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CHOLESTEROL SULFATE AND AMINO SUGAR COMPOSITIONS 
FOR ENHANCEMENT OF STRATUM CORNEUM FUNCTION 

FIELD OF THE INVENTION 

The present invention relates to cosmetic compositions. More specifically the invention relates to 
topical compositions containing a combination of cholesterol sulfate and an amino sugar for the treatment 
of skin. 

BACKGROUND OF THE INVENTION 

The stratum corneum represents the major chemical and physical barrier between the body and the 
environment. It is formed by a process in the epidermis which involves the transformation of germinative 
cells into terminally differentiated cells; the process of transformation takes approximately one month, by 
which time the terminally differentiated cells are shed from the skin surface. The cells at the outermost 
layer of the skin, which regularly slough off, are replaced by cells that generate originally at the basal layer 
of the epidermis and rise up to the outer surface as other newer cells are generated at the basal layer. As 
these cells migrate from the basal layers up to the outer levels of the skin, these cells produce and 
accumulate keratin, to the point at which there is virtually no cytoplasm remaining; at this point the cell 
dies and sheds off of the skin. The shed layer of dead skin reveals a fresh layer of healthy skin, another 
phalanx of migrating epidermal cells. The thickness of the stratum corneum and epidermis, in general, 
varies in different regions of the body, and plays a role in the rate of shedding dead skin layers. 

The cornified barrier performs a number of functions. As mentioned, a particularly important 
aspect of its presence is as a physical barrier, between the deeper layers of the skin as well as the internal 
organs and the environment. Prevention or attenuation of penetration of UV radiation, as well as other 
harmful stimuli such as free radicals, to the deeper skin layers are examples of the critical aspect of this 
skin layer. The skin acts as a permeability barrier and therefore, the skin functions to prevent the loss of 
body water to the external environment. Unfortunately, as with many other skin functions, the capacity of 
the stratum corneum to cyclically generate new layers of the skin progressively diminishes with age. The 
stratum corneum is a densely packed structure of intracellular fibrous elements that are hydrophilic and 
able to trap water. The intercellular space is filled with lipids that provide a diffusion pathway to channel 
substances with low solubility in water. Thus, the skin barrier of the stratum corneum resembles a brick 
wall the corneocytes are the bricks and the intercellular matrix is the mortar. The turnover rate of the 

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stratum corneum is considerably decreased in older individuals, however, and the cornified layer gradually 
becomes thinner, thereby reducing the efficacy of this physical barrier and making it easier for harmful 
stimuli such as UV rays to penetrate the skin barrier. This in turn leads to UV-damage to the dermal layers 
of the skin, degradation of collagen and elastin, and finally, wrinkling and skin atrophy. These are 
examples of a skin barrier that is compromised and unhealthy. Moreover, the thinning of the stratum 
corneum can enhance the visibility of wrinkling and atrophy, the cause of which is rooted in the dermis. 

To improve the signs of wrinkling and atrophy, exfoliation is a commonly used technique whereby 
dead skin cells are physically removed or sloughed from the skin surface by human intervention. An 
exfoliant breaks the bond holding individual squames together and allows them to detach and shed. This 
technique promotes a healthier and more youthful appearance to the skin. The skin cells are held together 
by a desmosome bond between corneocytes at the skin surface. The bond delays the desquamation of the 
skin cells, reinforces the barrier, and prevents water loss. The physical action of removing dead skin cells 
can be achieved by active agents as well as by manual scrubbing action. Several compounds are known to 
be useful as exfoliants such as for example, alpha hydroxy acid ("AHA"), beta hydroxy acid ("BHA"), 
retinoic acid ("retin A"), and enzymes. In addition, it is disclosed in PCT Patent Application No. WO 
US00/1 1203, that N-acetyl-D-glucosamine is useful as an exfoliant. 

In addition to the exfoliative process that improves the smoothness of the skin surface, the skin 
cells, before they die and slough off, need to maintain a cohesiveness to support the thickness and firmness 
of the skin. A thicker stratum corneum helps to prevent or retard the appearance of fine lines and wrinkles. 
Protease inhibitors are known to prevent the breakage of the desmosome bond between the corneocytes at 
the skin surface. In addition, cholesterol sulfate is also known to retard desquamation in the stratum 
corneum of the skin, as disclosed in PCT Publication No. WOOO/45786, the contents of which are 
incorporated herein. 

