Note: Descriptions are shown in the official language in which they were submitted.
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
TOPICAL UREA COMPOSITION
FIELD OF THE INVENTION
This invention relates to a topical skin composition containing an active
ingredient and urea
for enhancing delivery of the ingredient. The active ingredient can be, alone,
or in combination with another
active ingredient, one or more of an antioxidant, vitamin, a f3-glucan, or
other active ingredient. Particularly
useful is a composition containing vitamin E and urea, or a composition
containing urea, vitamins A, C and E,
and green tea extract.
BACKGROUND OF THE INVENTION
Topical compositions are widely used in the cosmetics and pharmaceutical
industries.
It is well known to include an active agent in a topical composition for the
purpose of
treating the skin. Such agents contribute to valuable effects, such as
controlling ageing or pigmentation of the
skin, promoting repair of damaged skin and contributing to skin cell renewal.
In terms of "active agents", those relating to this invention include
antioxidants, vitamins and
13-glucans, and others listed below in connection with detailed embodiments.
In the case of vitamins, some
have antioxidant properties, and others are useful primarily for other
beneficial effects. A particularly useful
ingredient in the context of this invention is vitamin E.
It is known to topically apply vitamins for treatment of sunlight damage to
skin',z,', physical
injury to skin°,5, ageing of skinb, and pollution-challenged skin.'
Exposure to sunlight has been found to
decrease amounts of antioxidants in skin.8~9 Vitamin C, topically administered
in a moisturizing cream base,
has been found to enhance the production of collagen'°~" which is
involved in stimulation of fibroblasts
necessary for the regeneration of older and damaged skin. Vitamin C
administration has also been found to
improve the lipid profile so as to enhance the barrier function of skin.'2
Topically applied vitamin C has also
been found to have anti-inflammatory properties." There are many studies
supporting the topical utility of
certain vitamins.
Topically applied vitamin E is known to behave as an antioxidant'",'s,'6,"
and can serve to decrease healing time's with reduction of the severity and
frequency of pathological damage to
cells.'9 Vitamin E has been shown to enhance the ability of skin to retain
moisture.2° A topically applied
mixture of vitamin E and vitamin C was shown to protect against sun damage to
the skin.2' There is evidence
vitamins E and C can protect the skin against oxidative damage caused by free
radicals.2Z
Vitamin A has also been found to offer protection of the skin from chemical
insult,2' but it
should be transported through the skin to effectively promote the metabolism
of skin cells 2' Topically applied
vitamin A palmitate has been found to improve skin elasticity.25 Vitamin A
also contributes to repair of photo-
damaged skin by stimulating growth of the collagenous matrix.Ze
Vitamins A, C and E are utilized by the body in defence against skin damage2'
and it has
been suggested that the three vitamins are most effective together.28 There
are studies which suggest that
vitamins C and E need to be present before sun damage occurs in order to be an
effective defence
thereagainst.29.'o.s~,3z,3a,3a S~dies have shown, however, that oral
administration of vitamin C and vitamin E
does not lead to appreciably increased amounts of the vitamin in the
skin.'S.3e
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The salutary effects of green tea are coming to be known. Green tea has been
shown to
counter the irritative effects of a-hydroxy acids and been found to be a
potent antioxidant"~'8, to contain free
radical scavengers'9, and to be a chemopreventive agent against skin tumors
and solar radiation damage.4°.°',~z
It has been shown that green tea antioxidants can protect against general free
radical damage and skin cancer in
animal models."
13-glucans are high molecular weight phosphorylated polysaccharides, generally
obtained
from oats, which can be solubilized and used as moisturizers and also aid in
the healing of wounds and
infections.°"
United States Patent No. 5,935,588, which issued August 10, 1999 to Afriat et
al., offers a
recent example from the patent literature of a topical composition which can
potentially include an active agent
such as green tea, vitamin C and/or vitamin A. The specification of this
patent describes an emulsion
composition containing a water-sensitive active agent. The activity of water
in an aqueous phase of the
emulsion is lowered to 0.85 or less by inclusion of a polyol so as to
stabilize the water-sensitve agent against
degradation. The active agent or agents can be used in the composition in an
amount ranging from 0.001 to
I S% by weight, preferably from 0.01 to 10% and more preferably from 0.05 to
5% by weight with respect to
the total weight of the composition. In specific embodiments, the water-
sensitive agent is an enzyme sold
under the tradename Subtilisine SP544 present in the amount of 0.1 %. The
specification states that other
water-sensitive active agents include green tea, ascorbic acid, vitamin A and
urea, but describes no specific
embodiment involving any of these agents.
United States Patent No. 5,935,994, which issued August 10, 1999 to Nimni,
describes a
topical composition containing Vitamins A and E and including an organic
penetrant. Such organic penetrants
include lower alkyl diols, C,° to Cz° fatty acids and esters
thereof, and C4 to CZ° aliphatic alcohols. Exemplary
of such penetrants are propylene glycol, oleic acid, butyl alcohol and,
preferably, benzyl alcohol. Generally
speaking, the amount of penetrant is suggested to vary between about 0.5 and
about 10 weight percent.
United States Patent No. 5,874,074, which issued to Smith on February 23,
1999, describes a
topical lotion containing a therapeutic agent which can be a dermatological
agent such as a vitamin A
derivative and a penetration enhancer. Particular enhancers that are said to
be useful in the lotions include
dimethyl sulfoxide, N,N-dimethyl acetamide, 2-pyrrolidone, 1-methyl-2-
pyrrolidone, Carbitol solvent (Union
Carbide), propylene carbonate, 1,5-dimethyl-2-pyrrolidone, 2-pyrrolidone-S-
carboxylic acid, and the like,
wherein the lotion includes a penetration enhancing agent in an amount of
about 0.01 to 20 weight percent.
