JPH07500117A - Lipid-soluble thioethers and dithioethers used in cosmetic formulations against aging human skin - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Lipid-soluble thioether used in cosmetic formulations against aging human skin and dithioether Detailed description of the invention Cell aging is caused by compounds that cause the following phenomena through biochemical reactions. Ru.

chromosomal changes, partial loss of the capacity for DNA repair, DNA replication and DNA transcription; Mutations that affect processes important to the immune system and ultimately to cellular biological responses (1) .

Free radicals and their related products, especially peroxides, are responsible for aging reactions. This theory has been the subject of numerous studies (2-4).

Free radicals are molecules or molecular fragments that have unpaired electrons in their outer molecular orbitals.

Free radicals are therefore highly reactive and can oxidize membrane lipids and damage proteins and nucleic acids. It can cause a damaging chain reaction.

Thus, for example, the known brown aging spots on the skin are composed of lipid-protein complexes. . It is produced when proteins combine with oxidation products of membrane lipids.

According to Cesarini (5), free radicals in cells are Produced by reaction.

activation of peroxisomes, synthesis of hormones, Synthesis of melanin.

Light, especially ultraviolet light and other ionizing light, creates free radicals in the skin. (6).

From a chemical point of view, free radicals and their related products are responsible for the polymerization of biochemical molecules (e.g. colloids). (polymerization of genes) or their decomposition (e.g. oxidation of lipids, especially unsaturated fatty acids). Become.

In the oxygenated medium of cells, oxidation of lipids by free radicals may cause some cellular damage. Free radicals are believed to play an important role in contributing to the aging phenomenon, as unsaturated fats Attacking the acid adds oxygen, resulting in hydroperoxide, which is It reacts further to form cyclic peroxides and cyclic endoperoxides. this These lipid peroxides decompose into short-chain aldehydes (e.g. malondialdehyde). ) or produce polymerized products (4).

That is, Dubouloz and co-workers (7) strongly heated Lipid peroxides appear on mouse skin when cooled or exposed to ultraviolet light. is detected to be generated.

According to Vladimirov (8), lipid peroxides are Reduces electrical resistance of body membranes.

In addition to lipids, bases are also produced within the nucleic acid radical (9).

Living cells are susceptible to the action of free radicals, especially oxygen radicals and lipid peroxides. It has various defense mechanisms. The most important of these is the super enzyme enzyme oxide dismutase, catalase and various peroxidases, the most Another well-known enzyme is glutathione peroxidase. cholesterin , uric acid, vitamins ASC, E and B vitamins are biological agents that inactivate free radicals. It is a powerful antioxidant.

To summarize the above, all living organisms composed of substances have a thermodynamic response to active oxygen. It can be said that it is unstable. Proteins, lipids, polysaccharides and nucleic acids interact with oxygen. React and inactivate. Aerobic metabolism is sensitive to the oxidation necessary to obtain energy and antioxidant activity that protects cellular components (10).

skin and free radicals The skin is subject to physical, chemical and biological attack, and is exposed to free radicals and peroxides. Sid is produced (light, air pollution, bacteria, immune response).

These attacks may overwhelm natural protection mechanisms or the skin may become deficient in vitamins and minerals. When the legs are weakened, the phenomena of skin inflammation and premature aging appear. For example, light It is a well-known fact that skin in areas that are exposed to the sun (hands, face, neck) ages faster. . Morelle provides an excellent review of this field up to 1988. (11).

Application of antioxidants to cosmetics It is used in large quantities industrially to stabilize

The use of free radical scavengers as active substances applied to the skin is currently limited and only occasionally used. It's too early. Oxygen free radicals (- stacked oxygen’ot, superoxide anion O! -, hydroxyl radical HO・, hydroperoxy radical HO2・ ) not only degrades collagen in fibroblasts; It can also be a cause (5).

Plant extracts such as ginseng, ginkgo leaf extract, wheat germ oil, and fufu Huflattig et al., whose action is at least partially an antioxidant. Those based on their activity as inhibitors are used in cosmetic formulations. The same thing is true Tamin A (carotene, vitamin A acid or ester), E (tocopherol) and This also applies to water-soluble B vitamins.

