Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02159201 2006-08-17
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COS(KETIC COMPOSITION
FIELD OF THE INVENTION
The invention relates to skin-conditioning compositions and
methods. It is particularly concerned with the stimulation
of ceramide production in the epidermis, leading to an
increase in the level of these lipid materials in the
stratum corneum of the skin. The composition is also
suitable for topical application to the hair and the nails.
BACKGROUND TO THE INVENTION
The stratum corneum, which is the outermost layer of the
mammalian skin, contains intercellular lipids consisting
predominantly of ceramides, cholesterol and fatty acids.
From studies involving lipid depletion of the corneum by
solvent extraction and from enzyme inhibition studies,
ceramide in particular has been shown to be essential for
the barrier function of the stratum corneum.
In normal skin, if there is perturbation of the barrier
function, the epidermis normally re-synthesises the
deficient lipids by inducing the expression or activation
of the appropriate enzymes. However, under certain
conditions, a reduced capacity for re-synthesis of the
lipids may occur. This is especially so with elderly
subjects, whose stratum corneum ceramide level is in any
case reportedly lower than that of younger subjects.
The present invention is based upon the concept of
stimulating the synthesis of ceramides in the epidermis by
the topical application of precursors thereof in the
biosynthetic pathway and/or by stimulation of the activity
of enzymes responsible for catalysing the steps in the
biosvnthetic pathway that yields ceramide (as described
later in this specification).
WO 94/23694 PCT/EP94/01117 =
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Synthesis of Ceramide
The synthesis of ceramide in the epidermis can be achieved
by a variety of biochemical pathways, for example, those
shown in Figure 1.
Common to each of these pathways are palmitoyl-CoA and
serine, which are converted initially to 3-ketosphinganine
in the presence of serine palmitoyl transferase. This is
a rate limiting step and can accordingly adversely affect
the rate of synthesis of ceramides via 3-ketosphinganine
and the other intermediates as shown in these pathways.
We have now discovered that the rate of synthesis of
ceramide in the epidermis can be increased following
topical application of one or more intermediates in these
biosynthetic pathways, especially those that are distal to
the rate limiting step. We have also discovered that
precursors comprising palmitoyl CoA and serine, can
together increase ceramide synthesis, even though these are
proximal to the rate limiting step.
The invention is accordingly concerned with the use of one
or more of these ceramide pathway intermediates, following
topical application, in enhancing the quality and condition
of human skin, especially the water barrier properties
thereof, in particular by increasing the rate of ceramide
biosynthesis in the epidermis.
DEFINITION OF THE INVENTION
According to the invention, there is provided a composition
suitable for topical application to human skin which
comprises:
(i) from 0.0001 to 10o by weight of a ceramide pathway
intermediate or a precursor thereof or mixtures thereof;
~ ~
S WO 94/23694 5 9 Fd 0 1 PCT/EP94/01117
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and
(ii) a balaiicing amount of a cosmetically acceptable
vehicle for the ceramide pathway intermediate or precursor
thereof.
The invention is also concerned with a method of treating
skin, particularly dry and aged skin, with topically
applied ceramide pathway intermediate, or a precursor
thereof or mixtures thereof, in order to maintain or repair
the skin barrier which controls moisture loss from the
skin.
The invention is also concerned with the use of one or more
ceramide pathway intermediates, or precursors thereof or
mixtures thereof in maintaining or enhancing the skin
barrier function which controls moisture loss from the skin
and in the treatment of skin to reduce or delay the
development of wrinkles associated with advancing age, or
with sun-induced skin ageing.
The invention is also concerned with the use of at least
0.0001% by weight based on the total composition, of a
ceramide pathway intermediate in a composition suitable for
topical application to human skin comprising a major
proportion of a cosmetically acceptable vehicle for the
ceramide pathway intermediate.
DISCLOSURE OF THE COMPOSITION OF THE INVENTION
The composition according to the invention comprises in its
simplest form a ceramide pathway intermediate or a
precursor thereof, or mixtures thereof together with a
cosmetically acceptable vehicle, the composition being
suited for topical application to human skin.
The primary function of the said intermediate or Drecursor
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thereof is to stimulate the synthesis of ceramide in the
epidermis which then leads to higher ceramide levels in the
stratum corneum. The water permeability barrier function
of the skin, is thereby improved and the ability of" the 5 skin to retain
moisture consequently enhanced.
The consumer perceived benefits that accordingly accrue
from higher levels of ceramide in the stratum corneum
achieved in this way are to be seen in the improvement in
skin condition, such as eradication or reversal of skin
ageing, including removal of age spots, keratoses,
wrinkles, skin lines, blotches, blemishes, nodules,
pigmented spots, coarse, rough and dry skin, together with
improvements in skin barrier function leading to fewer
problems of skin sensitivity, photodamaged skin, loss of
elasticity and flexibility.
The Ceramide Pathways
With reference to Figure 1, which shows three alternative
biosynthetic pathways for the production of ceramides in
human skin, it can be seen that each has a common rate
limiting step, namely the conversion of palmitoyl-CoA and
serine to 3-ketosphinganine in the presence of serine
palmitoyltransferase.
With reference to Ceramide Pathway I (Figure 1), 3-
ketosphinganine is then converted to sphinganine in the
presence of NADPH-dependant reductase and final conversion
to Ceramide(A), via sphinganine in the presence of fatty
acyl-CoA.
With reference to Ceramide Pathway II, 3-ketosphingosine is
converted firstly to sphinganine and then secondly to
sphingosine, and then to N-acyl sphingosine (Ceramide (B)).
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With reference to Ceramide Pathway III, 3-ketosphinganine
is converted to sphinganine in the presence of NADPH-
dependant reductase, as occurs in Ceramide Pathway I, but
then sphinganine is converted firstly to sphingosine, and
secondly to phytosphingosine and then to N-
acylphytosphingosine (Ceramide (C)).
The Ceramides produced via ceramide pathways I, II and III
are likely to be structurally different from each other and
for this purpose are designated Ceramides (A), (B) and (C).
It is to be understood that the above ceramide pathways are
purely illustrative and do not represent the only pathways
available for the production of ceramide.
The Ceramide Pathway Intermediates
As has been explained, the conversion of palmitoyl-CoA and
serine to 3-ketosphinganine in the presence of serine
palmitoyltransferase represents the rate limiting step, ie
the step which limits the formation of ceramide in the skin
and other tissues. Accordingly, in order to enhance the
rate at which ceramide is formed, particularly in the skin,
it is preferred to deliver to the skin an effective amount
of a precursor of ceramide which enters one or more of the
Ceramide Pathways distal to this rate limiting step.
