III III USOO5520905A United States Patent (19) 11 Patent Number: 5,520,905 Uhlmann et al. 45 Date of Patent: May 28, 1996

54 COSMETIC OR DERMATOLOGICAL 56) References Cited PREPARATION COMPRISING DELTA-AMNOLEVULINIC ACID CONTENT U.S. PATENT DOCUMENTS ASAN ACTIVE INGREDIENT 4,568,665 2/1986 Mitchell ...... 54/9 5,211,938 5/1993 Kennedy et al...... 424/7. (75) Inventors: Beate Uhlmann, Tobias Mann, both of Hamburg; Heinrich Gers-Barlag, FOREIGN PATENT DOCUMENTS Kummerfeld, Gerhard Sauermann, 202778 11/1986 European Pat. Off.. Wiemersdorf, all of Germany 2728242 1/1979 Germany. 9/01727 2/1991 WIPO 73) Assignee: Beiersdorf Aktiengesellschaft, Hamburg, Germany 92fO9635 6/1994 WIPO. Primary Examiner—C. Warren Ivy 21 Appl. No.: 260,843 Assistant Examiner-Evelyn Huang Attorney, Agent, or Firm-Sprung Horn Kramer & Woods 22 Filed: Jun. 16, 1994 (30) Foreign Application Priority Data 57 ABSTRACT Jun. 24, 1993 DE Germany ...... 432O 871. A cosmetic or dermatological preparation comprising 8-ami nolevulinic acid as an active ingredient. (51) Int. Cl...... A61K 7/42 (52) U.S. Cl...... 424/59; 424/60; 514/561 58) Field of Search ...... 424/59, 60, 514/561 20 Claims, No Drawings 5,520,905 2 COSMETIC ORDERMATOLOGICAL difficult to incorporate them satisfactorily into such formu PREPARATION COMPRSNG lations. DELTA-AMNOLEVULNCACD CONTENT It has already been suggested that Vitamin E, a substance ASAN ACTIVE INGREDIENT known to have an anti-oxidant action, should be used in light-protection formulations, but here too, the results have been far less satisfactory than expected. DESCRIPTION An object of the present invention is therefore to provide The invention in question concerns cosmetic and derma cosmetic and dermatological substances and preparations tological preparations. The invention mainly concerns containing active substances which would guarantee reliable preparations which alleviate the adverse effects caused by 10 protection from ultra-violet radiation and/or prevent the exposure to light, particularly exposure to ultra-violet light adverse effects caused by exposure to UV, alleviate existing and preparations which forestall such damage i.e. act as a damage or cure it completely. preventative against such damage when applied before In particular it is an object of the present invention to exposure to light, particularly exposure to ultra-violet light. provide cosmetic and dermatological substances and prepa The harmful effects of the Sun's ultra-violet radiation on 15 rations containing active substances which would counteract the skin is generally well-known. While rays with a wave the aging of the skin which is caused or exacerbated by length of less than 290 nm (the so-called UVC range) are exposure to UV. absorbed by the ozone layer in the earth's atmosphere, rays Finally it is an object of the present invention to provide in the range between 290 nm and 320 nm, the so-called UVB cosmetic and dermatological substances and preparations range, cause erythema, a simple sun-burn or even light to 20 containing active substances which would counteract acne severe burning. aestivalis. The erythema effect is at a maximum with sunlight in a A person skilled in the art could not predict-and this is the premise for the solution to these problems-that cos narrower range around 308 nm. metic ordermatological preparations comprising 8-aminole A number of compounds are known to protect against 25 UVB radiation. These are derivatives of 3-benzylidene cam vulinic acid as an active ingredient would remedy the phor, 4-aminobenzoic acid, cinnamic acid, salicylic acid, problems with the current state of the art. benzophenon and 2-phenylbenzimidazol. 8-aminolevulinic acid (also called 6-ALA, 5-amino-4- Filter substances for radiation in the range between 320 oxopentanoic acid, 8-amino-Y-keto-valeric acid) has the nm and approx. 