AU690075B2 - Use of radical catchers as immunomodulating agents in cosmetic and dermatological compositions - Google Patents

Abstract

Cosmetic or dermatological compositions for treating and/or preventing UVB radiation-induced immunosuppression are characterised by a therapeutically or cosmetically effective content of one or several radical catchers, as well as by the use of one or several cosmetically or dermatologically acceptable radical catchers for the cosmetic or dermatological treatment and/or prevention of UVBradiation-induced immunosuppression. The radical catchers are chosen from the group of thiols and/or thiol derivatives, that of tocopherols and derivatives thereof, and that consisting of 2,4-0-Furfurylidensorbitol and/or its alkyl ethers.

Description

INTERNATIONAL ANOUNCEMEITOTHETER PUBLCATION tTRAG 0 INTERNATIONAL OF INTERNATIONAL SEARCH REPORTS NTWESE (51) Internationale Patentklassiikatlon Iinternationale Verliffentlichungsnumnmer: A6lK 7/42, 31/40 31/13, 31/415 )A3 (43) Internationalcs 3115,3 /353134, 7/48 43 Verilflentlichungsdatumn: 3 IBER DIE NS (PCT) WO 94/041281 M~irz 1994 (03.03.94) (21) Internationales Aktenzeichen: PCT/DE93/00773 (22) Intcrnationales Annicldedatum: 24. August 1993 (24.08,93) Prioritfitsdaten: P 42 28455A4 P 43 05788.8 26. August 1992 (26.08.92) 25. Februar 1993 (25.02.93) (74) Gemeinsamer Vertreter: BEI ERS DORF AG; tUnnastrage 48, D-20245 Hamburg (DE).

(81) Bestimmungsstaaten: AU, JP, US, europ,,Iiscbes Patent (AT, BE, CH, DE, I)K, ES, FR, GB, GR, JE, IT, LU, MC, NL, PT, SE).

Vcr~ffcntlicht AM intcrnattnalen Rec/erclwnbericht.

Vor Ablauf der ffur Anderungen der Ansprihe zutgelassen Frist. Ver6ffentlichung ivird wiederzog falls Anderungen eintrcffcn.

(88) Veritfentlichuiigsdaturn des internationalen Recherchenberichts: 7. Juli 1994 (07.07.94) (71) Anmelder (ftir alle Bestimnnungssraaten ausser LUS): BEl- ERSDORF AG [DE/DE]; Unnastraae 48, D-20245 Hamburg RIJKSUNIVERSITEIT LEIDEN [NL/ NQ]; Stationsweg 46, NL-2312 Av Leiden (NL).

(72) Erfinder; und Erfinder/Anmelder (nur filr US) .DEOWERT, Joachim [DE/DE]; Am Buchweg 9, D-21255 Tostedt (DE).

GERS-BARLAG, Heinrich rDE/DE]; Heisterpohl 14, D-25495 Kummerfeld VAN DEN BROEKE, Loen, T. INL/NL]; Boerhaavelaan 264, NL-:2334 EZ Leiden VAN BEIJERSI3ERGEN VAN HENEGOU-: WEN, Gerhard, J. INL/NL]; Tollweide 2, NL-2396 VL Koudekerk a/d Rijn (NL).

I 007l (54)Title: USE OF RADICAL CATCHERS AS IMMUNOMODULATING AGENTS IN COSMETIC AND DERMATO- LOGICAL COMPOSITIONS (54) Bezeichnung: VERWENDUNG VON RADIKALFANGERN ALS IMMUNMODULIERENDE AGENTIEN IN KOS- METISCH EN UND DERMATOLOG ISCHEN ZUBEREITUN GEN (57) Abstract Cosmetic or dermatological compositions for treating and/or preventing UVI3 radiation-induced immunosuppression are characterised by a therapeutically or cosmetically effective content of one or several radical catchers, as well as by the use of one or several cosmetically or dermatologically acceptable radical catchers for the cosmetic or dermatological treatment and/or prevention of UVllradiation-induced immunosuppression. The radical catchers are chosen from the group of thiols and/or thiol derivatives, that of tocopherols and derivatives thereof, and that consisting of 2,4-0-Furfurylidensorbitol and/or its alkyl ethers.

(57) Zusammenfassung Kosmetische oder dermatclogische Zubereitungen zur Behandlung und/ode Prophylaxe der durch UVB-STrahlung induzierten Immunsuppression, gekennzeichnet durch einen therapeutisch oder kosmetisch wirksamen Gehalt an einem oder mehreren Radikalfingern sowie die Verwendung eines oder mehrerer kosmetisch oder dermatologisch unbedenklicher RadikalfAnger zur kosmctischen oder dermatologischen Behandlung und/oder Prophylaxe der durch UVB-STrahlung induzierten Immunsuppression. Die Radikalflinger werden gewllhlt aus der Gruppe der Thiole und/oder Thiolderivate, aus der Gruppe der Tocopherole und ihrer Derivate sowie aus der Gruppe bestehend aus 2,4-0-Furfurylidensorbitol und/oder seinen Alkylethern.

Beiersdorf Aktiengesellschaft Hamburg Description Use of free radical scavengers as inmunomodulating agents in cosmetic and dermatological preparations The present invention relates to active compounds and preparations containing such active compounds, for the cosmetic or dermatological treatment and/or prophylaxis of inflammatory, allergic or aut:oizmunoreactive symptoms, in particular dermatoses.

As a barrier organ of the human body, the skin, in particular the epidermis, is subjected to external effects to a particular extent. According to present scientific understanding, the skin represents an imimunological organ which, as inimunocompetent peripheral.

compartment, plays its own part in inductive, effective and regulative immune processes of the whole body.

Under the physical environmental influences, light has an important position. The harmful action of the ultraviolet part of the solar radiation on the skin is generally known. While rays having wavelengths of less than 290 =m (the so-called !3VC range) are absorbed by the ozone layer in the earth's atmozphere, rays in the range between 290 and 320 nim, the so-called UVB range, cause erythema, simple sunbu-1 or even more or less extensive burns. The relatively narrow range around 308 rim is given as a maximum of the erythema activity of sunlight.

