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Hydroxymatairesinol Topical Formulations Hydroxymatairesinol Topische Formulierungen Formulations Topiques De Hydroxymatairesinol

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Hydroxymatairesinol Topical Formulations Hydroxymatairesinol Topische Formulierungen Formulations Topiques De Hydroxymatairesinol (19) TZZ__¥__T (11) EP 1 513 514 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/341 (2006.01) A61K 8/49 (2006.01) 19.11.2014 Bulletin 2014/47 (86) International application number: (21) Application number: 03725242.6 PCT/FI2003/000375 (22) Date of filing: 15.05.2003 (87) International publication number: WO 2004/000304 (31.12.2003 Gazette 2004/01) (54) HYDROXYMATAIRESINOL TOPICAL FORMULATIONS HYDROXYMATAIRESINOL TOPISCHE FORMULIERUNGEN FORMULATIONS TOPIQUES DE HYDROXYMATAIRESINOL (84) Designated Contracting States: • LEHTOLA, Veli-Matti AT BE BG CH CY CZ DE DK EE ES FI FR GB GR FIN-20810 Turku (FI) HU IE IT LI LU MC NL PT RO SE SI SK TR • UNKILA, Mikko FIN-20660 Littoinen (FI) (30) Priority: 19.06.2002 FI 20021184 • HIILOVAARA-TEIJO, Mervi FIN-21870 Riihikoski (FI) (43) Date of publication of application: • AHOTUPA, Markku 16.03.2005 Bulletin 2005/11 FIN-20540 Turku (FI) (73) Proprietor: LINNEA SA (74) Representative: Colombo, Stefano Paolo et al 6595 Riazzino (Locarno) (CH) MARCHI & PARTNERS S.r.l. Via G.B. Pirelli, 19 (72) Inventors: 20124 Milano (IT) •KORTE,Helena FIN-20720 Turku (FI) (56) References cited: WO-A1-01/08651 WO-A2-01/03687 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 513 514 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 513 514 B1 Description FIELD OF THE INVENTION 5 [0001] This invention relates to topical formulations comprising hydroxymatairesinol to improve the physical appear- ance of the skin, or as preservatives or stabilizers for other active ingredients or vehicles in topical formulations. BACKGROUND OF THE INVENTION 10 [0002] Lignans are phenolic compounds widely distributed in plants. They can be found in different parts (roots, leafs, stem, seeds, fruits) but mainly in small amounts. In many sources (seeds, fruits), lignans are found as glycosidic con- jugates associated with fiber component of plants. The most common dietary sources of mammalian lignan precursors are unrefined grain products. The highest concentrations in edible plants have been found in flaxseed, followed by unrefined grain products, particularly rye. 15 [0003] Considerable amounts of lignans are also found in coniferous trees. The type of lignans differs in different species and the amounts of lignans vary in different parts of the trees. The typical lignans in heartwood of Norway spruce (Picea abies) are hydroxymatairesinol (HMR), alpha-conidendrin, alpha-conidendric acid, matairesinol, isolariciresinol, secoisolariciresinol, liovil, picearesinol, lariciresinol and pinoresinol (Ekman R: Distribution of lignans in Norway spruce. Acta Academiae Aboensis, Ser B, 39:1-6, 1979). The far most abundant single component of lignans in spruce is HMR, 20 about 60 per cent of total lignans, which occurs mainly in unconjugated free form. Plant lignans such as hydroxymataires- inol, matairesinol, lariciresinol and secoisolariciresinol, are converted by gut microflora to mammalian lignans, enterol- actone or enterodiol. The mammalian lignans can also be manufactured synthetically (MB Groen and J Leemhius, Tetrahedron Letters 21, 5043, 1980). [0004] Lignans are known to possess beneficial effects on human health. The health benefits obtained with lignan rich 25 diet are, for example, decreased risk for various cancers and cardiovascular diseases (Adlercreutz (1998) Phytoestrogens and human health, In: Reproductive and Developmental Toxicology (edited by Korach, K.). pp. 299-371, Marcel & Dekker, NY.). [0005] Lignans, such as hydroxymatairesinol, WO 00/59946, have also been reported to inhibit lipid peroxidation and LDL oxidation and thus be useful as antioxidants. 30 [0006] Also lignans other than hydroxymatairesinol have powerful antioxidant and anti-inflammatory potential. The antioxidant action involves all the major free radicals such as superoxide anions and peroxyl radicals (K Prasad: Anti- oxidant activity of secoisolariciresinol diglucoside-derived metabolites, secoisolariciresinol, enterodiol and enterolactone. Int J Angiology 9:220-225 (2000)). [0007] According to studies, lignans may also prevent skin cancers (Thompson L.U. (1993): Potential health benefits 35 and problems associated with antinutrients in foods. Food Res. Int. 26, 131-149). [0008] No topical preparations, either for cosmetic or pharmaceutical use, comprising lignans, especially lignans which can be derived from wood in great quantities, or lignans or lignan derivatives, such