400 nm, the co-called UVA range, are also 30 following structure: important as this radiation can also cause adverse effects. UVA radiation damages the elastic and collagenic fibres of the connective tissue which causes premature aging of the HOOC-CH2-CH-C-CH-NH2 skin and has been found to cause a number of photo-toxic and photo-allergenic reactions. Furthermore, the damaging 35 8-aminolevulinic acid is an intermediate product of the effect of UVB radiation can be exacerbated by UVA radia biosynthesis of porphyrin and is formed during the citric tion. acid cycle. Certain derivatives of dibenzoylmethane are predomi Heretofore, it was not known how to incorporate 8-ami nantly used to protect against rays in the UVA range. nolevulinic acid into cosmetic or dermatological formula However, UV radiation can also cause photo-chemical reac 40 tions. tions where the photo-chemical reaction products attack the B. Ortel, A. Tanew and H. Honigsmann (J. Photochem. skin's metabolism. Photobiol. B: Biol., 17 (1993), pp. 273-278) explain that Photo-chemical reaction products of this type are gener administering 8-aminolevulinic acid externally to tumour ally radical compounds, e.g. hydroxy radicals. Undefined cells induces the biosynthesis of porphyrins. The increased radical photo products, which occur in the skin itself may 45 photosensitivity caused by the increase in porphyrin con also cause uncontrolled reactions on account of their high centration facilitates the killing of these tumour cells by reactivity. Furthermore, UV radiation can also cause the means of radiation with light of the appropriate wave-length. appearance of singlet oxygen, a non-radical activated State However, a person skilled in the art and with knowledge of the oxygen molecule, in addition to short-lived epoxides of this document could not have arrived at the invention etc. For example, compared with the triplet oxygen gener 50 being submitted in this case. ally present (radical ground state), singlet oxygen is char Particularly valuable preparations are also obtained by acterised by an increase in reactivity, although activated, combining 8-aminolevulinic acid with antioxidants. reactive (radical) triplet states of the oxygen molecule also The antioxidants according to the invention may usefully eXSt. be selected from the standard group of cosmetic and der 55 matological antioxidants, particularly the group consisting Antioxidants and/or radical inhibitors can be incorporated of tocopherols and their derivatives, particularly O-toco into cosmetic and/or dermatological formulations to prevent pherol and/or O-tocopheryl esters, especially O-tocophery these reactions. lacetate, in addition to sesame oil, bile acid derivatives such It is known that certain types of photodermatosis can be as methyl, ethyl, propyl, amyl, butyl and lauric gallate, the triggered by certain emulsifiers and also by various types of 60 coniferylbenzoate of benzoin, nordihydroguaiacinic acid, fat with simultaneous exposure to sunlight. These types of nordihydroguaiaretic acid, butylhydroxyanisole, butylhy photodermatosis are called acne aestivalis. droxytoluol, ascorbic acid, citric acid, phosphoric acid, The compounds used as light protection agents in cos lecithin, trihydroxybutyrophenon, carotenes, vitamin A and metic and dermatological light protection formulations, its derivatives, particularly retinylpalmitate, ascorbic acid, some of which are mentioned above, are notable for their 65 ascorbylpalmitate, dilaurylthiodipropionate, distearylthio satisfactory light protection properties. However, a disad dipropionate, monoisopropylcitrate, thiodipropionic acid vantage of these products is that sometimes it has been and EDTA and EDTA derivatives. 5,520,905 3 4 It is preferable to select the antioxidants according to the 8-aminolevulinic acid as an active ingredient and/or the invention from the group of tocopherols and their deriva combinations according to the invention which consist of tives. 8-aminolevulinic acids and at least one other substance Tocopherols, also called vitamin E, are derived from the selected from the antioxidant group, particularly tocopherols parent substance tocol ((2-methyl-2-(4,8,12-trimethyltride 5 and tocopherylester, cyl)-chroman-Ö-ol) and have the following structures: would have sufficient stability for the application

R KO CH2 N / N / N ( H2 CH: ths CH3 C. C C yetH2 yetCH etectCH2 CH yetCH2 yetCH R /N C / N O /|\ CH2 CH2 CH2 CH2 CH2 CH2 CH3 CH3 R"