Among many other ingredients, it is also suggested that the dermatological
agent could also be an anti-psoriatic
compound such as anthralin (dithranol), coal tar extract, and the like; a
keratolytic agent such as salicylic acid,
urea, and the like.
One will fmd, in reviewing the literature relating to topical compositions,
that such
compositions generally include a variety of types of ingredients, each for
their own purpose(s). Thus, a person
skilled in the art, generally includes many such ingredients as taught in the
prior art. United States Patent No.
5,741,499, for example, which issued to Arnauld et al. April 21, 1998,
describes a homogeneous composition
for use in cosmetics and dermatology which includes an organic fluorinated
compound and provides a fair
description of the types of ingredients and examples of such that can be
included in topical compositions.
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Along this vein, United States Patent No. 5,935,585, which issued to Bernardon
et al. on August 10, 1999,
describes topical pharmaceutical and cosmetic compositions containing
biaromatic compounds. It is suggested
to include in the compositions various combinations of a retinoid compound, a
D vitamin, an anti-free radical
agent, an a-hydroxy acid, an ion channel Mocker, a moisturizing agent, a
wetting agent, a depigmenting agent,
an antiseborrhoeic or antiacne agent, an antibiotic, an antifungal agent, a
hair regrowth promoter, a non-
steroidal anti-inflammatory agent, or an anti-psoriatic agent, 5,8,11,14-
eicosatetraynoic or 5,8,11-eicosatrynoic
acid or ester or amide thereof.
Nonetheless, the inventors herein have invented what appears to be a new
composition for
the purpose of improved topical delivery of active ingredients, particularly
vitamins, antioxidants and f3-
glucans that are of benefit to the skin and most particular vitamin E.
SUMMARY OF THE INVENTION
In a broad aspect, the present invention is a topical composition containing
urea and one or
more active ingredient(s), in which the urea is present in the composition in
an amount sufficient to enhance
penetration of the active ingredients) of the composition. The invention
includes a method of treatment of
living skin (the viable epidermis, below the stratum corneum, and dermis)
enhancing delivery of active
ingredients) thereto by topically applying to the skin surface a composition
of the invention.
A preferred active ingredient is vitamin E and a preferred combination of
ingredients is
vitamins A, C and E, and green tea. Other active ingredients are antioxidants
such as retinyl palinitate,13-
carotene, tocopherol acetate, ascorbic acid, green tea, black tea, quercetin
(flavonoids), sea kelp, pycnogenols
(proanthocyanidins), selenium and alkylgylcerol-AKG (shark liver oil), taken
alone or in combination, and
others described below in connection with the detailed embodiments.
An amount of urea sufficient to enhance penetration of the antioxidant is
determined for each
ingredient or family of ingredients for inclusion in a single composition of
the invention. This is generally in
excess of 10% and up to about 50% urea by weight of the total composition.
Other agents that are typically included in topical compositions can be
included in
compositions of the invention, and are described in connection with detailed
embodiments.
Compositions of the invention are generally used in situations in which it
would be found
advantageous to have the active ingredients) delivered to living skin below
the stratum corneum.
Compositions of the present invention can fmd usefulness in application to
skin of subjects suffering from
diabetes, menopause, eczema, scleroderma, psoriasis, cancer, multiple
sclerosis, allergy sensitivities, Down's
syndrome, circulatory disorders, and so on.
In a particular aspect, the invention is a topical composition that includes
about 10 to about
50 % by weight urea with respect to the total composition weight of the
composition; and a topically effective
amount of an anti-oxidant compatible with skin. the anti-oxidant can be
selected from the group consisting of
vitamin E, vitamin C, vitamin D, retinyl palmitate,13-carotene, green tea,
black tea, quercetin, sea kelp,
pycnogenols (proanthocyanidins), selenium and alkylgylcerol-AKG, allopurinol,
a-lipoic acid, astaxanthin,
azulenic retinoid compounds, coenzyme Q-10, cysteine, zinc, copper, magnesium,
potassium, selenium, BHA,
BHT, melatonin; N-acetylcysteine, and combinations thereof.
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Preferably, the composition includes between about 10% and about 45% urea,
about 15%
and about 40% about urea, between about 20% and about 40% urea, between about
20% and about 35% urea,
between about 20% and about 30% urea, or more preferably, about 25% urea.
A preferred anti-oxidant is vitamin E, which can be in the form of tocopherol
acetate. The
composition can include up to about 10% by weight of vitamin E, but more
preferably, about 5% and at least
about 0.1% by weight of vitamin E. Other compositions include at least about
0.5%, or at least about 1% be
weight of vitamin E, between about 1% and about 4%, between about 1% and 2% by
weight of vitamin E, or
about 1 % by weight of vitamin E, or about 1.5%.
A preferred family of anti-oxidants present in a composition is vitamin A,
vitamin C, vitamin
E and green tea extract, although these ingredients can be taken separately or
in any combination. Preferably,
the entire family is present in the composition.
Such a composition can include up to about 5% by weight of vitamin A, at least
about 0.1%,
between about 0.2% and 4%, between about 0.3% and 3%, or about 0.3% by weight
of vitamin A. The
composition can include up to about 10% by weight of vitamin C, or at least
about 0.1%, between about 0.1%
and 5%, between about 0.1% and about 3%, between about 0.1 and 2%, between
about 0.1% and 1%, or about
0.1% or about 0.5% vitamin C. The composition can include up to about 10% by
weight of green tea extract.
37. The composition of any of claims 21 to 36, comprising at least about 0.1%
by weight of green tea extract,
between about 0.1% and 5%, between about 0.1% and 3%, between about 0.1% and
1%, or about 0.3%, or
about 0.5% by weight of green tea extract.
