfactants are those selected from the group
consisting of
behenamidopropyl PG dimonium chloride, dilauryl dimethyl ammonium chloride,
distearyl
dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmityl
dimethyl
ammonium chloride, distearyl dimethyl ammonium chloride, stearamidopropyl PG-
dimonium
chloride phosphate, stearamidopropyl ethyldiammonium ethosulfate,
stearamidopropyl dimethyl
(myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl
ammonium tosylate,
stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl
ammonium lactate,
and mixtures thereof.
Most preferred cationic surfactants are those selected from the group
consisting of
behenamidopropyl PG dimonium chloride, dilauryl dimethyl ammonium chloride,
distearyl
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WO 00/69408 PCT/US00/13647
dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmityl
dimethyl
ammonium chloride, and mixtures thereof.
A preferred combination of cationic surfactant and structuring agent is
behenamidopropyl
PG dimonium chloride and/or behenyl alcohol, wherein the ratio is preferably
optimized to
maintained to enhance physical and chemical stability, especially when such a
combination
contains ionic and/or highly polar solvents. This combination is especially
useful for delivery of
sunscreening agents such as zinc oxide and octyl methoxycinnamate.
A wide variety of anionic surfactants are also useful herein. See, e.g., U.S.
Patent No.
3,929,678, to Laughlin et al., issued December 30, 197, which is incorporated
herein by
reference in its entirety. Nonlimiting examples of anionic surfactants include
the alkoyl
isethionates, and the alkyl and alkyl ether sulfates. The alkoyl isethionates
typically have the
formula RCO-OCH2CH~S03M wherein R is alkyl or alkenyl of from about 10 to
about 30
carbon atoms, and M is a water-soluble canon such as ammonium, sodium,
potassium and
triethanolamine. Nonlimiting examples of these isethionates include those
alkoyl isethionates
selected from the group consisting of ammonium cocoyl isethionate, sodium
cocoyl isethionate,
sodium lauroyl isethionate, sodium stearoyl isethionate, and mixtures thereof.
The alkyl and alkyl ether sulfates typically have the respective formulae
ROS03M and
RO(C2H40)xS03M, wherein R is alkyl or alkenyl of from about 10 to about 30
carbon atoms, x
is from about 1 to about 10, and M is a water-soluble canon such as ammonium,
sodium,
potassium and triethanolamine. Another suitable class of anionic surfactants
are the
water-soluble salts of the organic, sulfuric acid reaction products of the
general formula:
R1__S03__M
wherein R1 is chosen from the group consisting of a straight or branched
chain, saturated
aliphatic hydrocarbon radical having from about 8 to about 24, preferably
about 10 to about 16,
carbon atoms; and M is a cation. Still other anionic synthetic surfactants
include the class
designated as succinamates, olefin sulfonates having about 12 to about 24
carbon atoms, and (3-
alkyloxy alkane sulfonates. Examples of these materials are sodium lauryl
sulfate and
ammonium lauryl sulfate.
Other anionic materials useful herein are soaps (i.e. alkali metal salts,
e.g., sodium or
potassium salts) of fatty acids, typically having from about 8 to about 24
carbon atoms,
preferably from about 10 to about 20 carbon atoms. The fatty acids used in
making the soaps
can be obtained from natural sources such as, for instance, plant or animal-
derived glycerides
(e.g., palm oil, coconut oil, soybean oil, castor oil, tallow, lard, etc.) The
fatty acids can also be
synthetically prepared. Soaps are described in more detail in U.S. Patent No.
4,557,853, cited
above.
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WO 00/69408 PCT/US00/13647
Amphoteric and zwitterionic surfactants are also useful herein. Examples of
amphoteric
and zwitterionic surfactants which can be used in the compositions of the
present invention are
those which are broadly described as derivatives of aliphatic secondary and
tertiary amines in
which the aliphatic radical can be straight or branched chain and wherein one
of the aliphatic
substituents contains from about 8 to about 22 carbon atoms (preferably Cg -
Clg) and one
contains an anionic water solubilizing group, e.g., carboxy, sulfonate,
sulfate, phosphate, or
phosphonate. Examples are alkyl imino acetates, and iminodialkanoates and
aminoalkanoates of
the formulas RN[CH2)mC02M]2 and RNH(CH2)mC02M wherein m is from 1 to 4, R is a
Cg-C22 alkyl or alkenyl, and M is H, alkali metal, alkaline earth metal
ammonium, or
alkanolammonium. Also included are imidazolinium and ammonium derivatives.
Specific
examples of suitable amphoteric surfactants include sodium 3-dodecyl-
aminopropionate, sodium
3-dodecylaminopropane sulfonate, N-alkyltaurines such as the one prepared by
reacting
dodecylamine with sodium isethionate according to the teaching of U.S. Patent
No. 2,658,072;
N-higher alkyl aspartic acids such as those produced according to the teaching
of U.S. Patent No.
2,438,091; and the products sold under the trade name "Miranol" and described
in U.S. Patent
No. 2,528,378. Other examples of useful amphoterics include phosphates, such
as
coamidopropyl PG-dimonium chloride phosphate (commercially available as
Monaquat PTC,
from Mona Corp.).
Also useful herein as amphoteric or zwitterionic surfactants are the betaines.
Examples
of betaines include the higher alkyl betaines, such as coco dimethyl
carboxymethyl betaine,
lauryl dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl
betaine, cetyl
dimethyl carboxymethyl betaine, cetyl dimethyl betaine (available as Lonzaine
16SP from Lonza
Corp.), lauryl bis-(2-hydroxyethyl) carboxymethyl betaine, stearyl bis-(2-
hydroxypropyl)
carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl betaine, lauryl
bis-(2-hydroxypropyl)alpha-carboxyethyl betaine, coco dimethyl sulfopropyl
betaine, stearyl
dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bis-
(2-hydroxyethyl)
sulfopropyl betaine, and amidobetaines and amidosulfobetaines (wherein the
RCONH(CH2)3
radical is attached to the nitrogen atom of the betaine), oleyl betaine
(available as amphoteric
Velvetex OLB-50 from Henkel), and cocamidopropyl betaine (available as
Velvetex BK-35 and
BA-35 from Henkel).
Other useful amphoteric and zwitterionic surfactants include the sultaines and
hydroxysultaines such as cocamidopropyl hydroxysultaine (available as
Mirataine CBS from
Rhone-Poulenc), and the alkanoyl sarcosinates corresponding to the formula
RCON(CH3)CH2CH2C02M wherein R is alkyl or alkenyl of about 10 to about 20
carbon
atoms, and M is a water-soluble cation such as ammonium, sodium, potassium and
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WO 00/69408 PCT/US00/13647
trialkanolamine (e.g., triethanolamine), a preferred example of which is
sodium lauroyl
sarcosinate.
iii Water
The preferred oil-in-water emulsion comprises from about 25% to about 98%,
preferably
from about 65% to about 95%, more preferably from about 70% to about 90% water
by weight of
the topical carrier.
The hydrophobic phase is dispersed in the continuous aqueous phase. The
hydrophobic
phase may contain water insoluble or partially soluble materials such as are
known in the art,
including but not limited to the silicones described herein in reference to
silicone-in-water
emulsions, and other oils and lipids such as described above in reference to
emulsions.
The topical compositions of the subject invention, including but not limited
to lotions
and creams, may comprise a dermatologically acceptable emollient. Such
compositions
preferably contain from about 2% to about 50°io of the emollient. As
used herein, "emollient"
refers to a material useful 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. Sagarin,
Cosmetics, Science and Technolo~y, 2nd Edition, Vol. 1, pp. 32-43 (1972),
contains numerous
examples of materials suitable as an emollient. A preferred emollient is
glycerin. Glycerin is
preferably used in an amount of from or about 0.001 to or about 20%, more
preferably from or
about 0.01 to or about 10%, most preferably from or about 0.1 to or about 5%,
e.g., 3%.
