Use of composition containing baked extract and xanthohumol

Abstract

The present invention relates generally to the specific use of a composition comprising a baked extract and xanthohumol for promoting health purposes. Specifically, the present invention relates to a composition comprising xanthohumol (XN) for (i) use in the treatment and / or prevention of cancer, and / or (ii) use in the treatment and / or prevention of osteoporosis, and / or (iii) use in the treatment and / or prevention of metabolic syndrome, and / or (iv) use in the treatment and / or prevention of diabetes, and / or (v) use in the treatment and / or prevention of cardiovascular disease, and / or (vi) use as an antioxidant, and / or (xiv) inhibiting NF-[kappa] B wherein the composition comprises or consists of: (a) a baked extract and (b) XN, and / or wherein the composition is obtainable by mixing: (a) a baked extract and (b) XN, and / or wherein the composition is obtainable by mixing: (a) a baked extract and (b) XN.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: July 26, 2013; application number: 201910035406.6; invention name: Use of a composition containing roasted extract and xanthohumol). Technical Field

[0002] The present invention is generally directed to the specific use of a composition containing a roasted extract and xanthohumol for health promoting purposes. Background Art

[0003] It is well known that xanthohumol has a very diverse range of positive effects on human and animal health. For example, in addition to antimicrobial effects, preventive activity against a wide range of diseases caused by various mechanisms has been observed.

[0004] For example, cancer preventive activity, protection against osteoporosis, metabolic syndrome, diabetes and cardiovascular disease have been reported.

[0005] It should be mentioned that these sub-divisions cannot be strict. For example, the antioxidant effect is positive in the prevention of tumors as well as in, for example, metabolic syndrome or other diseases, and no studies have been conducted so far in connection with xanthohumol.

[0006] Numerous studies have described cancer prevention mechanisms and have been conducted in vitro, primarily in cell culture. In vivo experiments are referenced separately. Tumorigenesis is a multifactorial phenomenon; multiple mechanisms interact, many known and many unknown. A frequently used classification summarizes early molecular events as "tumor initiation," mechanisms of tumor development and establishment as "tumor promotion," and tumor growth as "tumor progression." The effects of xanthohumol have been examined in a wide diversity of systems according to multiple mechanisms; these are summarized and described below.

[0007] Phase I enzymes are enzymes responsible for the metabolic conversion of procarcinogens into reactive carcinogenic metabolites, i.e., toxicity. The inhibitory effect of xanthohumol on these enzymes in cultured tumor cells, in rat liver and in recombinant human enzymes is described by Henderson et al. (2000), Xenobiotica, 30, 235-251; Miranda et al. (2000), Cancer Lett., 149, 21-29; Miranda et al. (2000), Drug Metab Dispos., 28, 1297-1302 and Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969.

[0008] The enzymes of the second phase are those which are responsible for the conjugation of reactive, carcinogenic metabolites in the organism, secreting them from the cells and thus detoxifying them. The stimulation of this class of enzymes is therefore protective. Stimulation by means of xanthohumol in cultured human liver tumor cells is also described by Henderson et al. (2000), Xenobiotica, 30, 235-251; Miranda et al. (2000), Cancer Lett., 149, 21-29; Miranda et al. (2000), Drug Metab Dispos., 28, 1297-1302 and Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969.

[0009] Cellular oxidation is a process necessary for the maintenance of life in the organism (energy security, respiration, defense against bacteria). In its process, oxidative damage is caused, which the healthy organism will eliminate using its own repair systems. If these systems are inadequate, either because of defects or because of excessive oxidative damage (for example in chronic inflammation), reactive, oxidative molecules can react with the body's own macromolecules and cause defects and mutagenesis that may be the cause of tumors and other diseases. For this reason, antioxidant properties are highly important for the prevention of tumors and other cell damage. Xanthohumol inhibits the formation and action of reactive oxygen and reactive hydrogen molecules in cell culture, rat liver fragments and enzyme model systems, as described in Miranda et al. (2000), J. Agric. Food Chern., 48, 3876-3884; Rodriguez et al. (2001), Food Chem. Toxicol., 39, 437-445; Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969, Stevens et al. (2003) Chem. Res. Toxicol., 16, 1277-1286 and Vogel et al. (2008), Natural and non-natural prenylated chalcones: Synthesis, cytotoxicity and anti-oxidative activity. Bioorg. Med. Chem, .e-pub. It should be noted that xanthohumol is not able to block the stable diphenylpicrylhydrazyl (DPPH) free radical in direct chemical interaction (Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969; Dietz et al. (2005), Chem Res. Taxeal., 18, 1296-1305; Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823; Jung et al. (2005), Arch. Pharm Res., 28, 534-540). The antioxidant effect of xanthohumol seems to originate from an indirect cellular mechanism.