In another aspect, the invention is a method of enhancing delivery of an anti-
oxidant to the
viable epidermis, the method comprising the step of topically applying a
composition of the invention to a skin
surface of a mammal.
In another aspect, the invention is the use of a composition of the invention
in the
preparation of a topical medicament for use in delivery of one or more anti-
oxidants to the viable epidermis of
a mammal.
In another aspect, the invention includes topical use of a composition of the
invention in the
delivery of one or more anti-oxidants to the viable epidermis of a mammal.
The invention also includes a method of manufacturing a topical preparation
comprising a
composition of the invention, the method comprising combining the one or more
anti-oxidants and urea so as
to form a homogeneous topical skin preparation. Preferably, the skin
preparation is a cosmetic preparation.
The method can include incorporating water into the preparation, wherein the
final amount of water is between
about 15% and 80% by weight, between about 30% and 80%, or between about 50%
and 70%. The method
can further include incorporating glycerin into the preparation, wherein the
final amount of glycerin is up to
about 20% by weight, but more preferably the amount of glycerin is between
about 55 and 15%.
DESCRIPTION OF THE DRAWINGS
Figures 1 (a) to 1 (e) graphically illustrates the effects of a composition
containing 15% urea
and vitamins A, C, and E, and green tea extract (plot above the most lightly
shaded area), and a similar
composition without any of vitamins A, C, and E, and green tea extract (plot
above the most darkly shaded
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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area) on the condition of skin as measured using a Corneometer, as evaluated
for five different subjects. The
condition of an untreated area (the remaining plot) was also evaluated.
Measurements were taken over a 10
1/2 day period as explained in detail below.
DESCRIPTION OF DETAILED EMBODIMENTS
The present invention is a topical composition that includes at least one
active ingredient in
combination with urea in which the urea is present in an amount sufficient to
enhance penetration of the active
ingredient(s).
The active ingredients) is selected for its beneficial effects to the skin,
which effect is to be
enhanced by exposure of the viable epidermis and/or dermis, which underlies
the stratum corneum, to the
I 0 ingredient. By including urea in a concentration sufficient to enhance
penetration of the agent through the
stratum corneum in a topical composition, such effect is enhanced. Generally
speaking, the proportion of the
composition which should be urea is at least 10 percent by weight. (100 gm of
a composition that is 10 percent
by weight of a component would contain 10 gm of that component.) Because of
the enhanced penetration, it is
possible to devise compositions containing less of a given active ingredient
than would be necessary to obtain
15 the same or comparable effect due to the the ingredient's activity in the
absence of a penetration enhancing
amount of urea.
The precise minimum amount of urea necessary to enhance penetration of a
particular active
ingredient agents) is determined according to the method given below. In
general, the minimum amount of
urea that is necessary to obtain penetration enhancement is at least about
10%, but it would generally be
20 higher, and could be as high as 50%. Typical compositions have about 15%,
or about 20%, or about 25%, or
about 30%, or about 35%, or about 40% urea. In the context of this invention,
percentages are given as
"weight percent".
A preferred active ingredient is selected from vitamins, antioxidants and 13-
glucans.
Preferred vitamins are vitamin E (particularly, alpha tocopherol, as well as
beta, delta, and
25 gamma-tocopherols and alpha, beta, delta and gamma tocotrienols), vitamin
C, and vitamin D. Of course,
certain vitamins, such as vitamin E, are known to have antioxidant properties.
Preferred antioxidants include retinyl palmitate,13-carotene, tocopherol
acetate, ascorbic
acid, green tea, black tea, quercetin (flavonoids), sea kelp, pycnogenols
(proanthocyanidins), selenium and
alkylgylcerol-AKG (shark liver oil).
30 It is generally considered that if 13-carotene is included, vitamin E
should also be included as
discolorization of the skin by vitamin A can be reduced in the presence of
vitamin E.°5 The
beneficial effects of certain vitamins, as far as the skin is concerned, are
known. For example, it has been
shown that vitamins E and C can protect the skin against oxidative damage
caused by free radicals.'6
Green tea is known to contain polyphenols and their use in antioxidant
formulations has been
35 suggested. See, for example, United States Patent No. 5,648,377, which
issued to Bombardelli et al. on July
15, 1997.
Other antioxidants include: Allopurinol; a-lipoic acid; astaxanthin; azulenic
retinoid
compounds; vitamin A related compounds such as l3-carotene, carotenoid,
lycopene, xanthophylls and
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lycopene; coenzyme Q-10; cysteine; metals such as zinc, copper, magnesium,
potassium selenium; BHA;
BHT; maharishi amrit kalash (MAK); melatonin; N-acetylcysteine (NAC); olive
oil; phenolics; pyrimidines;
activin (from seeds of red grapes); superoxide dismutase (SOD); prozyme
(Polbax); black tea in addition to
green tea (camelia sinensis); proanthocynidins (OPC); pycnogenol grape seed);
curcumin from tumeric;
silymarin, the flavonoid complex of milk thistle (Silybum marianum); cat's
claw; ginkgo biloba; silica hydride.
Urea is a well known component of topical compositions. In the bulk of
products in which is
it used, it is included as a moisturizing agent. This is true, for example,
where it is suggested for use in
compositions described in United States Patent No. 5,935,585. When used as a
moisturizing agent in a
composition, the amount of urea included is usually limited to small amounts.
Urea is also known to improve the elasticity of the stratum
corneum.°'
The influence of urea in topical compositions on penetration of other
ingredients, such as
hydrocortisone has been described in the past.°8
Use of urea in connection with analgesics is also known. United States Patent
No.
