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PCT 



WORLD INTELLECTUAL PROPERTY ORGANIZATION 
International Bureau 




INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) 



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



Al 



(11) International Publication Number: WO 00/67722 

(43) Internationa] Publication Date: 16 November 2000 (16.11.00) 



(21) International Application Number: PCT/USOO/11203 

(22) Internationa] Filing Date: 26 April 2000 (26.04.00) 



(30) Priority Data: 
09/306314 



6 May 1999 (06.05.99) 



US 



(71) Applicant: COLOR ACCESS, INC. IUS/US]; 7 Corporate 

Center Drive, Melville, NY 1 1747 (US). 

(72) Inventors: MAMMONE, Thomas; 4 Spencer Street, Farming- 

dale, NY 11735 (US). GAN, David, C; 50 Chichester 
Street, Huntington Station, NY 11746 CUS). 

(74) Agent: TSVEDOS, Estelle, L; Kenyon & Kenyon, One 
Broadway, New York, NY 10004 (US). 



(81) Designated States: AE, AG, AL, AM, AT, AU, AZ, BA, BB, 
BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, 
DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, BL, 
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, TT, TZ, 
UA, UG, UZ, VN, YU, ZA, ZW, AR1PO 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, a, 
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 
(57) Abstract 

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 pages of pamphlets publishing international applications under the PCT. 



AL 


Albania 


ES 


Spam 


LS 


Lesotho 


SI 


Slovenia 


AM 


Armenia 


PI 


Finland 


LT 


Uthuania 


SK 


Slovakia 


AT 


Austria 


FR 


France 


LU 


Luxembourg 


SN 


Senegal 


AU 


Australia 


GA 


Gabon 


LV 


Latvia 


sz 


Swaziland 


AZ 


Azerbaijan 


GB 


United Kingdom 


MC 


Monaco 


TD 


Chad 


BA 


Bosnia and Herzegovina 


GE 


Georgia 


MD 


Republic of Moldova 


TG 


Togo 


BB 


Barbados 


CH 


Ghana 


MG 


Madagascar 


TJ 


Tajikistan 


BE 


Belgium 


GN 


Guinea 


MK 


The former Yugoslav 


TM 




BF 


Burkina Faso 


GR 


Greece 




Republic of Macedonia 


TR 


Turkey 


BG 


Bulgaria 


HU 


Hungary 


ML 


Mali 


TT 


Trinidad and Tobago 


BJ 


Benin 


IE 


Ireland 


MN 


Mongolia 


UA 


Ukraine 


BR 
BY 


Brazil 


IL 


Israel 


MR 


Mauritania 


UG 


Uganda 


Belarus 


IS 


Iceland 


MW 


Malawi 


US 


United States of America 


CA 


Canada 


IT 


Italy 


MX 


Mexico 


UZ 


Uzbekistan 


CF 


Central African Republic 


JP 


Japan 


NE 


Niger 


VN 


Viet Nam 


CG 


Congo 


KB 


Kenya 


NL 


Netherlands 


YU 


Yugoslavia 


CH 


Switzerland 


KG 


Kyrgyzstan 


NO 


Norway 


ZW 


Zimbabwe 


a 


Cote dTvoirc 


KP 


Democratic Peopte'i 


NZ 


New Zealand 






CM 


Cameroon 




Republic or* Korea 


PL 


Poland 






CN 


China 


KR 


Republic of Korea 


FT 


Portugal 






CU 


Cuba 


KZ 


Kazakstan 


RO 


Romania 






CZ 


Czech Republic 


LC 


Sains Lucia 


RU 


Russian Federation 






DE 


Germany 


U 




SD 


Sudan 






DK 


Denmark 


LK 


SriLanlca 


SE 


Sweden 






EE 


Estonia 


LR 


Liberia 


SG 


Singapore 







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 

1 0 This invention relates to methods of using N-acetyl glucosamine to exfoliate the skin. The 

cells of the outermost layer of the stratum comeum 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 comeum, 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 corneocyte takes 1 4 
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'X 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. 