The use of the enzyme superoxide demutase (SOD) in cosmetics is particularly important. [KalopissiS] U.S. Pat. No. 4,1 No. 29,644, December 1978. On the other hand, Dixjt et al. Therefore, SOD is caused by the acid merit of lipids (Emerit) and According to recent studies by M. and Alaoui (29), hypersensitivity in mice SOD placed on exposed skin provides protection against UV absorption.

In particular, vitamin E (synthetic products of various isomers of α-tocopherol or mixtures of natural products) compounds) are useful in the body and on the skin as free radical scavengers in skin care formulations. produced by physiological and pathological processes in the human body.

In the next chain reaction, peroxide radicals and Hydroperoxides are formed and eventually damage the cell membrane.

In general, lipid peroxidation involves three reaction steps: initiation, propagation, and and a termination stage.

starting stage 4-1111 R@ Lipid lipid radical Free radicals include light (19,20), enzymes (21,22) and active oxygen (4°23), It is produced by the action of heat and metal ions (28).

propagation stage Lipid radical Peroxide radical ROO' + RH-ROOH+ R' New hydroperoxide, new active intact lipid, radical, chain reaction continues termination stage Formation of aldehydes, ketones, hydrocarbons and polymerization products (24,25°26).

For exact details and final effects on organisms, see references (14, 15). .

It is an antioxidant that reacts with radicals and interrupts the chain reaction mentioned above.

ROOo = AH-ROOH-1-A0 antioxidant inactivated antioxidant radical Hydroperoxides are not inactivated by AH and are further combined with cellular biochemicals. react. This is a first-class antioxidant before a large amount of hydroperoxide is generated. Why are primary antioxidants better if they are added into the new substrate from the beginning? This is the reason why it works. Antioxidants before cells come into contact with free radical generators When used, its effect is at its best.

The object of the invention is to act on lipid hydroperoxides even at a much later point in time. It is the use of special substances in cosmetic formulations.

Description of the invention Thioether (R-3-R) and dithioether (R-3-3-R) are Reacts with droperoxide to form sulfoxide and alcohol.

The sulfoxides produced are hydroxyl radicals ( Since it inactivates HO・) (17), it still has activity.

sulfinic acid This combinatorial effect ensures that one thioether molecule contains at least 20 molecules. Experimental evidence suggests that droperoxide molecules can be inactivated (18). It will be revealed.

Thioethers and dithioethers are used to stabilize synthetic resins, fats and oils. It is already used industrially for this purpose. However, it is used in cosmetic formulations for the skin. The effect of delaying aging is a new fact, and the surprising effects shown in the examples below Gives good results.

Example I Protective effect of R-8-R and R-3-8-R against heat allergy Age 55 years old Women with thick skin (who have reddish-brown, very delicate and sensitive skin) experience especially heat and irritation in the facial area. It was sensitive to light and sunlight. When cooking such as boiled and grilled foods, Even exposure to heat can cause intense redness on the skin that lasts for several days and can affect entire areas of the skin. Swelling occurred over time and epidermal desquamation later occurred. Perform various dermatological treatments However, this hypersensitivity to heat did not decrease.

Effects of R-8-R and R-8-8-R The following oily solution was applied to the animals every day ( Approximately 0.5g per serving).

Dilaurylthiodipropionate 1.0% Thiobis (stearylpropionate) g) 0.5% isopropyl palmitate 98.5% Redness of the skin is already visible after a few days. The burn has improved. After 2 weeks, normal heat allergy did not occur. .

Example 2 The effect of R-8-R on allergic skin reactions consists of chemical workers with small amounts of gerani Contact with the oar caused an allergic skin reaction (skin redness, epidermis). symptoms of peeling and cracking).

In order to conduct a retest, the treating dermatologist used an ointment with the following prescription. An application test was conducted on the subject's back.