The rate of formation of ceramide can thus be enhanced by
providing as precursors sphingoid bases, typical examples
of which are sphinganine, sphingosine and phytosphingosine
and derivatives thereof in accordance with structure (1):
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G,
t~N' ~
(1)
X Gf~.3
where X is represented by
20
and where R', R2, R3 and RS are each individually
represented by H-, CH3 ( CH2) õ-
0
11
CH3 ( CH2 ) ,, ( CHOH ) r, - , CH3 ( CH2 ) õ ( CHOH ) õC - or
0
11
CH3 (CH2) r,C -,
or phosphorylated, sulphated, glycosylated and benzoyl
derivatives thereof;
where n is 0, or an integer of from 1 to 10, and
R4 i S CHz ( CH2 ) m -
~ WO 94/23694 1~ ~ 2 01 PCTIEP94/01117
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where m is an integer of from 1 to 21.
One preferred group of ceramide pathway intermediates
includes: sphinganine, sphingosine and phytosphingosine
and their respective N-acyl, 0-acyl and N-alkyl
derivatives.
A particularly preferred ceramide pathway intermediate is
tetraacetyl phytosphingosine having the structure (2):
C)
~i3[i-v G
O-C C\a3 (2)
r1 Zi ~- ; c> -~- G r~3
p -t. c-e!3
Particularly preferred derivatives of sphinganine are
N-acetyl sphinganine having the structure (3):
N jC- C -
OH
(3)
H Z'IC +3 O t~
N-methyl sphinganine having the structure (4):
WO 94/23694 2159201 PCT/EP94/01117
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r\ (4)
The acyl substituent is suitably a C1_16 acyl group preferably
acetoxy. Conveniently, the pathway intermediate may be
acylated at teh N-atom and one or more of hte oxygen atom
present. The alkyl substituent is suitably C,_,b, preferably
C,-4, especially methyl. The nitrogen atom may be mono- or
di-alkylated.
N,N'-dimethylsphinganine having the structure (5):
~3C\ /LH3
H (5)
c=-+
~Z3L~3 c'"'
Particular preferred derivatives of sphingosine are
-acetylsphingosine having the structure (6):
G
1i3~ C - ;V
c; a
(6)
la .2 1C,3 ~:H =
N-methyl sphingosine having the structure (7):
~ WO 94/23694 2 15 9 2 0 1 PCT/EP94/01117
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(7)
- C'=e~
Y1~7C..'~ L7r1
N,N1-dimethylsphingosine having the structure (8):
ti (8)
c7.k
Other particularly preferred derivatives of
phytosphingosine are:
N-acetylphytosphingosine having the structure (9):
C,
tl
H3L-C-N.1
Ue~
(9)
H2ic cl,
o,m
N-methyl phytosphingosine having the structure (10):
6
WO 94/23694 PCT/EP94/01117
~~.~9 4a
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C> ek (10)
cl~a
and N,N' dimethyl phytosphingosine having the structure
(11)
G~ (11)
-{tl C13
It is to be understood that the above structures (2) to
(11) are illustrative of derivatives of ceramide pathway
intermediates which are useful in accordance with the
invention and that there are many other derivatives that
fit structure (1) that are also useful.
As has been explained earlier, it is also possible to
employ precursors of ceramide synthesis that occur proximal
to the rate limiting step in the ceramide pathway. These
precursors are preferably palmitoyl CoA and serine which
together are converted to 3-ketosphinganane by the enzyme
serine palmitoyltransferase.
The amount of a selected ceramide pathway intermediate
including precursors thereof or mixture thereof that should
be incorporated in the composition according to the
invention is from 0.0001 to 10%, preferably from 0.1 to 5%
and ideallv from 0.05 to 2% by weiaht of the composition.
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THE COSMETICALLY ACCEPTABLE VEHICLE
The composition according to the invention also comprises
a solid, semi-solid or liquid cosmetically and/or
physiologically acceptable vehicle, to enable the ceramide
pathway intermediate to be conveyed to the skin at an
appropriate dilution. The nature of the vehicle will
depend upon the method chosen for topical administration of
the composition. The vehicle can itself be inert or it can
possess physiological or pharmaceutical benefits of its
own.
The selection of a vehicle for this purpose presents a wide
range of possibilities depending on the required product
form of the composition. Suitable vehicles can be
classified as described hereinafter.
It should be explained that vehicles are substances which
can act as diluents, dispersants, or solvents for the
ceramide pathway intermediate which therefore ensure that
they can be applied to and distributed evenly over the
skin, hair or nails at an appropriate concentration. The
vehicle is preferably one which can aid penetration of the
ceramide pathway intermediate into the skin to enable it
more readily to influence the skin condition.
Compositions according to the invention can include water
as a vehicle, and/or at least one cosmetically acceptable
vehicle other than water.
Vehicles other than water can include liquid or solid
= emollients, solvents, humectants, thickeners and powders.
Examples of each of these types of vehicle, which can be
used singly or as mixtures of one or more vehicles, are as
follows:
Emollients, such as stearyl alcohol, glyceryl
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monoricinoleate, mink oil, cetyl alcohol, isopropyl
isostearate, stearic acid, isobutyl palmitate, isocetyl
stearate, oleyl aicohol, isopropyl laurate, hexyl laurate,
decyl oleate, octadecan-2-ol, isocetyl alcohol, eicosanyl
alcohol, behenyl alcohol, cetyl palmitate, silicone oils
such as dimethylpolysiloxane, di-n-butyl sebacate,
isopropyl myristate, isopropyl palmitate, isopropyl
stearate, butyl stearate, polyethylene glycol, triethylene
glycol, lanolin, cocoa butter, corn oil, cotton seed oil,
olive oil, palm kernel oil, rapeseed oil, safflower seed
oil, evening primrose oil, soybean oil, sunflower seed oil,
avocado oil, sesame seed oil, coconut oil, arachis oil,
castor oil, acetylated lanolin alcohols, petroleum jelly,
mineral oil, squalane, squalene, butyl myristate,
isostearic acid, palmitic acid, isopropyl linoleate, lauryl
lactate, myristyl lactate, decyl oleate, myristyl
myristate;
Propellants, such as propane, butane, isobutane, dimethyl
ether, carbon dioxide, nitrous oxide;
Solvents, such as ethyl alcohol, methylene chloride,
isopropanol, acetone, ethylene glycol monoethyl ether,
diethylene glycol monobutyl ether, diethylene glycol
monoethyl ether, dimethyl sulphoxide, dimethyl formamide,
tetrahydrofuran;
Powders, such as chalk, talc, fullers earth, kaolin,
starch, gums, colloidal silica sodium polyacrylate, tetra
alkyl and/or trialkyl aryl ammonium smectites, chemically
modified magnesium aluminium silicate, organically modified
montmorillonite clay, hydrated aluminium silicate, fumed
silica, carboxyvinyl polymer, sodium carboxymethyl
cellulose, ethylene glycol monostearate, ethylene glycol
distearate;
The cosmetically acceptable vehicle will usually form from
WO 94/23694 i: 1,., ~ 9 2 0 1 PCT'/EP94/01117
~
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to 99.9990, preferably from 10 to 9901 and most
preferably from 50 to 9926 by weight of the composition, and
can, in the absence of other cosmetic adjuncts, form the
balance of the composition.