Here K represents either H or an acyl group independently would lead to skin-compatible products of one another, R, R and R" mean H or a methyl group, e.g.: 20 would not attack the skin's own microorganism flora Ra Ras R"; K= H : Tocol would counteract light-induced aging of the skin R = R = R" = Methyl, K = H : O-tocopherol would counteract acne aestivalis. R=R"s Methyl, R's K = H : B-tocopherol acetate In particular, no one could have predicted that 8-aminole R = R = R" = methyl, Kc -C-CH3: o-Tocopherolacetate vulinic acid and/or cosmetic or dermatological preparations O 25 comprising 8-aminolevulinic acid as an active ingredient and/or the combinations according to the invention which and other variations. In these esters, K represents the acyl consist of 8-aminolevulinic acids and at least one other group as follows: substance selected from the antioxidant group, particularly tocopherols and tocopherylester, would be notable for a 30 marked delayed action. Furthermore, the 8-aminolevulinic acid and/or cosmetic or dermatological preparations comprising 6-aminolevulinic whereby R" can represent an alkyl or alkenyl group. acid as an active ingredient and/or the combinations accord R"=methyl is particularly common. ing to the invention which consist of 8-aminolevulinic acids In addition to the most frequently naturally occurring and 35 and at least one other substance selected from the antioxi important O-tocopherols there is also the configuration 2R, dant group, particularly tocopherois and tocopherylester, are 4R, 8R. Occasionally, it is also called RRR-o-tocopherol. particularly suitable for penetrating deeper layers of skin The preferred tocopherol derivatives in accordance with where they can display their effectiveness to particular the invention are O-tocopherol and its esters, especially advantage. O-tocopheryl-acetate. 40 In addition, the 6-aminolevulinic acid and/or cosmetic or While U.S. Pat. No. 4,144,325 and U.S. Pat. No. 4,248, dermatological preparations comprising 8-aminolevulinic 861 and many other documents describe the use of vitamin acid as an active ingredient and/or the combinations accord E in cosmetic and dermatological light protection formula ing to the invention, which consist of 8-aminolevulinic acids tions, the combinations in accordance with the invention and at least one other substance selected from the antioxi were previously unknown. Furthermore, the current state of 45 dant group, particularly tocopherols and tocopherylester, are the art does not provide any indications of the direction also particularly suited for use as a strategic prophylactic for taken by the invention submitted in this instance. and/or treatment of skin damage caused by UV. Surprisingly, 8-aminolevulinic acid has been found to The use of 6-aminolevulinic acid and/or cosmetic or counteract the processes which play a role in the degenera dermatological preparations comprising 8-aminolevulinic tion of the skin caused or exacerbated by ultra-violet light. 50 acid as an active ingredient and/or the combinations accord Nor could anyone have predicted that 8-aminolevulinic ing to the invention, which consist of 8-aminolevulinic acids acid and/or cosmetic or dermatological preparations com and at least one other substance selected from the antioxi prising 8-aminolevulinic acid as an active ingredient and/or dant group, particularly tocopherols and tocopherylester, to the combinations according to the invention which consist of protect the skin against the harmful effects of ultraviolet 6-aminolevulinic acids and at least one other substance 55 light is also in accordance with the invention. selected from the antioxidant group, particularly tocopherols Amazingly, it was found that 8-aminolevulinic acid and/ and tocopherylester, would be more effective or cosmetic or dermatological preparations comprising in providing protection against the adverse effects of UV 8-aminolevulinic acid as an active ingredient and/or the radiation combinations according to the invention, which consist of 60 8-aminolevulinic acids and at least one other substance as an antioxidant selected from the antioxidant group, particularly tocopherols as a radical inhibitor and tocopherylester, can inhibit photochemically produced in preventing the bonding of damaging photo products radicals, provide protection against uncontrolled oxidation with lipids, DNS and proteins processes which are photochemically induced and even than preparations based on the known state of the art. Nor 65 quench singlet oxygen, i.e. convert it to the triplet ground could anyone have predicted that 8-aminolevulinic acid state by a physicochemical process. Substances with this and/or cosmetic or dermatological preparations comprising property are also described as quenching agents. 