1. Pure lanolin [adeps lanae anhydricum (adeps 1an) ae anhydricum)] 2, lanolin with 1% geraniol synthetic product added 3. Added 1% geraniol synthetic product and 1% dilauryl thiodipropionate. lanolin , Apply 0.5 g of each of the above three ointments to approximately 5 cm of back skin side by side. Then cover and secure with gauze and zinc oxide-containing bandage.

Elapsed time until observation 24 hours 48 hours 72 hours 1. No red burn No red burn No red burn 2. Weak red burn Strong red burn Strong Red burn 3, No red burn, No red burn, No red burn In this case, probably (peroxy Allergic reactions thought to be related to dilaurylthiodipropyl Suppressed by Nate.

Emulsions of compositions 1 to 4 below have been tested over many years on various people exposed to sunlight. All of them were shown to have the following effects.

1. When applied before irradiation with sunlight, erythema was delayed and alleviated. after that The degree of skin browning was also less than in areas that were not treated.

2. The pain was clearly alleviated in areas where the sunburn had already occurred.

3. (Apply cream for sunburn) Regularly once a day on already browned skin When applied, fading of the skin was clearly delayed.

This emulsion does not have ultraviolet absorbing properties, so it is The effect of is attributed to R-5-H.

Sunburn, melanin production, and possibly melanin retention are also associated with free radicals and peroxides. It is known that it is caused by oxidation.

Example 4 Effect of R-5-R-containing skin emulsion on hypersensitive and irritated skin Blisters and itching caused by insect bites can be treated by applying an emulsion containing R-8-R. This was confirmed by various test subjects.

In general, 5-R-3-containing emulsions are also incompatible with any cosmetic formulations and have skin problems. Women who are troubled by problems can also use it to their advantage.

Old ladies say that weakened skin can regain a fresh look with regular application. Proven.

A notable example is the case of a 45-year-old woman who had spontaneous symptoms on her chin and cheeks. A red stain appeared, which remained for 1 to 2 weeks. Relapse despite treatment This was prevented.

Components of urban air such as ozone and nitrogen oxide act as initiators of radical reactions. It is known that (27). These ingredients act on the skin to produce lipid peroxides. Jiru. R-3-R-containing cream is a natural method against these air contaminations. Protect your skin.

Example 5 Photoprotective effect of dithioether R-3-8-H Ultraviolet light kills bacteria . This effect also results in the generation of free radicals and their associated peroxides. This can also cause erythema on human skin due to sunburn.

Method: A lipophilic test substance was mixed with a solubilizer [BASF's Cremophor] in a ratio of 1=4. Cremophor RH60 or Henke/1z (Henke I) Lamacit 877]. Add 1% of this mixture Dissolve evenly in agar [count a’gar] in a hot plate. Understand. Pour this into a Petri dish (9 cm in diameter) and transplant E. coli using the usual method. . The Petri dish was then placed in a Xenotest apparatus [Hanau ) and irradiate it.

result: Test: Samples that were not irradiated Comparative growth rate (%) 2, +D, La-toco-easy enol, synthetic product 6゜3 + dithiobis (steary In Test 3, R-3-3-R was affected by irradiation. However, it protects all bacteria.

Application composition The formulations prepared according to compositions 1 to 6 were continuously administered to approximately 60 subjects over a period of 7 years. used for.

Notably, it is effective against sensitive skin, which many commercially available cosmetics irritate. R-3-R containing emulsions are compatible. Positive effects already obtained after a short period of time .

Fresher, younger looking skin with less sensitivity to cold, heat and air pollution It is said to provide a soft feel, soft feel and smooth surface.

Climbers use Composition 1 W10 cream during the day as a sun protection foundation. I used it as a lotion and as a cream in the evening. Results depend on wind and weather. The weakened skin was clearly improved.

literature 1. E. Mignini et al., Aging and free radical generation, Cosmetic preparation A biochemical attempt to evaluate the effects of compounds, International Journal of Cosmetic Science (Int, Jour.

of Co5m, 5science) Vol. 11, pp. 21-26 (1989) 2, Sci. - Bonne (C, B o n n e), etc., prevents skin aging accelerated by the sun. Screening test for free radical scavengers, International Journal Journal of Nismetic Science, Vol. 10, pp. 247-252 (1988) 3. D. Harman, Free radical theory of aging: The origin of life and and the role of free radicals in evolutionary, aging and disease processes, New York, USA. Published by Alan Li5s Inc., 1986, G.E. ・Eds. J.E. Johnson et al., [Free Radicals, Aging and Degenerative Diseases] Free Radicals.