5
Ceramide Pathway Adjuncts
In the biosynthesis of ceramide as hereinbefore described,
the provision of ceramide pathway adjuncts in the
10 composition according to the invention is preferable.
For example, the ceramide pathway intermediates and
precursors thereof are preferably accompanied by saturated
or unsaturated, straight or branched chain fatty acids or
their esters, particularly their coenzyme A derivatives, or
adenosine monophosphate derivatives, or preferably alpha-,
beta or omega hydroxylated straight or branched chain fatty
acids and esters thereof, especially the omega hydroxy
linoleoyl ester.
The amount of selected ceramide pathway adjuncts, when
employed, can be similar to that of the ceramide pathway
intermediate or precursor thereof.
OPTIONAL SKIN BENEFIT MATERIALS AND COSMETIC ADJUNCTS
Penetration Enhancer
The composition according to the invention can also
optionally comprise a penetration enhancer which can
potentiate the benefit of the ceramide pathway intermediate
= or precursor thereof by improving its delivery through the
stratum corneum to its site of action in the epidermis.
The penetration enhancer can accordingly function in a
variety of ways. It can for example, improve the
distribution of the ceramide pathway intermediate on the
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skin surface or, it can increase its partition into the
skin from the composition when applied topically, so aiding
its passage to its site of action. Other mechanisms
enhancing the benefit of the ceramide pathway intermediate
may also be involved.
Examples of penetration enhancers include:
2-methyl propan-2-ol
Propan-2-ol
Ethyl-2-hydroxypropanoate
Hexan-2,5-diol
POE(2) ethyl ether
Di(2-hydroxypropyl) ether
Pentan-2,4-diol
Acetone
POE(2) methyl ether
2-hydroxypropionic acid
2-hydroxyoctanoic acid
Propan-l-ol
1,4 Dioxane
Tetrahydrofuran
Butan-l,4-diol
Propylene glycol dipelargonate
Polyoxypropylene 15 stearyl ether
Octyl alcohol
POE ester of oleyl alcohol
Oleyl alcohol
Lauryl alcohol
Dioctyl adipate
Dicapryl adipate
Diisopropyl adipate =
Diisopropyl sebacate
Dibutyl sebacate
Diethyl sebacate
Dimethyl sebacate
Dioctyl sebacate
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Dibutyl suberate
Dioctyl azelate
Dibenzyl sebacate
Dibutyl phthalate
Dibutyl azelate
Ethyl myristate
Dimethyl azelate
Butyl myristate
Dibutyl succinate
Didecyl phthalate
Decyl oleate
Ethyl caproate
Ethyl salicylate
Isopropyl palmitate
Ethyl laurate
2-ethyl-hexyl pelargonate
Isopropyl isostearate
Butyl laurate
Benzyl benzoate
Butyl benzoate
Hexyl laurate
Ethyl caprate
Ethyl caprylate
Butyl stearate
Benzyl salicylate
Dimethyl sulphoxide
N,N-Dimethyl acetamide
N,N-Dimethyl formamide
2-Pyrrolidone
1-Methyl-2-pyrrolidone
5-Methyl-2-pyrr_olidone
1,5-Dimethyl-2-pyrrolidone
i-Ethyl-2-pyrrolidone
Phosphine oxides
Sugar esters
Tetrahydrofurfural alcohol
Urea
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Diethyl-m-toluamide, and
1-Dodecylazacyloheptan-2-one
The amount of penetration enhancer, when employed in
accordance with the invention, will normally be from 0.1 to
50%, preferably from 0.5 to 25% and most preferably from
0.5 to 10% by weight of the composition.
A particularly convenient form of the composition according
to the invention is an emulsion, in which case an oil or
oily material will normally be present, together with an
emulsifier to provide either a water-in-oil emulsion or an
oil-in-water emulsion, depending largely on the average
hydrophillic-lyophilic balance (HLB) of the emulsifier
employed.
Oil or Oily Material
The composition according to the invention can optionally
comprise one or more oils or other materials having the
properties of an oil.
Examples of suitable oils include mineral oil and vegetable
oils, and oil materials, such as those already proposed
herein as emollients. Other oils or oily materials include
silicone oils, both volatile and non-volatile, such as
polydimethyl siloxanes.
The oil or oily material, when present for the purposes for
forming an emulsion, will normally form up to 90%,
preferably from 10 to 80o by volume of the composition.
Emulsifier
The composition according to the invention can also
optionally comprise one or more emulsifiers the choice of
which will normally determine whether a water-in-oil or
CA 02159201 2005-05-03
WO'94/23694 PCT/EP94/01117
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and oil-in-water emulsion is formed.
When a water-in-oil emulsion is required, the chosen
emulsifier or emulsifiers should normally have an average
HLB value of from 1 to 6. When an oil-in-water emulsion is
required, a chosen emulsifier or emulsifiers should have an
average HLB value of >6.
Examples of suitable emulsifiers are set below in Table 1
in which the chemical name of the emulsifiers is given
together with an example of a trade name as commercially
available, and the average HLB value.
