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WORLD INTELLECTUAL PROPERTY ORGANIZATION 
International Bureau 




INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCI) 



(51) International Patent Classification 4 
A61K 31/685, 31/56,31/20 



Al 



(11) International Publication Number: WO 90/01323 

(43) International Publication Date: 22 February 1990 (22.02.90) 



(21) International Application Number: PCT/US89/03551 

(22) International Filing Date: 9 August 1989 (09.08.89) 



(30) Priority data: 
231,848 



12 August 1988 (12.08.88) US 



(71X72) Applicant and Inventor: BERNSTEIN, Joel, E. [US/ 
US]; 615 Briarbill Road, DeerGeld, IL 60016 (US). 

(74) Agents: SORRENTTNO, Joseph, M; Dressier, Goldsmith, 
Shore, Sutker & Mibiamow, Ltd, 1800 Prudential Plaza, 
Chicago, IL 60601 (US) et aL 



(81) Designated States: AT (European patent), AU, BE (Euro- 
pean patent), CH (European patent), DE (European pa- 
tent), FR (European patent), GB (European patent), IT 
(European patent), JP, LU (European patent), NL (Euro- 
pean patent), 



SE (European patent). 



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) Tide: METHOD AND COMPOSITION FOR TREATING AND PREVENTING DRY SKIN DISORDERS 



(57) Abstract 



A method and composition for treating and preventing dry skin includes a lipid concentrate blended from a combination 
of the three natui^y-ocairring lipid groups found in the stratum oorneum. The concentrate may be applied topically as pre- 
pared, or may be blended with a therapeutically acceptable vehicle suitable for topical application. 



FOR THE PURPOSES OF INFORMATION ONLY 



Codes used to identify States 
applications under the PCT. 

AT Austin 

AD Atnrana 

BB Barbados 

BE Befeana 

BF Burkina Fasso 

BG Bazars 

BJ Bcdid 

BB Ri»n 

CA Canada 

CF Central African Repubfic 

CG Congo 

CH Switzerland 

CM Cameroon 

D£ Gcnim>y, Federal Rqwbfic of 

DK Dcmnnk 



rty to the PCT on the front pages 

ES Spain 



FI 


FtnlaUsd 


FR 


France 


CA 


Gabon 


GB 


United KragJum 


HU 


Hungary 


rx 


Italy 


jp 


Japan 


KP 


Democratic People? Repubfic 




of Korea 


KR 


Rcpubfic of Korea 


u 




LK 


Sri Lanka 


HI 


Luxembourg 


MC 


MOuSCO 



of pamphlets publishing international 



MG Madagascar 

ML Mafi 

MR Mauritania 

MW Mafawi 

NL Netherlands 

NO Norway 

RO Romania 

SD Sudan 

SB Sweden 

SN Senegal 

SU Soviet Union 

TD Chad 

TG Togo 

US United States of America 



WO 90/01323 



PCT/US89/03551 



- 1 - 

METHOD AND COMPOSITION FOR 
TREATING AND PREVENTING DRY SKIN DISORDERS 
This invention relates generally to 
dermatological preparations and f more particularly, to 
5 methods and compositions for treating and preventing dry 
skin* 

Background of the Invention 

Dry skin, also known as xerosis or asteatosis 
affects millions of Americans each year. Attempts to 
10 treat or prevent dry skin have led to the development of 
a large assortment of skin creams and lotions. All of 
these creams and lotions have been developed from either 
the point of view that applying an occlusive lipid such 
as petrolatum or mineral oil can retard moisture loss 
15 from the skin, or that the incorporation of water- 
soluble materials, such as free amino acids, organic 
acids, inorganic ions or urea, into the cream, ointment, 
gel or lotion can trap or retain water in the skin. 

It has been demonstrated over the last few 
20 years that the stratum corneum of the skin contains 

certain lipids which may form complicated layers within 
the stratum corneum thus forming a "water barrier" which 
prevents water loss from the skin. It has been 
discovered that formulations may be prepared composed of 
25 components of the skin»s natural water barrier forming 
lipid complex and that when these formulations are used 
by themselves or when they are incorporated into creams, 
ointments, gels and lotions, the resulting products 
provide unsurpassed protection against and treatment for 
30 dry skin conditions. 