5,814,659, which issued to Elden on September 29, 1998, (Canadian Patent
Application No. 2,203,456 laid
open October 23, 1997) describes the use of a chaotropic agent, particularly
urea, in combination with an
analgesic agent, particularly lidocaine. A product containing these
ingredients is currently on sale in the
United States under the name Lespain. In this context 10% urea is used.
Studies of the penetration enhancing abilities of urea have been
conducted°'~so,s~
Preliminary results have been obtained by the inventors. During a one-week
period, three
lotions were applied by a single subject to different skin areas to be equally
exposed to the sun. Lotion A
contained 2% by weight lactic acid and 0.2% by weight malic acid in an oil-in-
water emulsion. Lotion B was
the same as lotion A with urea added to make up 10% by weight of the total
composition. Lotion C was the
same as lotion B with 0.2% allantoin, 0.3% vitamin E, 0.25% vitamin A, 0.10%
vitamin C, and 0.3% green tea
extract, all percentages being weight percent.
The three areas of the subject were equally exposed to natural sunlight over a
one week
period. Results were evaluated by measuring skin impedance using a Surface
Characterizing Impedance
Monitor (SCIM) developed by Olimar, which measures bioelectrical impedance of
the skin at multiple
frequencies.s2.s3.s°,ss,s6.s~ .I-he instrument is basically an AC-
bridge fabricated from standard laboratory
instruments: a function generator, a digital oscilloscope, impedance
references, and a driver for the probe.
The results obtained are given in Table I.
Table
I
Impedance Lotion Lotion Lotion
A B C
dep befor afte chang chang chang
1 13.155 13.4228 0.266 0.2113 -0.082
-
2 13.0085 13.1488 0.1403 0.758 -0.042
3 12.71 13.7932 1.0772 0.4344 -0.058
4 12.038 12.6122 0.574 0.4727 0.279
5~ 11.777 12.4459 0.6683 0.4298 0.03
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The baseline is given as the "before" measurement in Table I. The depths of
skin measured
varied from the most superficial stratum corneum (1) to the live epidermis
(5).
Electrical impedance of skin is less for intact, more hydrated skin. The
results given in
Table I thus indicate that, while urea itself provides some benefit beyond the
components of lotion A, the
combined effect of urea and vitamin E, or urea and vitamin A, or urea and
vitamin C or urea and green tea
extract greatly exceeds that of urea alone.
The results obtained, although obtained in feasibility tests to establish
effectiveness of a
composition containing urea in combination with each of these agents in
improving skin condition, are
surprising in that the concentration of agent which obtains the result is very
small.
Particular compositions containing vitamins A, C, E and green tea extract are
contemplated
as follows:
Composition A:
INGREDIENT % (w/w)
Water 43.65
Urea 25.00
PEG-100 Stearate 6.00
Beeswax 5.00
Mineral oil 5.00
Lanolin 4.00
Cetyl Alcohol 3.00
Triethanolamine 2.50
Lactic acid 2.00
Silk Amino Acid 1.00
Imidazolidinyl urea 0.40
Green Tea Extract 0.30
Tocopheryl Acetate 1.00
Retinyl Palmitate 0.25
Malic Acid 0.20
Methyl Paraben 0.20
Allantoin 0.20
Ascorbic Acid 0.10
Propyl Paraben 0.10
Trisodium EDTA 0.10
100.00
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Composition A was obtained according to the following procedure:
PHASE I (aqueous phase)
(W~
Water 43.65
Urea 25.00
Imidazolidinyl urea 0.40
Methyl paraben 0.20
Malic acid 0.20
Allantoin 0.20
Ascorbic acid 0.10
Trisodium EDTA 0.10
PHASE II (oil phase)
(W~
PEG-100 stearate 6.00
Beeswax 5.00
Mineral oil 5.00
Lanolin 4.00
Cetyl alcohol 3.00
Tocopheryl acetate 1.00
Propyl paraben 0.10
PHASE III
(W~
Triethanolamine 2.50
PHASE IV
% (W~
Lactic acid 2.00
PHASE V
(W~
silk amino acid 1.00
Green tea extract 0.30
Retinyl palmitate 0.25
In a s.s. kettle the ingredients of phase I are combined and heated to
70° - 75°C and
maintained at that temperature. In a separate s.s. kettle the ingredients of
phase II are combined and heated to
75° - 80°C and maintained at that temperature. Phase II is added
at 75° - 80°C to phase I at 70° - 75°C with
W~ 01/17484 CA 02382833 2002-02-25
PCT/CA00/01031
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mixing to homogenous solution and the solution is permitted to cool. At 60 -
65°C, phase III is added and
cooling and mixing is continued. At 50° - 55°C, phase IV is
added and cooling and mixing is continued. At
35° - 40°C, the ingredients of phase V are added with mixing.
Cooling and mixing until a temperature of 30° -
35°C is reached and mixing is stopped.