Aging and Degemerative Diseases) J3-4 9 pages 4. J.M.C.Gutteridge et al., Damage caused by oxygen radicals in biological systems, Ibid., pp. 99-139. 5. J.P. Cesarini, Free radicals and skin aging Non-surgical extension of youthfulness, Blumière Symposium Deux Sauciés Te Française de Nismetologie Médicale (ler Symp, de Ia Soc, Francaise de Co5Co5m6tolo m6dical) Geneva September 8-10, 1988 6. M.A. Pathak, K. Stratton ( K, 5tratton), free radicals in human skin before and after exposure to light, - Archive of Biochemistry and Biophysics (Arch , Biochem, Biophys, ) vol. 13, pp. 468-476 (1968) 7. Dubou Ioz, various physical factors come into play Regarding the formation of lipid peroxides in the skin after Peroxides, Mechanisms, Regulation and Biological Consequences, New York, USA, Alan Li Published by Susha, 1986, edited by J.E. Johnson et al., “Free Radicals, Aging and Degenerative Properties.” 'Disease', pp. 141-1959, H. Esterbaue r), F Ka Gay (F, , ni, Ge y), Yoyto Fuchs (J, Fuchs), M.R. Clemens, Ver. H,5ies, Antioxidant Vitamins and Degenerative Diseases, German Chess Erzteblat Altliche Mitteilung (Deutsche A rzteblatte-Arztliche Mitteilungen) Magazine 8 Vol. 7, No. 47, pp. 3735-3741 (November 1990) 10, K.H. Schmidt, W.B. Year (W, Ba y e r), Vitamin E as a drug for inflammatory arthritis The Effects, New York, USA, Blennum Press 1 Published in 1990, edited by Emerit et al. Antioxidants in Thera py and Preventive meclizine)”,・ 11, J. Morelle, Lipid (-oxides, free radicals, aging) and lipid amino acids, parhium, cosmetics, engineering, aroma (par f, cosm, arlmes) magazine, no. 79. February 1988, March issue 71- p. 78, and no. 80. April 1988 peroxidation was performed using hydrogen peroxide and Evidence accompanying the generation of singlet oxygen, Biochemistry & Physics Research Communication (Biochem, and B iophys, Res, Commun,) Volume 105 (1982) No. 2 546 ~552 pages 13. B. Idson, Vitamins in Cosmetics, One Transformation, Part 11, Vitamin E1 Drug and Cosmetic Industry Tory (Drug and Cosmetic Industry) Magazine 1990 August issue, pp. 20-14, J. Feher, J./Mo. X (G.

Csomos), nee “Verecki” (A, Verecki), [In medicine Free Radical Reactions in Mede cine) J, Springer Verla g) Published 1987 15, edited by Ny Sevy-An (A, 5evanian), [ Lipid peroxidation in biological systems in Biological Systems) J, Chambe, Illinois, USA. (+:)Iampain), American Oil Chemistry Society -(American Oil Chemist'S.

ciety) Published in 1988 16. C, G, Borek, as drag lucinogen Antioxidants, International Society for ~20 days 17. C,F Babbs, M.B.