5,520,905 5 6 Therefore the use of 8-aminolevulinic acid and/or cos glycol monomethylether, propylene glycol monoethyl metic or dermatological preparations comprising 8-aminole ether, propylene glycol monobutylether, diethylene vulinic acid as an active ingredient and/or combinations glycol monomethylether, diethylene glycol monoet according to the invention which consist of 8-aminolevulinic hyelether and analogous products. acids and at least one other substance selected from the 5 Mixtures of the above-mentioned solvents are used in antioxidant group, particularly tocopherols and tocophery particular. Water may be another component in the case of lester, as a radical inhibitor, an antioxidant and/or a quench ing agent for photochemically produced reactive substances alcohol solvents. such as singlet oxygen, is also in accordance with the Emulsions according to the invention, e.g. in the form of invention. a sun protection cream, a Sun protection lotion or a Sun Cosmetic or dermatological preparations according to the 10 protection milk are useful and may contain the fats, oils, invention may actually use a conventional formulation base waxes and other fatty compounds mentioned, in addition to and be used in the treatment of skin and/or hair as a part of water and the usual type of emulsifier used for this type of a dermatological or cosmetic treatment. They should have a formulation. 8-aminolevulinic acid content of 0.1% to 10% by weight, When a product is required which aims to prevent or but in particular 0.1% to 6% by weight as a percentage of the 5 alleviate acne aestivalis, it is useful according to the inven total weight. tion, to incorporate the 8-aminolevulinic acid or a combi Cosmetic or dermatological preparations in accordance nation of substances based on 8-aminolevulinic acid accord with the invention should preferably contain 0.01% to 10% ing to the invention, into hydro-dispersions or gels. by weight, but in particular 0.1% to 6% by weight of one or Cosmetic and dermatological preparations for skin treat several of the antioxidant group of substances, as a percent 20 ment and skin care may be in the form of gels which, in age of the total weight. addition to 8-aminolevulinic acid and the usual solvents For use, the 8-aminolevulinic acid is applied in sufficient used for it, also contain organic thickening agents such as quantity in the usual way for cosmetics and dermatological gum arabic, Xanthan gum, sodium alginate, cellulose deriva products. tives, preferably methylcellulose, hydroxymethyl-cellulose, Cosmetic and dermatological preparations which come in 25 hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydrox the form of a sun-protection agent are particularly suitable. ypropylmethyl-cellulose or inorganic thickening agents e.g. Ideally they will also contain at least one UVA filter or at aluminium silicates such as bentonite or a mixture of poly least one UVB filter and/or at least one inorganic pigment. ethylene glycol and polyethylene glycol stearate or distear Preparations applied to the skin after exposure to light, i.e. ate. The percentage by weight of thickening agent in the gel after-sun products, are also extremely suitable. It is up to the 30 may be between 0.1% and 30%, ideally between 0.5% and person skilled in the art to decide whether further UV filter 15% by weight. substances should be used or not. Gels according to the invention generally contain alcohols Preparations to prevent or treat acne aestivalis are also with a low C number, e.g. ethanol, isopropanol, 1,2-pro seen as an effective embodiment of the present invention. panediol, glycerine and water and/or one of the above