TAFLE 1
----------------------------------------------------------
Chemical Name Trade Mark HLB Value
of Emulsifier
----------------------------------------------------------
Sorbitan trioleate Arlacel 85 1.8
Sorbitan tristearate Span 65 2.1
Glycerol monooleate Aldo MD 2.7
Glycerol monostearate Atmul 84S 2.8
Glycerol monolaurate Aldo MC 3.3
Sorbitan sesquicfleate Arlacel 83 3.7
Sorbitan monooleate Arlacel 80 4.3
Sorbitan monostearate Span 60 4.7
Poloxyethylene (2)
stearyl ether Brij 72 4.9
Poloxyethylene sorbitol
beeswax derivative G-1702 5
PEG 200 dilaurate Emerest 2622 6.3
Sorbitan monopalmitate Arlacel 40 6.7
Polyoxyethylene (3.5)
nonyl phenol Emulgen 903 7.8
PEG 200 monostearate Tegester PEG
200 MS 8.5
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Sorbitan monolaurate Arlacel 200 8.6
PEG 400 dioleate Tegester PEG
400-DO 8.8
Polyoxyethylene (5)
monostearate Ethofat 60-16 9.0
Polyoxyethylene (4) sorbitan
monostearate Tween 61 9.6
Polyoxyethylene (4) lauryl
ether Brij 30 9.7
Polyoxyethylene (5) sorbitan
monooleate Tween 81 10.0
PEG 300 monooleate Neutronyx 834 10.4
Polyoxyethylene (20)
sorbitan tristearate Tween 65 10.5
Polyoxyethylene (20)
sorbitan trioleate Tween 85 11.0
Polyoxyethylene (8)
monostearate Myrj 45 11.1
PEG 400 monooleate Emerest 2646 11.7
PEG 400 monostearate Tegester.PEG 400 11.9
Polyoxyethylene 10
monooleate Ethofat 0/20 12.2
Polyoxyethylene (10)
stearyl ether Brij 76 12.4
Polyoxyethylene (10)
cetyl ether Brij 56 12.9
Polyoxyethylene (9.3)
octyl phenol Triton X-100 13.0
Polyoxyethylene (4)
sorbitan monolaurate Tween 21 13.3
PEG 600 monooleate Emerest 2660 13.7
PEG 1000 dilaurate Kessco 13.9
Polyoxyethylene sorbitol
lanolin derivative G-1441 14.0
Polyoxyethylene (12)
lauryl ether Ethosperse LA-12 14.4
PEG 1500 dioleate Pegosperse 1500 14.6
~ WO 94/23694 ~ 1~ r. 9 2 0 1 PCTIEP94/01117
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Polyoxyethylene (14)
laurate Arosurf HFL-714 14.8
Folyoxyethylene (20)
sorbitan monostearate Tween 60 14.9
Polyoxyethylene 20 sorbitan
monooleate Tween 80 15.0
Polyoxyethylene (20)
stearate Myrj 49 15.0
Polyoxyethylene (20)
stearyl ether Brij 78 15.3
Polyoxyethylene (20)
sorbitan monopalmitate Tween 40 15.6
Polyoxyethylene (20) cetyl
ether Brij 58 15.7
Polyoxyethylene (25)
oxypropylene
monostearate G-2162 16.0
Polyoxyethylene (20)
sorbitol monolaurate Tween 20 16.7
Polyoxyethylene (23)
lauryl ether Brij 35 16.9
Polyoxyethylene (50)
monostearate Myrj 53 17.9
PEG 4000 monostearate Pegosperse 4000
MS 18.7
-----------------------------------------------------------
The foregoing list of emulsifiers is not intended to be
limiting and merely exemplifies selected emulsifiers which
are suitable for use in accordance with the invention.
It is to be understood that two or more emulsifiers can be
employed if desired.
The amount of emulsifier or mixtures thereof, to be
incorporated in the composition of the invention, when
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appropriate is from 1 to 50%, preferably from 2 to 20% and
most preferably from 2 to 10 s by weight of the composition.
Silicone Surfactant
The composition of the invention can also optionally
comprise a high molecular weight silicone surfactant which
can also act as an emulsifier, in place of or in addition
to the optional emulsifier(s) already mentioned.
The silicone surfactant is a high molecular weight polymer
of dimethyl polysiloxane with polyoxyethylene and/or
polyoxypropylene side chains having a molecular weight from
10,000 to 50,000.
The dimethyl polysiloxane polymer is conveniently provided
as a dispersion in a volatile siloxane, the dispersion
comprising, for example, from 1 to 20k by volume of the
polymer and from 80 to 99% by volume of the volatile
siloxane. Ideally, the dispersion consists of a 10% by
volume of the polymer dispersed in the volatile siloxane.
Examples of the volatile siloxanes in which the
polysiloxane polymer can be dispersed include polydimethyl
siloxane (pentamer and/or hexamer).
A particularly preferred silicone surfactant is
cyclomethicone and dimethicone copolyol, such as DC 3225C
Formulation Aid available from DOW CORNING. Another is
laurylmethicone copolyol, such as DC Q2-5200, also
available from Dow Corning.
The amount of silicone surfactant, when present in the
composition will normally be up to 25%, preferably from 0.5
to 15% by weight of the emulsion.
WO 94/23694 PCT/EP94/01117
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Retinoids
The composition according to the invention optionally can
also comprise a retinoid, such as retinoic acid or retinol
(Vitamin A) and/or derivative thereof, further to enhance
the benefits to skin of the ceramide pathway intermediate.
In addition to retinol itself, examples of derivatives of
retinol include:
Retinyl acetate
Retinyl butyrate
Retinyl propionate
Retinyl octanoate
Retinyl laurate
Retinyl palmitate
Retinyl oleate
Retinyl linoleate, and
Retinyl linolenate.
The amount of retinoid, when present in the composition
according to the invention is from 0.01 to 10= s and
preferably 0.1 to 5% by weight of the composition.
Tocopherol
The composition according to the invention optionally can
also comprise a tocopherol (vitamin E group) as an
antioxidant for the retinoid, when present in the
composition, and to limit oxidative damage to skin. The
vitamin E group comprises a-tocopherol, 0-tocopherol, -y-
tocopherol and b-tocopherol.
The amount of a tocopherol, when present in the composition
according to the invention, is from 0.0001 to 200,
preferably from 0.0001 to 10%- by weight of the composition.
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Water
The composition of the invention can also comprise water,
usually up to 90%~, preferably from 5 to 80% by volume.
Water can function as the cosmetically acceptable vehicle.