In preparing the formulations disclosed 
herein, combinations of components from three separate 
classes of stratum corneum lipids were utilized: (1) 
free fatty acids; (2) sterols and sterol esters; and (3) 
35 phospholipids and glycolipids. 



WO 90/01323 



PCT/US89/03551 



10 



- 2 - 

Summary of the Tmrep +^r, 

The present invention provides an improved 
method and composition for prophylaxis for or treatment 
of dry skin, consisting of preparing a formulation 
composed of representative lipids from the three classes 
of lipids naturally found in the stratum comeum. such 
a formulation may be applied directly or may be 
incorporated into a cream, ointment, gel or lotion and 
the resulting product applied in order to prevent or 
treat dryness of the skin. 

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
While other lipids may be utilized, the 
following members of the three stratum comeum lipid 
classes combined under this invention have been 
15 successfully utilized: 

1. Fatty acids: arachidonic, linoleic, 
linolenic, 

palmitic, stearic, oleic and docosanoic; 

2. Sterols and sterol esters: cholesterol 
20 and 

cholesterol sulfate; and 

3. Phospholipids and glycolipids: ceramides 
and lecithin. 

The proportions of the three classes vary in selected 
25 lipid concentrate formulations but generally fall within 
the following ranges: 

Fatty acids: 25 to 75% 
Sterols and sterol esters: io to 40% 
Phospholipids and glycolipids: 5 to 40% 
30 ^ resulting lipid concentrate formulation 

may then be added to cream, ointment, gel or lotion 
vehicles in weight/weight concentrations ranging from 
about 1% to about 50%. The following examples further 
illustrate the invention: 

35 



WO 90/01323 



PCT/US89/03551 



- 3 - 

A therapeutic skin formula to treat and 
prevent dry skin was formulated by adding 15 gm of a 
lipid concentrate composed of 30% W/W cholesterol 
(obtained under the trade designation Loralan- CH from 
5 the Lanaetex Products , Inc., Elizabeth, New Jersey), 20% 
W/W lecithin [obtained from American Lecithin Company, 
Inc., Atlanta Georgia), and 50% W/W of a mixture of 
linoleic acid, linolenic acid and arachidonic acid 
(obtained under the trade designation of EFA complex 
10 from Phillip Rockley, Ltd., New York, New York) to a 
lotion base as follows: 

Isopropyl Myristate 5.0% 7.5 gm 

Cetyl Alcohol 2.0% 3 . 0 gm 

Glyceryl Stearate and 
15 PEG-100 Stearate 

(Arlacel 165) 5,0% 7.5 gm 

Benzyl Alcohol 1.0% 1.5 gm 

Lipid Concentrate 10.0% 15.0 gm 
70% Sorbitol solution 25.0% 37.5 gm 

20 Distilled Water 52.0% 78.0 am 

TOTAL 100.0% 150.0 gm 

This formulation was applied to the dry skin 
of a 44 year old male and produced noticeably softer 
more supple skin after only one application. 
25 Example 2 

A therapeutic moisturizing formulation was 
prepared consisting of a lipid concentrate containing 10 
ml of linoleic acid (obtained from Emery Industries, 
Cincinnati, Ohio) , 10 ml linolenic acid (obtained from 

30 Fluka Chemical Corporation, Ronkonkoma, New York) , 10 gm 
of a mixture of lecithin, cephalin and lipositol 
(obtained under the trade designation of Asolectin from 
Fluka Chemical Corporation, Ronkonkoma, New York) , and 
10 gm of cholesterol (obtained under the trade 

35 designation of Loralan- CH from the Lanaetex Products, 



WO 90/01323 



PCT/US89/03551 



15 



- 4 - 

Inc. , Elizabeth, Mew Jersey) . The resulting mixture was 
blended to make a cream composed as follows: 

Isopropyl Myristate 5.0% 7.5 gm 

Cetyl Alcohol 3.0% 4.5 gm 

5 Glyceryl stearate and 

PEG -100 stearate 

(Arlacel 165) 5.0% 7.5 gm 

Benzyl Alcohol i. 0 % 1.5 gm 

Lipid Concentrate 5.0% 7.5 gm 

10 70 * sorbitol solution 25.0% 37.5 gm 

Distilled Water 56.0 % 84.0 am 

TOTAL 100.0% 150.0 gm 

This formulation was applied to the very dry 
skin on the lower legs of a 43 year old woman, within 
24 hours of twice daily application the treated skin was 
noticeably softer, more moist and supple. 