Cosmetic preparations according to the invention for 35 mentioned oils in the presence of a thickening agent which protecting the skin against UV radiation may come in is preferably silicon dioxide or an aluminium silicate in the different forms, as is generally the case for this type of case of oily alcohol gels, or a polyacrylate in the case of preparation. They may come as an aqueous, alcohol or aqueous-alcohol or alcohol gels. aqueous-alcohol solution, an emulsion of the water-in-oil Hydrodispersions represent dispersions of a liquid, half type (W/O) or the oil-in-water type (O/W) or a multiple 40 solid or solid inner (discontinuous) lipid phase in an outer emulsion, e.g. of the water-in-oil-in-water type (WIO/W), a aqueous (continuous) phase. gel, a hydrodispersion, a solid stick or an aerosol. Unlike O/W emulsions which are characterised by a The cosmetic preparations according to the invention may similar phase arrangement, hydrodispersions are predomi contain the type of cosmetic adjuvants generally used for nantly free of emulsifiers. Hydrodispersions represent meta such preparations, e.g. preservatives, bactericides, perfumes, 45 stable systems-as do emulsions-and tend to be converted foam-inhibitors, dyestuffs, pigments which act as a colorant, into a state of two connected but discrete phases. In emul thickening agents, surface-active substances, emulsifiers, sions, the selection of a suitable emulsifer prevents phase plasticising substances, moisturising and/or moisture-reten separation. tion substances, fats, oils, waxes and other components In the case of hydrodispersions of a liquid lipid phase in generally used in cosmetic formulations such as alcohols, 50 an extremely aqueous phase, the stability of this type of polyols, polymers, foam stabilisers, electrolytes, organic system may be assured by creating a gel structure in the solvents or silicon derivatives. aqueous phase in which the lipid drops are in stable sus Where the cosmetic or dermatological preparation is a pension. solution or lotion, solvents which may be used are: Solid sticks according to the invention could contain 55 natural or synthetic waxes, fatty alcohols or fatty acid esters Water or aqueous solutions; for example. Lipsticks for lip care are preferable. Oils such as triglycerides of caprio or caprylic acid, but Conventional readily volatile, liquefied propellants such preferably castor oil; as hydrocarbons (propane, butane, isobutane), used singly or Fats, waxes and other natural and synthetic fatty con in combination, are suitable as propellants for spray cans pounds, preferably esters of fatty acids with alcohols 60 containing cosmetic or dermatological preparations accord with a low C number, e.g. with isopropanol, propylene ing to the invention. Compressed air may also be used glycol or glycerine or esters of fatty alcohols with effectively. alkanic acids with a low C number or with fatty acids; Of course a person skilled in the art knows that there are Alcohols, diols or polyols with a low C number and their non-toxic propellants which would be suitable for this ethers, preferably ethanol, isopropanol, propylene gly 65 invention per se but which should not be used due to the col, glycerine, ethylene glycol, ethylene glycol mono harmful impact on the environment or other problems, in ethylether, ethylene glycol monobutylether, propylene particular fluorocarbons and chlorofluorocarbons (CFCs). 5,520,905 7 8 In order to provide cosmetic preparations which protect skin against UVrays. The pigments in question are oxides of the skin against the entire range of ultraviolet radiation, titanium, zinc, iron, Zirconium, silicon, manganese, alu preparations according to the invention may also usefully minium, cerium and mixtures of same, in addition to modi contain substances which absorb UV-radiation in the UWB fications whereby the oxides are the active agents. Pigments range, whereby the total amount of filter substances could be based on titanium dioxide are particularly effective. 0.1% to 30% by weight, preferably 0.5% to 10% by weight Combinations of and in particular 1% to 6% by weight as a percentage of the total weight of the preparation. They may also be used as a 8-aminolevulinic acid and inorganic pigments Sun protection agent. 