OTHER COSMETIC ADJUNCTS
Examples of other cosmetic adjuncts which can optionally be
employed in the composition according to the invention
include preservatives, such as para-hydroxy benzoate
esters; antioxidants, such as butyl hydroxy toluene;
humectants, such as glycerol, sorbitol, 2-pyrrolidone-5-
carboxylate, dibutylphthalate, gelatin, polyethylene,
glycol, preferably PEG 200-600; buffers, such as lactic
acid together with a base such as triethanolamine or sodium
hydroxide; surfactants, such as glycerol ethers; ceramides
of synthetic, animal or plant origin; pseudoceramides;
phospholipids; vitamins, such as 1,25 dihydroxy
cholecalciferol; waxes, such as beeswax, ozokerite wax,
paraffin wax, plant extracts, such as Aloe vera,
cornflower, witch hazel, elderflower, cucumber, thickeners;
activity enhancers; colourants; perfumes; and sunscreen
materials such as ultrafine titanium dioxide and organic
sunscreens such as p-aminobenzoic acid and esters thereof,
ethylhexyl p-methoxycinnamate, 2-ethoxyethyl p-
methoxycinnamate and butyl methoxydibenzoylmethane, and
mixtures thereof.
In a further preferred composition, the ceramide pathway
intermediate is combined with ceramides, pseudoceramides,
polyol fatty acid polyesters, sterols, particularly
cholesterol, galactosyldiacyl-glycerols,
glycosphingolipids, fatty acids and esters thereof and
mixtures thereof and other ingredients, such as mevalonic
acid, hexadecylsuccinic acid monobehenyl ester ethoxylate
(7.3 EO) and/or derivatives thereof to produce a liposomal
WO 94/23694 2159201 PCT/EP94/01117
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dispersion. Preferred ceramide pathway adjuncts include
ceramides, cholesterol, cholesterol pathways intermediates
or precursors thereof such as mevalonic acid and fatty acid
pathway intermediates or precursors thereof such as acetic
acid and malonic acid.
A further preferred composition may also contain in
combination with the ceramide pathway intermediate and
optional additional ingredients disclosed above, an organic
acid component chosen from hydroxy carboxylic acids, such
as alpha, beta and omega hydroxyacids, especially glycolic
acid, lactic acid and 2-hydroxyoctanoic acid, and keto
carboxylic acids, esters thereof and mixtures thereof. It
will be appreciated that the invention includes within its
scope all enantiomers, diasteromers and mixtures thereof.
In yet another preferred composition, the ceramide pathway
intermediate is dissolved in squalene or squalane,
optionally together with ceramides and other ingredients,
such as mevalonic acid and malonic acid and/or derivatives
thereof and formulated with volatile and non-volatile
silicones to produce an anhydrous or nearly anhydrous
single phase system.
Cosmetic adjuncts can form the balance of the composition.
PRESERVATION OF THE COMPOSITION
The composition according to the invention is preferably
preserved in such a manner that it will enjoy an extended
shelf life following manufacture and prior to sale and use.
Ideally the composition will have an indefinite shelf life.
It is accordingly apparent that the ceramide pathway
intermediate is likely to be prone to attack by bacteria,
moulds and fungi and other microbial influences,
particularly at pH values near that of the skin that
characterise the preferred composition. The shelf-life of
WO 94/23694 24 - PCT/EP94/01117
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the composition can therefore be unacceptably short due to
the biodegradation of the precursor unless steps are taken
to preserve the composition.
In order to be preserved, the composition should preferably
be free, or substantially free, from viable microbial
contaminants that are capable of resulting in microbial
spoilage of the composition, and/or biodegradation of the
precursor prior to topical application of the composition
to mammalian skin or hair. It is to be understood,
however, that the invention is also concerned with
compositions, as herein defined, which may contain viable
but dormant microorganisms, such as bacterial spores,
provided that the conditions of preservation do not result
in substantial proliferation of the microorganisms prior to
use of the composition.
Examples of the methods that can be employed to achieve
preservation of the composition, includes the following:
(i) Sterilisation
The composition according to the invention can be preserved
by sterilisation to remove or kill substantially all viable
microbial contaminants. This can be achieved for example
by irradiation using a lethal dose of gamma rays, by heat
sterilisation or by ultrafiltration using techniques that
are well established in the pharmaceutical industry.
(ii) Chemical Preservative
The composition according to the invention can also be
preserved by including in it a chemical preservative which
functions to prevent the growth of or kill bacteria, fungi
or other microorganisms.
Examples of chemical preservatives include ethanol, benzoic
WO 94/23694 2 1 D 9201 PCT/EP94/01117
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acid, sodium benzoate, sorbic acid, potassium sorbate,
sodium propionate and the methyl, ethyl, propyl and butyl
esters of p-hydroxybenzoic acid. The amount of chemical
preservative that can be incorporated in the composition
according to the invention will generally be from 0.05 to
50, preferably from 0.1 to 2%- by weight, the amount chosen
being sufficient to arrest microbial proliferation.
(iii) Water activity depressants
The composition according to the invention can also be
preserved by the inclusion of a water activity depressant
such as glycerol, propylene glycol, sorbitol, sugars and
salts, for examples alkali metal halides sulphates and
carboxylates. When employing a water activity depressant,
sufficient should be incorporated in the composition
according to the invention to reduce the water activity (aW)
from 1 to < 0.9, preferably to < 0.85 and most preferably
< 0.8, the lowest of these values being that at which
yeasts, moulds and fungi will not proliferate.
PROCESS
The invention also provides a process for preparing a
composition according to the invention which comprises the
steps of mixing an effective amount of a ceramide pathway
intermediate, as herein defined, together with a
cosmetically acceptable carrier for the intermediate.
USE OF THE COMPOSITION
The composition according to the invention is intended
primarily as a product for topical application to human
skin, for maintaining or enhancing the skin barrier
function, particularly by stimulating the synthesis of
ceramides. The composition is particularly useful for
treating dry, ageing or damaged skin to reduce moisture
WO 94/23694 PCT/EP94/01117
% i ,~~~'~ - 26 -
loss, increase stratum corneum flexibility and to enhance
the quality of skin. The composition can also be applied
to the hair or nails.
In use, a small quantity of the composition, for example
from 1 to 5m1, is applied to exposed areas of the skin,
hair or nails, from a suitable container or applicator and,
if necessary, it is then spread over and/or rubbed into the
area to be treated using the hand or fingers or a suitable
device.
PRODUCT FORM AND PACKAGING
The topical skin and/or hair and/or nail treatment
composition of the invention can be formulated as a lotion
having a viscosity of from 4,000 to 10,000 mPas, a fluid
cream having a viscosity of from 10,000 to 20,000 mPas or
a cream having a viscosity of from 20,000 to 100,000 mPas,
or above. The composition can be packaged in a suitable
container to suit its viscosity and intended use by the
consumer.