Tests were also performed to assess the 
efficacy of the present invention in preventing water 
loss. Baseline measurements of 15 healthy adult test 
subjects were performed to determine the barrier-forming 
properties of different formulations of the present 
invention, and to compare these properties with those of 
two commercially-available skin creams, Eucerin*, 
manufactured by Beiersdorf, inc., Norwalk, Connecicut, 
25 and Moisturel*, manufactured by Westwood 

Pharmaceuticals, Inc. Buffalo, N.Y.. a Servo Med 
Evaporimeter was used to measure rate of water loss from 
a 4.9 cm 8 * patch of unprotected skin. Thereafter, 
formulations of the present invention were applied to 
the test subjects at separate 4.9 cm** test sites, as 
were applications of Eucerin* and Moisturel* skin 
creams. Each application consisted of 25 microliters of 
each formulation. 

Lipid Concentrate I consisted of 30% w/w of 
cholesterol, 20% w/w of lecithin and ceramides, and 50% 
w/w of the linoleic, linolenic and arachidonic acid mix. 



20 



30 



35 



WO 90/01323 



PCT/US89/03551 



Lipid Concentrate II consisted of 15% w/w of 
cholesterol, 10% w/w lecithin and ceramides, and 75% w/w 
of the linoleic, linolenic and arachidonic acid mix. 

The formulations tested were prepared as 

5 follows : 

FORMULA 1 



10 



15 



20 



25 



Percent bv Weicrht 


Isopropyl Myristate 


5.0 


Cetyl Alcohol 


3.0 


Arlacel 165 


5.0 


Benzyl Alcohol 


1.0 


Lipid Concentrate II 


10.0 


70% Sorbitol Solution 


25.0 


Distilled Water 


51.0 


TOTAL 


100.0 


FORMtTIA 2 




Percent bv Weicrht 


Isopropyl Myristate 


5.0 


Cetyl Alcohol 


3.0 


Arlacel 165 


5.0 


Benzyl Alcohol 


1.0 


Lipid Concentrate II 


5.0 


70% Sorbitol Solution 


25.0 


Distilled Water 


56.0 


TOTAL 


100.0 



WO 90/01323 



PCT/US89/03551 



10 



- 6 - 

FORMULA 3 

Percent bv w*Hrrht 


Isopropyl Myristate 


5.0 


Cetyl Alcohol 


3.0 


Arlacel 165 


5.0 


Benzyl Alcohol 


1.0 


Lipid Concentrate I 


10.0 


Vitamin E 


1.0 


70% Sorbitol Solution 


25.0 


Distilled Water 


50.0 


TOTAL 


100.0 



Water loss measurements showed that all five 
formulations tested reduced water loss as compared to 
15 the untreated site, with the formulations of the present 
invention establishing a stronger barrier to water loss 
than the commercially available preparations. The test 
results were as follows: 

% change in 

20 evaporat ive wafca-r incc 

Formula l 3.4 
Formula 2 3.5 
Formula 3 2.6 
Eucerin R 3.7 
25 Mdisturel R 3.9 

Untreated Site 4.5 
While the foregoing has presented specific 
embodiments of the present invention, it is to be 
understood that these embodiments have been presented by 
30 way of example only, it is expected that others will 
perceive variations which, while varying from the 
foregoing, do not depart from the spirit and scope of 
the invention as herein described and claimed. None of 
the foregoing is attempted to in any manner limit the 
35 scope of the present invention. 



WO 90/01323 



PCT/US89/03551 



- 7 - 

What is claimed is: 

1. A method for prophylaxis or treatment of dry 
skin, said method comprising topical application to the 
skin of a concentrate of one or more constituents from 

5 each of the three classes of naturally-occurring stratum 
corneum lipids. 

2. The method of Claim 1 wherein said three 
classes of lipids are fatty acids, sterol and sterol 
esters, and phospholipids and glycolipids. 