Lotions and creams according to the present invention generally comprise a
solution
carrier system and one or more emollients. Lotions typically comprise from
about 1 % to about
20%, preferably from about 5% to about 10%, of emollient; from about 50% to
about 90%,
preferably from about 60% to about 80%, water; and the xanthine compound in
the above
described amounts. A cream typically comprises from about 5% to about 50%,
preferably from
about 10% to about 20%, of emollient; from about 45% to about 85%, preferably
from about
50% to about 75%, water; and the xanthine compound in the above described
amounts.
Ointments of the present invention may comprise a simple carrier base of
animal or
vegetable oils or semi-solid hydrocarbons (oleaginous); absorption ointment
bases which absorb
water to form emulsions; or water soluble carriers, e.g., a water soluble
solution carrier.
Ointments may further comprise a thickening agent, such as described in
Sagarin, Cosmetics,
Science and Technolo~y, 2nd Edition, Vol. l, pp. 72-73 (1972), and/or an
emollient. For
example, an ointment may comprise from about 2% to about 10% of an emollient;
from about
0.1% to about 2% of a thickening agent; and the xanthine compound in the above
described
amount.
Compositions of this invention useful for cleansing ("cleansers") are
formulated with a
suitable carrier, e.g., as described above, and preferably contain, in
addition to the xanthine
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WO 00/69408 PCT/US00/13647
compound in the above described amounts, from about 1 % to about 90%. more
preferably from
about 5% to about 10%, of a dermatologically acceptable surfactant. The
surfactant is suitably
selected from anionic, nonionic, zwitterionic, amphoteric and ampholytic
surfactants, as well as
mixtures of these surfactants. Such surfactants are well known to those
skilled in the detergency
art. Nonlimiting examples of possible surfactants include isoceteth-20, sodium
methyl cocoyl
taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. See U.S.
Patent No. 4,800,197,
to Kowcz et al., issued January 24, 1989, which is incorporated herein by
reference in its entirety,
for exemplary surfactants useful herein. Examples of a broad variety of
additional surfactants
useful herein are described in McCutcheon's Detergents and Emulsifiers, North
American Edition
(1986), published by Allured Publishing Corporation. The cleansing
compositions can optionally
contain, at their art-established levels, other materials which are
conventionally used in cleansing
compositions.
The physical form of the cleansing compositions is not critical. The
compositions can
be, for example, formulated as toilet bars, liquids, shampoos, bath gels, hair
conditioners, hair
tonics, pastes, or mousses. Toilet bars are most preferred since this is the
form of cleansing agent
most commonly used to wash the skin. Rinse-off cleansing compositions, such as
shampoos,
require a delivery system adequate to deposit sufficient levels of actives on
the skin and scalp. A
preferred delivery system involves the use of insoluble complexes. For a more
complete
disclosure of such delivery systems, see U.S. Patent No. 4,835,148, Barford et
al., issued May 30,
1989.
As used herein, the term "foundation" refers to a liquid, semi-liquid, semi-
solid, or solid
skin cosmetic which includes, but is not limited to lotions, creams, gels,
pastes, cakes, and the
like. Typically the foundation is used over a large area of the skin, such as
over the face, to
provide a particular look. Foundations are typically used to provide an
adherent base for color
cosmetics such as rouge, blusher, powder and the like, and tend to hide skin
imperfections and
impart a smooth, even appearance to the skin. Foundations of the present
invention include a
dermatologically acceptable carrier for the xanthine compound and may include
conventional
ingredients such as oils, colorants, pigments, emollients, fragrances, waxes,
stabilizers, and the
like. Exemplary carriers and such other ingredients which are suitable for use
herein are
described, for example, in copending patent application Serial No. 08/430,961,
filed on April 28,
1995 in the names of Marcia L. Canter, Brain D. Barford, and Brian D.
Hofrichter, and U.K.
Patent Application GB 2274585-A, published on Jan. 23, 1993.
The compositions of the present invention preferably exhibit a pH of from
about 4 to
about 10. More preferably, the pH is from about 4.5 to 9.5, even more
preferably from about 5 to
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WO 00/69408 PCT/US00/13647
9, and most preferably from about 7 to 9. In even more preferred embodiments,
the pH is from
about 4 to about 6 or from about 8 to 10, more preferably from about S to
about 6 or from about 8
to about 9. Without being limited by theory, it is believed that such a
defined pH aids in
penetration of the xanthine compound of the present compositions into the
skin, hair, or nails of a
mammal. This penetration occurs due to charge distribution on the xanthine
molecule, thereby
making it more amenable to penetration. Additionally, it is possible that
higher pH levels allow
for alterations in the permeation pathways through the skin (e.g., lipid
distribution and protein
interactions in stratum corneum), thereby allowing for greater penetration of
the xanthine
molecules.
Optional Components
The compositions of the present invention may contain a variety of other
ingredients
such as are conventionally used in a given product type provided that they do
not unacceptably
alter the benefits of the invention.
In a preferred embodiment, where the composition is to be in contact with
human skin,
the optional components should be suitable for application to skin, that is,
when incorporated into
the composition they are suitable for use in contact with human skin without
undue toxicity,
incompatibility, instability, allergic response, and the like within the scope
of sound medical
judgment. The CTFA Cosmetic Ingredient Handbook, Second Edition (1992)
describes a wide
variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used
in the skin care
industry, which are suitable for use in the compositions of the present
invention. Examples of
these ingredient classes include: abrasives, absorbents, aesthetic components
such as fragrances,
pigments, colorings/colorants, essential oils, skin sensates, astringents,
etc. (e.g., clove oil,
menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel
distillate), anti-acne
agents, anti-caking agents, antifoaming agents, antimicrobial agents (e.g.,
iodopropyl
butylcarbamate), antioxidants, binders, biological additives, buffering
agents, bulking agents,
chelating agents, chemical additives, colorants, cosmetic astringents,
cosmetic biocides,
denaturants, drug astringents, external analgesics, film formers or materials,
e.g., polymers, for
aiding the film-forming properties and substantivity of the composition (e.g.,
copolymer of
eicosene and vinyl pyrrolidone), opacifying agents, pH adjusters, propellants,
reducing agents,
sequestrants, skin bleaching and lightening agents (e.g., hydroquinone, kojic
acid, ascorbic acid,
magnesium ascorbyl phosphate, ascorbyl glucosamine), skin-conditioning agents
(e.g.,
humectants, including miscellaneous and occlusive), skin soothing and/or
healing agents (e.g.,
panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid
and its derivatives,
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WO 00/69408 PCT/US00/13647
allantoin, bisabolol, and dipotassium glycyrrhizinate), skin treating agents,
thickeners, and
vitamins and derivatives thereof.
In any embodiment of the present invention, however, the actives useful herein
can be
categorized by the benefit they provide or by their postulated mode of action.
However, it is to
be understood that the actives useful herein can in some instances provide
more than one benefit
or operate via more than one mode of action. Therefore, classifications herein
are made for the
sake of convenience and are not intended to limit the active to that
particular application or
applications listed.
Desquamation Actives
A safe and effective amount of a desquamation active may be added to the
compositions
of the present invention, more preferably from about 0.1% to about 10%, even
more preferably
from about 0.2% to about 5%. also preferably from about 0.5% to about 4%, by
weight of the
composition. Desquamation actives enhance the skin appearance benefits of the
present
invention. For example, the desquamation actives tend to improve the texture
of the skin (e.g.,
smoothness). One desquamation system that is suitable for use herein comprises
sulfhydryl
compounds and zwitterionic surfactants and is described in copending
application Serial No.