Composition B:
INGREDIENT /a, W/W
Water 46.75
Urea 20.00
PEG-100 Stearate 6.00
Cetyl Alcohol 6.00
Beeswax 4.00
Isopropyl Myristate 4.00
Triethanolamine 2.50
Emulsifying Wax 2.00
Lactic Acid 2.00
Petrolatum 2.00
Mineral oil 1.00
Silk Amino Acid 1.00
Imidazolidinyl Urea 0.30
Green Tea Extract 0.30
Tocopheryl Acetate 1.00
Retinyl Palmitate 0.25
Methyl Paraben 0.20
Allantoin 0.20
Malic Acid 0.20
Propyl Paraben 0.10
Ascorbic Acid 0.10
Trisodium EDTA 0.10
100.00
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Composition B was obtained according to the following procedure:
PHASE I (aqueous phase)
% (W~
Water 46.75
Urea 20.00
Imidazolidinyl urea 0.30
Methyl paraben 0.20
Allantoin 0.20
Malic acid 0.20
Ascorbic acid 0.10
Trisodium EDTA 0.10
PHASE II (oil phase)
(W~
PEG-100 stearate 6.00
Cetyl alcohol 6.00
Beeswax ' 4.00
Isopropyl myristate 4.00
Emulsifying wax 2.00
Petrolatum 2.00
Mineral oil 1.00
Tocopheryl acetate 1.00
Propyl paraben 0.10
PHASE III
% (W/V~
Triethanolamine 2.50
PHASE IV
(W~
Lactic acid 2.00
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PHASE V
~W~
silk amino acid 1.00
Green tea extract 0.30
Retinyl palinitate 0.25
In a s.s. kettle the ingredients of phase I are combined and heated to
70° - 75°C and the
temperature maintained. In a second s.s. kettle the ingredients of phase II
are combined and heated to 75° -
80°C and the temperature maintained. Phase II, at 75° -
80°C is added to phase I at 70° - 75°C with mixing. A
homogeneous solution is obtained and the mixture is permitted to cool with
mixing. At 60° - 65°C, phase III is
added to the solution and cooling and mixing is continued. At 50° -
55°C, phase IV is added and mixing and
cooling is continued.
At 35° - 40°C, ingredients of phase V are added in the order
indicated with mixing and mixing is continued
until the solution reaches a temperture of 35° - 35°C.
Composition C:
INGREDIENT % (W/V1~
Water 58.55
Urea 15.00
Glycerin 6.00
PEG-100 Stearate 3.50
Emulsifying Wax 3.00
Squalene 3.00
Cetyl Alcohol 2.50
Triethanolamine 2.50
Lactic Acid 2.00
Silk Amino Acid 1.00
Imidazolidinyl Urea 0.40
Tocopheryl Acetate 1.00
Green Tea Extract 0.30
Retinyl Palmitate 0.25
Methyl Paraben 0.20
Allantoin 0.20
Malic Acid 0.20
Propyl Paraben 0.10
Ascorbic Acid 0.10
Trisodium EDTA 0.10
Carbomer 934P 0.10
100.00
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Composition C was obtained according to the following procedure:
PHASE I (aqueous phase)
(W~
Water 58.55
Carbomer 934 P 0.10
Urea 15.00
Imidazolidinyl urea 0.40
Methyl paraben 0.20
Allantoin 0.20
Ascorbic acid 0.10
Malic acid 0.20
Trisodium EDTA 0.10
Glycerin 6.00
PHASE II (oil phase)
% (W/V1~
PEG-100 stearate 3.50
Emulsifying wax 3.00
Squalane 3.00
Cetyl alcohol 2.50
Tocopheryl acetate 1.00
Propyl paraben 0.10
PHASE III
% (W/W)
Triethanolamine 2.50
PHASE IV
(W~
Lactic acid 2.00
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PHASE V
% (W/W)
Silk amino acid 1.00
Green tea extract 0.30
Retinyl palmitate 0.25
In a s.s. kettle the ingredients of phase I are added the order indicated and
mixed until the
carborner is completely dispersed and hydrated. The solution is headed to
70° - 75° C and the temperature
maintained. In a separate s.s. kettle the ingredients of phase II are combined
and heated to 75° - 80°C with
mixing and the temperature maintained. The phase II mixture at 75° -
80° C is added to the phase I solution at
70° - 75°C with mixing. The batch is mixted to obtain a
homogeneous solution and the solution is permitted to
cool. At 60° - 65°C, phase III is added with mixing and cooling
is continued. At 50° - 55°C, phase IV is
added with mixting and cooling continued. At 35° - 40°C, the
ingredients of phase V are added with mixing in
the order indicated. Mixing is stopped when a temperature of 30° -
35°C is reached.
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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Composition D:
INGREDIENT % (W/V~
Water 63.25
Urea 10.00
Propylene Glycol 5.00
Squalene 4.50
Isopropyl Myristate 4.00
Triethanolamine 2.50
PEG-100 Stearate 2.00
Lactic Acid 2.00
Cetyl Alcohol 2.00
Emulsifying Wax 1.00
Silk Amino Acid 1.00
Imidazolidinyl Urea 0.40
Green Tea Extract 0.30
Tocopheryl Acetate 1.00
Retinyl Pahnitate 0.25
Allantoin 0.20
Malic Acid 0.20
Ascorbic Acid 0.10
Quaternium - I S 0.10
Trisodium EDTA 0.10
Carbomer 941 0.10
100.00
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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Composition D was obtained according to the following procedure:
PHASE I (aqueous phase)
(W~
Water 62.75
Carbomer 941 0.10
Urea 10.00
Imidazolidinyl urea 0.40
Allantoin 0.20
Ascorbic acid 0.10
Malic acid 0.20
Trisodium EDTA 0.10
Propylene glycol 5.00
PHASE II (oil phase)
(W~
Squalane 4.50
Isopropyl myristate 4.00
PEG-100 stearate 2.00
Emulsifying wax 1.00
Cetyl alcohol 2.00
Tocopheryl acetate 1.00
PHASE III
(W~
Triethanolamine 2.50
PHASE IV
% (W/W)
Lactic acid 2.00
PHASE V
(W~
Water 0.50
Quaternium-15 0.10
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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PHASE VI
(W~
Silk Amino acid 1.00
Green tea extract 0.30
Retinyl palmitate 0.25
In a s.s. kettle, the ingredients of phase I are combined in the order
indicated and mixed until
carborner is completely dispersed and hydrated. The mixturue is heated to
70° - 75°C and the temperature
maintained. In a separate s.s. kettle the ingredients of phase II are combined
and heated to 75° - 80°C with
mixing and the temperature maintained. The phase II mixture is added at
75° - 80°C to phase I at 70° -75°C
with mixing. The mixture is mixed to obtain a homogeneous solution and
permitted to cool with mixing. At
60° - 65°C, phase III is added to the batch and mixing and
cooling are continued. At 50° - 55°C, phase IV is
added to the batch and mixing and cooling are continued. At 45° -
50°C, phase V is added to the batch and
mixing and cooling is continued. At 35° - 40°C, the ingredients
of phase VI are added to the batch in the order
indicated and mixing is continued until a temperature of 30° -
35°C is reached.