For example, a lotion or fluid cream can be packaged in a
bottle or a roll-ball applicator or a propellant-driven
aerosol device or a container fitted with a pump suitable
for finger operation. When the composition is a cream, it
can simply be stored in a non-deformable bottle or squeeze
container, such as a tube or a lidded jar.
The invention accordingly also provides a closed container
containing a cosmetically acceptable composition as herein
defined.
EVIDENCE OF EPIDERMAL LIPID (CERAMIDE) BIOSYNTHESIS
The biosynthesis of epidermal lipid, especially ceramides,
can be determined by the method described below.
WO 94/23694 PCTIEP94/01117
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Results of ceramide biosynthesis from sphingosine as the
ceramide pathway intermediate are also given.
In-vitro measurement of epidermal lipid biosynthesis
The stimulatory effect of ceramide pathway intermediates
(CPI) on lipid levels in the epidermis can be quantified by
in-vitro measurements of the level of incorporation of
radiolabelled lipid precursors into epidermal lipids over
relatively short periods of time (24 hours).
1. Method
Punch biopsies (6mm) were taken of full thickness skin
scraped free of subcutaneous fat, and floated dermis side
downwards onto 3ml of culture medium (MCDB 153 without
animal sera, growth factors, or hormones ex Sigma Chemical
Co.), containing radiolabelled lipid precursor (4 Ci/ml of
1-14C acetic acid, sodium salt, 7.4 MBq/ml ex Amersham) and
CPI (in 9601 v/v ethanol vehicle). Following a 24 hour
incubation at 37C in air (Harvard/LTE incubator), epidermis
was isolated from the dermis by incubation in 10mM
ethylenediaminetetraacetic acid solution at 37C for 30
minutes, and placed into 3ml of chloroform:methanol (2:1
v/v) solution for lipid extraction. After 18 hours 0.75m1
of potassium chloride solution (0.88%- w/v) was added with
mixing which after centrifugation produced 2 liquid phases,
an upper aqueous phase, and a lower organic phase
containing the lipids. Beckman ReadySafe scintillation
fluid (4ml) was added to 100 1 aliquots of the organic
phase and counted in a Beckman LS 6000IC scintillation
counter to determine the radioactivity present in the
lipids.
Subsequently 1ml aliquots of the organic phase were
evaporated to dryness under nitrogen, redissolved in 100 1
of chloroform:methanol (2:1 v/v) , and transferred to a high
WO 94/23694 PCT/EP94/01117
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performance thin layer chromotography plate (HPTLC, silica
gel 60, 10x20 cm ex Merck). To resolve the various lipid
classes, the plate was run successively with i)
chloroform:methanol:acetone (76:20:4) to 15 and then 30mm,
ii) chloroform:methanol:acetone (79:12.5:8.5) to 80mm, and
finally iii) chloroform:ethyl acetate:diethyl
ether:methanol (72:20:6:2) to 95mm. After drying at 120C
the plate was saturated with 15m1 of acidic copper sulphate
solution (10% copper sulphate, 8t phosphoric acid) for 1
minute and then the lipids charred by heating to 120C for
1 minute and then 160C for 10 minutes. Lipid bands were
identified using authentic lipid standards (Sigma Chemical
Co.) and were quantified by reflectance densitometric
scanning at 420nm using a Shimadzu CS-9000 flying spot
densitometer. Plates were then placed onto X-ray film
(Amersham Multipurpose MP) in cassettes with intensifying
screens and exposed for 1 to 4 weeks. Films were developed
with a Fuji RGII X-ray film processor and bands quantified
by transmission densitometric scanning at 530nm using a
Shimadzu CS-9000 flying spot densitometer.
Specific activity was calculated by dividing the
radioactivity in each band by the mass of lipid in each
band. Each lipid class was identified using authentic
lipid standards.
2. Statistical Analysis
Mean values were compared using Students t test and
significance was set at the 5s level.
3. Results
The effect of the CPI, sphingosine, on epidermal lipid
biosynthesis on three separate occasions: (Experiments A,
B & C), is shown in Figure 2. An increase in the level of
radiolabelled acetate incorporated into epidermal lipids
WO 94/23694 ~ . = PCT/EP94/01117
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was evident when sphingosine (SPH) was present in the
medium at a level of 0.08mM, producing a consistent 20-25%
increase over control (C, incubated without sphingosine)
after 24 hours, indicating a reproducible stimulation of
epidermal lipid biosynthesis.
The effect of sphingosine on individual lipid classes was
determined using HPTLC. For each lipid class examined
sphingosine at 0.08mM increased the level of incorporation
of radiolabelled acetate in comparison to the control (no
sphingosine). The specific activity (radioactivity/lipid
mass) for each lipid class and the ratio of sphingosine
treated to control is shown in Table 1. The ceramide and
glucosylceramide class showed the greatest increase in
radioactivity incorporation following sphingosine treatment
followed by non-polar lipids and finally phospholipids and
cholesterol sulphate.
Table 1: Effect of sphingosine on the specific activity of
various lipid classes
Lipid Specific Activity (radio activity/mass)
Control Sphingosine Ratio SPH/C
Non-polar 0.031(0.017) 0.066(0.059) 2.13
Ceramide 0.0085(0.0044) 0.029(0.028 3.40
Glucosylceramide 0.045(0.024) 0.136(0.140) 3.02
Chol. sulphate 0.297(0.0762) 0.424(0.150) 1.43
Phospholipid 0.264(0.105) 0.412(0.193) 1.56
Data shown as Mean (standard deviation), n=4 for control
and sphingosine treated.
4. Conclusions
Sphingosine stimulates epidermal lipid biosynthesis,
WO 94/23694 ~1~"9201 PCT/EP94/01117
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increasing the synthesis of all the lipid classes examined,
but particularly the glucosylceramide and ceramide class.
Effect of ceramide percursors on keratinocvte
glucosvlcerainide synthesis
1. Method
Human keratinocytes (ex clonetics were seeded in 6 well
plates and allowed to reach 80% confluency after incubation
in Keratinocyte Growth Medium (KGM ex clonetics, 0.15mM
calcium) at 37C, 5% C02. Fresh medium was added containing
radiolabelled lipid precursor (21LCi/ml of 1-14C acetic
acid, sodium salt, 7.4 MBq/ml ex Amersham) and CPI (in 96%
v/v ethanol vehicle) and incubated for 24 hours as above.
