CH686285A5 - Cosmetic or pharmaceutical preparation used to delay the aging of human skin. - Google Patents

Description

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CH 686 285 A5

Description

The present invention relates to cosmetic or pharmaceutical preparations containing active substances according to the definition of claim 1.

Aging of the cell is linked to biochemical reactions which cause the following phenomena:

- Change of chromosomes

- Partial loss of repairing, replicating or transcribing DNA

- These mutations influence the immunological system and ultimately the vital reactions of the cell (1).

Numerous scientific studies indicate that free radicals and their reaction products, especially peroxides, cause these reactions (2-4).

Free radicals are molecules or molecular fractions that have a free electron in their outer orbital layer. Therefore they are very reactive and can produce chain reactions. These oxidize membrane lipids but also harm proteins and nucleic acids.

Age spots on the skin are for example lipoprotein complexes. They are formed by a protein bridging reaction with oxidized membrane lipids.

According to Cesarini (5), the formation of free radicals in the cells themselves is caused by the following reactions:

- phagocytosis

- mitochondria respiration

- activation of peroxisomes

- synthesis of hormones

- synthesis of melanin.

In the skin, free radicals are induced by ionizing rays such as UV (6) but also by atmospheric pollution (ozone, nitric oxides, organochlorines).

Chemically speaking free radicals and their reaction products cause either a polymerization of biomolecules (eg bridging of collagen), or their scission (eg oxidation of unsaturated lipids).

The cellular medium contains oxygen. Here the oxidation of lipids by free radicals easily causes cell damage which leads to aging of the skin.

In an oxygenated environment the attack of free radicals on unsaturated fatty acids produces hydroperoxides which then form peroxides and cyclic endoperoxides. These peroxides can decompose (formation of short chain aldehydes eg malondialdehyde) or they form polymerization products (4).

Dubouloz et al. have proven the formation of lipid peroxides in the skin of rats after burns, frostbite or irradiation with UV rays (7).

According to Vladimirov (8) lipid peroxides reduce the electrical resistance of biomembranes. The bases of nucleic acids can also form peroxide radicals (9).

The living cell has developed several protective mechanisms against the action of free radicals and lipid peroxides.

The most important are the enzymes superoxide dismutase, catalase and various peroxidases of which glutathionperoxidase is the best known. Cholesterol, ureic acid, vitamins A, C, E and B are biological antioxidants that inactivate free radicals.

In conclusion we can say that all living things are composed of thermodynamically unstable substances against active oxygen. Proteins, lipids, Polysaccharides and nucleic acids can react with oxygen and are therefore inactivated. Aerobic metabolism is a balance between the oxidation required to produce energy and the antioxidant that protects sensitive cellular constituents (10).

Our skin is exposed to a multitude of physical, chemical or biological attacks which cause the formation of free radicals (light, air pollution, bacteria, immune reactions).

When these attacks go beyond natural protective mechanisms or when protection is weakened by a lack of vitamins or minerals, the skin shows signs of inflammation or early aging. It is known, for example, that the skin ages faster in places constantly exposed to light (face, hands, neck, etc.). Morelle gave a fairly comprehensive collection of literature until 1988 (11).

Antioxidants (free radical scavengers) inactivate free radicals. They are used industrially in large quantities to stabilize plastics, food and cosmetic products (soaps, perfumes, creams).

The use of free radical scanners on human skin is currently much discussed.

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It seems that free oxygen radicals (1C> 2 = singlet oxygen, Oâ = anion superoxide, HO "= hydroxylradical, HO20 = hydroperoxylradical) not only destroy cell membranes, but induce collagen synthesis at the right time. in fibroblasts (5).

The cosmetic action of plant extracts such as ginseng, ginko biloba and wheat germ oil is based particularly on their antioxidant action. Vitamins A (carotene, acid or ester of vitamin A), E (tocopherol), water-soluble vitamins of group B and vitamin C also act as antioxidants.