It is preferable to have homogeneous formulations.
In vitro skin penetration studies can be used to evaluate a suitable amount of
urea to be used
in connection with a particular ingredient. The penetration of vitamins
through human skin can be measured
using various formulations with and without urea.
Transepidermal water loss (TEWL) can be measured by evaporimetery using a
Servo-Med
evaporimeter or similar device, for example.
In vivo dermatopharmacokinetic studies can be carried out to determine the
effects of urea on
penetration enhancement of active ingredients. Test compositions including an
ingredient to be evaulated are
prepared along with control compositions, which are the same except that the
urea is omitted. Each
composition is applied to the skin surface at 2 mg/square cm for between about
0.5 to 6 hours. After the
specified period of time the site is washed thoroughly with mild detergent and
water. The site is dried. The
site is then tape stripped using D-Squame adhesive disks. Five strips are
taken and combined and then five
more and five more for a total of 25. The tapes are then extracted and
analyzed for the active ingredient, say
vitamin E, using HPLC. Higher levels of vitamin E in the lower tape strips
from sites to which urea-containing
compositions were applied indicate a positve effect on vitamin penetration.
In vivo skin penetration studies can also be carried out using
dermatopharmacokinetics using
tape stripping in order to determine a suitable amount of urea to be included
in a composition in combination
with a particular active ingredient. Studies similar to the foregoing are
carried out for a number of
concentrations of urea, say varying from 10 to 50%, at increments of 5%.
In a feasibility study, Composition E, containing 25 % urea and vitamin E was
tested. The
formulations of compositions used in the studies are as follows:
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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Ingredients (w/w%)
Control Composition E
Propyl paraben 0.1 0.1
Tetra sodium EDTA 0.1 0.1
Methyl paraben 0.2 0.2
Triethanolamine 99% 0.25 0.25
Imidazolidinyl urea 0.4 0.4
Silk protein (amino acid) 2 2
Cetyl alcohol 3 3
Lactic acid 3 3
Malic acid 3 3
Lanolin 4 4
Beeswax (synthetic) 5 5
Mineral oil - medium 5 5
Vitamin E (tocopheryl acetate)5 5
GMS/peg 100 stearate 6 6
Urea USP 0 25
Deionized water 62.95 37.95
In this case, 2.0 mg/cm of the composition was applied to 5 cm2 of the
forearm. After 120
minutes, each of the test areas was rinsed with warm water for 20 seconds. The
disks were extracted with
acetone:chloroform (50:50) with 10 minutes of sonication and then the residue
was extracted again with 5
minutes of sonication. The extracts were dried under NZ and then resuspended
with ethanol. The ethanol
solution was filtered through a nylon syringe filter. An aliquot was analyzed
by HPLC.
The vitamin E (vitamin E acetate) was determined using an isocratic HPLC
method. The
wavelength was 290 nm, mobile phase was methanol, and the flow rate was 0.9
ml/min. A 20-pl sample was
injected into the HPLC. Retention time was 4.3 min or 5.4 min for vitamin E
and vitamin E acetate,
respectively. The linear range was: 0.002036 - 0.3054 mg/ml (rz = 0.9997).
The results shown in Table One, are given as the area under the peak from the
HPLC
analysis. Statistical analysis was performed using 2 tailed paired t. The
level of vitamin E was found to be
higher for the composition containing urea and vitamin E but because of the
small sample size and high
variability the results were only statistically significant at the deepest
level.
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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Table
One
Level Level Level
I 2 3
(Tapes (Tapes (Tapes
2-6) 7-11) 12-16)
SubjectUreaControlDifferenceUreaControlDifferenceUrea ControlDifference
1 69373452 3485 1785789 996 2400 1272 1128
2 1506903 603 7190 719 622 0 622
3 54455396 49 47802888 1892 2640 1306 1334
Average46293250 1379 24281226 1202 1887 859 1028
T
test
P 0.32 0.08 0.04
value
Also observed was that the percent increase in vitamin E, comparing urea to
the control, was
greatest at the lowest level tested:
Level Urea Control Percent Increase
1 4629 3250 42
2 2428 1226 98
3 1887 859 120
These results establish that urea is effective in enhancing delivery of
vitamin E to the viable
epidermis.
An especially preferred composition of the present invention thus is one that
contains
between 10 and 50 % urea, more preferably between 1 S and 50 % urea, more
preferably between 20 and 45%
urea, and more preferably still between 25 and 40%, and most preferrably about
25%.
Further feasibility studies were conducted using a formula containing 15%
urea,
Composition F. Composition F had the same composition as that set out above
for Composition C. In these
studies, five subjects were tested over a period of 10 '/~ days. For each
subject, three different areas of skin
were tested. The first area was not treated. The second area was treated with
a control containing urea but no
vitamin E, here called Composition F'. The third area was treated with
Composition F.