8-aminolevulinic acid and antioxidants and inorganic The UVB filters may be oil-soluble or water-soluble. 10 pigments Examples of oil-soluble substances which could be used: 8-aminolevulinic acid and UV filter substances and inor 3-benzylidene camphor derivatives, preferably 3-(4-me ganic pigments thylbenzylidene)camphor, 3-benzylidene-camphor; 8-aminolevulinic acid and antioxidants and UV filter 4-aminobenzoic acid derivatives, preferably 4-(dimethy substances and inorganic pigments lamino)-benzoic-acid (2-ethylhexyl)ester, 4-(dimethy 15 are also the subject matter of the invention. The quantities lamino)benzoic-acid-amylester; mentioned for the above combinations may be used. Esters of cinnamic acid, preferably 4-methoxycinnamic The process used in the manufacture of cosmetic prepa acid-(2-ethylhexyl)ester, 4-methoxycinnamic-acid-iso rations according to the invention, which is characterised in pentylester; that 8-aminolevulinic acid is incorporated into cosmetic or 20 dermatological formulations by a method which is actually Esters of salicylic acids, preferably salicylic acid (2-eth well-known, is also the subject matter of the invention. ylhexyl)ester, salicylic acid (4-isopropylbenzyl)ester, The following examples should clarify the present inven salicylic acid-homomenthylester; tion without limiting it. All the given quantities, ratios and Derivatives of benzophenone, preferably 2-hydroxy-4- percentages relate to the weight and the overall volume methoxybenzophenone, 2-hydroxy-4-methoxy-4'-me 25 and/or total weight of the preparations unless otherwise thylbenzophenone, 2,2'-dihydroxy-4-methoxyben Stated. Zophenone; Esters of benzalmalonic acids, preferably 4-methoxyben Zalmalonic-acid-di(2-ethylhexyl)ester; Example l 2,4,6-trianilino-(p-carbo-2'-ethyl-1'-hexyloxy)-1,3,5-tri 30 Sun Gel LF 4 (transparent) Percentage by weight azin. Benzophenone-4 0.5 Water-soluble substances which could be used: Phenylbenzimidazolsulphonic acid 1.3 8-aminolevulinic acid 1.0 Salts of 2-phenylbenzimidazol-5-sulphonic acid such as Acrylamide/sodium acrylate-copolymer 6 its sodium, potassium or triethanolammonium salt and 35 Ethanol 5.0 the sulphonic acid itself; Glycerine 15.0 Sulphonic acid derivatives of benzophenones, preferably NaOH (15%) C.S., Perfume, preservatives C.S. 2-hydroxy-4-methoxybenzophenon-5-sulphonic acid Water, fully demineralised make up to 100.0 and its salts. Sulphonic acid derivatives of 3-benzylidene camphor 40 Example 2 such as 4-(2-oxo-3-bornylidene methyl)benzolsul phonic acid, 2-methyl-5-(2-oxo-3-bornylidenemethyl Hydrodispersion LF 6 Percentage by weight )Sulphonic acid and its salts. Octylmethoxycinnamate 5.O The combination of 6-aminolevulinic acid with one or Butylmethoxydibenzoylmethane 10 Phenyltrimethicone 10 more UV filters and/or cosmetic or dermatological prepara 45 Carbomer (Carbopol 981) O tions according to the invention and containing one or more Hydroxypropylmethyl-cellulose 0.2 UVB filters is also a subject matter of the invention. Butylene glycol 3.0 S-aminolevulinic acid 0.5 It may also be useful to combine 8-aminolevulinic acid Tromethamine C.S. with UVA filters which have generally been a component of EDTA solution (14%) 0.5 cosmetic and/or dermatological preparations in the past. 50 Ethanol 5.0 These substances should preferably be derivatives of diben Perfume, preservatives C.S. Zoylmethane, particularly 1-(4'-tert.butylphenyl)-3-(4'- Water, fully demineralised make up to 100.0 methoxyphenyl)propane-1,3-dione and 1-phenyl-3-(4-iso Example 3 propylphenyl)propane-1,3-dione. These combinations and/ or preparations containing these combinations are also a 55 Sun Mik OIW Percentage by weight subject matter of the invention. The amounts used for the Octylmethoxycinnamate 5.0 UVB combination may be used. Butylmethoxydibenzoylmethane 10 Further effective preparations may also be obtained when Cetearylalcohol + PEG-40 castor oil + 2.5 8-aminolevulinic acid is combined with UVA and UVB Sodiumcetearylsulphate filters. 