The use of the enzyme Superoxide dismutase (SOD) in cosmetic products is a patented subject (Kalopissis et al. Ü.S.P. 4, 129, 644 Dec. 12, 1978). On the other hand, Dixit et al. have shown that SOD does not protect skin lipids from oxidation (12).

Recent work by Emerit and Alaoui has shown that SOD has a protective effect on the sensitized skin of mice against the action of UVA rays (29).

Currently it is especially vitamin E (synthetic alpha tocopherol or a natural mixture of to-copherols) which is recommended as a free radical scavenger in cosmetic preparations.

As mentioned above, free radicals (abbreviation - R °) are formed by exogenous influences and by physiological processes in the skin and in the cells of the body. The reactions which are linked then cause the deterioration of the cell membranes by means of peroxides and hydroperoxides.

Chemically, there are 3 stages of lipid oxidation:

1) Initiation, 2) Propagation, 3) Termination 1) Initiation;

rh 5- r °

lipidradical lipid

Formation of free radicals by the action of rays (19, 20) and enzymes (21, 22) and active oxygen (4, 23) of heat and metal ions (28).

2) Spread:

+ o2 roo

O

lipidradical peroxydradical roo '

+ rh - ■

-s- rooh new intact lipid hydroperoxide r °

new free radical that continues the reaction.

3) Termination:

Formation of aldehydes, ketones, hydrocarbons and polymerization products (24, 25, 26). Detailed description and effects on the organism see (14, 15).

The free radical scanners currently used in cosmetic preparations are primary antioxidants (HA). They react in place of an intact lipid with free radicals or peroxide radicals and therefore interrupt the chain reactions described above:

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CH 686 285 A5

Ro RH

or or

ROO "+ AH> - ROOH + A °

antioxidant inactive radical hydroperoxide of the antioxidant

Once formed, hydroperoxides cannot be inactive by HAs and continue to attack other oxidizable molecules. This is the reason why HAs are only effective when added to the fresh substrate before the formation of hydroperoxides. They exert their best protection when they are still applied before the cells are exposed to the formation of free radicals (16).

The subject of the invention presented are cosmetic or pharmaceutical preparations according to claim 1. These preparations comprise antioxidants which are active against lipid hydroperoxides already formed in the skin.

Thioethers (R1-S-R2) and dithioethers (R1-S-S-R2) react with lipid hydroperoxides to form sulfoxides and alcohols.

Ri / Rl 1> - ROH + 0-S "T

ROOH + S \ R

^ 2

Sulfoxid

Ri and R2 are defined as in claim 1. The sulfoxides formed have an additional action. They inactivate the hydroxyl radical (HO °) which is very harmful to cells (17).

r1 R1

o = s '"' + 2ho •> - o = + r2oh oh r2

tallow acid

This combined action against hydroperoxides and the HO ° radical explains the experimental fact that one molecule of thioether can inactivate at least 20 molecules of hydroperoxide (18).

Some thio- and dithioethers are used industrially to stabilize plastics and greases. Their effectiveness in delaying or preventing, in cosmetic preparations skin aging is new and has given excellent results (see examples).

EXAMPLE 1

Protection exercised by R1-S-R2 and R1-S-S-R2 against heat allergy.

A 55 year old lady (light blond hair, very thin and sensitive skin) was irritated in the face very easily.

Short exposures to the sun or heat during kitchen work caused edema inflammation followed by the formation of dandruff. Despite different dermatological treatments, this sensitivity was not cured.

Ri-S-R action? and R1-S-S-R?

The following solution was applied once a day to the face (0.5 g per application):

1.0% Dilaurylthiodipropionate 0.5% Dithiobis (stearylpropionate)

98.5% Isopropylpalmitate

Already after a few days the skin inflammation regressed. After two weeks the skin condition was normal. Even after exposure to heat (cooking) the skin remained normal with sporadic application of the above solution.