Notwithstanding the obvious importance of the stratum corneum in maintaining a healthy youthful 
appearance of the skin, rehabilitation and maintenance of the dermis has been a major cosmetic focus in 
preventing the appearance of aging; relatively little attention has been paid to developing a cosmetic means 
for maintaining a fairly consistent level of stratum corneum function into old age. Producing one cosmetic 
composition for the skin that achieves a variety of interdependent activities in the skin to maintain the 
health and beauty of the skin surface (i.e., a healthy skin barrier) is a desirable and beneficial need. 
Further, the availability of alternative methods to exfoliate different skin types and meet various individual 
skincare needs of consumers is beneficial. Thus, there is a continued effort to find additional alternative 



ways of aiding the sloughing ability of the skin and promoting the health of various types of skin. This is, 
therefore, an object of the present invention. 

Summary of the Invention 

The invention relates to a composition for topical application to the skin that is a mixture of an 
effective amount of an exfoliant and cholesterol sulfate. The exfoliant is an amino sugar selected from the 
group consisting of N-acetyl-D-glucosamine, N-acetylgalactosamine, and combinations thereof. The 
cholesterol sulfate is present in the composition in an amount of between about 0.05 to about 5.00 percent 
and the exfoliant is present in an amount of about 0. 1 to about 10.0 percent. The combination of these two 
components enhances the protective barrier of the skin and repairs the barrier if it has been damaged by 
chronological aging or other environmental factors. Thus, the present invention also includes a method of 
improving or maintaining a healthy skin barrier by applying to the skin an effective amount of the mixture 
of two components. Because the skin barrier can be improved or maintained, another method of the present 
invention is treating or preventing damage to the skin, when the damage is associated with a reduction or a 
loss of skin barrier function, by topically applying to the skin a mixture of the two components. 

Detailed Description of the Invention 

The present invention, in its various embodiments, is predicated on the surprising observation that 
effective amounts of cholesterol sulfate, which is known to reduce desquamation, and an exfoliant, can be 
combined in a mixture to improve the quality of the protective barrier of the skin. As mentioned above, 
cholesterol sulfate enhances the cohesion of the stratum comeurn resulting in a more prolonged retention of 
the layers of the stratum comeurn. Further, it has been observed that application of cholesterol sulfate to 
skin cells results in a distinct, dose-dependent, increase in the thickness of the layers of the stratum 
corneum. The observation is important for a number of different applications; a particularly significant 
application is in the maintenance of the texture of older skin. Thus, application of cholesterol sulfate to 
retard desquamation and maintain stratum comeurn thickness treats and maintains older, t hinn i ng skin. A 
thicker stratum comeurn aids in preventing or retarding the appearance of fine lines and wrinkles which so 
frequently characterize thinning skin. At the same time, the enhanced cohesion of the stratum comeurn 
results in an effective strengthening of the protective lipid barrier naturally provided therein. However, the 
skin surface can become rough and feel tough because dead skin cells at the surface of the skin buildup on 
the skin surface. As a result the skin can look dry and flaky because it is unhealthy. 



A current and common means of enhancing smoothness of the skin is to encourage exfoliation. 
However, exfoliation necessarily involves a high rate of turnover of the stratum corneum, and consequent 
thinning of this layer of the skin. While not an issue in youthful skin, desquamation in older skin can, in 
some cases, simply exacerbate a problem already established, namely, the natural thinning observed with 
age. Therefore, it is not known to use an exfoliant in combination with cholesterol sulfate when it is 
desired to thicken and strengthen the protective barrier of the skin. The present invention of improving or 
protecting the barrier of the stratum corneum is surprising because it is achieved with a combination of two 
components having opposing activities. One component acts to desquamate the skin and the other 
component acts to retard desquamation. However, a balanced nurturing result is achieved with the present 
invention on the skin barrier of the stratum corneum. 

The discovery that two opposing components do not cancel each other out in a composition for the 
skin was unexpected. In addition, the beneficial effect can be appreciated by individuals of all ages. The 
stratum corneum represents an important physical barrier between the environment and the deeper skin 
layers as well as the internal organs. The present invention produces a thicker layer of the stratum corneum 
while also promoting the cycle of removing dead skin cell layers of the stratum corneum.. Therefore, 
moisture is retained in the skin. The skin is firmer, lines and wrinkles are less apparent, and the skin 
surface is soft and smooth. Maintaining the health of the skin is a complex and integrated process requiring 
a delicate balance between promotion of proliferation, support of differentiation, and regulating 
desquamation. For example, increased proliferation activity of the epidermis is known to be the cause or a 
factor in skin disorders such as psoriasis, ichthyoses, and essential fatty acid deficiency. While not wishing 
to be bound by any theory it is believed that the combination of these two components work on different 
skin surface layers to produce a positive result on the skin barrier function. The ability to achieve these 
integrated results in one composition containing two components that act in opposite ways has not 
heretofore been known. 

To achieve this effect, one component of the mixture in the present invention is cholesterol sulfate 
or salts thereof The salts can be sodium, potassium, magnesium, or other similar salts. Preferably, the 
salt is potassium cholesterol sulfate. The other component of the mixture is the exfoliant and can be an 
amino sugar such as N-acetyl-D-glucosamine, ^acetylgalactosamine, or a combination of the two. 
Preferably, the amino sugar is N-acetyl-D-glucosamine. Although the upper limit is not critical, cholesterol 
sulfate is effective in the mixture when provided in an amount of from about 0.05 to about 5.00 percent, 
preferably 0.1 to about 2.0 percent, and most preferably about 0.04 to about 1.00 percent, all by weight of 



the total composition. The amino sugar is present in the mixture in an amount of about 0. 1 to about 10.0 
percent, preferably about 0.5 to about 8.0 percent of the weight of the composition; and more preferably 
about 0.8 to about 2.0 percent of the weight of the composition. Similarly, the upper limit of the amounts 
of the exfoliant is not critical. As used herein the effective amounts of cholesterol sulfate and the exfoliant 
means amounts of each of the two components sufficient to maintain a healthy skin barrier, or to enhance 
or repair the skin barrier at least about 10 percent over a formula without the two components in 
combination, preferably about 20 percent over the formula without the two components, and more 
preferably about 50 percent over the formula without the two components. The maintenance of a healthy 
skin barrier, or the enhancement or repair of the skin barrier can be measured by detennining the 
transepidermal water loss after a barrier challenge, or other standard methods known to one skilled in the 
art. 

The combination of these two components can be applied in any type of cosmetically or 
pharmaceutically acceptable vehicle for topical application with which the active component is compatible, 
§ e.g., a gel, a cream, a lotion, an ointment, a mousse, a spray, a solid stick, a powder, a suspension, a 
^ dispersion, and the like. Techniques for formulation of various types of vehicles are well known to those 
j skilled in the art, and can be found, for example, in Chemistry and Technology of the Cosmetics and 
! j Toiletries Industry, Williams and Schmitt, eds., Blackie Academic and Professional, Second Edition, 1996, 
and Remington's Pharmaceutical Sciences, 18th Edition, 1990, the contents of which are incorporated 
herein by reference. 

In addition to its use in therapeutic products, the mixture of cholesterol sulfate and amino sugar 
can also be beneficially added to color cosmetic products. In this regard, effective amounts of the mixture 
3 are added to makeup formulations such as foundations, blushes, lipsticks and glosses, eyeliners, 
eyeshadows, and the like. A particular advantage may be obtained with such formulations, in that the 
retardation of desquamation may enhance makeup retention on the skin to which it is applied but the 
sloughing activity softens the skin and reduces the appearance of fine lines and wrinkles. 

In all formulations in which enhancement of the protective barrier of the skin is involved, it is 
preferred that the mixture of cholesterol sulfate and the exfoliant be combined with other components of the 
naturally occurring skin barrier. In a particularly preferred embodiment, the cholesterol sulfate is 
combined with at least one fatty acid and cholesterol. Fatty acids may be up to 24 carbon atoms in length. 
Examples of fatty acids include butyric acid, caproic acid, octanoic acid, decanoic acid, dodecanoic acid. 



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tetradecanoic acid, palmitic acid, stearic acid, linoleic acid and oleic acid. A preferred fatty acid is linoleic 
acid. 

In addition to the two components of the present invention, the compositions can also include one 
or more ceramides. The ceramides to be employed in the compositions of the invention are sphingolipids, 
having a sphingosine or related molecule backbone with fatty acids or a-esterified fatty acids linked to an 
amino group on the sphingosine, and in some cases, with saccharide moieties linked to the terminal 
hydroxyl of the sphingosine. In particular, the compositions may contain o-esterified ceramides or 
acylceramides, cerebrosides, o-esterified cerebrosides, or acylglycosyl sphingolipids. Particularly 
preferred types of ceramides for the present compositions are ceramide III and cerebrosides. Other similar 
lipids that can be included in the compositions of the present invention are, for example, wheat bran 
extract, olive extract, wheat germ extract, barley extract, and other similar lipid containing extracts. 

In those compositions in which cholesterol sulfate is combined with these lipids, the lipid 
components each can be used in an amount of from about 0.01 to 1.00 percent, preferably 0.02 to about 
3 0.50 percent, most preferably about 0.02 to about 0. 10 percent, all by weight of the total composition. In a 
particularly preferred embodiment, the cholesterol sulfate, the fatty acid, cholesterol, and the lipid 
components are premixed before adding to the exfoliant in the composition. It will be understood from the 
jj foregoing that the lipid component need not be pure lipid, but rather may be natural extracts containing one 
or more desirable lipids, and used in amounts consistent with attaining the concentrations recommended 
above. 

In another embodiment of the present invention, the compositions contain sclareolide and white 
birch. It has been reported in U.S. Patent No. 6,150,381 that sclareol-like and sclareolide-like compounds 
are useful in treating microbial infections. Sclareol is an important bioactive diterpene obtained from clary 
sage (Salvia sclarea Labiatae) The clary sage extract is believed to contain about 70 percent sclareol. In 
addition, another useful species of the genus Salvia, is Salvia officinalis L. Methods of using Salvia 
officinalis in an external ointment have been disclosed in U.S. Patent No. 5,660,831 for controlling high 
blood-pressure, circulatory problems, and incomplete cicatrization of wounds. The characteristic 
constituents of Salvia officinalis (Dalmation sage) are believed to be alpha- (about 30 to 40 percent) and 
beta- thujone (about 10 percent). As used in the present invention, the source of sclareolide can be derived 
naturally from either species of Salvia, or can be synthetically obtained as substantially pure sclareolide. 
Substantially pure sclareolide contains greater than 70 percent sclareolide. In the composition, sclareolide 
is effective in an amount of about 0.001 to about 5.000 percent by weight of the total composition. 



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The use of white birch as a protease inhibitor in combination with a cell differentiation enhancer 
has been disclosed in copending U.S. Application Serial No. 09/554984, the contents of which are 
incorporated herein. Although the presence of cholesterol sulfate provides the surprising ability to retard 
desquamation in the presence of the exfoliant additional retardation of desquamation can be provided cell 
differentiation enhancers, such as, for example white birch. Other useful protease inhibitors include, but 
are not limited to, triterpenoid-containing extracts and refined compounds, for example, silver birch bark 
extract Boswellia extract, bearberry extract, Centella asiatica extract, or Pygeum (Pninus) africanum 
extract, and individual protease inhibitor compounds that may be present in these extracts, including 
betulinol (betulin), betulinic acid, boswellic acid, ursolic acid, oleanolic acid, oleanol, asiaticoside, asiatic 
acid, and madagassic acid; phenolic-containing extracts, such as green tea extracts and apple extracts, and 
compounds contained therein, such as EGCG, ECG, catechins, phenylpropanoids, and phloretin; protein- 
based extracts, such as soy protein, or egg protease inhibitors, or other phytosterol sulfates. The preferred 
protease inhibitor is white birch bark extract. If an additional cell differentiation enhancer is incorporated 
in the compositions of the present invention, it is present in an amount of about 0.001 to about 1.000 
percent by weight of the total composition, and preferably about 0.05 to about 0.5 percent. 

The present invention may include applying in addition to the two components of the mixture, other 
optional components, including, but are not limited to, additional exfoliants, preservatives, fragrances, 
emollients, antiseptics, antiinflammatories, antibacterials, stabilizers, antioxidants, vitamins, pigments, 
dyes, humectants, surfactants, and propellants, as well as other classes of materials the presence of which 
in the compositions may be cosmetically, medicinally, or otherwise desired. Such components can be found 
in the CTFA International Cosmetics Ingredients Dictionary. Examples of additional exfoliants include but 
are not limited to chemical exfoliants such as AHAs, for example, lactic acid, or BHAs, for example, 
salicylic acid, or physical exfoliants such as pumice, polyethylene, walnut shell powder, and the like, or 
combinations thereof. The amount of additional exfoliants alone or in combination will depend on the type 
of exfoliant and the strength of exfoliation desired. Surfactants that are useful, include but are not limited 
to DEA-oleth-3 phosphate, oleth-3, oleth-5, choleth-24, ceteth-24 s and the like. Preservatives employed, 
may be in an amount of from about 0.01 to about 2.00 percent, preferably from about 0.02 to about 1.50 
percent, of the formula weight. Examples of suitable preservatives are BHA, BHT, phenoxyethanol, ethyl 
paraben, propyl paraben, butyl paraben, or methyl paraben or an isomer, homolog, analog or derivative 
thereof. 



The compositions of the invention are applied to the skin in a manner appropriate to the intended 
end result. For example, for the general promotion of the appearance of young, healthy skin by 
maintenance of the protective barrier of the stratum corneum, the best results are achieved after regular 
application over a period of time. A preferred method of obtaining the benefits of the composition is via 
chronic topical application of a safe and effective amount of a composition containing a mixture of 
cholesterol sulfate and the exfoliant It is suggested as an example that topical application of the 
composition, in an amount of from about 0. 1 mg/cm 2 to 2 mg/cm 2 of skin, be performed from about once 
per week to about 4 or 5 times daily, preferably from about 3 times a week to about 3 times daily, most 
preferably about once or twice per day. By "chronic" application, it is meant herein that the period of 
topical application may be over the lifetime of the user, preferably for a period of at least about one month, 
more preferably from about three months to about twenty years, more preferably from about six months to 
about ten years, more preferably still from about one year to about five years, thereby resulting in the 
treatment or prevention of damage to the skin experiencing a reduction or loss in barrier function. 

When the composition is used in conjunction with a sunscreen, it is applied in the same amounts as 
specified above, on an as-needed basis, to mitigate the effects of exposure to the sun. When used in 
combination with a self-tanner, the composition is also applied in similar amounts, on the portion of the 
skin to be tanned, with repetition, again, on an as-needed basis. 

The invention is further illustrated by the following non-limiting examples: 

Example I 

This example illustrates the ability of cholesterol sulfate and an exfoliant to maintain protective 
barrier of the stratum corneum. 



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Ingredient 


Product 1 


Surfactant 


1.10 


Propylene glycol 


0.20 


Squalane 


0.50 


BUT 


0.10 


Sclareolide 


0.10 


Cholesterol 


0.20 


Potassium Cholesterol sulfate 


0.20 


White birch 


0.20 


Butylene glycol 


1.00 


Chamomile 


0.03 


Bisabolol 


0.10 


Water 


64.31 


Carbowax PEG 3350 


4.00 


Dimethicone copolyol 


2.00 


Glycereth-26 


1.00 


Glucam-E20 


4.00 


Methyl pa raben 


0.30 


Trisodium EDTA 


0.10 


Allantoin 


0.10 


Keltrol 


7.50 


Carbopol 981 


11.00 


W-acetyl-D-glucosamine 


0.20 


Triethanolamine 


0.45 


Phenoxyethanol 


0.70 


Benzyl alcohol 


0.10 


Wheat bran extract 


0.10 


Olive extract 


0.10 


Linoleic acid 


0.20 


Pigments 


0.11 



The compositions are prepared according to the formula above and tested for their ability to repair 
the skin barrier after physical insult. The barrier condition is evaluated by challenging the skin with a tape 
strip and measuring the Trans Epidermal Water Loss (TEWL) for 3 days. Thirty female participants are 
used in the study. The participants have normal skin, are in good general health, and are free of any 
dermatological disorders. The participants apply the composition to one side of the face 2 times a day and 
the other side of the face is the untreated control. Their skin barrier is challenged by a method of tape 
stripping. The participants are acclimated to the test room conditions of about 40 percent relative 
humidity, and 70° F for about 15 to 20 minutes. An area is marked on the lower right cheek about 5 x 1 
cm 2 near the jaw line and initial water evaporation measurements are taken in 3 separate spots about 1 cm 
apart in a row. Cello-tape, about 5 cm, is placed on the skin in the outlined area, starting from the top of 
the cheek. After one firm stroke is applied in each direction, the tap is removed by gently pulling in a 



downward direction parallel to the skin. This procedure is repeated and water evaporation is measured 
after every 5 strips until the barrier is disrupted as indicated by a minimum of 28 g/m 2 hr on one of the 3 
spots. Both sides of the face are stripped in the same way. The participants return for TEWL evaluation 
1. 2, and 3 days after tape stripping of the skin to monitor the repair of the skin barrier. 

Barrier repair is the increase in the recovery of the skin on the stripped and treated side of the face 
compared with the stripped untreated side of the face. The total barrier repair over 3 days is calculated by 
determining the change in the area parameter. A small area indicates fast reparation of the skin barrier. 
The percent change in the area between the treated side of the face and the untreated side of the face is the 
difference in the total repair. The composition applied to the skin results in an 88 percent barrier repair 
over a placebo. 



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