60 Glyceryllanolate O Laurylmethicon copolyol 0.5 Combinations of 8-aminolevulinic acid, one or more Mineral oil (DAB 9) 5.0 antioxidants and one or more UVA filters and one or more Caprylicicapric triglyceride 5.0 UVB filters are particularly effective according to the inven Acrylamide/sodiumacrylate copolymer 0.3 tion. Cyclomethicone 2.0 TiO2 10 Cosmetic or dermatological preparations which contain 65 6-aminolevulinic acid 10 8-aminolevulinic acid may also contain inorganic pigments Glycerine 3.0 which are generally used in the cosmetic industry to protect 5,520,905 9 10 -continued Experiment EDTA solution (14%) 0.5 The antioxidation action of 8-aminolevulinic acid was Ethanol 5.0 ascertained by chemiluminescence measurement. Chemilu Perfume, preservative C.S. minescence shows the oxidation processes in the skin and a Water, fully demineralised make up to 100.0 reduction in chemiluminescence is synonymous with a Example 4 reduction in oxidation processes. Test Material: Acrylate gel with 5% by weight of 8-ami Skin-care lotion WHO Percentage by weight molevulinic acid (ALA) Cyclomethicone 3.0 10 Method: Measurement of chemiluminescence in hands PEG-1-glycerine sorbitan oleostearate 17 before treatment and 3 hours after treatment with ALA PEG-7 hydrated castor oil 6.3 Mineral oil (DAB 9) 13.0 and/or placebo (Gel without 8-aminolevulinic acid) Caprylic?capric triglyceride 13.0 Test Subjects: 12 people, 4 male, 8 female. 8-aminolevulinic acid 3.0 Test Period: 3 days. Glycerine 4.0 MgSO 0.7 15 Application: ALA is measured out volumetrically (90 ul) Perfume, preservative C.S. and applied with a finger stall to the back of the right Water, fully demineralised make up to 100.0 and/or left hand over a 5.6 cmx8 cm area. The placebo is applied to the back of the other hand. The application Example 5 sites (right hand-left hand) are selected at random. Day-car skin cream OW Percentage by weight 20 Test Procedure: 1st Day An area on the back of the hand between the base of the thumb and the metacarpal bone PEG-5 Glycerylstearate 2.00 is marked and measured by reflection spectra. Chemi Glycerylstearate 3.00 luminescence measurements before and after 30 sec Cyclomethicone 3.00 Caprylicicapric triglyceride 3.00 onds of UVA radiation using a UVA Spot (from H Cetylalcohol 3.00 25 onle). Treatment with 8-aminolevulinic acid and pla Octylmethoxycinnamate 2.50 cebo, both applied at the rate of 2 mg/cm. Measure 8-aminolevulinic acid 5.00 ments repeated 3 hours later. Ethanoi 100 Hyaluronic acid 0.05 2nd and 3rd Day The test procedure described above was Tocopherylacetate 0.50 carried out with 4 further test subjects. Glycerine 4.00 30 Measurement conditions for LS 50: Synchron Modus, Perfume, preservatives 9.S. interval: 0 nm, range: 300-500 nm, ex slit: 4 nm, em Water, fully demineralised make up to 100.00 slit: 3.5 nm, scan speed: 500 nm/min., 4% attenuator. Example 6 Results: 3 hours after treatment, there was a reduction of 11.8% in luminescence in the hands treated with ALA Sun Crean WIO Percentage by weight 35 compared with the initial situation. As expected, there PEG-22-dodecyl glycol copolymer 3.0 was almost no change in the hands treated with the Cetyl dimethicon copolyol 2.0 placebo. Cyclomethicone 40 We claim: Octylmethoxycinnamate T.O Methylbenzylidene camphor 3.4 1. A method of alleviating the skin from the damage Butylmethoxydibenzoylmethane O 40 resulting from exposure to the sun, which comprises apply Mineral oil (DAB 9) 40 ing thereto an amount effective therefor of a composition Caprylicicapric triglyceride 40 comprising a carrier and a cosmetically or dermatologically 8-aminolevulinic acid 2.5 effective amount of 6-aminolevulinic acid. Glycerine 400 Perfume, preservatives C.S. 2. A method according to claim 1, wherein the 6-ami Water, fully demineralised make up to 100.00 45 molevulinic acid is present in about 0.01 to 10% by weight. 