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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Composition F':
Ingredient %(w/w)
Carbomer 934P 0.1
Cetyl alcohol 2.5
Deionized water 56.1
Emulsifying wax NF (polawax) 3
Glycerin 6
GMS/peg 100 stearate 3.5
Hydrogenated polyisobutene 3
Imidazolidinyl urea 0.4
Lactic acid 3
Malic acid 2
Methyl paraben 0.2
Propyl paraben 0.1
Silk protein (amino acid) 1
Tetra sodium EDTA 0.1
Triethanolamine 99% 4
Urea USP 15
The effects of the two treatments relative to the non-treated area and to each
other were
followed using a Corneometer (COURAGE+KHAZAKA electronic GmbH, Mathias-
Briiggen-Str. 91, D
50829 Koln - Germany, **www.courage-khazaka.de**), which provides a
measurement of skin moisture based
on a capacitance method. The measurement is based on the different dielectric
constant of water and other
substances. The measuring capacitor shows changes of capacitance according to
the moisture content. Used
according to the manufacturer's protocol, there is a probe which is touched to
the skin for about a second to
take a given measurement.
To begin, Compositions F and F', were applied to the two treatment areas. The
compositions were similarly applied and measurements taken 12 hours later and
at 12 hour intervals thereafter.
Treatment with Compositions F and F' were stopped after the eighth day (i.e.,
after the 16th treatment) but
measurements were continued, for a total of twenty-two measurements. Results
are plotted in Figures 1(a) to
1 (e), one plot for each of the five subjects. The plot above the most lightly
shaded area in each figure is that
obtained by taking measurement using the Corneometer of the area treated with
Composition F. The initial
measurement taken of a particular area was substracted from each measurement
before plotting of the results.
The plot above the most darkly shaded area in each figure is that obtained
from measurements taken of the area
treated with Composition F'. The remaining plot shows measurements obtained
from the untreated area.
WO 01/17484 cA 02382833 2002-02-25 PCT/CA00/01031
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The x-coordinate of each plot shows the number of the measurement taken, at 12-
hour
intervals. The y-coordinate is the reading taken from the Corneometer having
the initial reading for the area
subtracted. The higher the reading the greater the moisture content of the
skin.
As can be seen from the plots of Figures I(a) to 1(e), although changes in
moisture content
vary in about the same direction from site to site of a given subject, the
plot obtained from the area treated with
Composition F is generally higher than that obtained from Composition F',
which is in turn generally higher
than the plot obtained from the untreated area.
Further, it can be seen that the salutary effect continued for the three day
test period after
cessation of treatment.
There is mention in the art of the penetration enhancing properties of urea in
connection with
various active substances. For example, Wohlrab states that the promotion of
drug penetration by urea can be
exploited so as to improve therapeutic efficacy at the same concentration of
an active substance and to achieve
the same therapeutic efficacy with a considerably lower concentration. With
respect to hydrocortisone, it has
been shown that when low concentrations of urea are used, enhancement of
penetration is barely apparent,
whereas with a urea content of between 5% and 10% there is a particular
increase, but apparently, when the
urea concentrations are raised further, no further decisive changes are
detectable.
Raab also suggests that urea increases the bioavailablity, or topical
activity, of other drugs.
In addition to the combination of glucocorticoids, e.g., 1 % hydrocortisone
with 10% urea, Raab describes
improvement in the antisporiatic action of anthralin in a composition
containing 17% urea. Raab also
describes treatment of certain severe ichthyoses with a combination of 0.03%
tretinoin (all-traps-retinoic acid)
and 10% urea, and the treatment of hyperkeratoses with a combination of 10%
urea and 10% salicylate.
Beastall et al. describe a study in which a decrease in the time taken to
induce erythema by
topically applied nicotinate was observed as the nicotinate was combined with
increasing amounts of urea.
United States Patent No. 5,879,690 (Perricone et al.) describes the use of
catecholamines
and related compounds in combination with percutaneous penetration enhancers
for topical administration of
sagging subcutaneous muscle. The use of several enhancers is suggested,
including urea, as is the inclusion of
compounds that scavenge free radicals and anti-oxidants, for example, vitamins
E and C. While the use of
enhancers up to a concentration of about 10% is suggested, the teachings in
regard to enhancers are quite
general and there does not appear to be any suggestion that the use of urea
would produce any benefits beyond
those known in the art at the time.
There are commercially available skin moisturizers that contain up to about
25% urea for aid
in softening and hydrating hard dry skin.
WO 86/00014 (Weiner), published January 3, 1986, describes topical cream
compositions
that includes 15% urea, possibly up to 40% urea, in combination with UV
absorbing sun screen agents, for the
purposes of prevention and/or reduction of skin damage caused by reactive
chemical substances generated in
the skin by ultraviolet radiation.
In the context of this invention, the amount of vitamin A to be included in a
composition
would be from about 0.1 to about 5%, vitamin E would be from about 0.1 to
about 10%.
WO 01/17484 cA 02382833 2002-02-25 pCT/CA00/01031
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In vivo efficacy can be evaluated against dry skin in the case of active
ingredients that would
be thought to be helpful to such condition. Subjects with dry itchy skin use a
product containing urea in
combination with the test ingredient in a controlled clinical test. The skin
is graded, subjective assessments are
obtained and a number of different instruments are used to determine effects
on skin. Again systematic studies
using various concentrations of urea, various concentrations of the test
ingredient, test times and controls
(compositions lacking the test ingredient and/or urea, for example) are
carried out to determine optimal
composition makeup.
In vivo barrier repair can be tested for ingredients thought to play a role in
wound repair.
Tape stripping, for example, is used to damage skin and the damage is then
judged by measuring trans-
epidermal water loss and erythema. Test compositions can be applied to the
damage area and effects on the
rate of healing determined. Again, various concentrations of the test
ingredient, in combination with various
concentrations of urea, and appropriate controls, etc., would be used.
Additionally, of course, different
application methods might also be tested.
Protection against UV damage can also be studies in in vivo experiments.