Stainer (M, B, 5steiner), dimethyl sulfur as a molecular pirobe Determination of HO using Oxide (DMSO), International Society E for Free Radical Research, 5th Annual Disability Conference, November 1990 Month 14-20 18, Liu R Jerutong (J, R, She　to n), Stabilization against thermal oxidation, W. L. Hawkins (W, L. , Hawk i n s), Wiley Interscience (Wiley) Published by Intersc, ) in 1972 [Stabilization of Polymers (Polymer Stabilization)] Stabili sat 1on) J19, C.L. Greenstock (C, L, Greenstock), radiation-induced aging, and biological Induction and promotion of damage to - E. Johnson et al., eds., Free Radicals, Aging, and Degenerative Diseases, 197-219. Page 20, 7-/l/-L-Wilson (R,L, Will Is on ), Enzyme Inactivation and Iron and Hydroxyl Free Radicals in Cancer, DC ・H. McBrien (D, C, H, McBrien), T.F. Slater (T, F, Slater) Ig, Academic Press (Ac, P Free Radicals, Lipid Peroxidation, and Cancer (Fre. ress), published in 1982. e Radicals, Lipid Peroxidation and Ca ncer) J275-303, A. J. Rodgers), E. L. Power. Edited by E. L. Powers, published by Academic Press, 1981. Oxygen and oxy groups in science and biology Radicals in Chemistry and Biology) J1 pages 47-152 22, D. C. Paws (D, C, Borg) et al., autoxidation and cytotoxicity. , Ibid., pp. 177-196. 23, M. Nakamura et al., phagocyte-specific NADPH Oxidase, edited by Hayaishi et al., Elsevier ( Biological Role of Reactive Oxygen Species in the Skin, published by Elsevier (1987). (The Biological Role of Reactive Oxyg en 5pecies in sk in) J pages 15-23 24 H.Esterbauer ()1. Esterbauer), lipid par Aldehydic products of oxidation, DC H. Matsukubrien; Edited by T.F. Slater, Academic Press, 1982, [Free Radicals] , Lipid peroxidation and cancer (Fr e Radicals, Lipi d　peroxidation　andCancer)J　pages 102-128 25, M.V. Dianzani, saturated and unsaturated Biochemical effects of saturated aldehydes, Ibid., pp. 129-158 26, Yi Shaue Tumor Cells and Tumor Growth Effect of low-aldehydes on, ibid., pp. 159-171. 27. In biological systems The Role of Free Radical Reactions in Reactions, edited by W. N. Pryor, Academic Press. Free Radicals in Biology, published in 1976. Biology) Volume 1, pp. 1-49 28, C, 5cott , “Atmospheric Oxidation and Antioxidants” ion and Antioxidants) J, Elsevier Inc., 1965 Row 29, Ai Efrit (1, Eme r i t), Ni, Alalai (A .

Alaoui), free radical and photoaging, superoxide dismutase Protection by topical application, 5FRR Symposium, Paris, September 1991 20-28 days Composition 1 Care cream, "anti-aging", Wlo , thixotropic composition A% Hostaserin (IIO3TACERIN), Wlo 5.0 Dehymulus (DEH YMULS) F 5.0 Lunacera (LUNACERA) P 1.0 Lunacera Ml, 0 Paraffin oil 150cP 5.0 Isopropyl balmite =, 1-3.2 Ceteiol (CETIOL) SN 12.0*DLTDP 2.5 LANESTA 3 1.0 ALCOLEC D SA 2.07'/AVOCADIN t, 0nko Karten (S ICOCAROTEN) to SKo 10% MIP (for coloring) 0.05~ 0.1 NIPASOL M O, I mineral-free water 56. 9 Glycerin, 86% 4.0 KATION CG 0.1 Fragrance 0.1 Total 100.0 *R-8-R: Dilaurylthiodipropionate composition 2 Night cream, Wlo, soft cream, for dry and normal skin % Isopropyl palmitate 5.0 Ceteiol (CETiOL) ■ 4.07'jth') / (AVOCAD IN) 1.0 CUTINA HR1.0 Beeswax 2.0 *DLTDP 2.0 ACETULAN 3.0 Demineralized water 73.4 GLYDANT PLUS 0.3 total ioo,.