3. A method according to claim 1, wherein the 6-ami Example 7 nolevulinic acid is present in about 0.01 to 6% by weight. After Sun Lotion Percentage by weight 4. A method according to claim 1, further containing an antioxidant. Cetearylalcohol + PEG-40 castor oil + 2.50 5. A method according to claim 2, wherein the antioxidant sodiumcetearylsulphate 50 Glycerylstearate SE 0.60 is at least one member selected from the group consisting of Mineral oil (DAB 9) 4.00 a tocopherol or ester thereof, sesame oil, methyl, ethyl, Caprylicicapric triglyceride 2.00 propyl, amyl, butyl or lauryl gallate, the coniferylbenzoate Sheabutter 2.00 of benzoin, nordihydroguaiacinic acid, nordihydroguaiaretic Avocado oil 200 Tocopherylacetate 3.00 55 acid, butylhydroxyanisole, butylhydroxytoluol, ascorbic 8-aminolevulinic acid 2.00 acid, citric acid, phosphoric acid, lecithin, trihydroxybuty Acrylamidelsodiumacrylate copolymer 0.30 rophenon, a caroteine, vitamin A or a derivative thereof, Glycerine 400 retinyl palmitate, ascorbyl palmitate, dilaurylthiodipropi Hyaluronic acid 0.05 onate, distearylthiodipropionate, monoisopropylcitrate, Bisabolol 0.05 Perfume, preservatives G.S. 60 thiodipropionic acid and ethylenediaminetetraacetic acid or Water, fully demineralised make up to 100.00 a derivative thereof. 6. A method according to claim 5, wherein the antioxidant is present in about 0.01 to 10% by weight. The following experiment demonstrates the effective 7. A method according to claim 5, wherein the antioxidant action of 8-aminolevulinic acid. 65 is present in about 0.01 to 6% by weight. 5,520,905 11 12 8. A method according to claim 1, further containing a ethyl, propyl, amyl, butyl or lauryl gallate, the coniferyl substance which absorbs UV radiation in the UVA or UVB benzoate of benzoin, nordihydroguaicinic acid, nordihy range. droguaiaretic acid, butylhydroxyanisole, butylhydroxy 9. A method according to claim 5, further containing a toluol, ascorbic acid, citric acid, phosphoric acid, lecithin, substance which absorbs UV radiation in the UWA or UVB trihydroxybutyrophenon, a carotene, vitamin A or a deriva range. tive thereof, retinyl palmitate, ascorbyl palmitate, dilaurylth 10. A method according to claim 9, wherein each of the iodipropionate, distearylthiodipropionate, monoisopropylci 8-aminolevulinic acid and antioxidant is present in about 0.1 trate, thiodipropionic acid and ethylenediaminetetraacetic to 6% by weight, the antioxidant is tocopherol or an ester acid or a derivative thereof. thereof, and the composition further contains a substance O 16. A method according to claim 15, wherein the antioxi which absorbs UV radiation in the UVA or UVB range. 11. In the exposure of skin to sunlight under conditions dant is present in about 0.01 to 10% by weight. which would otherwise result in light to severe burning is 17. A method according to claim 15, wherein the antioxi improvement which comprises, applying thereto an amount dant is present in about 0.01 to 6% by weight. effective therefor of a composition comprising a carrier and 5 18. A method according to claim 11, further containing a a cosmetically or dermaologically effective amount of substance which absorbs UV radiation in the UVA or UVB 8-aminolevulinic acid, whereby the skin is protected from range. such burning. 19. A method according to claim 15, further containing a 12. A method according to claim 11, wherein the ami substance which absorbs UV radiation in the UVA or UVB nolevulinic acid is present in about 0.01 to 10% by weight. 20 range. 13. A method according to claim 11, wherein the ami 20. A method according to claim 19, wherein each of the nolevulinic acid is present in about 0.01 to 6% by weight. 8-aminolevulinic acid and antioxidant is present in about 0.1 14. A method according to claim 11, wherein the com to 6% by weight, the antioxidant is tocopherol or an ester positions further contains an antioxidant. thereof, and the composition further contains a substance 15. A method according to claim 12, wherein the antioxi 25 which absorbs UV radiation in the UVA or UVB range. dant is at least one member selected from the group con sisting of a tocopherol or ester thereof, sesame oil, methyl, k k k k : UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 5,520, 905 DATED : May 28, 1996 INVENTOR(S) : Uhlmann, et al. It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby Corrected as shown below: Col. il, line l9 After " the " insert - 6--- Col. ll, line 21 After " the " insert - 8---

Signed and Sealed this Twenty-ninth Day of October 1996

BRUCELEHMAN Attesting Officer Commissioner of Patents and Trademarks