1 



WO 00/67722 



PCT/USOO/11203 



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 exfol iating-effecti ve amount ofN-acety I- 
1 0 D-glucosamine, N-acetylgalactosam ine, 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, 
in 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 W097/1 2597 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 



WO 00/67722 



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 W098/52576. In U.S. Patent No. 5,866,142, 
a composition for exfoliating the skin has been disclosed, which includes N-acetyl-D- 

1 0 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 81 88526. 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 

20 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 

2 5 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 



3 



WO 00/67722 



PCT/US00/11203 



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 
5 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 

10 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 N-acetyl-D-glucosamine or N-acetylgalactosamine, other optional 
components, depending on the intended end use of the compositions. These include, but are not 

15 limited to, additional exfoliants, preservatives, fragrances, emollients, antiseptics, 
antiinflammatories, antibacterials, stabilizers, antioxidants, vitamins, pigments, dyes, humectants, 
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 

20 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, 

25 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 pharmaceutical ly 

30 acceptable vehicles. Accordingly, the compositions of the present invention comprise a 
pharmaceutical^ or cosmetically acceptable carrier, in an amount appropriate to accommodate 
the other components of the formulation. The term "pharmaceutical ly and/or cosmetically 
acceptable vehicle" refers to a base, for either pharmaceutical or cosmetic use, within which N- 



4 



WO 00/67722 



PCT/US00/11203 



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 for topical 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 H 

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 IM-acetyl-D-glucosamine, 
30 is studied to determine the effect on desquamation. A panel of individuals is selected to 
participate in the test The selected participants are IS 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 



WO 00/67722 



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 1 63 percent decrease in skin flakiness, 
thereby showing its utility in desquamation. 



6 



WO 00/67722 



PCI7USOO/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. 
1 0. The method according to claim 1 wherein the composition further comprises chitin. 



7 



INTERNATIONAL SEARCH REPORT 



Men nal Application No 
PCT/US 00/11203 



A. CLASSIFICATION OF SUBJECT HATTER 

IPC 7 A61K7/48 



According to International Patent Classification (IPC) or to both national classification and IPC 



a FIELDS SEARCHED 



Nfcnimum documentation searched (classification system followed by classification symbols) 

IPC 7 A61K 



Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched 



Electronic data base consulted during the international search (name of data base and. where practical, search terms used) 

EPO-Internal , CHEM ABS Data 



C. DOCUMENTS CONSIDERED TO BE RELEVANT 



Category 0 Citation of document, with indication, where appropriate, of the relevant passages 



Relevant to claim No. 



EP 0 852 946 A (PAOLI AMBROSI GIANFRANCO 

DE) 15 July 1998 (1998-07-15) 

abstract 

page 4, line 37 

page 10, line 14 - line 18 

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



1-10 



1-10 



□ 



Further documents are listed in the continuation of box C. 



10 



Patent family members are listed in annex. 



° Special categories of cited documents : 

"A" document defining the general state of the art which is not 

considered to be of particular relevance 
*E* earlier document but published on or after the international 

filing date 

V document which may throw doubts on priority daimfs) or 
which is cited to establish the publication date of another 
citation or other special reason (as specified) 

*0" document referring to an oral disclosure, use, exhibition or 
other means 

"P* document published prior to the international filing date but 
later than the priority date claimed 



T* later document published after the international filing date 
or priority date and not in conflict with the application but 
cited to understand the prtrtctpie or theory underlying the 
invention 

"X" document of particular relevance; the claimed invention 
cannot be considered novel or cannot be considered to 
involve an inventive step when the document is taken alone 

*Y" document of particular relevance; the claimed invention 

cannot be considered to involve an inventive step when the 
document is combined with one or more other such docu- 
ments, such combination being obvious to a person skilled 
in the art 

"V document member of the same patent family 



Date of the actual completion of the international search 



28 August 2000 



Date of mailing of the international search report 



04/09/2000 



Name and mailing address of the ISA 

European Patent Office, P.B. 581 8 Patentlaan 2 
NL-2280HV Rifswijk 
Tel. (401-70) 340-2040, Tx. 31 651 eporf. 
Fax: (+31-70)340-3016 



Authorized officer 



Pel 1 i Uablat, B 



Form PCT/ISAOIO (second shaet) (July 1992) 



INTERNATIONAL SEARCH REPORT 

Biffonnatlon on patent family members 



PCT/US 00/11203 



Patent document 
cited in search report 



Publication 
date 



Patent family 
members) 



Publication 
date 



EP 0852946 



15-07-1998 



IT 
CA 



BS960094 A 
2219849 A 



29-05-1998 
29-05-1998 



W0 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 



Form PCT/ISA/210 (pitont tardy annex) (Jtfy 19821