08/480,632, filed on June 7, 1995 in the name of Donald L. Bissett,
corresponding to PCT
Application No. U.S. 95/08136, filed 6/29/95. Another desquamation system that
is suitable for
use herein comprises salicylic acid and zwitterionic surfactants and is
described in copending
patent application Serial No. 08/554,944, filed on November 13, 1995 as a
continuation of Serial
No. 08/209,401, filed on March 9, 1994 in the name of Bissett, corresponding
to PCT
Application No. 94/12745, Eled 11/4/94, published 5/18/95. Zwitterionic
surfactants such as
described in these applications are also useful as desquamatory agents herein,
with cetyl betaine
being particularly preferred.
Anti-Acne Actives
The compositions of the present invention may comprise a safe and effective
amount of
one or more anti-acne actives. Examples of useful anti-acne actives include
resorcinol, sulfur,
salicylic acid, erythromycin, zinc, etc. Further examples of suitable anti-
acne actives are
described in further detail in U. S. Patent No. 5,607,980, issued to McAtee et
al, on March 4,
1997.
Anti-Wrinkle Actives/Anti-Atro~hy Actives
The compositions of the present invention may further comprise a safe and
effective
amount of one or more anti-wrinkle actives or anti-atrophy actives. Exemplary
anti-wrinkle/anti-
atrophy actives suitable for use in the compositions of the present invention
include sulfur-
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containing D and L amino acids and their derivatives and salts, particularly
the N-acetyl
derivatives, a preferred example of which is N-acetyl-L-cysteine; thiols, e.g.
ethane thiol;
hydroxy acids, phytic acid, lipoic acid; lysophosphatidic acid, skin peel
agents (e.g., phenol and
the like), vitamin B3 compounds and retinoids which enhance the skin
appearance benefits of the
present invention.
a) Vitamin B, Compounds
The compositions of the present invention may comprise a safe and effective
amount of a
vitamin B3 compound. Vitamin B= compounds are particularly useful for
regulating skin
condition as described in co-pending U. S. Application Serial No. 08/834,010,
filed April 11,
1997 (corresponding to international publication WO 97/39733 Al, published
October 30, 1997).
When vitamin B, compounds are present in the compositions of the instant
invention, the
compositions preferably comprise from about 0.01 % to about 50%, more
preferably from about
0.1% to about 10%, even more preferably from about 0.5% to about 10%, and
still more
preferably from about 1% to about 5%, most preferably from about 2% to about
5%, by weight
of the composition, of the vitamin B3 compound.
As used herein, "vitamin B3 compound" means a compound having the formula:
~R
wherein R is - CONH2 (i.e., niacinamide), - COOH (i.e., nicotinic acid) or -
CH20H (i.e.,
nicotinyl alcohol); derivatives thereof; and salts of any of the foregoing.
Exemplary derivatives of the foregoing vitamin B3 compounds include nicotinic
acid
esters, including non-vasodilating esters of nicotinic acid (e.g., tocpheryl
nicotinate), nicotinyl
amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-
oxide and niacinamide
N-oxide.
Examples of suitable vitamin B3 compounds are well known in the art and are
commercially available from a number of sources, e.g., the Sigma Chemical
Company (St. Louis,
MO); ICN Biomedicals, Inc. (Irvin, CA) and Aldrich Chemical Company
(Milwaukee, WI).
Preferably, the vitamin B3 compound is niacinamide
The vitamin compounds may be included as the substantially pure material, or
as an
extract obtained by suitable physical and/or chemical isolation from natural
(e.g., plant) sources.
b) Retinoids
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The compositions of the present invention may also comprise a retinoid unless
otherwise
specified. As used herein, "retinoid" includes all natural and/or synthetic
analogs of Vitamin A
or retinol-like compounds which possess the biological activity of Vitamin A
in the skin as well
as the geometric isomers and stereoisomers of these compounds. The retinoid is
preferably
S retinol, retinol esters (e.g., C2 - C22 alkyl esters of retinol, including
retinyl palmitate, retinyl
acetate, retinyl propionate), retinal, and/or retinoic acid (including all-
trans retinoic acid and/or
13-cis-retinoic acid), more preferably retinoids other than retinoic acid.
These compounds are
well known in the art and are commercially available from a number of sources,
e.g., Sigma
Chemical Company (St. Louis, MO), and Boerhinger Mannheim (Indianapolis, IN).
Other
retinoids which are useful herein are described in U.S. Patent Nos. 4,677,120,
issued Jun. 30,
1987 to Parish et al.; 4,885,311, issued Dec. 5, 1989 to Parish et al.;
5,049,584, issued Sep. 17,
1991 to Purcell et al.; x,124,356, issued Jun. 23, 1992 to Purcell et al.; and
Reissue 34,075, issued
Sep. 22, 1992 to Purcell et al.. Other suitable retinoids are tocopheryl-
retinoate [tocopherol ester
of retinoic acid (trans- or cis-), adapalene {6-[3-(1-adamantyl)-4-
methoxyphenyl]-2-naphthoic
acid}, and tazarotene (ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-
ethynyl]nicotinate). Preferred
retinoids are retinol, retinyl palmitate, retinyl acetate, retinyl
proprionate, retinal and
combinations thereof.
The retinoid may be included as the substantially pure material, or as an
extract obtained
by suitable physical and/or chemical isolation from natural (e.g., plant)
sources. The retinoid is
preferably substantially pure, more preferably essentially pure.
The compositions of this invention may contain a safe and effective amount of
the
retinoid, such that the resultant composition is safe and effective for
regulating keratinous tissue
condition, preferably for regulating visible and/or tactile discontinuities in
skin texture. The
compositions preferably contain from or about 0.005% to or about 2%, more
preferably 0.01% to
or about 2%, retinoid. Retinol is most preferably used in an amount of from or
about 0.01% to or
about 0.15%; retinol esters are most preferably used in an amount of from or
about 0.01% to or
about 2% (e.g., about 1 %); retinoic acids are most preferably used in an
amount of from or about
0.01% to or about 0.25%; tocopheryl-retinoate, adapalene, and tazarotene are
most preferably
used in an amount of from or about 0.01 % to or about 2%.
Where the compositions of the present invention contain both a retinoid and a
Vitamin
B3 compound, the retinoid is preferably used in the above amounts, and the
vitamin B3
compound is preferably used in an amount of from or about 0.1 % to or about
10%, more
preferably from or about 2% to or about 5%.
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Anti-Oxidants/Radical Scavengers
The compositions of the present invention may include a safe and effective
amount of an
anti-oxidant/radical scavenger. The anti-oxidant/radical scavenger is
especially useful for
providing protection against UV radiation which can cause increased scaling or
texture changes
in the stratum corneum and against other environmental agents which can cause
skin damage.
A safe and effective amount of an anti-oxidant/radical scavenger may be added
to the
compositions of the subject invention, preferably from about 0.1 % to about
10%, more preferably
from about 1% to about 5%, of the composition.
Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) and its
salts, ascorbyl
esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl
phosphate), tocopherol
(vitamin E), tocopherol sorbate, tocopherol acetate, other esters of
tocopherol, butylated hydroxy
benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxylic acid
(commercially available under the tradename TroloxR), gallic acid and its
alkyl esters, especially
propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its
salts, amines (e.g., N,N-
1~ diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,
glutathione), dihydroxy
fumaric acid and its salts, lycine pidolate, arginine pilolate,
nordihydroguaiaretic acid,
bioflavonoids, lysine, methionine, proline, superoxide dismutase, silymarin,
tea extracts, grape
skin/seed extracts, melanin, and rosemary extracts may be used. Preferred anti-
oxidants/radical
scavengers are selected from tocopherol sorbate and other esters of
tocopherol, more preferably
tocopherol sorbate. For example, the use of tocopherol sorbate in topical
compositions and
applicable to the present invention is described in U.S. Patent No. 4,847,071,
issued on July 11,
1989 to Donald L. Bissett, Rodney D. Bush and Ranjit Chatterjee.