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CH 686 285 A5

EXAMPLE 2

Protection against allergic skin reactions by R1-S-R2

One patient suffered from allergic reactions (inflammation, dandruff and skin tears) in contact with minimal amounts of geraniol.

The treating dermatologist carried out patch tests on the patient's back with the following ointments:

1. Pure lanolin

2. Lanolin containing 1% synthetic geraniol

3. Lanolin containing 1% synthetic geraniol and 1% dilaurylthiodipropionate.

0.5 g of each ointment was distributed over 5 cm2 of the dorsal skin, covered with gauze and fixed with a plaster.

observation after:

24h

48 h

72 h

1. without inflammation without inflammation without inflammation

2. mild inflammation strong inflammation strong inflammation

3. without inflammation without inflammation without inflammation

The allergic inflammation in this case probably caused by a reaction passing through peroxides was inhibited by dilaurylthiodipropionate.

EXAMPLE 3

Action of R1-S-R2 on skin exposed to the sun

The emulsions of formulas 1-4 have been examined by several people on the skin. The actions noted are as follows:

1. Application before sun exposure: Perythema was delayed and weaker than on untreated places.

2. Application to an existing erythema: very marked reduction in itching.

3. Application to already tanned skin (after sun cream): the disappearance of the tan is delayed.

The emulsions do not contain UV absorbents. The actions described are due to the inactivation of peroxides by thioether.

It is known that solar erythema, melanin formation and probably also its decomposition in the skin is caused by free radicals or peroxides.

EXAMPLE 4

Action of creams containing thioethers on sensitive or irritated skin

Several people have found that the swelling and itching after insect bites has been reduced by creams containing thioethers.

People who do not normally support cosmetic products and who are faced with skin problems have very well tolerated preparations containing thioethers.

Older women have found that their skin becomes fresher and prettier after regular use of creams containing thioether.

Among the most obvious examples, we can cite the case of a 45-year-old woman who had sporadically red spots on her cheeks and her chin that could remain for two weeks. The treating dermatologist could not find the reason or the adequate cream. After regular use of the cream (formula 1) the spots disappeared after a few days.

Air pollutants (ozone, nitric oxides) are known to generate free radicals (27). They cause the formation of lipid peroxides on the skin. Creams containing thioether ideally protect the skin against this atmospheric pollution.

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EXAMPLE 5

Protection against UV rays by thioether R1-S-S-R2

UV rays kill bacteria. This effect is based, as well as solar erythema of the skin, on the formation of free radicals and subsequent peroxides.

Test method:

Thioether R1-S-S-R2 and as comparison D, L alpha tocopherol synth. are mixed with a 1: 4 solubilizer (Cremophor RH-40 from BASF or Lamacit 877 from HENKEL).

1% of this mixture is dissolved in the hot agar plate count, which is then poured into petri dishes (9 cm in diameter). After cooling, the gel surface is inoculated according to standard methods with E.coli.

Finally, these plates are irradiated for 50 minutes in a Xenotest device (Heraeus, Hanau).

Results:

Test

% growth compared

with plates not

irradiated

1. Agar without additives

25

2. + D, L alpha tocopherol synth.

60

3. + Dithio-bis (stearylpropionate)

100

Thioether has protected bacteria from the action of UV rays.

Example 6

APPLICATION FORMULAS

The emulsions prepared according to formulas 1 to 6 were tested and regularly used for 7 years.

The most astonishing fact is that even people with sensitive skin, regularly irritated by commercial cosmetic products, have well endured the creams containing the substance R1-S-R2 which is the subject of the patent.

After a period of time (2-3 weeks) already a positive effect was noticed:

- fresher and youthful appearance of the skin

- soft touch and smoother skin surface

- less sensitivity of the facial skin against cold, heat and air pollution.

Mountaineers have used W / O formula 1 cream during the day as a base (first layer on the skin) for a UV filter and in the evening as a night cream. As a result they could see a clear improvement in the skin which was previously damaged by the wind and the sun.

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CH 686 285 A5

FORMULA 1

B

s anti aging treatment, W / O

thixotropic

%

HOSTACERIN W / O

5.0

DEHYMULS F

5.0

LUNACERA P

1.0

LUNACERA M

1.0

VASELIN OIL 150 cp

5.0

ISOPROPYLE PALMITATE

3.2

CETIOL SN

12.0

• DLTDP

2.5

LANESTA S

1.0

ALCOLEC DSA

2.0

LAWYER

1.0

SICO CAROTENE 10 SKO 10% MIP

0.05-0.1

NIPASOL M

0.1

DEMINERALIZED WATER

56.9

GLYCERINE 86%

4.0

KATHON CG

0.1

PERFUME

0.1

TOTAL

100.0

according to color

* R1S-R2: Dilaurylthiodipropionate

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CH 686 285 A5

FORM 2

W / O night cream

flexible, for skin

dry and normal

%

ABIL WE 09

5.0

ABIL WAX 2434

2.0

ISOPROPYLE PALMITATE

5.0

CETIOL V

4.0

AVOCADI N

1.0

CUTINA HR

1.0

BEES WAX

2.0

♦ DLTDP

2.0

ACETULAN

3.0

DEMINERALIZED WATER

73.4

NaCL

0.8

D-PANTHENOL

0.2

GLYDANT PLUS

0.3

PERFUME

0.3

TOTAL

100.0

* R1-S-R2: Dilaurylthiodipropionate

FORM 3 A

W / O thick milk

brilliant white,

(Nivea body milk type)

a little fatter

%

ARLACEL 481

1.5

ARLACEL 989

6.0

VASELIN OIL 30 cP

12.0

ISOPROPYLE MYRIST

5.0

LANTROL

0.5

ACETULAN

2.0

* DLTDP

1.5

NIPASOL M

0.2

DEMINERALIZED WATER

64.0

MgSO "x 7.20 AM

0.7

NIPAGIN M-Na

0.1

SORBITOL 70%

6.0

PERFUME

0.5

TOTAL

100.0

* R1-S-R2: Dilaurylthiodipropionate

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CH 686 285 A5

FORM 4

Soft cream W / O "Avocado", nutritious white and shiny, pleasant on the skin, penetrates faster,

less fat%

ARLACEL 581

4.0

ARLATONE T

1.0

VASELIN OIL 30 cP

14.0

ISOPROPYLE MYRIST

8.0

LAWYER

2.0

JOJOBA OIL

2.0

a TOCOPHEROLACETAT

1.0

* DLTDP

1.5

PHENONIP

0.2

DEMINERALIZED WATER

58.4

PROPYLENE GLYCOL

3.0

ALLANTOINE

0.1

D-PANTHENOL

1.5

MgS04 x 7H20

0.7

ARLAGARD E

0.3

COLLAGEN

2.0

PERFUME

0.3

TOTAL

100.0

* R1-S-R2: Dilaurylthiodipropionate

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CH 686 285 A5

FORM 5

Sunscreen milk W / O

shiny, flows well, not too oily on the skin

%

ABIL WE 09

5.0

ABIL WAX 2434

2.0

ISOPROPYLE PALMITATE

5.0

CETIOL V

4.0

LAWYER

1.0

CASTOR OIL

0.5

BEES WAX

0.8

PALM OIL NOT DEC.

1.5

• DLTDP

2.0

PHENONIP

0.2

EUSOLEX 8020

2.0

ESCALOL 507

5.0

DEMINERALIZED WATER

69.4

NaCL

0.8

ARLAGARD E

0.3

D-PANTHENOL

0.2

PERFUME

0.3

TOTAL

100.0

* R1-S-R2: Dilaurylthiodipropionate

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CH 686 285 A5

FORM 6

White Day Cream, shiny, does not shine on the skin,

penetrates quickly%

LAMECRÈME AOM

5.0

CETYL ALCOHOL

1.5

STEARINE

1.5

ISOPROPYLE PALMITATE

5.0

EUTANOL G

4.0

VASELIN OIL 30 cP

5.0

ACETULAN

2.0

* DLTDP

1.6

DEMIN WATER.

69.5

SORBITOL 70%

3.5

ARLAGARD E

0.2

GERMALL II

0.3

HOSTACERIN PN 73

0.5

PERFUME

0.4

TOTAL

100.0

* R1-S-R2: Dilaurylthiodipropionate

LITERATURE

1. E. Mignini et al., Aging and free radical formation, A biochemical approach to evaluate the efficacy of sometic preparations.

Int. Daily of Cosm. Science 11, 21-26 (1989).

2. C. Bonne et al., Screening tests of free radical scavengers for preventing sun-accelerated cuta-neous aging.

Int. Daily of Cosm. Science 10, 247-252 (188)

3. D. Harman, Free radical theory of aging: role of free radicals in the origination and evolution of life, aging and disease processes, in: Free Radicals, Aging and Degenerative Diseases, ed.by J. E. Johson et al. pp. 3-49, Alan Liss, Inc., New York (1986)

4. J. M. C. Gutteridge et al., Oxygen radical damage in biological systems, ibid, pp 99-139.

5. J. P. Cesarini, Free radicals and skin aging, Non-surgical extension of youth, 1st Symp. of the Soc. French Medical Cosmetology, Geneva 8-10 Sep 1988.

6. M. A. Pathak, K. Stratton, Free radicals in human skin before and after exposure to light. Arch.Bio-chem.Biophys. 13, 468-476 (1968)

7. P. Dubouloz, on the formation of lipid peroxides in the skin after the action of various physical agents, these 097 896, 1954, fac. of Univ Sciences. from Marseille.

8. Y. A. Vladimirov, Free radical lipid peroxidation in biomembranes: mechanism, regulation and biological consequences, in: Free Radicals, Aging and Degenerative Diseases, ed.by J. E. Johnson et al. pp. 141-195, Alan R. Liss, Ine ,. New York (1986).

9. H. Esterbauer, F. K. Gey, J. Fuchs, M. R. Clemens, H. Sies; Antioxidative Vitamine und degenerative Erkrankungen, Deutsches Ärzteblatt-Ärztliche Mitteilungen, 87, Heft 47, pp. 3735-3741, Nov. 1990.

10. K. H. Schmidt, W. Bayer, Efficacy of Vitamin E as a Drug in inflammatory Joint Diseases, in: An-tioxidants in Therapy and Preventive medizine, ed. By I. Emerit et al. Plenum Press, New York, 1990.

11. J. Morelle, Lipid peroxides, free radicals, aging and lipoamino acids, perf. cosm. arômes, no 79, Feb-Mar 1988, pp. 71-78 and no 80, April-May 1988, pp. 91-103.

12. R. Dixit et al., Evidence that lipid peroxidation in microsomal membranes of epidermis is associa-ted with generation of hydrogen peroxide and singlet oxygen, Biochem. and Biophys. Res. Commun., Vol. 105, n ° 2, 1982, pp. 546-552.

13. B. Idson, Vitamins in Cosmetics, an Update, Part II: Vitamin E, Drug & Cosmetic Industry, Aug. 1990, pp. 20 u.f.

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CH 686 285 A5

14. J. Feher, G. Csomos, A. Verecki, Free Radical Reactions in Medecine, Springer-Verlag 1987.

15. A. Sevanian (Ed.), Lipid Peroxidation in Biological Systems, American Oil Chemists' Society, Champaign, Illinois, 1988.

16. C. G. Borek, Antioxidants as Anticarcinogens, 5. bienal meeting of the Int. Soc. for Free Radical Research, Nov. 14-20, 1990.

17. C. F. Babbs, M. B. Steiner, Quantitation of HO • using dimethylsulfoxide (DMSO) as a molecular probe, 5. bienal meeting of the Int. Soc. for Free Radical Res., Nov. 14-20, 1990.

18. J. R. Shelton, Stabilisation against thermal oxidation, in: Polymer Stabilisation, W. L. Hawkins Ed., Wiley Intersc., 1972.

19. C. L. Greenstock, Radiation induced aging and induction and promotion of biological damage, in: Free Raideals, Aging and Degenerative Diseases, ed.by J. E. Johnson et al. pp. 197-219, Alan Liss, Inc., New York (1986).

20. R. L. Willson, iron and hydroxyl free radicals in enzyme inactivation and cancer, in: Free Radicals, Lipid Peroxidation and Cancer, pp. 275-303, ed.by D. C. H. McBrien and T. F. Slater, Ac. Press 1982.

21. Ming Tien et al., Initiation of lipid peroxidation by perferyl complexes, in: Oxygen and Oxy-Radi-cals in Chemistry and Biology, ed.by M. A. J. Rodgers and E. L. Powers, pp. 147-152, Ac. Press 1981.

22. D. C. Borg et al., Autoxidation and Cytotoxicity, ibid, pp. 177-196.

23. M. Nakamura et al., Oxygen activation by phagocyte specific NADPH Oxidase, in: The Biological Rôle of Reactive Oxygen Species in Skin, ed. by O. Hayaishi et al., pp. 15-23, Elsevier 1987.

24. H. Esterbauer, Aldehydic products of lipid peroxidation in: Free Radicals, Lipid peroxidation and Cancer, ed.by D. C. H. McBrien and T. F. Slater, pp. 102-128, Ac. Press 1982.

25. M. V. Dianzani, Biochemical effects of saturated and unsaturated aldehydes, ibid, pp. 129-158.

26. E. Schauenstein, Effect of low concentrations of aldehydes on tumor cells and tumor growth, ibid, pp. 159-171.

27. W. A. Pryor, The role of free radical reactions in biological systems, in: Free Radicals in Biology, Vol I, ed.by W. A. Pryor, pp. 1-49, Ac. Press 1976.

28. G. Scott, Atmospheric Oxidation and Antioxidants, Elsevier Pubi. Co. 1965.

29. I. Emerit, A. Alaoui, Free Radicals and Photoaging, protection by local application of Superoxide dismutase, SFRR Symposium Paris, Sept. 20-28, 1991.

Claims (5)

Claims 1. Cosmetic or pharmaceutical preparation used to delay the aging of human skin, characterized in that it contains as active substance a) a lipophilic thioether of the formula (R1-S-R2) or a lipophilic dithioether of the formula (R1 -SS-R2) or a lipophilic sulfoxide of the formula (R1-SO-R2) or a substituted thiuramdisulfide of the formula (I) Rl * 3 n-c-s-s-c-n / i 1 \ R2 s s R4 (I) in which the residues Ri, R2, R3 and R4 are chosen from lipophilic residues which give the whole molecule good solubility in lipids, and the residues of polymers of ethylene or propylene oxide which give according to their degree of polymerization with whole molecules the desired lipophilic-hydrophilic balance, and / or b) thio- or dithioethers having residues of thiodipropionic acid, of dithiodipropionic acid, of thioditartaric acid, of acid dithiodiglycolic, carboxymethylmercaptotartaric acid or thioacetic acid. 2. Cosmetic or pharmaceutical preparation according to claim 1, characterized in that the active substance is dilaurylthiodipropionate. 3. Cosmetic or pharmaceutical preparation according to claim 1, characterized in that the active substance is dithiobis (stearylpropionate). 4. Cosmetic or pharmaceutical preparation according to claim 1, characterized in that the active substance is a tetraalkylthiuramdisulfide of formula (I), in which the residues Ri, R2, R3 and R4 are alkyl. 5. Cosmetic or pharmaceutical preparation according to one of claims 1 to 4, characterized in that the active substances mentioned are used in combination with standard antioxidants which collect free radicals. 12