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PCT 



INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) 



(51) International Patent Classification 7 : 
A61K 7/48 



(11) International Publication Number: WO 00/67722 

(43) International Publication Date: 16 November 2000 ( 1 6. 1 1 .00) 



(21) International Application Number: PCT/USOO/l 1203 

(22) International Filing Date: 26 April 2000 (26.04.00) 



(72) Inventors: MAMMONE, Thomas; 4 Spencer Street, Farming- 
dale, NY 11735 (US). GAN, David, C; 50 Chichester 
Street, Huntington Station, NY 1 1746 (US). 



(81) Designated States: AE, AG, AL, AM, AT, AU, AZ, BA, 

BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, 
DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, 
IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, 
LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, 
RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, IT, TZ, 
UA, UG, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, 
KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent 
(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent 
(AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, 
LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, 
CM, GA, GN, GW, ML, MR, NE, SN, TD, TG). 



Published 

With international search report. 
Before the expiration of the time limit for amending the 
claims and to be republished in the event of the receipt of 
amendments. 



(54) Title: METHODS OF EXFOLIATION USING N-ACETYL GLUCOSAMINE 



The present invention relates to a method of exfoliating and moisturizing the skin comprising the steps of topically applying a cosmetic 
or pharmaceutical composition. The composition comprises an amino sugar, N-acetyl-D-glucosamine and related compounds. 



FOR THE PURPOSES OF INFORMATION ONLY 



Codes used to identify States party to the PCT on the front pi 



is of pamphlets publishing international applications under the PCT. 

i Lesotho SI Slovenia 



Bulgaria 



Republic i 
Madagasc 



Trinidad and Tobago 



WO 00/67722 



PCT/US00/11203 



METHODS OF EXFOLIATION USING 
N- ACETYL GLUCOSAMINE 

Field of the Invention 

5 The present invention relates to methods of substantially exfoliating the skin. In 

particular, the invention relates to topically applied compositions containing an amino sugar in 
the form of N-acetyl glucosamine. 

Background of the Invention 
10 This invention relates to methods of using N-acetyl glucosamine to exfoliate the skin. The 

cells of the outermost layer of the stratum corneum are constantly shed naturally, by the normal 
process of desquamation, as minute particles. When fully keratinised tissue loses its cellular 
structure and reaches the surface of the stratum corneum. it breaks up into microscopic squames 
and sheds off the surface of the skin. Microscopic squames at the skin surface are commonly 
15 referred to as dead skin cells and make up a dead skin layer on the skin surface. The process of 
desquamation has been estimated to cause a loss of tissue in an amount of up to 1 4 grams per day. 
This loss is constantly replenished with cells from lower layers of the epidermis. Thus, the layers 
of the epidermis are composed of cells moving up towards the surface in successive stages of 
differentiation until death when they are finally sloughed off and lost to the environment. 
2 0 Desquamation is one of the processes by which skin maintains its health and vitality as nutrients 
and moisture are continuously replaced on the surface of the skin when dead skin cells are 
removed. Normally, the desquamation process takes about 14 days (i.e., the comeocyte takes 14 
days to reach the outermost layer of the strateum corneum to be shed). When desquamation does 
not take place regularly, the surface of the skin tends to become rougher and more wrinkles and 
25 other undesirable effects appear on the surface of the skin. However, in addition to or as an 
alternative to the natural desquamation process, exfoliation is often used to rejuvenate and 
enhance the health of the skin. 

Exfoliation is a technique whereby dead skin cells are removed or sloughed from the skin 
surface to promote a healthier and more youthful appearance to the skin. Several compounds are 
3 0 known to be useful as exfoliants such as for example, alpha hydroxy acid ("AHA"), beta hydroxy 
acid ("BHA"), retinoic acid ("retin A"), and enzymes. An exfoliant such as AHA breaks the bond 
holding individual squames together and allows them to detach and shed. 



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Producing a variety of alternatives for exfoliation is desirable because skin types vary 
among consumers and therefore, having a variety of exfoliants available to 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 its health for 
5 various types of skin. This is, therefore, an object of the present invention. 