Ultraviolet light of the wavelength range between about 320 and 400 rim (UVA range) can likewise cause subsequent damage to the skin. It has thus been proved that even U.VA radiation leads to damage to the elastic and collagen fibres of the connective tissue, which can prematurely age the skin (so-called photoageing) and that it is to be regarded as a cause of numerous phototoxic and photoallergic reactions. The harmful influence of the UVB radiation can be increased by UVA radiation.

In the development of topical sunscreens, the UVE radiation is of particular interest, since the spectrum 2 of action for the acutely inflammatory processes (sunburn) and chronic damage (photoageing) resides here.

In addition to these effects, under the action of UVB a serious change in the intraepidermal immunological situation can additionally occur, which is called UVBinduced immunosuppression. Under certain circumstances, depending on the dose of radiation, far-reaching changes in the immunological processes of the skin, with both local and systemic effects, are possible consequences here.

Immunosuppression, in general, is the suppression or attenuation of the reactivity of the immune system.

The UVB-induced immunosuppression can be broken down into local and systemic effects. In the end it comprises a multiplicity of very different aspects, which all include a reduction in the normal immunological defence mechanisms of the skin. Thus in the UVB-irradiated mice model, the relationship of increased tumour growth to immunosuppressant action of the UVB light were connected even at a very early stage. This UVB-induced immunosuppression is nowadays discussed as the mechanism by means of which UVB-induced neoplastic cells which are highly immunogenic per se evade the immunological defence, and thus their own destruction.

Furthermore, under UVB irradiation a great decrease in the contact hypersensitivity reaction to some skin-sensitizing agents occurs. The reason for this could lie in a drastic decrease in the number of epidermal Langerhans cells and/or a change in their morphology and functionality. Langerhans cells, however, represent the afferent arm of the immunological defence of the skin.

Effective defence reactions against infectious microorganisms such as e.g. Candida albicans or Herpes simples [sic] also cease.

Finally, as a consequence of dermatologically relevant UVB exposure, the expression of the "intercellular adhesion molecule-l" in epidermal keratinocytes is suppressed. This cell-surface glycoprotein (also called ICAM-1) is one of the most important cellular

I,

3communication structures by means of which direct cellcell contacts between epidermal keratinocytes and leucocytes such as, e.g. T lymphocytes and monocytes, are regulated.

The UVB-induced immunosuppression thus relates to a broad spectrum of immunological dysfunctions which result in a reduction in the normally occurring defence reactions.

It is in fact widely known to use absorbing agents, namely the the [sic] customary lightscreen substances, ag.,inst the immediate action of the ultraviolet radiation: For protection against the rays of the UVA range, for example, nainly derivatives of dibenzoylmethane are used.

For protection against UVB radiation, many compounds are known which are mainly derivatives of 3-benzylidenecamphor, of 4-aminobenzoic acid, of cinnamic acid, of salicylic acid, of benzophenone and also of 2-phenylbenzimidazole.

It was also furthermore known to employ free radical scavengers as agents acting against photooxidative symptoms in the skin induced by UV radiation.

As is known, such photochemical reaction products are mainly free radical compounds, for example hydroxyl radicals. Even undefined free radical photochemical products which are formed in the skin itself may show uncontrolled subsequent reactions on account of their high reactivity. However, even singlet oxygen, a non-free radical excited state of the oxygen molecule, can occur on UV irradiation, as well as short-lived epoxides and many others. Singlet oxygen, for example, is distinguished compared with the normally present triplet oxygen (free radical ground state) by increased reactivity. However, excited, reactive (free radical) triplet states of the oxygen molecule also exist.

Thus it has already been proposed to employ vitamin E, a substance having a known antioxidative action, in lightscreen formulations. The background, -II II 4 however, was always UV protection by means of light absorption or protection against photooxidative processes.

It was therefore an object of the present invention to make available active compounds and preparations containing such active compounds, with the aid of which effective prophylaxis against the UVB immunosuppression can be produced the immune system already damaged by the UVB immunosuppression can be strengthened again.

It was surprising and, for the person skilled in the art, not to be foreseen that the cosmetic or dermatological preparations for the treatment and/or prophylaxis of the immunosuppression induced by UVB radiation, characterized by a therapeutically or cosmetically active content of free radical scavengers and the use of cosmetically or dermatologically acceptable free radical scavengers for the cosmetic or dermatological treatment and/or prophylaxis of the immunosuppression induced by UVB radiation would represent the solution to these objects.

Particularly advantageous free radical scavengers according to the invention are those selected from the thiol and/or thiol derivatives group, from the tocopherols group and their derivatives and from the group consisting of 2,4-0-furfurylidenesorbitol and/or its alkyl ethers.

Preparations which contain N-acetylcysteine acting as bronzing agents were in fact disclosed in EP-A 219 455. In particular, this specification refers to the fact that N-acetylcysteine should promote pigment formation and should be employed mainly for this purpose.

A certain additional antierythematous action, which is claimed loc. cit., would make it suitable for cosmetic preparations. This specification, however, does not teach the advantageous properties of the present invention, namely the advantages outlined above.

In EP-A 138 262 a combination of panthenol, ill 5 carrageenan and compounds selected from the group consisting of methionine, cysteine, N-acetylcysteine, Sacetylcysteine and also other constituents is [lacuna].

This combination is used for the treatment of eczema and dishydrosis [sic] caused by sunlight. No teaching is provided even by this specification which could point in the direction of the present invention.

Thiols in the sense of the present inventions [sic] are to be understood as meaning organic compounds which are distinguished by the -SH group. Thiol deryvatives within the meaning of the present invention are organic compounds which are either derivatives retaining the -SH group or else thioethers or thioesters, the -SH group then being converted to the -SR group.

As with the thiols or thiol derivatives according to the invention those compounds are to be understood within the meaning of the present invention as being identical which are formed by tautomerism, di- or oligomerization by hydrogen bonding, hydration or other spontaneous rearrangement from the thiols or thiol derivatives according to the invention. If a derivative is in equilibrium with an isomer as a result of another type of rearrangement, for example an alkyl group migration, this isomer counts as beiig included in the thiols and thiol derivatives according to the invention.

If several mesomeric or tautomeric forms are conceivable with the thiols according to the invention, as is customary in chemistry one only mesomeric or tautomeric form is given for characterization.