Vitamins E and C,
especially in combination with each other, have been shown to protect against
sunburn even though they do not
absorb significant amounts of UV light. This is because they reduce damage
caused by free radicals that result
from UV exposure.
In terms of the minimum amount of urea that is to be included in a composition
in
combination with a particular active ingredient, it may be found that there is
a particular minimum associated
with a group of ingredients that are chemically related to the one tested. For
example, if it is found that at least
20% urea is suitable for two or more compounds of a family of compounds that a
person skilled in the art
would understand to share hydrophilic properties, have similar molecular
weights, etc., then it would be
reasonably expected that 20% urea would be a suitable amount of urea to be
used in combination with other
compounds of that family. Of course, the greater the number of compounds
within a family that are actually
tested and found to behave similarly, the greater the certainty that other
compounds of the family that are not
tested will behave similarly to those that have been tested.
Various active ingredients that can be included in compositions of the present
invention,
alone or in combination, are described below.
Allopurinol is not, strictly speaking, an antioxidant. This ingredient is
though to suppress the
body's production of an oxidation catalyst, xanthine oxidase.
Alpha lipoic acid (ALA) is a water soluble and lipid soluble antioxidant.
Apparently, ALA
prorates the regeneration of the redox reaction between vitamin C, E, and
glutathione.ss
Astaxanthin is a carotenoid produced by a microalgae called Haematocococcus
pluvialis.
Azulenic retinoid compounds are compounds related to Vitamin A and retinoic
acid. A new
type of azulene-containing retinoid has been synthesised and is similar in
size and shape to Vitamin A, but its
electronic properties are different.
Vitamin A (b-carotene, carotenoid, lycopene, xanthophylls and lycopene) is a
term loosely
used to describe members of a family of anti-oxidant substances called
carotenoids. These carotenoids have
antioxidant and other qualities and can be converted by the body into vitamin
A.
WO 01/17484 CA 02382833 2002-02-25 pCT/CA00/01031
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Vitamin C (ascorbic acid) must be obtained from food or vitamin supplements.
This anti
oxidant is thought to slow down loss of glutathione to neutralise some
destructive cell oxidants.
Vitamin E occurs in nature in several forms - alpha, beta, delta, and gamma-
tocopherols and
alpha, beta, delta and gamma tocotrienols. Most vitamin E supplements contain
alpha tocopherol form which
is thought to have significant biological activity.s9
Melatonin has been found to rescue DA neurons from cell death in several
experimental
paradigms associated with oxidative stress.b° The combined findings
suggest that melatonin counteracts the in
vitro destructive effects of NMDA or hypoxia/reperfusion by preventing
accumulation of excessive free
radicals.b' Melatonin protects primary cultures of rat cortical neurones from
NMDA excitotoxicity and
hypoxia/reoxygenation 62
Silica hydride. This silica mineral is 5 nanometers in total area - the
smallest nutritional
particle ever discovered. When combined, this molecule is a million times
smaller than the next smallest
antioxidant.
N-Acetylcysteine (NAC) can be derived from the amino acid cysteine. NAC is a
natural
1 S sulfur-containing amino acid derivative found naturally in foods and is
thought to have antioxidant properties.b'
Phenolics are naturally occurring anti oxidants found in the skins of many
fruits, vegetables
and herbs.
Pyrimidines are a group of antioxidant compounds, the pyrrolopyrimidines,
discovered
recently. They appear to quench lipid peroxidation reactions by electron-
donating and/or radical-trapping
mechanisms.'
Activin (TM) can be obtained from the seeds of the red grape.
Superoxide Dimutase (SOD) is available in oral an form called Prozyme (or
Polbax in
Sweden).bs
Black and green teas (camelia sinensis) have anti oxidant properties. Black
tea is though to
have similar anti oxidant properties to those of green tea.
OPC or proanthocynidins. (Pycnogenol (grape seed extract) is described in U.S.
Patent
4,698,360).
Coenzyme Q-10 (ubiquinone) is an essential cofactor of the electron transport
chain as well
as a potent free radical scavenger in lipid and mitochondria) membranes.b'
Coenzyme Q 10 administration is
though to increase brain mitochondria) concentrations and to exert
neuroprotective effects.b8
There are many examples of herbal antioxidants. For example, silymarin, the
flavonoid
complex of milk thistle (Silybum marianum) and Ginkgo biloba extract is
thought to be an antioxidant.
Other herbal antioxidants include Silymarin (liver); Ginkgo biloba (brain and
circulation);
pycnogenols (veins); and bilberry (retina).
Curcumin can be obtained from tumeric. Curcurnin is the yellow pigment of
turmeric
(Curcuma Tonga), an ingredient of curry powder and prepared mustard. Curcurnin
is though to be an
antioxidant.
The amount of active ingredient to be included in a composition is a topically
effective
amount, and can be determined by a person skilled in the art according to the
purposes for which the ingredient
WO 01/17484 CA 02382833 2002-02-25 PCT/CA00/01031
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is being applied. Thus, for example, in the foregoing example involving
Composition E, it was found that the
amount of vitamin E measured at the skin level just above the viable epidermis
is between two and three times
that found when no urea was used (control). Thus the amount of vitamin E to be
included in a composition
containing 25% urea can be 1/3 to 1/2 the amount that would be included in a
composition lacking urea. Of
course, a person skilled in the art, provided with this specification would be
readily capable of deriving other
formulations within the scope of the invention described herein.
This application claims priority from United States Provisional Patent
Application Serial No.
60/152,637 filed September 7, 1999, the contents of which are incorporated
herein by reference.
All references cited herein are incorporated into this document in their
entirety by reference
thereto.
WO 01/17484 CA 02382833 2002-02-25 pCT/CA00/01031
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