Summary of the Invention 

The present invention relates to a method for exfoliating the skin by topically applying 
pharmaceutical or cosmetic compositions containing an exfoliating-effective amount ofN-acetyl- 
1 0 D-glucosamine, N -acetylgalactosamine, or a combination thereof. This method provides a natural 
alternative to the exfoliation process that is as effective as other typical exfoliation techniques. 

Detailed Description of the Invention 

It has now been unexpectedly discovered that topically applied N-acetyl-D-glucosamine 
15 or N-acetylgalactosamine containing compositions exfoliate the skin. Combinations of N-acetyl- 
D-glucosamine and N-acetylgalactosamine can also be used. These compositions which exfoliate 
the skin can also include chitin to enhance the process of exfoliation. 

It is known that amino sugars are capable of modulating the adhesion of keratinocytes, 
m vitro . It is disclosed by Brysk, M. in "Glycoproteins modulate adhesion in terminally 
20 differentiated keratinocytes," that N-acetylglucosamine, N-acetylneuraminic acid and N- 
acetylgalactosamine are involved in the dissociation of aggregates of glycoproteins that bind 
corneocytes together. Specifically, amino sugars are known to inhibit the reaggregation of 
corneocytes which have been dissociated into single squames by homogenization in ether. 
Further, amino sugars in the form of N-acetylglucosamine have been used as an oral nutrient 

2 5 supplement in conjunction with other topical cosmetic products, such as for example, products 

offered by Life-Force, Inc. which include N-acetyl-D-glucosamine in the form of a pill taken as 
a nutritional supplement. However, it is not suggested in the prior art to formulate a 
pharmaceutical or cosmetic composition for topical application to the skin using N- 
acetylglucosamine as an exfoliant. In fact, in W097/12597 it is disclosed that when studied to 

3 0 determine its efficacy as a topical desquamating agent, N-acetyl-D-glucosamine was not found 

to be effective. The exfoliant in W097/12597 is a compound comprising a chain of carbohydrates 
linked by a linking moiety to an alkyl or alkenyl chain. Further, W097/12597, incorporated 
herein by reference, only includes N-acetyl-D-glucosamine as one of the units forming the 



2 



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PCT/US00/11203 



carbohydrate portion which is linked by the linking moiety to the alkyl or alkenyl chain for 
desquamation of the skin. It is not disclosed in W097/1 2597 that N-acetyl-D-glucosamine alone 
can exfoliate the skin. 

Compositions for topical application containing N-acetyl-D-glucosamine have been 
5 disclosed for example, in JP 59013708, WO 98/52576, and U.S. Patent No. 5,866,142, each 
incorporated herein by reference. To soften and moisturize the skin, a cosmetic containing an N- 
acetyl amino sugar is disclosed in JP 59013708. A composition for alleviating itching and pain 
containing N-acetyl-D-glucosamine is disclosed in WO 98/52576. In U.S. Patent No. 5,866,142, 
a composition for exfoliating the skin has been disclosed, which includes N-acetyl-D- 
10 glucosamine. The presence of N-acetyl-D-glucosamine contributes to enhancing the amount of 
hyaluronic acid which the skin naturally produces in greater quantities in response to exfoliation, 
induced by other compounds such as histidine. However, no exfoliating activity is attributed to 
N-acetyl-D-glucosamine. A cosmetic composition containing N-acetylglucosamine and having 
good adhesion to the skin (i.e., does not lift off of the skin) is disclosed in JP 8188526. However, 
15 the prior art does not disclose the ability of glucosamine, and particularly, N-acetyl-D- 
glucosamine, to exfoliate the skin. 

The composition of the present invention contains an exfoliating-effective amount of N- 
acetyl-D-glucosamine, N-acetylgalactosamine, or a combination thereof. By the term 
"exfoliating-effective amount," as used in the present specification, is meant an amount which is 

2 0 effective to cause exfoliation of the skin. The amount of N-acetyl-D-glucosamine, N- 

acetylgalactosamine, or a combination thereof, in the present invention will vary depending on 
the desired strength or intensity of exfoliation. The N-acetyl-D-glucosamine or N- 
acetylgalactosamine is present in the composition in an amount of about 0.01 to about 25.0 
percent of the weight of the composition; preferably 0.5 to about 10.0 percent, and more 
25 preferably about 1.0 to 5.0 percent of the weight of the composition. 