10 3. The method of Claim 2 wherein said fatty 

acid is selected as one or more of the following: 
arachidonic acid, linoleic acid, linolenic acid, palmitic 
acid, stearic acid, oleic acid and docosanoic acid. 

4. The method of Claim 2 wherein said sterol 
15 and/or sterol ester is selected from the group consisting 

of cholesterol and cholesterol sulfate. 

5. The method of Claim 2 wherein said 
phospholipids and/or glycolipids are selected from the 
group consisting of ceramides and lecithin. 

20 6. The method of in Claim 2 wherein said lipids 

are present in said concentrate in the following 
concentrations: fatty acids about 25% to about 75% by 
weight; sterols and sterol esters about 10% to about %40 
by weight; and phospholipids and glycolipids about 5% to 

25 about 40% by weight* 

7. The method of Claim 2 including the step of 
incorporating said concentrate into a pharmaceutically 
acceptable vehicle for topical application. 

8. The method of Claim 7 wherein said vehicle 
30 is a cream, a gel, a lotion or an ointment. 

9. A lipid concentrate for the prophylaxis and 
treatment of dry skin, said concentrate comprising at 
least one constituent from each of the following groups of 
naturally-occurring stratum corneum lipids: fatty acids, 

35 sterols and sterol esters, and phospholipids and 
glycolipids. 



WO 90/01323 



PCIYUS89/03551 



10 



- 8 - 

10. The concentrate of Claim 9 wherein said 
fatty acids are present in a proportion of about 25% to 
about 75% by weight, said sterol and sterol esters are 
present in a proportion of about 10% to about 40% by 
weight, and said phospholipids and glycolipids are present 
in a proportion from about 5% to about 40% by weight. 

11. The concentrate of Claim 9, wherein said 
fatty acid is selected as one or more of the following: 
arachidonic acid, linoleic acid, linolenic acid palmitic 
acid, stearic acid oleic acid and docosanoic acid. 

12. The concentrate of Claim 9 wherein said 
sterol and sterol ester is selected from the group 
comprising of cholesterol and cholesterol sulfate. 

13. The concentrate of Claim 9 wherein said 

15 phospholipids and glycolipids are selected from the group 
comprising ceramides and lecithin. 

14. The concentrate of Claim 9 including a 
pharmaceutical^ acceptable vehicle suitable for topical 
application of said concentrate. 

20 15 • The composition of Claim 14 wherein said 

vehicle is selected from the group of creams, gels, 
lotions and ointments. 

16. The composition of Claim 14 comprising the 
following constituents, by weight: 

25 Isopropyl Myristate about 5.0% 

Cetyl Alcohol about 2.0% 

Glyceryl stearate and 
PEG -100 stearate 

(Arlacel 165) about 5.0% 

30 Benzyl Alcohol about 1.0% 

Lipid Concentrate about 10.0% 

70% Sorbitol solution about 25.0% 
Distilled Water about 52.0% 

17. The composition of Claim 16 wherein said 
35 lipid concentrate comprises, by weight, 30% cholesterol, 



WO 90/01323 



PCT/US89/03551 



10 



15 



20 



25 



30 



- 9 - 

20% lecithin and 50% of a mixture of linoleic acid, 
linolenic acid and arachidonic acid. 

18. The composition of Claim 14 comprising the 
following constituents , by weight: 

Isopropyl Myristate 
Cetyl Alcohol 
Glyceryl stearate and 
PEG -100 stearate 
(Arlacel 165) 
Benzyl Alcohol 
Lipid Concentrate 
70% Sorbitol solution 
Distilled Water 

19. The composition of Claim 18 wherein said 
lipid concentrate comprises about 10ml of linoleic acid, 
about 10 ml. of linolenic acid, about 10 gm of a mixture 
of lecithin, cephalin and liposital, and about 10 gm of 
cholesterol . 

20. The composition of Claim 14 comprising the 
following constituents by weight: 



about 
about 



about 
about 
about 
about 
about 



5.0% 
3.0% 



5.0% 
1.0% 
5.0% 
25.0% 
56.0% 



Isopropyl Myristate 


about 


5.0% 


Cetyl Alcohol 


about 


3.0% 


Arlacel 165 


about 


5.0% 


Benzyl Alcohol 


about 


1.0% 


Lipid Concentrate 


about 


10.0% 


70% Sorbitol Solution 


about 


25.0% 


Distilled Water 


about 


51.0% 



21. The composition of Claim 20 wherein said 
lipid concentrate comprises, by weight, about 15% 
cholesterol, about 10% lecithin and ceramides, and about 
75% linoleic, linolenic and arachidonic acids. 