as phenolic esters, manufactured from such wood-derivable lignans, have been described in the art. [0009] WO 01/03687 discloses pharmaceutical preparations, also topical preparations comprising a phytosterol and 40 a phytoestrogen. The phytoestrogen can according to one alternative be a lignan. Certain lignans, for example mataire- sionol, lariciresinol, isolariciresinol, secoisolariciresinol etc. are explicitly mentioned. However, the lignan hydroxy- matairesinol is not mentioned. Furthermore, phenolic esters of lignans are not either mentioned. Furthermore, this is a combined preparation which also must contain a phytosterol component. [0010] WO 01/08651 discloses a topical preparation, which may be a pharmaceutical or a cosmetic preparation, 45 comprising petroselinic acid, a phenolic compound, and a suitable vehicle. There is a long list of suitable phenolic compounds, and lignans are mentioned as one example of such compounds. However, no specific examples of lignans are mentioned. Lignan esters are not either mentioned. [0011] EP 0038600 discloses acetyl esters of enterolactone and the use thereof in ointments, gels or pastes for local application. 50 [0012] US 4,343,796 disclosed acetyl- and propionyl esters of enterodiol as useful ingredients in topical formulations. [0013] M. Takasaki et al., Cancer Letters 158 (2000) 53-59 discloses the use of the lignan arctigenin in combination with a promoter in a topical formulation as anticancer agent. [0014] S.I.Oikarainen et al., Cancer Letters 161 (2000) 253-258 discloses an animal study where hydroxymatairesinol was given orally and antitumor effects was noted. No topical use of hydroxymatairesinol was disclosed or suggested. 55 [0015] The international patent publication WO 00/13661 discloses i.a. the lignans enterodiol, enterolactone and matairesinol as useful ingredients in topical preparations. The patent publications EP 38600 and EP 43150 disclose acetyl esters of enterolactone and enterodiol, and propionyl esters of enterodiol as useful ingredients in topical formu- lations. 2 EP 1 513 514 B1 SUMMARY OF THE INVENTION [0016] One object of the present invention is to provide topical formulations comprising hydroxymatairesinol as an active ingredient for cosmetic use. 5 [0017] Another object is to provide topical formulations comprising hydroxymatairesinol active as a preservative or stabilizer for other active ingredients and/or vehicle components, wherein said formulations are useful as cosmetics. [0018] Thus, the present invention concerns the use of an active agent, which is hydroxymatairesinol or a geometric isomer or a stereoisomer thereof, in a cosmetic topical formulation comprising said active agent in a dermatologically acceptable vehicle, 10 wherein The formulation is - a liquid formulation selected from the group consisting of emulsions, microemulsions, lotions, suspensions or solu- tions; 15 - a semisolid formulation; or - a foam, shampoo, spray, patch, stick, batch, additive or sponge. DETAILED DESCRIPTION OF THE INVENTION 20 Definitions: [0019] A "topical formulation" refers to a composition intended to be directly laid onto or spread on the surface of skin. [0020] A "dermatologically acceptable vehicle" refers to excipients that are suitable for use in direct contact with human tissues without undue adverse effects or toxicity, and that further is compatible with other components in the formulation. 25 Good aesthetic properties are also needed when said formulation is intended for cosmetic purposes. [0021] In the following, by lignans are meant hydroxymatairesinol and their geometric isomers and stereoisomers. [0022] The lignans can either be derived from natural sources, such as flaxseed, rye etc., or from wood, especially coniferous wood. Alternatively, the lignans can be manufactured synthetically or by use of microbiological methods. 30 Activity of the lignans or lignan derivatives: [0023] The lignans may be useful as active agents in topical cosmetic preparations, especially as anti-aging substances for treating signs of dermatological aging, both photoaging and intrinsic aging, including skin wrinkles such as fine wrinkling in the eye area or "crows feet" or fine wrinkles around the mouth area, irregular pigmentation, sallowness, loss 35 of skin resilience and elasticity. [0024] The following table shows the antioxidant effect of lignans using an in vitro model for inhibition of lipid peroxi- dation. In this model, lignan compounds were compared to the well known, potent antioxidant Trolox, which is a water- soluble derivative of vitamin E. 40 Test compound: Inhibition of lipid peroxidation 1: Hydroxymatairesinol (HMR) 0,06 Trolox 0,22 1Peroxidation of microsomal lipids initiated
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