The N-acetyl-D-glucosamine or N-acetylgalactosamine per se is added directly to the 
cosmetic or pharmaceutical composition by admixing; alternatively, extracts of materials 
containing substantial quantities of N-acetylglucosamine or N-acetylgalactosamine as a 
component can be used to provide the same concentration. These compositions can also contain 

3 0 chitin. The amounts of chitin in the composition are also present in exfoliating-effective amounts 

as previously described. 

The intensity of exfoliation can also be controlled by the frequency with which the 
compositions are applied to the skin and the compositions are applied periodically for a period 

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PCT/US00/112O3 



of time sufficient to exfoliate the skin. Accordingly, the compositions are applied to the skin for 
a period of at least 2 months, and preferably for at least 4 months, during which time the 
compositions are applied on a weekly basis. However, a preferred method of obtaining the 
benefits of the composition is via chronic topical application of the composition to exfoliate the 
skin. It is suggested, as an example, that "chronic" application be within a range of from about 
once per week to about 4 to 5 times weekly, preferably daily, most preferably twice daily. 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 6 months to about 20 years, more 
preferably from about 1 year to about 10 years, and still more preferably from about 2 years to 
about 5 years, thereby resulting in regular desquamation, which may aid in reducing the 
appearance of fine lines and wrinkles due to chronological aging or photoaging. 

The method of the present invention may include applying in addition to the exfoliating 
effective amount of iN-acetyl-D-glucosamine or N-acetylgalactosamine, other optional 
components, depending on the intended end use of the compositions. These include, but are not 
limited to, additional exfoliants, preservatives, fragrances, emollients, antiseptics, 
antiinflammatories, antibacterials, stabilizers, antioxidants, vitamins, pigments, dyes, humectants, 
and propel lants, 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 1 nternational 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. 
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 .00 percent, of the formula weight. Examples of suitable 
preservatives are BHA, BHT, propyl paraben, butyl paraben or methyl paraben or an isomer, 
homolog, analog or derivative thereof. 

For topical application, according to the method of the present invention, the 
compositions can also be formulated with a variety of cosmetically and/or pharmaceutically 
acceptable vehicles. Accordingly, the compositions of the present invention comprise a 
pharmaceutically or cosmetically acceptable carrier, in an amount appropriate to accommodate 
the other components of the formulation. The term "pharmaceutically and/or cosmetically 
acceptable vehicle" refers to a base, for either pharmaceutical or cosmetic use, within which N- 



WO 00/67722 



PCT/USOO/11203 



acetyl-D-glucosamine or N-acetylgalactosamine is soluble and which will not cause harm to 
humans or other recipients. As used herein, "pharmaceutical" or "cosmetic" will be understood 
to encompass both human and animal pharmaceuticals or cosmetics. There are few limitations 
on the type of base which is suitable for the compositions containing N-acetyl-D-glucosamine or 
5 N-acetylgalactosamine. The vehicle may be aqueous, nonaqueous or a combination thereof 
appropriate for the formulation desired. 

The compositions can be prepared in any form convenient fortopical application to the skin. 
Such forms include, but are not limited to gels, creams, dispersions, emulsions (water-in-oil or oil- 
in-water), suspensions, creams, lotions, gels, foams, mousses and the like. In a preferred 
1 0 embodiment, the carrier is a suspension, dispersion or emulsion. The emulsion may be an oil-in- 
water emulsion, or a water-in-oil emulsion. These emulsions contain one or more oil components, 
an aqueous component, and a specific emulsifier component chosen depending on the nature of 
the desired emulsion. 

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

15 

Example 1 

A composition, according to the present invention is prepared as follows: 

To prepare the composition, the materials are combined in the order above by mixing. 
2 0 The composition is topically applied to the skin for exfoliation. 

Example]] 

A composition, according to the present invention is prepared as follows: 

25 To prepare the composition, the materials are combined in the order above by mixing. 

The composition is topically applied to the skin for exfoliation. 