Cells were harvested by scraping, lyophilized, and lipids
extracted using 3ml of chloroform:methanol solution (2:1
v/v) as above. Scintiverse BD scintillation fluid (lOml ex
Fisher) was added to 100 1 aliqouts of the organic phase
and counted in a Beckman LS 6000 IC Scintillation counter
to determine the radioactivity present in the lipids.
Subsequently, 200 1 aliqouts of the organic phase were
applied to icc aminopropyl-silica columns (ex Walters) and
lipid fractions eluted by successive washes of hexane,
chloroform:isopropanol (2:1 v/v), and acetic acid (2% v/v)
in methanol. Radioactivity in each fraction was determined
as above and compared to the total radioactivity of all the
lipids. Furthermore fractions were evaporated to dryness,
redissolved in 20u1 of chloroform:isopropanol (2:1 v/v) and
lipid species present in each fraction identified by high
performance thin layer chromatography as described in HPTLC
for the organ culture experiments.
2. Statistical analysis
Mean values were compared using students t test and
WO 94/23694 PCT/EP94/01117
_ 31 _ aoa d 1
significance was set at the 5a level.
3. Results
The effects of the CPI's sphingosine (SPH),
phytosphingosine (PHYT), and tetraacetylphytosphingosine
(TAPS) on glucosylceramide synthesis (as identified by
HPTLC) is shown in Figure 3. A significant increase above
control (no CPI present) over 24 hours in the proportion of
radiolabelled acetate incorporated into all lipid was
evident when CPI was present in the medium as a level of
0.02mM, indicating a stimulation of keratinocyte
glucosylceramide synthesis. Furthermore, TAPS produced a
significantly higher proportion of radiolabel incorporated
that SPH (Figure 3) indicating that TAPS stimulates the
synthesis of glucosylceramide more than SPH. PHYT was more
effective that SPH, but less effective than TAPS.
Incorporation of LiAid Precursors into
Ceramides/Cerebrosides in Keratinocytes in culture
METHOD
Cell Culture-
Human Keratinocytes were grown to 90% confluency in serum-
free Keratinocyte Growth Medium (KGM, Clonetics
Corporation, San Diego CA) containing 0.15mM calcium.
Cells were incubated with lipid precursors
(phytosphingosine, tetraacetylphytosphingosine and
juniperic acid) dissolved in ethanol for 24h. Following
incubation the cells were harvested in 1.8mL of potassium
chloride solution (0.88% w/v), the lipids extracted using
chloroform:methanol, and the chloroform layer containing
the lipids was anlysed by high performance thin layer
chromatography.
WO 94/23694 PCTIEP94/01117 - 32 -
Lipid Analysis:
The organic phase was dried under nitrogen, and resuspended
in 206 L of chloroform. Different lipid classes were
separated based upon their polarity, using aminopropyl
column chromatography. 200 L of lipid was eluted with
successive washes of hexane, hexane:ethyl acetate (85:15
v/v), and chloroform:isopropanol (2:1 v/v). The fractions
were then evaporated to dryness under nitrogen, and
resuspended in 100gL of chloroform:methanol (2:1 v/v). 1/3
of the lipid was spotted onto high performance thin layer
chromatography (HPTLC) silica gel plates and developed with
an appropriate solvent system. Following lipid separation,
the plate was dipped in a 10% copper sulphate solution,
charred at 165 C for 20 minutes, and quantified via
reflectance densitometry.
Results:
Tetra-acetyl phytosphingosine (TAPS) and phytosphingosine
(PHYT) and juniperic acid (HA) were examined for their
potential to generate phytoceramide 1, a ceramide 1-like
molecule. Due to the extra hydroxyl group present on TAPS
and PHYT compared with sphingosine the ceramide generated
chromatographically migrates between ceramide 1 and 2. As
can be seen from the results TAPS and HA produce
significant amounts of phytoceramide 1. PHYT and HA,
however, produce more of the glucosyl derivatives.
Conclusions:
The combination of a sphingoid-base and an omega hydroxy
fatty acid is capable of being used by keratinocytes to
generate a ceramide 1-like molecule.
Effect of Ceramide I Precursors on Phytoceramide I Levels
WO 94/23694 2159401' PCT/EP94/01117
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Phytoceramide I as Standard
0 of total lipid Deviation
1 Control 0.881 0.048
2 HA 0.816 0.125
3 PHYT 0.659 ** 0.113
4 HA+PHYT 0.357 * 0.070
5 TAPS 1.310 ** 0.204
6 HA+TAPS 3.896 ** 0.863
* P < 0.1
** P < 0.5
Glucosylceramide I Standard
as k of total lipid Deviation
1 Control 1.340 0.527
2 HA 1.526 0.284
3 PHYT 4.217 * 1.000
4 HA+PHYT 5.417 * 0.900
5 TAPS 4.424 * 0.535
6 HA+TAPS 1.577 0.493
* P s 0.05
CLINICAL STUDIES
1. Stratum corneum ceramide levels followincr topical TAPS
treatment
In a one-month clinical study on 10 subjects, a 1%- solution
of tetraacetylphytosphinosine (TAPS) in an
WO 94/23694 PCTIEP94/01117
a1~67
~c~,
- 34 -
ethanol/propylene glycol (1:1) vehicle was applied to the
volar forearm twice daily; an adjacent site on the forearm
was treated with vehicle alone. The dosage amount was
100 1 applied to approximately 35 sq cm. After one month 5 of treatment, a
skin surface biopsy was taken from each
site by tape-stripping with sellotape polyester tape. Each
'biopsy' consisted of eight consecutive tape strips of 2x3
cm each. Stratum corneum material was released from the
tape by sonication in methanol, the methanol was dried off,
and lipids were extracted in 2:1 chloroform:methanol.
Solid phase extraction columns were used for preliminary
lipid separation, followed by high performance thin layer
chromatography (HPTLC) and densitometry for ceramide
quantitation. The delipidized squames were incubated in
protein extraction buffer, and protein content was
determined by Pierce BCA assay.