WO 90/01323 



PCT/US89/03551 



- 10 - 

22. The composition of Claim 14 comprising the 
allowing constituents, by weight: 



10 



Isopropyl Myristate 


about 


5-0% 


Cetyl Alcohol 


about 


3.0% 


Arlacel 165 


about 


5.0% 


Benzyl Alcohol 


about 


1.0% 


Lipid Concentrate 


about 


5.0% 


70% Sorbitol Solution 


about 


25.0% 


Distilled Water 


about 


56.0% 


23. The composition of 


Claim 22 


wherein said 



lipid concentrate comprises, by weight about 15% 
cholesterol, about 10% lecithin and ceramides, and about 
75% linoleic, Linolenic and arachidonic acids. 

24. The composition of Claim 14 compressing the 
15 following constituents, by weight: 



20 



Isopropyl Myristate 


about 


5.0% 


Cetyl Alcohol 


about 


3.0% 


Arlacel 165 


about 


5.0% 


Benzyl Alcohol 


about 


1*0% 


Lipid Concentrate 


about 


10.0% 


Vitamin E 


about 


1.0% 


70% Sorbitol Solution 


about 


25.0% 


Distilled Hater 


about 


50.0% 



25. The composition of Claim 24 wherein said 
25 lipid concentrate comprises, by weight about 30% 

cholesterol, about 20% lecithin and ceramides, and about 
50% linoleic, linolenic and arachidonic acids. 

26. The composition of Claim 14 wherein said 
lipid concentrate is present in a weight proportion of 

30 about 1% to about 50%. 



INTERNATIONAL SEARCH REPORT 

International Application NopCXAK89/0355 1 



CLASSIFICATION OF SUBJECT MATTER (it several clasBificahon symbol* aoply. indicate all) • 



According *b >ȣrnahOMl Patent .CtassifiMiion (IPC) or to both National Classification and IPC 

IPC(4): A6K 31/68S, 31/56, 31/20 
U.S.C1-: 514/77,78,171,558 



II. FIELDS SEARCHED 



Minimum Documentation Searched 7 



Classification System 



IKS. 



Classification Symbols 



514/77,78,171,558 



Documentation Searched other than Minimum Documentation 
to the Extent that such Documents are Included m the Fields Searched • 



III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 



Category * 


Citation of Document "with indication, where appropriate, of the relevant passages w 


Relevant to Claim No. " 


X 


US, A 4 f 760 096 (SAKAI ET AL) 26 July 
1988. See column 8, lines 1-30 


1 


-26 


X 


N. 


Chemical Abstracts Vol. 93, Abstract 
No. 120270E, Moria et al., Jpn. Kokai - 
Tokkyo Koho 80 33 451 08 March 1980. 


1 


-26 


X 


N. 


Chemical Abstracts, Vol. 105, Abstract 
No. 66280 J, Hanjani et al. Ger- Of fen. 
DE 3 537 723 24 April 1986. 


1 


-26 


X 


N. 


Chemical Abstracts Vol 106 Abstract 
No. 162393Q, Kaneko et al, Jpn. Kokai 
Tokkyo Koho JP 61,289,013 19 December 
1986. 


1 


-26 



* Special categories of cited documents: 10 
**A" document defining the general state of the art which Is not 
considered to be of particular relevance 

**£" earlier document but published on or after the international 
filing date 

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

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

M P* document published prior to the International filing date but 
later man the priority date claimed 



IV. CERTtRCATtON 


Data of the Actual Completion of the International Search 
21 NOVEMBER 1989 


Date of Mailing of this tmernattonal Search Report 

0 8 DEC 1933' 


International Searching Authority 

„ 


StoujfaOT^Au^ 

r/lTOffflffl A. TTPntfFKY 



FomKrcQAmojecond steel (f»v.tt-e7) 



*T* later document published alter the international filing date 
or priority date and not in conflict with the application but 
cited to understand the principle 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 

"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 

**«?* document member of the same patent family