Chelators
The compositions of the present invention may also comprise a safe and
effective amount
of a chelator or chelating agent. As used herein, "chelator" or "chelating
agent" means an active
agent capable of removing a metal ion from a system by forming a complex so
that the metal ion
cannot readily participate in or catalyze chemical reactions. The inclusion of
a chelating agent is
especially useful for providing protection against UV radiation which can
contribute to excessive
scaling or skin texture changes and against other environmental agents which
can cause skin
damage.
A safe and effective amount of a chelating agent may be added to the
compositions of the
subject invention, preferably from about 0.1% to about 10%, more preferably
from about 1% to
about 5%, of the composition. Exemplary chelators that are useful herein are
disclosed in U.S.
Patent No. 5,487,884, issued 1/30/96 to Bissett et al.; International
Publication No. 91/16035,
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WO 00/69408 PCT/US00/13647
Bush et al., published 10/31/95; and International Publication No. 91/16034,
Bush et al.,
published 10/31/95. Preferred chelators useful in compositions of the subject
invention are
furildioxime and derivatives thereof.
Flavonoids
The compositions of the present invention may optionally comprise a flavonoid
compound. Flavonoids are broadly disclosed in U.S. Patents Nos. 5,686,082 and
5,686,367.
Flavonoids suitable for use in the present invention are flavanones selected
from the group
consisting of unsubstituted flavanones, mono-substituted flavanones, and
mixtures thereof;
chalcones selected from the group consisting of unsubstituted chalcones, mono-
substituted
chalcones, di-substituted chalcones, tri-substituted chalcones, and mixtures
thereof; flavones
selected from the group consisting of unsubstituted flavones, mono-substituted
flavones, di-
substituted flavones, and mixtures thereof; one or more isoflavones; coumarins
selected from the
group consisting of unsubstituted coumarins, mono-substituted coumarins, di-
substituted
coumarins, and mixtures thereof; chromones selected from the group consisting
of unsubstituted
chromones, mono-substituted chromones, di-substituted chromones, and mixtures
thereof; one or
more dicoumarols; one or more chromanones; one or more chromanols; isomers
(e.g., cis/trans
isomers) thereof; and mixtures thereof. By the term "substituted" as used
herein means
flavonoids wherein one or more hydrogen atom of the flavonoid has been
independently replaced
with hydroxyl, C1-C8 alkyl, C1-C4 alkoxyl, O-glycoside, and the like or a
mixture of these
substituents.
Examples of suitable flavonoids include, but are not limited to, unsubstituted
flavanone,
mono-hydroxy flavanones (e.g., 2'-hydroxy flavanone, 6-hydroxy flavanone, 7-
hydroxy
flavanone, etc.), mono-alkoxy flavanones (e.g., 5-methoxy flavanone, 6-methoxy
flavanone, 7-
methoxy flavanone, 4'-methoxy flavanone, etc.), unsubstituted chalcone
(especially unsubstituted
trans-chalcone), mono-hydroxy chalcones (e.g., 2'-hydroxy chalcone. 4'-hydroxy
chalcone, etc.),
di-hydroxy chalcones (e.g., 2',4-dihydroxy chalcone, 2',4'-dihydroxy chalcone,
2,2'-dihydroxy
chalcone, 2',3-dihydroxy chalcone, 2',5'-dihydroxy chalcone, etc.), and tri-
hydroxy chalcones
(e.g., 2',3',4'-trihydroxy chalcone, 4,2',4'-trihydroxy chalcone, 2,2',4'-
trihydroxy chalcone,
etc.), unsubstituted flavone, 7,2'-dihydroxy flavone, 3',4'-dihydroxy
naphthoflavone, 4'-hydroxy
flavone, 5,6-benzoflavone, and 7,8-benzoflavone, unsubstituted isoflavone,
daidzein (7,4'-
dihydroxy isoflavone), 5,7-dihydroxy-4'-methoxy isoflavone, soy isoflavones (a
mixture
extracted from soy), unsubstituted coumarin, 4-hydroxy coumarin. 7-hydroxy
coumarin, 6-
hydroxy-4-methyl coumarin, unsubstituted chromone, 3-formyl chromone, 3-formyl-
6-isopropyl
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WO 00/69408 PCT/US00/13647
chromone, unsubstituted dicoumarol, unsubstituted chromanone, unsubstituted
chromanol, and
mixtures thereof.
Preferred for use herein are coumarins, unsubstituted flavanone, methoxy
flavanones,
unsubstituted chalcone, 2',4-dihydroxy chalcone, and mixtures thereof. Most
preferred are
S unsubstituted flavanone, unsubstituted chalcone (especially the trans
isomer), and mixtures
thereof.
They can be synthetic materials or obtained as extracts from natural sources
(e.g.,
plants). The naturally sourced material can also further be derivatized (e.g.,
an ester or ether
derivative prepared following extraction from a natural source). Flavonoid
compounds useful
herein are commercially available from a number of sources, e.g., Indofme
Chemical Company,
Inc. (Somerville, New Jersey), Steraloids, Inc. (Wilton, New Hampshire), and
Aldrich Chemical
Company, Inc. (Milwaukee, Wisconsin).
Mixtures of the above flavonoid compounds may also be used.
The herein described flavonoid compounds are preferably present in the instant
invention
at concentrations of from about 0.01% to about 20%, more preferably from about
0.1% to about
10% , and most preferably from about 0.5% to about 5%.
Anti-Inflammatory Agents
A safe and effective amount of an anti-inflammatory agent may be added to the
compositions of the present invention, preferably from about 0.1 % to about
10%, more
preferably from about 0.5% to about 5%, of the composition. The anti-
inflammatory agent
enhances the skin appearance benefits of the present invention, e.g., such
agents contribute to a
more uniform and acceptable skin tone or color. The exact amount of anti-
inflammatory agent to
be used in the compositions will depend on the particular anti-inflammatory
agent utilized since
such agents vary widely in potency.
Steroidal anti-inflammatory agents, including but not limited to,
corticosteroids such as
hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,
dexamethasone-
phosphate, beclomethasone dipropionates, clobetasol valerate, desonide,
desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone
diacetate, diflucortolone
valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone
pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone,
fluprednidene
(fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone
acetate, hydrocortisone
butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone,
flucetonide,
fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone,
diflurosone diacetate,
fluradrenolone acetonide, medrysone, amcinafel, amcinaflde, betamethasone and
the balance of
CA 02373194 2001-11-05
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its esters, chloroprednisone, chlorprednisone acetate, clocortelone,
clescinolone, dichlorisone,
diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,
fluprednisolone,
hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate,
meprednisone,
paramethasone, prednisolone, prednisone, beclomethasone dipropionate,
triamcinolone, and
mixtures thereof may be used. The preferred steroidal anti-inflammatory for
use is
hydrocortisone.
A second class of anti-inflammatory agents which is useful in the compositions
includes
the nonsteroidal anti-inflammatory agents. The variety of compounds
encompassed by this
group are well-known to those skilled in the art. For detailed disclosure of
the chemical
structure, synthesis, side effects, etc. of non-steroidal anti-inflammatory
agents, one may refer to
standard texts, including Anti-inflammatory and Anti-Rheumatic Drugs, K. D.
Rainsford, Vol.
I-III, CRC Press, Boca Raton, (1985), and Anti-inflammator~~ents. Chemistry
and
Pharmacoloey, 1, R. A. Scherrer, et al., Academic Press, New York (1974).
Specific non-steroidal anti-inflammatory agents useful in the composition
invention
1 S include, but are not limited to:
1) the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and
CP-14,304;
2) the salicylates, such as aspirin, disalcid, benorylate, trilisate,
safapryn, solprin,
diflunisal, and fendosal;
3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin,
sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin,
fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac;
4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and
tolfenamic acids;
5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen,
flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen,
carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen,
alminoprofen, and tiaprofenic; and
6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone,
azapropazone, and trimethazone.