*R-3-R: Dilauryl thiodipropionate composition 3A Thick liquid body emulsion, Wlo, soft and shiny, with some R1J properties. [Nivea type body emulsion]% ARILACEL 481 1.5 ARILACEL 989 6.0 Paraffin oil, 30cP 12.0 Isopropyl myristate 5.0 LANTROL 0.5 ACETULAN 2.0*DLTDP 1.5 Nipazole MO92 Demineralized water 64.0 Mg5O,・7H,00,7 NIPAGIN: / (NIPAGIN) M-Na 0.1 Sorbitol, 70% 6. 0 Fragrance 0.5 Total 100.0 *R-3-R: Dilauryl thiodipropionate composition 4A Soft cream, Wlo, “Avoicado” nutritional cream , soft and shiny, comfortable on the skin% Allacel 581 4.0 ARLATONE 1.0 paraffin oil, 30cP 14.0 Isopropyl myristate 8.0 Avokadin 2.0 Jojoba oil 2,0α-tocopherol acetate 1.0 *DLTDP 1.5 PHENONIP 0.2 Mineral removed water 58.4 Propylene glycol 3.0 Mg5O,・7820 0.7 ARLAGARD E 0.3 Collagen 2,0 Fragrance 0,3 Total 100.0 *R-8-R: Dilaurylthiodipropionate composition 5 Anti-sun emulsion, glossy, good spring flow, no lipids on the skin % Abil WEO95,0 Avil Wax 2434 2.0 Isopropyl palmitate 5.0 Cetiol V4.0 Avokadin 1.0 Himan oil 0.5 Beeswax 0,8 Unbleached palm oil 1.5 DLTDP 2.0 72nip 0.2 EUSOLEX 8020 2.0 ESCΔL OL) 507 5.0 Mineral removed water 69.4 NaCI　0.8 Al Lagarde E 003 D-panthenol 0.2 Fragrance 0.3 Composition 6 Daytime cream, O/W, soft and shiny, very opaque on the skin , penetrate quickly % LAMECREME AOM 5.0 Cetyl Alcohol 1.5 Stearin 1.5 Isopropyl palmitate 5.0 EUTANOL G 4.0 paraffin oil, 30cP 5.0 Acetyuran 2.0 *DLTDP 1.6 Demineralized water 69.5 Sorbitol, 70% 3.5 Al Lagarde EO12 GERMALL I I O,3 Hostaserine PN73 or 0 ．． 5NA-CARBOMER PNC430 Fragrance 0.3 Total ioo.

*R-3-R: Continuation of dilauryl thiodib oral pionate front page (51) Int, C1,' Identification symbol Internal reference number C07C317/14 7419-4H3211047419-4H 321/24 7419-4H 333/30 7106-4H I

Claims (6)

[Claims] 1. a lipophilic thioether of the general formula R1-S-R2, or a lipophilic thioether of the general formula R1-S-S- R2 lipophilic dithioether or lipophilic sulfoether of general formula R1-SO-R2 Oxide or general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Containing lipophilic tetraalkylthiuram disulfide as active substance Cosmetic or pharmaceutical preparations that prevent or delay the aging process of human skin characterized by: thing. 2. R1, R2, R3 and R4 are lipophilic aliphatic or aromatic groups; Claim 1, characterized in that the whole molecule has relatively good oil solubility. Cosmetic formulations. 3. The above R1, R2, R3 and R4 are cosmetics such as vitamins and antioxidants. Claims 1 to 3 characterized in that the substance can act as a product. or the cosmetic formulation described in 2. 4. The above R1, R2, R3 and R4 are ethylene or propylene oxide polymers. polymerization, which imparts the desired lipophilic balance to the active molecule according to its degree of polymerization. 3. Cosmetic formulation according to claim 1 or 2, characterized in that: 5. The agent is thiodipropionic acid, or dithiodipropionic acid, or thiodipropionic acid. Oditartrate, or dithiodiglycolic acid, or carboxymethyl mercapto Characterized by being an ester or amide of tartaric acid or alkylthioacetic acid Cosmetic formulation according to claim 1, 2, 3 or 4. 6. The active substance is intended to be used together with customary antioxidants (free radical scavengers). Cosmetic formulation according to claims 1, 2, 3, 4 or 5, characterized in: