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Treatment of Diseases and Conditions Mediated By (19) TZZ_ ___T (11) EP 1 572 115 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/07 (2006.01) A61K 38/08 (2006.01) 21.01.2015 Bulletin 2015/04 A61K 38/17 (2006.01) A61K 38/38 (2006.01) (21) Application number: 03799853.1 (86) International application number: PCT/US2003/037901 (22) Date of filing: 25.11.2003 (87) International publication number: WO 2004/050023 (17.06.2004 Gazette 2004/25) (54) TREATMENT OF DISEASES AND CONDITIONS MEDIATED BY INCREASED PHOSPHORYLATION BEHANDLUNG VON ERKRANKUNGEN UND ZUSTÄNDEN,DIE DURCH ERHÖHTE PHOSPHORYLIERUNG VERMITTELT WERDEN TRAITEMENT DE MALADIES ET D’ETATS A MEDIATION DE PHOSPHORYLATION ACCRUE (84) Designated Contracting States: • JIANG B ET AL: "Phosphopeptides derived from AT BE BG CH CY CZ DE DK EE ES FI FR GB GR hen egg yolk phosvitin: effect of molecular size HU IE IT LI LU MC NL PT RO SE SI SK TR on the calcium-binding properties." BIOSCIENCE, BIOTECHNOLOGY, AND (30) Priority: 27.11.2002 US 429924 P BIOCHEMISTRY MAY 2001, vol. 65, no. 5, May 2001 (2001-05), pages 1187-1190, XP002549556 (43) Date of publication of application: ISSN: 0916-8451 14.09.2005 Bulletin 2005/37 • KATAYAMA SHIGERU ET AL: "Antioxidative stress activity of oligophosphopeptides derived (73) Proprietor: Ampio Pharmaceuticals, Inc. from hen egg yolk phosvitin in Caco-2 cells." Englewood, CO 80112 (US) JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 8 FEB 2006, vol. 54, no. 3, 8 February (72) Inventor: BAR-OR, David 2006 (2006-02-08), pages 773-778, XP002549557 Englewood, CO 80110 (US) ISSN: 0021-8561 • OKAMOTO ET AL: ’The interleukin-8 AP-1 and (74) Representative: Weber, Joachim kappa B-like sites are genetic end targets of Hoefer & Partner FK506-sensitive pathway accompanied by Patentanwälte calcium mobilization.’ JOURNAL OF Pilgersheimer Strasse 20 BIOLOGICAL CHEMISTRY vol. 269, no. 11, 01 81543 München (DE) March 1994, pages 8582 - 8589, XP055032227 ISSN: 0021-9258 (56) References cited: • STRIETER ET AL: ’Role of C- X-C chemokines as WO-A-00/08946 WO-A1-82/03008 regulators of angiogenesis in lung cancer.’ JP-A- 5 025 032 US-A- 3 966 915 JOURNAL OF LEUKOCYTE BIOLOGY vol. 57, no. US-A- 5 279 814 5, 01 May 1995, pages 752 - 762, XP055032228 ISSN: 0741-5400 • JIANG B ET AL: "Preparation of novel functional • BELPERIO J A ET AL: "CXC chemokines in oligophosphopeptides from hen egg yolk angiogenesis", JOURNAL OF LEUKOCYTE phosvitin." JOURNAL OF AGRICULTURAL AND BIOLOGY, FEDERATION OF AMERICAN FOOD CHEMISTRY APR 2000, vol. 48, no. 4, April SOCIETIES FOR EXPERIMENTAL BIOLOGY, US, 2000 (2000-04), pages 990-994, XP002549555 vol. 68, no. 1, 1 July 2000 (2000-07-01), pages 1-8, ISSN: 0021-8561 XP002440747, ISSN: 0741-5400 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 1 572 115 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 572 115 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to a pharmaceutical composition for topical administration comprising a phosvitin, a dephosphorylated phosvitin, a personal care composition comprising said phosvitin and a kit comprising said personal care composition. BACKGROUND OF THE INVENTION 10 [0002] Signal transduction is the cascade of processes by which an extracellular signal interacts with a receptor at the cell surface to ultimately effect a change in cell functioning. Protein phosphorylation plays a key role in signal transduction. Protein phosphorylation is performed by protein kinases, and virtually all aspects of cell functioning in one way or another depend on kinase activity. Not surprisingly, then, abnormal (usually increased) kinase activity has been 15 related to a host of diseases and disorders. [0003] Protein kinases catalyze the transfer of phosphate from adenosine triphosphate (ATP) to specific amino acid residues (almost always a serine, threonine or tyrosine residue) of proteins. Several features of kinases make them ideally suited to function in signal transduction. One is that they often have overlapping target substrate specificities which allows "cross-talk" among different signaling pathways, allowing for the integration of different signals. A second 20 feature is that the kinases are organized into several modular functional domains. These domains appear to have been mixed and matched through evolution to produce the large protein kinase family, and the kinases are structurally and catalytically similar. A third feature is their speed. The kinetics of phosphorylation and dephosphorylation are extremely rapid, providing for rapid responses and short recovery times, which in turn makes repeated signal transmission possible. [0004] Given their roles in numerous diseases and in signal transduction, considerable effort has been made to develop 25 protein kinase inhibitors. As far as is known, all of this effort has been directed at developing specific inhibitors that inhi bit only a single kinase. However, the effort to find specific inhibitors of single kinases is a daunting task. Recent estimates predict the presence of greater than 2,000 protein kinase genes in the human genome. Shanley, Crit. Care Med., 30 (No. 1, Suppl):S80-S88 (2002); Cohen, Current Opinion in Chemical Biology, 3:459-465 (1999). Also, the very features described above which make kinases so useful in signal transduction, and which have made them evolve to become 30 central to almost every cellular function, also make them extremely difficult to study and understand. U.S. Patent No. 6,383,790. Unfortunately, the enormous number of kinases and the similarities between them have frustrated the dis- covery and design of specific inhibitors. U.S. Patent No. 6,383,790. Further, because the kinase networks are highly degenerate and interconnected in unknown ways, there is considerable uncertainty with regard to which kinases should be targeted for inhibition to treat many diseases. U.S. Patent No. 6,383,790. Moreover, it is by no means clear that a 35 specific inhibitor of a given kinase will have any effect on a given disease. U.S. Patent No. 6,383,790. Since kinases can be highly promiscuous, there is a significant chance that inhibiting one kinase will simply force another kinase to take its place. U.S. Patent No. 6,383,790. [0005] Jiang et al, 2001, BIOSCIENCE BIOTECHNOLOGY BIOCHEMISTRY, 20010501, JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRY, TOKYO, JAPAN teaches partially dephosphorylated 40 phosvitin (PPP) in form of an aqueous solution (it is referred to page 1187, 2 nd column). Jiang et al. further teaches that a PPP with a MW of 1 to 3 kDa has a calcium binding constant similar to that of casein phosphopeptides (CPP) with high bio availability in vivo for the formation of calcium phosphate salts and it is asserted that this PPP will provide a potentially valuable new nutraceutical as a means for increasing calcium intake. [0006] From the foregoing it is clear that it would be desirable to have methods and products for reducing unwanted 45 phosphorylation without the need to identify specific inhibitors for individual kinases. It would further be desirable to have methods and products for the effective treatment of diseases and conditions mediated by increased phosphorylation without the need to identify specific inhibitors for individual kinases. The invention provides such products. SUMMARY OF THE INVENTION 50 [0007] In particular, the invention provides a pharmaceutical composition according to claim 1, a phosvitin according to claim 7, a personal care composition according to claim 18 and a kit according to claim 22. Further described but not part of the invention are methods for the treatment of diseases and conditions mediated by increased phosphorylation. Further described but not part of the invention are methods and products for inhibiting increased phosphorylation in 55 cells, tissues and organs.The methods and products utilize a phosphateacceptor compound (PAC).A PACis acompound that is capable of being phosphorylated. Phosphorylation of PACs has the effect of reducing the amount of ATP and phosphate groups available for phosphorylation by kinases of their normal substrates, thereby inhibiting the unwanted increased phosphorylation. Thus, the identity of the PACs is not crucial, and it is not necessary to know which specific 2 EP 1 572 115 B1 kinases are involved in causing the unwanted increased phosphorylation. BRIEF DESCRIPTION OF THE DRAWING 5 [0008] Figure 1: A bar graph showing the amount interleukin 8 (IL-8) versus treatment. DETAILED DESCRIPTION OF THE PRESENTLY- PREFERRED EMBODIMENTS OF THE INVENTION 10 [0009] As described above, there are described methods and products for the treatment of diseases and conditions mediated by increased phosphorylation. Provided are methods and products for inhibiting increased phosphorylation in cells, tissues and organs. The methods and products utilize a phosphate acceptor compound (PAC). [0010] "Treat" and variations thereof are used herein to mean to cure, prevent, eliminate, ameliorate, alleviate or 15 reduce the severity of a disease or condition, or of at least some of the symptoms or effects thereof. [0011] As used herein a "disease or condition mediated by increased phosphorylation" means a disease or condition caused by, exacerbated by or involving increased phosphorylation of proteins and/or peptides of the animal suffering from the disease or condition. [0012] "Increased phosphorylation" means a level of phosphorylation above the normal level found in the absence of 20 such a disease or condition. Increased phosphorylation is caused by a net increase in kinase activity which, in turn, is caused by increased kinase activity, decreased phosphatase activity, or both.
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