Mixtures of these non-steroidal anti-inflammatory agents may also be employed,
as well
as the dermatologically acceptable salts and esters of these agents. For
example, etofenamate, a
flufenamic acid derivative, is particularly useful for topical application. Of
the nonsteroidal anti-
inflammatory agents, ibuprofen, naproxen, flufenamic acid, etofenamate,
aspirin, mefenamic
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WO 00/69408 PCT/US00/13647
acid, meclofenamic acid, piroxicam and felbinac are preferred; ibuprofen,
naproxen, ketoprofen,
etofenamate, aspirin and flufenamic acid are most preferred.
Finally, so-called "natural" anti-inflammatory agents are useful in methods of
the present
invention. Such agents may suitably be obtained as an extract by suitable
physical and/or
chemical isolation from natural sources (e.g., plants, fungi, by-products of
microorganisms). For
example, candelilla wax, alpha bisabolol, aloe vera, Manjistha (extracted from
plants in the genus
Rubia, particularly Rubia Cordifolia), and Guggal (extracted from plants in
the genus
Commiphora, particularly Commiphora Mukul), kola extract, chamomile, and sea
whip extract,
may be used.
Additional anti-inflammatory agents useful herein include compounds of the
Licorice
(the plant genus/species Glycvrrhiza ~labra) family, including glycyrrhetic
acid, glycyrrhizic
acid, and derivatives thereof (e.g., salts and esters). Suitable salts of the
foregoing compounds
include metal and ammonium salts. Suitable esters include C2 - C24 saturated
or unsaturated
esters of the acids, preferably C 1 p - C24, more preferably C 16 - C24.
Specific examples of the
foregoing include oil soluble licorice extract, the glycyrrhizic and
glycyrrhetic acids themselves,
monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, dipotassium
glycyrrhizinate,
1-beta-glycyrrhetic acid, stearyl glycyrrhetinate, and 3-stearyloxy-
glycyrrhetinic acid, and
disodium 3-succinyloxy-beta-glycyrrhetinate. Stearyl glycyrrhetinate is
preferred.
Topical Anesthetics
The compositions of the present invention may also comprise a safe and
effective amount
of a topical anesthetic. Examples of topical anesthetic drugs include
benzocaine, lidocaine,
bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine,
dyclonine, hexyl-
caine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically
acceptable salts
thereof.
Tanning Actives
The compositions of the present invention may comprise a tanning active. When
present,
it is preferable that the compositions comprise from about 0.1 % to about 20%,
more preferably
from about 2% to about 7%, and most preferably from about 3% to about 6%, by
weight of the
composition, of dihydroxyacetone as an artificial tanning active.
Dihydroxyacetone, which is also known as DHA or 1,3-dihydroxy-2-propanone, is
a
white to off white, crystalline powder. This material can be represented by
the chemical formula
C3H603 and the following chemical structure.
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WO 00/69408 PCT/US00/13647
O
HOH~C-C -CH~OH
The compound can exist as a mixture of monomers and dimers, with the dimers
predominating in
the solid crystalline state. Upon heating or melting, the dimers break down to
yield the
monomers. This conversion of the dimeric form to the monomeric form also
occurs in aqueous
solution. Dihydroxyacetone is also known to be more stable at acidic pH
values. See The Merck
Index, Tenth Edition, entry 3167, p. 463 (1983), and "Dihydroxyacetone for
Cosmetics", E.
Merck Technical Bulletin, 03-304 110, 319 897. 180 588.
Skin Li~htenin~ A ents
The compositions of the present invention may comprise a skin lightening
agent. When
used, the compositions preferably comprise from about 0.1 % to about 10%, more
preferably from
about 0.2% to about 5%, also preferably from about 0.5% to about 2%, by weight
of the
composition, of a skin lightening agent. Suitable skin lightening agents
include those known in
the art, including kojic acid, arbutin, ascorbic acid and derivatives thereof,
e.g., magnesium
ascorbyl phosphate or sodium ascorbyl phosphate. Skin lightening agents
suitable for use herein
also include those described in copending patent application Serial No.
08/479,935, filed on June
7, 1995 in the name of Hillebrand, corresponding to PCT Application No. L1.S.
95/07432, filed
6/12/95; and copending patent application Serial No. 08/390,152, filed on
February 24, 1995 in
the names of Kalla L. Kvalnes, Mitchell A. DeLong, Barton J. Bradbury, Curtis
B. Motley, and
John D. Carter, corresponding to PCT Application No. U.S. 95/02809, filed
3/1/95, published
9/8/95.
Antimicrobial and AntifunQal Actives
The compositions of the present invention may comprise an antimicrobial or
antifungal
active. Such actives are capable of destroying microbes, preventing the
development of microbes
or preventing the pathogenic action of microbes. A safe and effective amount
of an antimicrobial
or antifungal active may be added to the present compositions, preferably,
from about 0.001 % to
about 10%, more preferably from about 0.01 % to about 5%, and most preferably
from about
0.05% to about 2%.
Examples of antimicrobial and antifungal actives include 13-lactam drugs,
quinolone
drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin,
2,4,4'-triehloro-2'-
hydroxy diphenyl ether, 3,4,4'-trichlorobanilide, phenoxyethanol, phenoxy
propanol,
phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine,
chlortetracycline,
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WO 00/69408 PCT/US00/13647
oxytetracycline, clindamycin, ethambutol, hexamidine isethionate,
metronidazole, pentamidine,
gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline,
neomycin,
netilmicin, paromomycin, streptomycin, tobramycin, miconazole, tetracycline
hydrochloride,
erythromycin, zinc erythromycin, erythromycin estolate, erythromycin stearate,
amikacin sulfate,
doxycycline hydrochloride, capreomycin sulfate, chlorhexidine gluconate,
chlorhexidine
hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride,
clindamycin
hydrochloride, ethambutol hydrochloride, metronidazole hydrochloride,
pentamidine
hydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycin
hydrochloride, methacycline
hydrochloride, methenamine hippurate, methenamine mandelate, minocvcline
hydrochloride,
neomycin sulfate, netilmicin sulfate, paromomycin sulfate, streptomycin
sulfate, tobramycin
sulfate, miconazole hydrochloride, amanfadine hydrochloride, amanfadine
sulfate, octopirox,
parachlorometa xylenol, nystatin, tolnaftate, zinc pyrithione and
clotrimazole.
Preferred examples of actives useful herein include those selected from the
group
consisting of salicylic acid, benzoyl peroxide, 3-hydroxy benzoic acid,
glycolic acid, lactic acid,
4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, 2-
hydroxypentanoic acid,
2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, phyic
acid, N-acetyl-L-
cysteine, lipoic acid, azelaic acid, arachidonic acid, benzoylperoxide,
tetracycline, ibuprofen,
naproxen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol,
phenoxypropanol,
phenoxyisopropanol, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-
trichlorocarbanilide,
octopirox, lidocaine hydrochloride, clotrimazole, miconazole, neocycin
sulfate, and mixtures
thereof.
Sunscreen Actives
Exposure to ultraviolet light can result in excessive scaling and texture
changes of the
stratum corneum. Therefore, the compositions of the subject invention may
optionally contain a
sunscreen active. As used herein, "sunscreen active" includes both sunscreen
agents and physical
sunblocks. Suitable sunscreen actives may be organic or inorganic.
A wide variety of conventional sunscreen actives are suitable for use herein.
Sagarin, et
al., at Chapter VIII, pages 189 et seq., of Cosmetics Science and Technology
(1972), discloses
numerous suitable actives. Specific suitable sunscreen actives include. for
example: p-
aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl
esters; p-
dimethylaminobenzoic acid); anthranilates (i.e., o-amino-benzoates; methyl,
menthyl, phenyl,
benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); salicylates
(amyl, phenyl, octyl,
benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters); cinnamic acid
derivatives (menthyl
and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate);
dihydroxycinnamic acid
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WO 00/69408 PCT/US00/13647
derivatives (umbelliferone, methylumbelliferone, methylaceto-umbelliferone);
trihydroxy-
cinnamic acid derivatives (esculetin, methylesculetin, daphnetin, and the
glucosides, esculin and
daphnin); hydrocarbons (diphenylbutadiene, stilbene); dibenzalacetone and
benzalacetophenone;
naphtholsulfonates (sodium salts of 2-naphthol-3,6-disulfonic and of 2-
naphthol-6,8-disulfonic
acids); di-hydroxynaphthoic acid and its salts; o- and p-
hydroxybiphenyldisulfonates; coumarin
derivatives (7-hydroxy, 7-methyl, 3-phenyl); diazoles (2-acetyl-3-
bromoindazole, phenyl
benzoxazole, methyl naphthoxazole, various aryl benzothiazoles); quinine salts
(bisulfate,
sulfate, chloride, oleate, and tannate); quinoline derivatives (8-
hydroxyquinoline salts, 2-
phenylquinoline); hydroxy- or methoxy-substituted benzophenones; uric and
violuric acids;
tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol) (6-
propyl piperonyl) ether;
hydroquinone; benzophenones (oxybenzene, sulisobenzone, dioxybenzone,
benzoresorcinol,
2,2',4,4'-tetrahydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone,
octabenzone;
4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;
octocrylene; [3-(4'-
methylbenzylidene bornan-2-one) and 4-isopropyl-di-benzoylmethane.
Of these, 2-ethylhexyl-p-methoxycinnamate (commercially available as PARSOL
MCX), 4,4'-t-butyl methoxydibenzoyl-methane (commercially available as PARSOL
1789), 2-
hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid,
digalloyltrioleate, 2,2-
dihydroxy-4-methoxybenzophenone, ethyl-4-(bis(hydroxy-propyl))aminobenzoate, 2-
ethylhexyl-
2-cyano-3,3-diphenylacrylate, 2-ethylhexyl-salicylate, glyceryl-p-
aminobenzoate, 3,3,5-tri-
methylcyclohexylsalicylate, methylanthranilate, p-dimethyl-aminobenzoic acid
or
aminobenzoate, 2-ethylhexyl-p-dimethyl-amino-benzoate, 2-phenylbenzimidazole-S-
sulfonic
acid, 2-(p-dimethylaminophenyl)-5-sulfonicbenzoxazoic acid, octocrylene and
mixtures of these
compounds, are preferred.
More preferred organic sunscreen actives useful in the compositions useful in
the subject
invention are 2-ethylhexyl-p-methoxycinnamate, butylmethoxydibenzoyl-methane,
2-hydroxy-4-
methoxybenzo-phenone, 2-phenylbenzimidazole-5-sulfonic acid, octyldimethyl-p-
aminobenzoic
acid, octocrylene and mixtures thereof.
Also particularly useful in the compositions are sunscreen actives such as
those disclosed
in U.S. Patent No. 4,937,370 issued to Sabatelli on June 26, 1990, and U.S.
Patent No. 4,999,186
issued to Sabatelli & Spirnak on March 12, 1991. The sunscreening agents
disclosed therein
have, in a single molecule, two distinct chromophore moieties which exhibit
different ultra-violet
radiation absorption spectra. One of the chromophore moieties absorbs
predominantly in the
UVB radiation range and the other absorbs strongly in the UVA radiation range.
CA 02373194 2001-11-05
WO 00/69408 PCT/US00/13647
Preferred members of this class of sunscreening agents are :1-IV,N-(2-
ethylhexyl)methyl-
aminobenzoic acid ester of 2.4-dihydroxybenzophenone; N,N-di-(2-ethylhexyl)-4-
aminobenzoic
acid ester with 4-hydroxydibenzoylmethane; 4-N,N-(2-ethylhexyl)methyl-
aminobenzoic acid
ester with 4-hydroxydibenzoylmethane; 4-N,N-(2-ethylhexyl)methyl-aminobenzoic
acid ester of
2-hydroxy-4-(2-hydroxyethoxy)benzophenone; 4-N,N-(2-ethylhexyl)-
methylaminobenzoic acid
ester of 4-(2-hydroxyethoxy)dibenzoylmethane; N,N-di-(2-ethylhexyl)-4-
aminobenzoic acid
ester of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone; and N,N-di-(2-ethylhexyl)-
4-
aminobenzoic acid ester of 4-(2-hydroxyethoxy)dibenzoylmethane and mixtures
thereof.
Especially preferred sunscreen actives include 4,4'-
butylmethoxydibenzoylmethane, 2-
ethylhexyl-p-methoxycinnamate, phenyl benzimidazole sulfonic acid. and
octocrylene.
A safe and effective amount of the sunscreen active is used, Wpically from
about 1% to
about 20%, more typically from about 2% to about 10°io by weight of the
composition. Exact
amounts will vary depending upon the sunscreen chosen and the desired Sun
Protection Factor
(SPF).
Conditionin> Agents
The compositions of the present invention may comprise a conditioning agent
selected
from the group consisting of humectants, moisturizers, or skin conditioners. A
variety of these
materials can be employed and each can be present at a level of from about
0.01% to about 20%,
more preferably from about 0.1 % to about 10%, and most preferably from about
0.5% to about
7% by weight of the composition. These materials include, but are not limited
to, guanidine;
glycolic acid and glycolate salts (e.g. ammonium and quaternary alkyl
ammonium); salicylic
acid; lactic acid and lactate salts (e.g., ammonium and quaternary alk~~l
ammonium); aloe vera in
any of its variety of forms (e.g., aloe vera gel); polyhydroxy alcohols such
as sorbitol, glycerol,
hexanetriol, butanetriol, propylene glycol, butylene glycol, hexylene glycol
and the like;
polyethylene glycols; sugars (e.g., melibiose) and starches; sugar and starch
derivatives (e.g.,
alkoxylated glucose and fucose); hyaluronic acid; lactamide monoethanolamine;
acetamide
monoethanolamine; and mixtures thereof. Also useful herein are the
propoxylated glycerols
described in U. S. Patent No. 4,976,953, to Orr et al, issued December 11,
1990.
Also useful are various C,-C3° monoesters and polyesters of sugars and
related materials.
These esters are derived from a sugar or polyol moiety and one or more
carboxylic acid moieties.
Such ester materials are further described in, U. S. Patent No. 2.831,854, U.
S. Patent No.
4,005,196, to Jandacek, issued January 25, 1977; U. S. Patent No. 4,005,195,
to Jandacek, issued
January 25, 1977, U. S. Patent No. 5,306,516, to Letton et al, issued April
26, 1994; U. S. Patent
No. 5,306,515, to Letton et al, issued April 26, 1994; U. S. Patent No.
5,305,514, to Letton et al,
31
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WO 00/69408 PCT/US00/13647
issued April 26, 1994; U. S. Patent No. 4,797.300, to Jandacek et al, issued
January 10. 1989; U.
S. Patent No. 3,963,699, to Rizzi et al, issued June 1 ~, 1976; U. S. Patent
No. 4,518,772, to
Volpenhein, issued May 21, 1985; and U. S. Patent No. 4,517,360, to
Volpenhein, issued May
21, 1985.
Thickening Agent (includine thickeners and elline a e~ nts)
The compositions of the present invention can comprise one or more thickening
agents,
preferably from about 0.1% to about 5%, more preferably from about 0.1% to
about 3%, and
most preferably from about 0.25% to about 2%, by weight of the composition.
Nonlimiting classes of thickening agents include those selected from the group
consisting of:
a) Carboxylic Acid Polymers
These polymers are crosslinked compounds containing one or more monomers
derived
from acrylic acid, substituted acrylic acids, and salts and esters of these
acrylic acids and the
substituted acrylic acids, wherein the crosslinking agent contains two or more
carbon-carbon
double bonds and is derived from a polyhydric alcohol. Polymers useful in the
present invention
are more fully described in U. S. Patent No. 5,087,445, to Haffey et al,
issued February 11, 1992;
U. S. Patent No. 4,509,949, to Huang et al, issued April 5, 1985; U. S. Patent
No. 2,798,053, to
Brown, issued July 2, 1957; and in CTFA International Cosmetic Ingredient
Dictionary, Fourth
Edition, 1991, pp. 12 and 80.
Examples of commercially available carboxylic acid polymers useful herein
include the
carbomers, which are homopolymers of acrylic acid crosslinked with allyl
ethers of sucrose or
pentaerytritol. The carbomers are available as the Carbopol~ 900 series from
B.F. Goodrich
(e.g., Carbopol~ 954). In addition, other suitable carboxylic acid polymeric
agents include
copolymers of C10-30 alkyl acrylates with one or more monomers of acrylic
acid, methacrylic
acid, or one of their short chain (i.e., C1_4 alcohol) esters, wherein the
crosslinking agent is an
allyl ether of sucrose or pentaerytritol. These copolymers are known as
acrylates/C,°_3° alkyl
acrylate crosspolymers and are commercially available as Carbopol~ 1342,
Carbopol~ 1382,
Pemulen TR-l, and Pemulen TR-2, from B.F. Goodrich. In other words, examples
of carboxylic
acid polymer thickeners useful herein are those selected from the group
consisting of carbomers,
acrylates/C,o C,° alkyl acrylate crosspolymers, and mixtures thereof.
b) Crosslinked Polvacrylate Polymers
The compositions of the present invention can optionally comprise crosslinked
polyacrylate polymers useful as thickeners or gelling agents including both
cationic and nonionic
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WO 00/69408 PCT/US00/13647
polymers, with the cationics being generally preferred. Examples of useful
crosslinked nonionic
polyacrylate polymers and crosslinked cationic polyacrylate polymers are those
described in U.
S. Patent No. 5,100,660, to Hawe et al, issued March 31, 1992; U. S. Patent
No. 4,849,484, to
Heard, issued July 18, 1989; U. S. Patent No. 4,835,206, to Farrar et al,
issued May 30, 1989;
U.S. Patent No. 4,628,078 to Glover et al issued December 9, 1986; U.S. Patent
No. 4,599,379 to
Flesher et al issued July 8, 1986; and EP 228,868, to Farrar et al, published
July 15, 1987.
c) Polyacrvlamide Polymers
The compositions of the present invention can optionally comprise
polyacrylamide
polymers, especially nonionic polyacrylamide polymers including substituted
branched or
unbranched polymers. Most preferred among these polyacrylamide polymers is the
nonionic
polymer given the CTFA designation polyacrylamide and isoparaffin and laureth-
7, available
under the Tradename Sepigel 305 from Seppic Corporation (Fairfield, NJ).
Other polyacrylamide polymers useful herein include multi-block copolymers of
acrylamides and substituted acryMamides with acrylic acids and substituted
acrylic acids.
Commercially available examples of these multi-block copolymers include Hypan
SR150H,
SS500V, SS500W, SSSAl00H, from Lipo Chemicals, Inc., (Patterson, NJ).
d) Polysaccharides
A wide variety of polysaccharides are useful herein. "Polysaccharides" refer
to gelling
agents which contain a backbone of repeating sugar (i.e., carbohydrate) units.
Nonlimiting
examples of polysaccharide gelling agents include those selected from the
group consisting of
cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate
carboxylate,
hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropylcellulose,
hydroxypropyl
methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose,
sodium cellulose
sulfate, and mixtures thereof. Also useful herein are the alkyl substituted
celluloses. In these
polymers, the hydroxy groups of the cellulose polymer is hydroxyalkylated
(preferably
hydroxyethylated or hydroxypropylated) to form a hydroxyalkylated cellulose
which is then
further modified with a C,o-C3o straight chain or branched chain alkyl group
through an ether
linkage. Typically these polymers are ethers of C,o-C,~ straight or branched
chain alcohols with
hydroxyalkylcelluloses. Examples of alkyl groups useful herein include those
selected from the
group consisting of stearyl, isostearyl, lauryl, myristyl, cetyl, isocetyl,
cocoyl (i.e. alkyl groups
derived from the alcohols of coconut oil), palmityl, oleyl, linoleyl,
linolenyl, ricinoleyl, behenyl,
and mixtures thereof. Preferred among the alkyl hydroxyalkyl cellulose ethers
is the material
given the CTFA designation cetyl hydroxyethylcellulose, which is the ether of
cetyl alcohol and
33
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WO 00/69408 PCT/US00/13647
hydroxyethylcellulose. This material is sold under the tradename Natrosol~ CS
Plus from
Aqualon Corporation (Wilmington, DE).
Other useful polysaccharides include scleroglucans comprising a linear chain
of (1-3)
linked glucose units with a (1-6) linked glucose every three units, a
commercially available
example of which is ClearogelT"' CS11 from Michel Mercier Products Inc.
(Mountainside, NJ).
e) Gums
Other thickening and gelling agents useful herein include materials which are
primarily
derived from natural sources. Nonlimiting examples of these gelling agent gums
include
materials selected from the group consisting of acacia, agar, algin, alginic
acid, ammonium
alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine,
carrageenan, dextrin,
gelatin, gellan gum, guar gum, guar hydroxypropyltrimonium chloride,
hectorite, hyaluroinic
acid, hydrated silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum,
kelp, locust bean
gum, natto gum, potassium alginate, potassium carrageenan, propylene glycol
alginate,
sclerotium gum, sodium carboyxmethyl dextran, sodium carrageenan, tragacanth
gum, xanthan
gum, and mixtures thereof.
Preferred compositions of the present invention include a thickening agent
selected from
the group consisting of carboxylic acid polymers, crosslinked polyacrylate
polymers,
polyacrylamide polymers, and mixtures thereof, more preferably selected from
the group
consisting of carboxylic acid polymers, polyacrylamide polymers, and mixtures
thereof.
While a variety of optional components may be included in the compositions of
the
presently claimed methods, the compositions are preferably free of retinoids,
especially when
such compositions are intended for regulating visible and/or tactile
discontinuities in mammalian
skin texture. Furthermore, the compositions are preferably free of procaine
when such
compositions are utilized for prevention and relief of itch. As used herein,
"free of means that
the compound or component may not be detected in the compositions.
Composition Preparation
The compositions of the present invention are generally prepared by
conventional
methods such as are known in the art of making topical compositions. Such
methods typically
involve mixing of the ingredients in one or more steps to a relatively uniform
state, with or
without heating, cooling, application of vacuum, and the like.
Methods for Regulating Keratinous Tissue Condition
The compositions of the present invention are useful for regulating mammalian
keratinous tissue condition, namely skin condition. Such regulation includes
prophylactic and
therapeutic regulation. More specifically, such regulating methods are
directed to preventing
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WO 00/69408 PCT/US00/13647
andlor retarding the appearance of spider vessels and/or red blotchiness on
mammalian skin.
preventing and/or retarding the appearance of puffy eyes and/or dark circles
under the eye of a
mammal, desquamating mammalian skin, preventing and/or retarding sallowness of
mammalian
skin, preventing and/or retarding sagging of mammalian skin, softening and/or
smoothing lips,
hair and nails of a mammal, and preventing and/or relieving itch of mammalian
skin.
Regulating keratinous tissue condition involves topically applying to the
keratinous
tissue of a mammal in need of treatment a safe and effective amount of a
composition of the
present invention. The amount of the composition which is applied. the
frequency of application
and the period of use will vary widely depending upon the level of the
xanthine compound and/or
other components of a given composition and the level of regulation desired,
e.g., in light of the
level of skin damage present or expected to occur.
In a preferred embodiment, the composition is chronically applied to the skin.
By
"chronic topical application" is meant continued topical application of the
composition over an
extended period during the subject's lifetime, preferably for a period of at
least about one week,
more preferably for a period of at least about one month, even more preferably
for at least about
three months, even more preferably for at least about six months, and more
preferably still for at
least about one year. While benefits are obtainable after various maximum
periods of use (e.g.,
five, ten or twenty years), it is preferred that chronic application continue
throughout the subject's
lifetime. Typically applications would be on the order of about once per day
over such extended
periods, however application rates can vary from about once per week up to
about three times per
day or more.
A wide range of quantities of the compositions of the present invention can be
employed
to provide a keratinous tissue appearance and/or feel benefit. Quantities of
the present
compositions which are typically applied per application are, in mg
composition/cm2 skin, from
about 0.1 mg/cm2 to about 10 mg/cm2. A particularly useful application amount
is about 1
mg/cm' to about 2 mg/cm2.
Regulating skin condition, in particular, is preferably practiced by applying
a
composition in the form of a skin lotion, cream, gel, foam, emulsion, spray,
conditioner, tonic,
cosmetic, lipstick, foundation, nail polish, after-shave, or the like which is
intended to be left on
the skin or other keratin structure for some esthetic, prophylactic,
therapeutic or other benefit
(i.e., a "leave-on" composition). After applying the composition to the skin,
it is preferably left
on the skin for a period of at least about I S minutes, more preferably at
least about 30 minutes,
even more preferably at least about 1 hour, most preferably for at least
several hours, e.g., up to
about 12 hours. Any part of the external portion of the face, hair, and/or
nails can be treated, e.g.,
CA 02373194 2001-11-05
WO 00/69408 PCT/US00/13647
face, lips. under-eye area, eyelids, scalp, neck. torso, arms, hands, legs,
fingernails, toenails,
scalp hair, eyelashes, eyebrows, etc.
Another approach to ensure a continuous exposure of the skin to at least a
minimum level
of the xanthine compound is to apply the compound by use of a patch applied,
e.g., to the face.
Such an approach is particularly useful for problem skin areas needing more
intensive treatment
(e.g., facial crows feet area, under eye area, and the like). The patch can be
occlusive, semi-
occlusive or non-occlusive. The xanthine compound-containing composition can
be contained
within the patch or be applied to the skin prior to application of the patch.
The patch can also
include additional actives such as chemical initiators for exothermic
reactions such as those
described in PCT application WO 9701313 to Burkett et al. The patch is
preferably left on the
skin for a period of at least about 5 minutes, more preferably at least about
15 minutes, more
preferably still at least about 30 minutes, even more preferably at least
about 1 hour, most
preferably at night as a form of night therapy.
The compositions of the present invention may be presented to a user or
potential user
(hereinafter "users") of the composition in association with information which
informs such
users that use of the composition will provide one or more benefits,
including, but not limited to,
preventing and/or retarding the appearance of spider vessels and/or red
blotchiness on
mammalian skin, preventing and/or retarding the appearance of puffy eyes
and/or dark circles
under the eye of a mammal, desquamating mammalian skin, preventing and/or
retarding
sallowness of mammalian skin, preventing and/or retarding sagging of mammalian
skin,
softening and/or smoothing lips, hair and nails of a mammal, and preventing
and/or relieving itch
of mammalian skin, and the like. Such information may also include
instructions for use to
obtain such benefits, e.g., including the method steps described above. By "in
association with
information" it is meant that the information is either directly printed on
the container for the
composition itself (including direct printing on the container per se or
indirectly via a label or the
like affixed to the container), or presented in a different manner including,
but not limited to, a
brochure, print advertisement, electronic advertisement and/or other
advertisement, so as to
communicate the information to a consumer of the composition. Such information
may
accordingly comprise words, pictures, and the like.
Examples
The following examples further describe and demonstrate embodiments within the
scope
of the present invention. The examples are given solely for the purpose of
illustration and are not
to be construed as limitations of the present invention, as many variations
thereof are possible
without departing from the spirit and scope of the invention.
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WO 00/69408 PCT/US00/13647
Example 1
A skin cream is prepared by conventional methods from the following
components.
Ingredient (CTFA Name) Weight
PHASE A: Water U.S.P. 2.00
Butylene glycol 0.25
Glydant Plus 0.10
PHASE B: Water U.S.P. 70.55
Disodium EDTA 0.10
Panthenol 0.50
Glycerin 10.00
Theophylline 5.00
PHASE C: DC200/10 cst 2.00
Arlamol E 3.00
Cetyl Palmitate 0.50
Cetyl Alcohol 0.75
Stearyl Alcohol 0.75
Brij 721 0.80
Brij 72 1.20
PHASE D: Sepigel 305 2.50
Blend the A phase components with a suitable mixer (e.g., Tekmar model
RW20DZM),
and heat with mixing to melt the components. Separately, blend the B phase
components except
for theophylline with a suitable mixer and heat while stirring to a
temperature of 70-75°C. At
temperature add theophylline. Separately, blend the C phase components and
heat while stirring
to a temperature of 70-75° C. At temperature, add phase C to phase B
and mill for 5 minutes
(e.g., using a Tekmar T50 Mill). Then add phase D and mix for 5 minutes. Allow
to cool to
50°C and then add phase A.
Apply the composition to the facial skin of a subject in need of treatment at
the rate of 2
mg composition/cm2 skin once or twice daily for a period of at least 3-6
months.
Example 2
An emulsion is prepared by conventional methods from the following components:
Ingredient (CTFA Name) Weight
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WO 00/69408 PCT/US00/13647
PHASE A: Water U.S.P. 66.80
Glycerin 7.00
Glydant Plus 0.10
Theophylline 5.00
Disodium EDTA 0.10
PHASE B: Arlamol E 5.00
Mineral Oil 5.00
Sefa Cottonate 2.00
Permethyl 1 O 1 A 3.00
Arlacel P135 4.00
Petrolatum 2.00
Form Phase A (water phase) in a suitable vessel charged with the water as
follows:
gradually add the remaining components with stirring and heat to 55°C.
Form Phase B (oil phase) in a separate suitable vessel by adding and stirring
together the
components of Phase B. Begin heating and stirring to 50°C.
S Add Phase A to Phase B slowly with stirring and mill for 15 minutes.
Apply the composition to the facial skin of a subject in need of treatment at
the rate of 2
mg composition/cm2 skin once or twice daily for a period of at least 3-6
months.
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WO 00/69408 PCT/US00/13647
Example 3
A skin cream is prepared by conventional methods from the following
components.
Ingredient (CTFA Name) Weight
PHASE A: Water U.S.P. 2.00
Butylene glycol 0.25
Glydant Plus 0.10
PHASE B: Water U.S.P. 70.55
Disodium EDTA 0.10
Panthenol 0.50
Glycerin 10.00
Theobromine 5.00
PHASE C: DC200/10 cst 2.00
Arlamol E 3.00
Cetyl Palmitate 0.50
Cetyl Alcohol 0.75
Stearyl Alcohol 0.75
Brij 721 0.80
Brij 72 1.20
PHASE D: Sepigel 305 2.50
Blend the A phase components with a suitable mixer (e.g., Tekmar model
RW20DZM),
and heat with mixing to melt the components. Separately, blend the B phase
components except
for theobromine with a suitable mixer and heat while stirring to a temperature
of 70-75°C. At
temperature add theobromine. Separately, blend the C phase components and heat
while stirring
to a temperature of 70-75° C. At temperature, add phase C to phase B
and mill for 5 minutes
(e.g., using a Tekmar T50 Mill). Then add phase D and mix for ~ minutes. Allow
to cool to
50°C and then add phase A.
Apply the composition to the facial skin of a subject in need of treatment at
the rate of 2
mg composition/cm2 skin once or twice daily for a period of at least 3-6
months.
While particular embodiments of the subject invention have been described, it
will be
obvious to those skilled in the art that various changes and modifications to
the subject invention
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WO 00/69408 PCT/US00/13647
can be made without departing from the spirit and scope of the invention. It
is intended to cover,
in the appended claims, all such modifications that are within the scope of
the subject invention.