WO 94/23694 2159201 PCT/EP94/01117
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ng Ceramide/ g Protein
Subject Vehicle-treated TAPS-treated Change
1 34.42 45.21 +
2 36.22 42.09 +
3 59.16 90.61 +
4 44.27 48.02 +
5 25.96 43.31 +
6 44.10 52.51 +
7 52.66 59.85 +
8 80.26 42.20 -
9 75.81 56.43 -
10 40.56 27.82 -
Mean 49.3 50.8
S.D. 17.8 16.6
Paired t-test: Means not significantly different
Subiects showina increased ceramide levels following TAPS
treatment (N=7):
ng Lipid/ug Protein
Treatment Ceramide Cholesterol Fatty Acid
TAPS 54.5 (17.1) 24.2 (10.1) 75.0 (49.1)
Vehicle 42.4 (11.3) 18.5 (4.4) 55.7 (21.1)
Paired t-test p=0.015 n.s.d. n.s.d.
WO 94/23694 PCT/EP94/01117
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Conclusions
These results show that TAPS improves the levels of
ceramides in the stratum corneum but has no effect on
cholesterol and fatty acid levels, indicating its
specificity as a ceramide precursor.
EXAMPLES
The invention is illustrated by the following examples.
Example 1
This example illustrates a high internal phase water-in-oil
emulsion.
A high internal phase water-in-oil emulsion having the
following formulation was prepared:
%- w/w
Fully hydrogenated coconut oil 3.9
phytosphingosine 0.1
Brij 92* 5
Bentone 38 0.5
Preservative 0.3
MgSO47H2O 0.3
Butylated hydroxy toluene 0.01
Perfume qs
Water to 100
*Brij 92 is polyoxyethylene (2) oleyl ether
Example 2
This example also illustrates a high internal phase water-
in-oil emulsion in which the formulation of Example 1 was
prepared but with the following changes:
WO 94/23694 ~159201 PCT/EP94/01117
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i. liquid paraffin replaced the fully hydrogenated
coconut oil, and
ii. partially esterified phytosphingosine having the
structure (11), replaced phytosphingosine per se.
Example 3
This example also illustrates a high internal phase water-
in-oil emulsion in which the formulation of Example 1 was
prepared, except that sphingosine replaced phytosphingosine
per se.
Example 4
This example illustrates an oil-in-water cream.
An oil-in-water cream emulsion having the following
formulation was prepared:
% w w
Mineral oil 4
Sphingosine derivative having the
structure (8) 0.1
Brij 56* 4
Alfol 16RD* 4
Triethanolamine 0.75
Butane-1,3-diol 3
Xanthan gum 0.3
Preservative 0.4
Perfume qs
Butylated hydroxy toluene 0.01
Water to 100
*Brij 56 is cetyl alcohol POE (10)
Alfol 16RD is cetyl alcohol
WO 94/23694 PCT/EP94/01117
38 -
Exam le 5
This example also illustrates an oil-in-water emulsion, in
which the formulation of example 4 was prepared, except 5 that the sphinganine
derivative having the structure (5)
replaced the sphingosine derivative having the structure
(8).
Example 6
This example also illustrates an oil-in-water emulsion in
which the formulation of example 4 was prepared, except
that sphinganine replaced the sphingosine derivative having
the structure (8).
Example 7
This example illustrates an alcoholic lotion according to
the invention.
The lotion had the following formulation:
~ w w
Phytosphingosine derivative
having the structure (10) 0.2
Ethanol 40
Perfume qs
Butylated hydroxy toluene 0.01
Water to 100
Example 8
This example illustrates an alcoholic lotion containing a
sphingosine derivative of the invention.
The lotion had the following formulations:
WO 94/23694 21.59201 PCT/EP94/01117
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w w
Sphingosine derivative
having the structure (6) 0.2
Dimethylsulphoxide 10
Ethanol 40
Antioxidant 0.1
Perfume qs
Water to 100
Examples 9 and 10
The following compositions according to the invention
represent lotions which can be used in the treatment of dry
skin:
w/w
9 10
phytosphingosine 1.5 -
Sphingosine 0.5
having the structure (7)
Perfume 0.1 0.1
Hydroxyethyl cellulose 0.4 0.4
Absolute ethanol 25 25
p-methyl benzoate 0.2 0.2
Sterilised demineralised water to 100 to 100
Examples 11 and 12
The following compositions according to the invention represent
lotions which can be used in the treatment of dry skin:
WO 94/23694 PCT/EP94/01117
40 -
% w w
11 12
sphinganine derivative having
the structure (4) 0.08 - 5 sphinganine - 0.15
Ethanol 10 10
Perfume 0.5 0.5
Distilled water to 100 to 100
Example 13
This example illustrates a high internal phase water-in-oil
emulsion.
A high internal phase water-in-oil emulsion having the following
formulation was prepared:
w/w
Fully hydrogenated coconut oil 3.9
tetraacetyl phytosphingosine (Structure 2) 0.1
Brij 92* 5
Bentone 38 0.5
Preservative 0.3
MgSO47H2O 0.3
Butylated hydroxy toluene 0.01
Perfume qs
Water to 100
*Brij 92 is polyoxyethylene (2) oleyl ether
Example 14
This example illustrates an oil-in-water cream.
An oil-in-water cream emulsion having the following formulation
was prepared:
PCTIEP94/01117
WO 94/23694
- 41 -
% w w
Mineral oil 4
Sphingosine 0.2
Phytosphingosine 0.1
Brij 56* 4
Alfol 16RD* 4
Triethanolamine 0.75
Butane-l,3-diol 3
Xanthan gum 0.3
Preservative 0.4
Perfume qs
Butylated hydroxy toluene 0.01
Water to 100
*Brij 56 is cetyl alcohol POE (10)
Alfol 16RD is cetyl alcohol
Example 15
This example illustrates an alcoholic lotion.
The lotion had the following formulation:
~ w w
Tetraacetyl phytosphingosine 0.5
Sphingosine 0.2
Ethanol 40
Perfume qs
Butylated hydroxy toluene 0.01
Water to 100
Example 16
This example illustrates an alcoholic lotion containing a
sphinganine derivative of the invention.
The lotion had the following formulations:
WO 94/23694 PCTIEP94/01117 0
- 42 -
's w/w
Sphinganine derivative
having the structure (3) 0.2
Dimethylsulphoxide 10
Ethanol 40
Antioxidant 0.1
Perfume qs
Water to 100
Examples 17 and 18
The following compositions according to the invention represent
lotions which can be used in the treatment of dry skin:
%- w w
N-acetyl phytosphingosine (Structure 9) 1.5
Perfume 0.1
Hydroxyethyl cellulose 0.4
Absolute ethanol 25
p-methyl benzoate 0.2
Sterilised demineralised water to 100