Preferred thiols are

H

0 0

F

0=C C C C S-H C N C S-H H 2 N C C C

C

(Captopril) (Cysteamine) I II 6 0 C C C C C 0-H N N Me-N+Me C Me

-H

(Ergothioneine)

NH

t 2 Me C- OH Me-C C SH 0 S-H 0 S-H H 0 I It C N C Me C C It 0 (Mercaptopropionylglycine) 0

C

0-H C S-H

H

2 N C (Penicillamine) (Cysteine) The hydrogen atoms on the carbon atoms in this description are mainly omitted for the sake of simplicity. In order to avoid uncertainties, a departure is made from this simplification in the case of derivatives and groups are more accurately characterized where it appears useful: e.g. Me methyl) or Et ethyl).

Particularly preferred derivatives within the meaning according to the invention are derived from the basic structure cysteine as follows: 0. X RHN C The radical X can be selected from the group and -NRR'. The radicals R, R' and R" independently of one another are: H, C 1 .,-alkyl or -alkenyl or CIa 1 acyl.

It is preferred here to select the organic radicals such that the organic radicals R, R' and R" ~IIL I ~ILIIY _I _sa 7independently of one another are: H, ethyl or acetyl. X can additionally advantageously symbolize the group -NH 2 However, it may also be advantageous to select the thiol derivatives according to the invention from the following group: X 0 0 C C C C S-R' O N/ C N C S-R RR"N C C C

C

0 C C S-R R' 0 I I tf C C C X C N C N MeN Me Me C C X Me 0

S-R

NR'

Me C X N Me-C C S-R '0.

The radical X can be selected from the group and -NRR'. The radicals R, R' and R" independently of one another are: H, C 1 1 ,,-alkyl or -alkenyl or

C

1 1 a-acyl.

It is preferred here to select the organic radicals such that the organic radicals R, R' and R" independently of one another are: H, ethyl or acetyl. X can advantageously symbolize the group -NH 2 The salts or acid or base adducts of the thiols or thiol derivatives according to the invention are also advantageous.

Examples of particularly preferred thiols or thiol derivatives according to the invention are eL I I-' -8 0 0-H 0 C Me' N~ c

H

(N-Acetylcysteine) 0 0-H C s ME H N C c H 0 (S-acetylcysteine) 0 0-H

S-H

Compound I Compound 11' s c me' S-Diacetylcysteine) 0 NH 2 0 C Me el N C C i

II

H 0 S-Diacetylaystinamide) Compound III Compound IV 9 0 0-Et

C

C S-H

H

2 N' C (Cysteine ethyl ester) Compound V 0 0-Et 0 C C C S-H Me/ Me N C

H

(N-Acetylcysteine ethyl ester) Compound VI 0 1 O-Et

C

C S Me S\

H

2 N C C 2 If 0 (S-Acetylcysteine ethyl ester) Compound VII 0 0-Et 0 C 1 I C C S Me Me N C C I I H 0 (N,S-Diacetylcysteine ethyl ester) Compound VIII The salts or acid or base adducts of these particularly preferred thiols or thiol derivatives are also preferred.

Free radical scavengers which are advantageous according to the invention are also to be understood as meaning 2,4-O-furfurylidenesorbitol and/or its alkyl S ethers.

L1 L~I -Q I I~bll 10 2,4-0-Furfurylidenesorbitol is synonymous with the names 2,4-0-furfurylideneglucitol, 2,4-0-(2-furanylmethylene)glucitol and 2,4-monofurfurylidenesorbitol. It is distinguished by the following structure: H H CH -O-R 1 C--C H-C/ C--C-H H-C-O-R 2 0 3 1 R -O-C-H CH2-O-R4 and is to be retrieved in Chemical Abstracts under the registry number 7089-59-0.

R

1 4 according to the invention, independently of one another are H, methyl groups and/or ethyl groups.

Particularly preferably according to the invention, R 1 4 are identical and ard H or methyl groups.

(2,4-Monofurfurylidene-tetra-O-methyl-sorbitol).

The configuration of the four asymmetric carbon atoms in the part of the molecule derived from sorbitol preferably corresponds to that of the carbon atoms in natural sorbitol, although the other stereoisomers are fundamentally also advantageous.

The configuration of the asymmetric carbon atom of the furfurylidene group can equally advantageously be R or S. A racemate of R and S configuration, relative to this carbon atom, is particularly advantageous according to the invention.

Moreover, the free radical scavengers according to the invention can advantageously be selected from the group of customary cosmetic and dermatological free radical scavengers, in particular from the group consisting of tocopherols and their derivatives, particularly a-tocopherol and a-tocopheryl esters, in particular .L a-tocopheryl acetate, also sesame oil, bile [sic] acid I ~ell, ~IIIIA- a r ICl~lrr~ l 11 derivatives such as methyl, ethyl, propyl, amyl, butyl and lauryl gallate, the conyferylbenzoate [sic] of benzoin, butylhydroxyanisole, butylhydroxytoluene, citric acid, phosphoric acid, lecithin, trihydroxybutyrophenone, carotenes, vitamin A and its derivatives, in particular retinyl palmitate, ascorbic acid, ascorbyl palmitate, dilauryl thiodipropionate, distearyl thiodipropionate, monoisopropyl citrate, phytic acid and its salts, thiodipropionic acid and EDTA and EDTA derivatives.

The tocopherols, also called vitamin E, are derived from the basic structure tocol ((2-methyl-2- (4,8,12-trimethyltridecyl) chroman-6-ol) and are characterized by the following structures:

R

C CH 2 C C CH2 CH3 CH3 CH3 SC C CH CH CH CH CH CH C 0 CH 2

CH

2

CH

2

CH

2

CH

2

CH

2 CH3 R"

CH

3 K here is either H or an acyl radical, R, R' and R" independently of one another are H or a methyl group, e.g.: R R' R" K H tocol R R' R" methyl, K H a-tocopherol R R' methyl, R' K H P-tocopherol R R' R" methyl, K -C-CH 3 a-tocopherol acetate

II

0 and further variants. In these esters, the following holds good for the acyl radical K: K

(I

0 where can be an alkyl or alkenyl radical having 1 to 21 atoms. is particularly preferably methyl.

The naturally most frequently occurring and most important a-tocopherol is ascribed the configuracion I t~ r;~Y~t~C~QI~~ I ~I *I 12 2R,4'R,8'R. It is occasionally also illed RRR-atocopherol.

The tocopherol derivatives preferred according to the invention are a-tocopherol and its esters, in particular a-tocopheryl acetate.

It is disclosed in EP Patent Application 345 362 to employ 2,4-furfurylidenesorbitol in cosmetic and dermatological formulations in such formulations it is used primarily as a scavenging agent for free radicals which can be produced, inter alia, by UV radiation [sic].

The use according to the invention of 2,4-furfurylidenesorbitol for the cosmetic or dermatological prophylaxis of the immunosuppression induced by UVB radiation was not suggested, however, by the prior art.

It is also disclosed in US Patent 4,144,325 and 4,248,861 and in numerous other documents to employ vitamin E in cosmetic and dermatological lightscreen formulations.

The use according to the invention of vitamin E and its derivatives for the cosmetic or dermatological prophylaxis of the immunosuppression induced by UVB radiation was not suggested, however, by the prior art.

The cosmetic and/or dermatological formulations according to the invention can be made up in the customary manner and used for the prophylaxis and/or for the treatment of the skin within the meaning of a dermatological treatment or of a prophylaxis and/or treatment within the meaning of cosmetics. However, they can also be employed in make-up products in decorative cosmetics.

They preferably contain 0.01 by weight to 10 by weight, but in particular 0.1 by weight to 6 by weight, relative to the total weight of one or more free radical scavengers.

It is particularly advantageous according to the invention to use combinations of several free radical scavengers, in particular if at least one of the components is selected from the thiol and/or thiol derivatives group and 2,4-0-furfurylidenesorbitol and its alkyl Bt. ethers.

I

13 It is particularly advantageous to use combinations of 2,4-0-furfurylidenesorbitol or its alkyl ethers and one or more tocopherols or its [sic] derivatives.

For use, the free radical scavengers or preparations according to the invention containing such free radical scavengers, preferably ore or more thiols or thiol derivatives or one or more tocopherols or their derivatives or 2,4-0-furfurylidenesorbitol or its alkyl ethers, are applied to the skin in sufficient amount in the manner customary for cosmetics or dermatics.

Those cosmetic and dermatological preparations are particularly preferred which are present in the form of a sunscreen composition. Advantageously, these additionally contain at least one UVA filter and/or at least one UVB filter and/or at least one inorganic pigment.

Cosmetic preparations according to the invention for the protection of the skin from UV rays can be present in various forms, such as e.g. are customarily employed for this type of preparations. They can thus be e.g. a solution, an emulsion of the water-in-oil type or of the oil-in-water type or a multiple emulsions [sic], for example of the water-in-oil-in-water type a gel, a hydrodispersion, a solid stick or even an aerosol.

The cosmetic preparations according to the invention can contain cosmetic auxiliaries such as are customarily used in such preparations, e.g. preservatives, bactericides, perfumes, agents for preventing foaming, colorants, pigments which have a colouring effect, thickening agents, surface-active substances, emulsifiers, plasticizing substances, moisturizing and/or moisture-retaining substances, fats, oils, waxes or other customary constituents of a cosmetic formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

If the cosmetic or dermatological preparation is a solution or lotion, the solvent used can be: water or aqueous solutions; oils, such as triglycerides of capric or caprylic ll~rrm 14 acid, but preferably castor oil; fats, waxes and other natural and synthetic fatty compounds, preferably esters of fatty acids with alcohols of low C number, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids; alcohols, diols or polyols of low C number, and also their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products.

In particular, mixtures of the abovementioned solvents are used. In the case of alcoholic solvents water can be a further constituent.

Emulsions according to the invention e.g. in the form of a sunscreen cream, a sunscreen lotion or a sunscreen milk, are advantageous and contain e.g. the fats, oils, waxes and other fatty compounds mentioned, as well as water and an emulsifier, such as is customarily used for such a type of formulation.

Gels according to the invention customarily contain alcohols of low C number, e.g. ethanol, isopropanol, 1,2-propanediol, glycerol and water or an abovementioned oil in the presence of a thickening agent which, in the case of oily-alcoholic gels, is preferably silica or an aluminium silicate, in the case of aqueousalcoholic or alcoholic gels, preferably a polyacrylate.

Solid sticks according to the invention contain e.g. natural or synthetic waxes, fatty alcohols or fatty acid esters. Lip-care sticks are preferred.

Suitable propellants for cosmetic or dermatological preparations according to the invention which can be sprayed from aerosol containers are the customary known readily volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which can be employed on their own or in a mixture with one I L Ir 15 another. Compressed air can also be used advantageously.

Of course, the person skilled in the art knows that there are per se non-toxic propellent gases which would be fundamentally suitable for the present invention which, however, should nevertheless be ignored, in particular fluorohydrocarbons and fluorochlorohydrocarbons (CFCs), because of questionable action on the environment or other attendant circumstances.

Preferably, the preparations according to the invention can additionally contain substances which absorb the UV radiation in the UVB range, the total amount of -the filter substances being e.g. 0.1 by weight to 30 by weight, preferably 0.5 to 10 by weight, in particular 1 to 6 by weight, relative to the total weight of the preparation, in order to make available cosmetic preparations which protect the skin from the entire range of the ultraviolet radiation. They can also be used as sunscreens.

The UVB filters can be oil-soluble or watersoluble. Oil-soluble substances which can be mentioned are, e.g.: 3-benzylidenecamphor derivatives, preferably 3-(4methylbenzylidene)camphor, 3-benzylidenecamphor; 4-aminobenzoic acid derivatives, preferably 2-ethylhexyl 4-(dimethylamino)benzoate, amyl 4-(dimethylamino)benzoate; esters of cinnamic acid, preferably 2-ethylhexyl 4-methoxycinnamate, isopentyl 4-methoxycinnamate; esters of salicylic acid, preferably 2-ethylhexyl salicylate, 4-isopropylbenzyl salicylate, homomenthyl salicylate; derivatives of benzophenone, preferably 2-hydroxy-4methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone; I xlu*~ rmm~ lla~-rrCsll~-r~~ 311111111R~llC111 h-rn 16 esters of benzylidenemalonic acid, preferably 2-ethylhexyl 4-methoxybenzylidenemalonate; 2,4,6-trianilino-(p-carbo-2'-ethyl-l'-hexyloxy)- 1,3,5-triazine.

Water-soluble substances which may be mentioned are, e.g.: salts of 2-phenylbenzimidazole-5-sulphonic acid such as its sodium, potassium or triethanolammonium salt, and also the sulphonic acid itself; sulphonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone-5-sulphonic acid and their salts; sulphonic acid derivatives of 3-benzylidenecamphor, such as e.g. 4-(2-oxo-3-bornylidenemethyl)benzenesulphonic acid, 2-methyl-5-(2-oxo-3-bornylidenemethyl)su3phonic acid and their salts.

The list of the UVB filters mentioned, which can be used in combination with the free radical scavengers according to the invention, is of course intended to be non-limiting.

The invention also relates to the combination of one or more free radical scavengers according to the invention with one or more UVB filters or cosmetic or dermato-logical preparations according to the invention, which also contain one or more UVB filters.

It can also be advantageous to combine one or more free radical scavengers according to the invention with UVA filters which to date are customarily contained in cosmetic and/or dermatological [lacuna]. These substances are preferably derivatives of dibenzoylmethane, in particular 1-(4'-tert-butylphenyl)-3-(4'-methoxyphenyl)propane-l,3-dione and l-phenyl-3-(4'-isopropylphenyl)propane-1,3-dione. The invention also relates to these combinations or preparations which contain these preparations. The amounts used for the UVB combination can be employed.

~-~111~11~ Ir q r 17 Advantageous preparations are also obtained if the free radical scavengers according to the invention are combined with UVA and UVB filters.

Cosmetic preparations containing free radical scavengers according to the invention can also contain inorganic pigments which are customaril.y used in cosmetics for the protection of skin from UV rays. These are oxides of titanium, zinc, iron, zirconium, silicon, manganese, aluminium, cerium and mixtures thereof, as well as modifications in which the oxides are the active agents. They are particularly preferably pigments based on titanium dioxide.

The invention also relates to these combinations of UVA filters and/or UVB filters and pigment [sic] or preparations which contain this combination. The amounts mentioned for the above combinations can be used.

Cosmetic preparations for the protection of the scalp from UV rays according to the invention are, for example, shampooing compositions, preparations which are used in rinsing the hair before or after shampooing, before or after permanent waving, or before or after dyeing or bleaching the hair, preparations for drying or setting the hair, preparations for dyeing or bleaching, a hairdressing or treatment lotion, a hair lacquer or permanent waving composition. The cosmetic preparations contain active compounds and auxiliaries, such as are customarily used for this type of preparations for hair care and hair treatment. Auxiliaries used are preservatives, surface-active substances, substances for preventing foaming, emulsifiers, thickening agents, fats, oils, waxes, organic solvents, bactericides, perfumes, dyes or pigments whose object is to colour the hair or the preparation itself, electrolytes, preparations against the hair becoming greasy.

Cosmetic preparations which are a shampooing composition preferably contain at least one anionic, nonionic or amphoteric surface-active substance or mixtures thereof, at least one free radical scavenger according to I the invention in the aqueous medium and auxiliaries, such 1 I 131)1 I*"ICrrCIIIIII~-~---I 18 as are customarily used therefor. The surface-active substance can be present in a concentration of between 1 by weight and 50 by weight in the shampooing composition.

If the cosmetic or dermatological preparation is present in the form of a lotion which is rinsed out and applied e.g. before or after bleaching, before or after shampooing, between two shampooing steps, or before or after permanent wave treatment, it is in this case, e.g.

aqueous or aqueous-alcoholic solutions which optionally contain surface-active substances, preferably non-ionic or cationic surface-active substances whose concentration can be between 0.1 and 10 by weight, preferably between 0.2 and 5 by weight. This cosmetic or dermatological preparation can also be an aerosol containing the auxiliaries customarily used therefor.

A cosmetic preparation in the form of a lotion which is not rinsed out, in particular a lotion for setting the hair, a lotion which is used in drying the hair, or a hairdressing and treatment lotion, is in general an aqueous, alcoholic or aqueous-alcoholic solution and contains at least one cationic, anionic, nonionic or amphoteric polymer or even mixtures thereof, and at least one free radical scavenger according to the invention. The amount of the polymers used is e.g.

between 0.1 and 10 by weight, preferably between 0.1 and 3 by weight.

All quantitative data, proportions and percentages are related, if not stated otherwise, to the weight and the total amount or to the total weight of the preparations.

The following examples are intended to clarify the present invention without restricting it.

Example 1 by weight Cyclomethicone 2.000 Cetyldimethicone copolyol 0.200 PEG-22 dodecyl copolymer 3.000 S Liquid paraffin (GP 9) 2.000 I lr Csa~l mrslrrrr*ramr~l*r~~~ 19 Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylmethoxydibenzoylmethane Compound I ZnSO 4 Na 4

EDTA

Perfume, preservative, colorants Demineralized water Example 2 Cyclomethicone Cetyldimethicone copolyol PEG-22 dodecyl copolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylmethoxydibenzoylmethane Compound II ZnSO 4 Na 4

EDTA

Perfume, preservative, colorants Demineralized water 5.800 5.800 4.000 0.300 0.700 0.300 desired 100.000 by weight 2.000 0.200 3.000 2.000 5.800 5.800 4.000 0.500 0.700 0.300 as desired to 100.000 Example 3 Cyclomethicone Cetyldimethicone copolyol PEG-22 dodecyl ccpolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylmethoxydibenzoylmethane Compound III ZnSO 4 Na 4

EDTA

Perfume, preservative, colorants Demineralized water by weight 2.000 0.200 3.000 2.000 5.800 5.800 4.000 2.500 0.700 0.300 as desired to 100.000 IIld at -r 20 Example 4 Cyclomethicone Cetyldimethicone copolyol PEG-22 dodecyl copolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylmathoxydibenzoylmethane Compound IV ZnSO 4 Na 4

EDTA

Perfume, preservative, colorants Demineralized water Example Cyclomethicone Cetearyl alcohol castor oil sodium cetearyl sulphate Glyceryl lanolate Caprylic acid/capric acid triglyceride Laurylmethicone copolyol Octyl stearate Castor oil Glycerol Acrylamide/sodium acrylate copolymer Hydroxypropylmethylcellulose Octyl methoxycinnamate Butylmethoxydibenzoylmethane Compound V Na3HDTA [sic] Perfume, preservative, colorants Demineralized water Example 6 Cyclomethicone Cetearyl alcohol castor oil by weight 2.000 0.200 3.000 2.000 5.800 5.800 4.000 3.000 0.700 0.300 as desired to 100.000 2.000 2.500 1.000 0.100 2.000 3.000 4.000 3.000 0.300 0.300 5.000 0.500 1.750 1.500 as desired to 100.000 2.000 1 la 'L II I~F~Trr~ C 11III 1IIC~; 21 sodium cetearyl sulphate 2.500 Glyceryl lanolate 1.000 Caprylic acid/capric acid triglyceride 0.100 Laurylmethicone copolyol 2.000 Octyl stearate 3.000 Castor oil 4.000 Glycerol 3.000 Acrylamide/sodium acrylate copolymer 0.300 Hydroxypropylmethylcellulose 0.300 Octyl methoxycinnamate 5.000 Butylmethoxydibenzoylmethane 0.750 Compound VI- 2.500 Na 3 HTA [sic] 1.500 Perfume, preservative, colorants as desired Demineralized water to 100.000 Example 7 Cyclomethicone 2.000 Cetearyl alcohol castor oil sodium cetearyl sulphate 2.500 Glyceryl lanolate 1.000 Caprylic acid/capric acid triglyceride 0.100 Laurylmethicone copolyol 2.000 Octyl stearate 3.000 Castor oil 4.000 Glycerol 3.000 Acrylamide/sodium acrylate copolymer 0.300 Hydroxypropylmethylcellulose 0.300 Octyl methoxycinnamate 5.000 Butylmethoxydibenzoylmethane 1.000 Compound VII 0.700 Na 3 MA [sic] 1.500 Perfume, preservative, colorants as desired DeminAralized water to 100.000 Example 8 Cyclomethicone 2.000 Cetearyl alcohol rr -1 I dlDBF--UP~c I 22 castor oil sodium cetearyl sulphate 2.500 Glyceryl lanolate 1.000 Caprylic acid/capric acid triglyceride 0.100 Laurylmethicone copolyol 2.000 Octyl stearate 3.000 Castor oil 4.000 Glycerol 3.000 Acrylamide/sodium acrylate copolymer 0.300 Hydroxypropylmethylcellulose 0.300 Octyl methoxycinnamate 5.000 Butylmethoxydibenzoylmethane 0.500 Compound VIII 1.600 Na3HTA [sic] 1.500 Perfume, preservative, colorants as desired Demineralized water to 100.000 The following details on the compositions of the active compound combinations I V relate to the total weight-of the active compound combinations.

Active compound combination I by weight Furfurylidenesorbitol 10.00 Vitamin E acetate 90.00 Active compound combination II by weight Furfurylidenesorbitol 25.00 Vitamin E acetate 75.00 Active compound combination III by weight Furfurylidenesorbitol 50.00 Vitamin E acetate 50.00 Active compound combination IV by weight Furfurylidenesorbitol 75.00 Vitamin E acetate 25.00 Active compound combination V by weight Furfurylidenesorbitol 90.00 Vitamin E acetate 10.00 Example 9 by weight Cyclomethicone 2.000 u s r, I I 23 Cetyldimethicone copolyol PEG-22 dodecyl copolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylmethoxydibenzoylme thane Active Compound Combination I ZnSO 4 Na 4

EDTA

Perfume, preser-vative, colorants Demineralized water 0.200 3.000 2.000 5.800 5.800 4.000 0.300 0.700 0.300 as desired to 100.000 Exampl1e -Cyclomethicone Cetyldimethicone copolyol PEG-22 dodecyl copolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylmethoxydibenzoylmethane Active Compound Combination 11 ZnSO, *NaEDr; Perfumez, preservative, colorants Demineralized water %by weight 2.000 0.200 3.000 2.000 5. 800 5.800 4.000 0.500 0.700 0.300 as desired to 100.000 Example 11 Cyclomethicone Cetyldimethicone copolyol PEG-22 dodecyl copolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxyc.iniamate Bu tylme thoxydibenz oylme thane Active Compound Combination III ZnSO 4 Na 4

EDTA

by weight 2.000 0.200 3.000 2.000 5.800 5.800 4.000 2.500 0.700 0.300 24 Perfume, preservative, colorrxits Demineralized. water Exampile 12 as desired to 100.000 Cyclomethicone Cetyldimethicone copolyol PEG-22 dodecyl copolymer Liquid paraffin (GP 9) Caprylic acid/capric acid triglyceride Octyl methoxycinnamate Butylme thoxyldibenzoylmethane Active compound combination IV ZnSQ 4 -Na 4

EDTA

Perfume, preservative, colorants Dexpineralized water Examt~le 13 Cyclomethicone Cetearyl alcohol PEG-40-hydrogenated castor oil sodium cetearyl sulphate *G-"-,reryl lanolate Caprylic acid/capric acid triglyceride Laurylmethicone copolyol Octyl stearate Castor oil Glycerol Acrylamide/sodium acrylate copolymer Hydroxypropylmethylcellulose Octyl methoxycinnamate Butylme thoxydibenzoylmethane Active compound combination V Na 3 1.TA (sic] Perfume, preservative, colorants Demineralized water by weight 2.000 0.200 3.000 2.000 5.800 5.800 4.000 3 .000 0.700 0.300 as desired to 100.000 2.000 2.500 1.000 0 .100 2.000 3.000 4.000 3.000 0.300 0 .300 5.000 0.500 1.750 1.500 as desired to 100.000 25 Example 14 Cyclomethicone 2.000 Cetearyl alcohol castor oil sodium cetearyl sulphate 2.500 Glyceryl lanolate 1.000 Caprylic acid/capric acid triglyceride 0.100 Laurylmethicone copolyol 2.000 Octyl stearate 3.000 Castor oil 4.000 Glycerol 3.000 Acrylamide/sodium. acrylate copolymer 0.300 Hydroxypropylmethyic ellulo se 0.3 00 Oc tyl methoxycinnaxate 5.000 Butylmethoxydibenzoylmethane 0.750 Active compound combination 1 2.500 Na 3 WTA Esic] 1.500 Perfume, preservative, colorants as desired Demineralized water to 100.000 ExgMle Cyclomethicone 2.000 Cetearyl alcohol castor oil sodium cetearyl sulphate 2.500 Glyeryl lanolate 1.000 Caprylic acid/capric acid triglyceride 0.100 Laurylmethicone copolyol 2.000 Octyl stearate 3.000 Castor oil 4.000 Glycerol 3.000 Acrylainide/sodium acrylate copolymer 0.300 Hydroxypropylme thylcellulose 0.300 Octyl methoxycinnamate 5.000 Butylme thoxydibenzoylme thane 1.000 Active compound :ombination 11 0.700 Na 3 m,?A (sic] 1.500 Perfume, preservative, colorants as desired Demineralized water to 100.000 Lnsr~lmnrL*nrr~-~l-~--~--.*r -Ic-;l---llrriml.- I 26 Example 16 Cyclomethicone 2.000 Cetearyl alcohol castor oil sodium cetearyl sulphate 2.500 Glyceryl lanolate 1.000 Caprylic acid/capric acid triglyceride 0.100 Laurylmethicone copolyol 2.000 Octyl stearate 3.000 Castor oil 4.000 Glycerol 3.000 Acrylamide/sodium acrylate copolymer 0.300 Hydroxypropylmethylcellulose 0.300 Octyl methoxycinnamate 5.000 Butylmethoxydibenzoylmethane 0.500 Active compound combination III 1.600 Na 3 DTA [sic] 1.500 Perfume, preservative, colorants as desired Demineralized water to 100.000 Demonstration of action: The c.dvantageous properties of the present invention are intended to be clarified below with the aid of a test.

The UVB mixed lymphocyte reaction method (UVB- MLR) was used as a model for the immunosuppressant action of the UVB radiation. The UVB-MLR is a method to analyse effects of test substances on the UVB-induced suppression of a cellular immune response. It is a modification of the MLR, an immunological in vitro standard process, whi-h is used as a measure of the activation and functionalization of the T lymphocyte system.

To this end, the test substances are added to the cell cultures in various concentrations. The irradiation source used was a Phillips TL 20W/12 lamp.

7.5 mJ UVB/cm 2 15 mJ UVB/cm 2 and 30 mJ UVB/cm 2 were employed as irradiation dose.

Mononuclear cells of the peripheral blood of two healthy human donors are purified by means of density I I~ I IZLs~- 27 gradient centrifugation and cultured together in microtitre plates. The individual culture is composed in this case of 3.0 x 105 mitocytin-treated stimulator cells (donor A) and 2.5 x 105 responder cells (donor B) (incubation at 37 0 C, 7.5 CO,, 10 FCS (foetal calf serum) in RPMI 1640 medium).

In a "one-way" MLR, the stimulator cells are physiologically stopped by the treatment with mitocytin such that only they are used as the cellular antigen for the responder cells, whose proliferation is determined via the incorporation of 3 H-thymidine. The responder cells are -no longer recognized as antigen by the stimulator cells.

The incorporation of 3 H-thymidine is analysed after separation of all cells, i.e. stimulator and responder cells. The amount of incorporated 3 H-thymidine correlates with the ability for immune response: the less 'H-thymidine incorporated, the stronger the UVB immunosuppression.

In order now to determine the influence of UV light on cell proliferation (responder cells), the stimulator cells are irradiated with the appropriate UVB dose before their incubation with the responder cells. In corresponding parallel batches, the appropriate test substance is added in the culture medium during irradiation.

By [sic] Comparisons of the proliferation of the responder cells which can be achieved in the absence and presence of test substances, after co-culturing with the stimulator cells has taken place, makes possible statements about immunoprotective properties of these substances on the plane of UVB-induced immunosuppression.

Agents according to the invention active against UVB immunosupression tested in the experiment: Compounds I VIII (thiols or thiol derivatives), 2,4-0-furfurylidenesorbitol, of-tocopherol, a-tocopheryl acetate, citric acid, retinyl palmitate, ascorbic acid and ascorbyl palmitate were used as test substance.

28 Results: A significant immunoprotective action could be observed in all previously mentioned agents according to the invention active against UVB immunosuppression tested.

References to the method used: Blain, B. et al. (1964), Blood 23, p. 108 Meo, T. et al. (1975), Transplant. Proc. 7, p. 127 Mommaas, A.M. et al. (1990), J. Invest. Dermatol. 95, p.

313 Marinus, C.G. et al. (1991), J. Invest. Dermatol. 97, p.

6.29

Claims (7)

1. A method of treatment and/or prophylaxis of the immunosuppression induced by UVB radiation comprising the step of administering one or more cosmetically or dermatologically acceptable free radical scavengers.

2. A method according to claim 1, wherein one or more free radical scavengers are selected from the thiol and/or thiol derivatives group, from the tocopherols group and their derivatives, from the group consisting of 2,4-O-furfurylidenesorbitol and/or its alkyl ethers, from the group of carotenes, from the group of vitamin A and its derivatives, in particular retinyl palmitate, and also thiodipropionic acid. 10 3. A method according to claim 2, wherein the thiol or thiol derivative is selected from the compound group which is described by the generic formula 0 I I C-X H-C-C -S-R" i R-N-H oooo• the radical X being selected from the group and -NRR' and the R, R' and R" radicals independently of one another being: H, C 1 1 8 -alkyl or -alkenyl, or Cg 1 8 -acyl. b

4. A method according to claim 3, wherein the organic radicals are selected such that the radical X is selected from the group and -NRR', and in that R, R' and R" independently of one another represent: H, ethyl or acetyl. DATED this 22nd day of November, 1996 BEIERSDORF AG ANI RIJKSUNIVERSITEIT LEIDEN Attorney: IAN T. ERNST SFellow Institute of Patent Attorneys of Australia RA of SHELSTON WATERS I780.00DOC/lntm I 1 Abstract: Cosmetic or dermatological preparations for the treatment and/or prophylaxis of the immunosuppression induced by UVB radiation, characterized by a therapeuti- cally or cosmetically active content of one or more free radical scavengers and the use of one or more cosmetic- ally or dermatologically acceptable free radical scavengers for the cosmetic or dermatological treatment and/or prophylaxis of the immunosuppression induced by UVB radiation. I INTERNATIONAL, SiEAIRCII REPO(T iinti )al Appliuation No PCT/DE 93/00773 A. CLASSIFICATION OF SUBJECT MATTPER IPC 5 A61K7/42 A61K31/40 A61K31/13 A61K31/415 A61K31/195 A61K31/355 A61K31/34 A61K7/48 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classfication system followed by classification symbols) IPC 5 A61K C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during tt internatonal search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Caiegory Citation of docment, with indication, where appropriate, of the relevant passages Relevant to claim No. X FR,A,2 340 932 (SqUIBB SONS INC.) 9 1-3,7-9 September 1977 see page 13, line 25 page 14, line 28 see page 1, line 1 page 2, line X DE,A,35 42 309 (CARDONA 4 June 1987 1-4,7-9 see the whole document X EP,A,0 238 302 (CHARLES OF THE RITZ GROUPE 1-3,7-9 LTD) 23 September 1987 see the whole document X FR,A,2 666 226 (THOREL J N) 6 March 1992 1-3,7-9 see the whole document i-- Further documents are listed in the continuation of box C. Patent family members are listed in annex. 'Special categories of cted documents: SSpeial catgors of dd documnts T later document published after the international filin date or prionty date and not in conflict with the application but document defining the general state of the art which is not cit to undercand the pinciple or theoy underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority cainrrs) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report April 1994 g h. 05. 94 Name and mailing address of the ISA Authorized office European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 340-2040, Tx. 31 651 epo n, Couckuyt, P Fax: 3170) 340-3016 Form PCT/ISA/210 (second sheet) (July 1992) page 1 of 3 INTEIRNA''IONAL, 8EAC HI RUEPORT' Int /DE Aj93il007uo Nu PCT/DE 93/00773 C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVAN'T Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A A A A P,X A INTERNATIONAL JOURNAL OF COSMETIC SCIENCE vol. 12, no. 1 February 1990 LONDON pages 1 4 BADER ET AL. 'fural glucitol as free radical scavenger in the process of skin ageing' FR,A,2 233 998 (HENKEL KGAA) 17 January 1975 see the whole document DATABASE WPI Week 7801, Derwent Publications Ltd., London, GB; AN 78-00904A JP,A,52 136 925 (SANSEI SEIYAKU KK) 16 November 1977 see abstract FR,A,2 608 425 (ROFSA-CERD) 24 June 1988 see claims 1,5,13,15 WO,A,93 10755 (RICHARDSON-VICKS INC.) 10 June 1993 see page 10, line 23 page 11, line 7 see page 12, line 17 page 13, line 17; claims EP,A,0 500 332 (NATIONAL FOOD RESEARCH INSTITUTE MINISTRY OF AGRICULTURE FORESTRY) 26 August 1992 see claims 1,4,12 1,2,6-8, 12 1,2,6-8, 12 1-4,7-10 1-5,7-11 1,2,4,7, 8,10 1,2,4,7, 8,10 LI Form PCT/ISA/210 (continution of secnd sheet) (July 1992) page 3 of 3 I I I~u I1M1jY1.INA TIONAL SHARC1 I )UPORT j~ fAApU~ON tflfriiiti~ on M~fl f~~iy rembti 93/00773 Patent document I Publicaio Patent 1amil* Publlcatlon cited in search report daemember(s) date FR-A-2340932 09-09-77 US-A- AT-B- AT-B- AT-B- AT-B- AT-B- AT-B- AU-B- AU-A- BE-A- CA-A- CA-A- CA-A- CA-A- CA-A- CH-A- CH-A- CH-A- DE-A, C DE-C- GB-A- Jp-C- JP-A- JP-B- JP-c- JP-A- jp-B- JP-c- JP-A- jp-B- JP-A- NL-A- NL-A- NL-A- NL-A- NL-A- NL-A- SE-B- SE-A- SE-B- 4046889 371435 365571 365572 365573 365574 365569 509899 2134777 851361 1101864 1102337 1303255 1103256 1103257 624931 624932 622503 2703828 2759862 1576161 1281133 52116457 60004815 1336162 58189158 60059226 1331807 58169159 60056705 58189113 7701457 8104046 8104047 8104048 8104049 8104050 423812 7701561 426697

06-09-77

27-06-83 25-01-82 25-01-82 25-01-82 25-01-82 25-01-82

29-05-80 20-07-78 11-08-77 26-05-81 02-06-81 16-06-81 16-06-81 16-06-81

31-08-81 31-08-81 15-04-81 18-08-77 07-12-89 01-10-80 13-09-85 29-09-77 06-02-85 11-09-86 04-11-83 24-12-85 14-08-86 04-11-83 11-12-85 04-11-83 16-08-77 04-01-82 04-01-82 04-01-82 04-01-82 04-01-82 07-06-82 23-09-77 07-02-83 Form PCT/ISA/110 (patent family annex) (July 1992) page 1 of 3 ITiUR NJA'TIONA L SIHAR(C1I 10,10'O I-n(nnAUo OnIW~n f~fily t~hWjok nwi Applicaltin No lnfnn~en n pL~1 (rniy mmtiiiPCT/DE 93/00773 Patent document I Publication IPatent famiy I Publication cited in search report due member(s) I date EP-A-0496433 JP-A- 1265018 23-10-89 US-A-4248861 03-02-81 NONE EP-A-0313304 26-04-89 US-A- 4847072 11-07-89 AU-A- 2408388 27-04-89 DE-A- 3877690 04-03-93 JP-A- 1255014 23-10-89 EP-A-0345362 13-12-89 DE-A- 3873525 10-09-92 US-A- 5135946 04-08-92 FR-A-2233998 17-01-75 DE-A- 2331821 23-01-75 BE-A- 816691 23-12-74 CH-A- 598819 12-05-78 GB-A- 1427479 10-03-76 JP-A- 50035347 04-04-75 NL-A- 7407302 24-12-74 SE-A- 7407194 23-12-74 US-A- 3987189 19-10-76 FR-A-2608425 24-06-88 NONE WO-A-9310755 10-06-93 AU-A- 3073692 28-06-93 CN-A- 1073859 07-07-93 EP-A-0500332 26-08-92 JP-A- 5065275 19-03-93 Form PCT/ISA/210 (patent family annex) (July 1992) page 3 of 3