Example III 

A composition according to the present invention, containing N-acetyl-D-glucosamine, 
3 0 is studied to determine the effect on desquamation. A panel of individuals is selected to 
participate in the test. The selected participants are 15 females between ages 21 and 65 years. 
Participants are given the composition to take home and self administer on their right hand two 
times a day, once in the morning after washing and once in the evening at least 1 5 minutes before 



5 



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PCT/US00/11203 



bedtime for 4 weeks. The left hand is the untreated control sample. Participants are allowed to 
use only the composition being studied and are to log its use in a daily diary. At intervals of 2 and 
4 weeks, the participants return for testing without applying the composition for at least 1 2 hours. 
The participants are tested without moisturizer or any other product on the skin of their hands. 
5 Their skin is acclimated to an environment of about 70° F, and about 40 percent relative humidity 
for about 20 minutes. 

Skin exfoliation is measured with D-Squame discs and image analysis. Specifically, the 
amount of flakes removed from the skin surface using D-Squame discs are measured. Firmly and 
evenly, 4 D-Squame discs are pressed on the back of each hand using a hand held uniform 
10 pressure device. The discs are removed by gently pulling them away from the skin. After 
removal, the discs are mounted on clear microscope slides and evaluated with an image analyzer, 
OPTIMA. A camera takes a picture of the slide and the average gray value is measured to 
determine the corresponding density of stratum corneocytes. Denser samples have higher gray 
value differences. 

15 Results show that the composition reduces skin flakiness after 2 weeks and 4 weeks of 

treatment when compared to untreated control hand area. After 2 weeks there is about a 15.8 
percent decrease and after 4 weeks there was about 16.3 percent decrease in skin flakiness, 
thereby showing its utility in desquamation. 



6 



WO 00/67722 



PCTYUSOO/11203 



What we claim is: 

1. A method for exfoliation of the skin comprising applying to the skin a composition 
comprising an exfoliating-effective amount of an amino sugar selected from the group 
consisting of N-acetyl-D-glucosamine, N-acetylgalactosamine, and a combination thereof. 

2. The method according to claim 1 wherein the amino sugar is present in an amount 
from about 0.01 percent to about 25.0 percent of the weight of the composition. 

3. The method according to claim 2 wherein the amino sugar is present in an amount 
from about 0.5 percent to about 10.0 percent of the weight of the composition. 

4. The method according to claim 3 wherein the amino sugar is present in an amount 
from about 1 .0 percent to about 5.0 percent of the weight of the composition. 

5. The method according to claim 1 wherein the composition is applied to the skin for 
a period of at least 4 months. 

6. The method according to claim 5 wherein the composition is applied weekly. 

7. The method according to claim 1 wherein the composition is applied to the skin for 
a period of at least 2 months. 

8. The method according to claim 1 wherein the compositions are applied from about 
4 to about 5 times a week. 

9 The method according to claim 8 wherein the composition is applied two times a day. 
10. The method according to claim 1 wherein the composition further comprises chitin. 



7 





INTERNATIONAL SEARCH REPORT i 1 

Interi nal Application No 

PCT/US 00/11203 




CATION OF SUBJECT MATTER 

A61K7/48 








EPO-Internal , CHEM ABS Data 










Relevant to daim No. 




A 
A 


EP 0 852 946 A (PAOLI AMBROSI GIANFRANCO 
DE) 15 July 1998 (1998-07-15) 

page 4, 1 ine 37 

page 10, 1 ine 14 - 1 ine 18 

WO 97 12597 A (L 'OREAL) 
10 April 1997 (1997-04-10) 
cited in the application 
the whole document 


1-10 
1-10 






■L" document which may throw doubte on P" 0 "^ claim(s) or 






04/09/2000 




Pel T i Wablat, B 



INTERNATIONAL SEARCH REPORT 

information on patent family members 



Inter mal Application No 
PCT/US 00/11203 



IT BS960094 A 
CA 2219849 A 



29-05-1998 
29-05-1998 



WO 9712597 


A 


10-04-1997 


FR 


2739556 A 


11-04-1997 








CA 


2231553 A 


10-04-1997 








EP 


0853472 A 


22-07-1998 








JP 


11501940 T 


16-02-1999