[0010] As already described, inflammatory processes are often the cause of the formation of oxidative toxic substances, which may be associated with a variety of diseases. Moreover, substances detected in many human tumors indicate involvement in inflammatory processes. For this reason, anti-inflammatory agents play a preventive role against tumors. In Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969; Zhao et al. (2003), BioIPharm. Bull., 26, 61-65 and Cho et al. (2008), Int.lmmunopharmacol., 8, 567-573, xanthohumol is described as anti-inflammatory in cell culture; in Monteiro et al. (2008) Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts, J. Cell Biochem, e-pub, an inhibitory effect on inflammation was also established in vivo in mice after oral administration (doses of 4-6 mg / kg per day for 60 days in drinking water).

[0011] Estrogen is a growth factor and provides cells with degeneration at the edge of growth. For this reason, antiestrogens are considered to have a cancer-preventive effect on hormone-dependent tumors. The in vitro antiestrogenic effect of xanthohumol is also described in Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969; Effenberger et al. (2005), J. Steroid Biochem. Mol. Biol., 96, 387-399; Monteiro et al. (2006), J. Agric. Food Chern., 54, 2938-2943 and Monteiro et al. (2007) J. Steroid Biochem. Mol. Biol., 105, 124130; this is also described in Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969 in an organ culture model of the mouse mammary gland. In in vivo studies on rats, it was also possible to detect an antiestrogenic effect after oral application of 3 x 100 mg / kg xanthohumol over a period of 3 days (Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823).

[0012] A significant feature in the development and growth of tumors is the significant growth of tumor cells. Inhibition of proliferation is used to prevent cancer and provide tumor therapy. For this reason, antiproliferative substances are sought that inhibit the growth of tumor cells but at the same time do not destroy healthy cells. Of course, in many cases, this is a question of dosage and the onset of action of the active substance.Xanthohumol has been described as inhibiting growth in 24 different tumor cell lines (Miranda et al. (1999), Food Chern. Toxicol., 37, 271-285; Gerhauser et al. (2002), Mol. Cancer Ther., 1, 959-969; Herath et al. (2003), Chem Pharm. Bull. (Tokyo), 51, 1237-1240; Dietz et al. (2005), Chem Res. Taxeal., 18, 1296-1305; Goto et al. (2005), Cancer Lett., 219, 215-222; Lust et al. (2005), Mol. Nutr. Food Res., 49, 844-850; Pan et al. (2005), Mol. Nutr. Food Res., 49, 837-843; Albini et al. (2006), FASEB J., 20, 527-529; Oelmulle et al. (2006), Phytomedicine., 13, 732-734; Colgate et al. (2007), Cancer Lett., 246, 201-209; Dell'Eva et al. (2007), Cancer, 110, 2007-2011; Lee et al. (2007), Arch Pharrn. Res., 30, 14351439; Monteiro et al. (2007), J. Steroid Biochem. Mol. Biol., 105, 124130; Delmulle et al. (2008), Phytother Res., 22, 197-203; Monteiro et al. (2008), Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts, J. Cell Biochem, e-pub and Vogel et al. (2008) Natural and non-natural prenylated chalcones: Synthesis, cytotoxicity and anti-oxidative activity, Bioorg. Med. Chem, e-pub).

[0013] Apoptosis is a paradoxical phenomenon that is considered harmful in healthy tissues. However, it is desirable to remove damaged and cancerous cells. Therefore, apoptosis-inducing substances can be both cancer preventive and therapeutic. Xanthohumol-induced apoptosis can be detected in cell culture (Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821-823; Lust et al. (2005), Mol. Nutr. Food Res., 49, 844-850; Pan et al. (2005), Mol. Nutr. Food Res., 49, 837-843; Vanhoecke (2005), Int. J Cancer, 117, 889-895; Colgate et al. (2007), Cancer Lett., 246, 201-209; Dell'Eva et al. (2007), Cancer, 110, 2007-2011; Yang et al. (2007), Apoptosis., 12, 1953-1963), and xanthohumol-induced apoptosis was detected in vivo in mice after administration (4-6 mg / kg per day for 60 days in drinking water) (Monteiro et al. (2008) Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts, J. Cell Biochem., e-pub).

[0014] In order to grow, tumors need to be supplied with nutrients. Once a certain size has been reached, new blood vessels are formed for this purpose, without which the growth of the tumor would stagnate. Angiogenesis inhibitors are therefore useful in preventing cancer and in the treatment of cancer. The anti-angiogenic effect of xanthohumol has been described in cell culture (Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823; Albini et al. (2006), FASEB J., 20, 527-529; Dell'Eva et al., Cancer, 110, 2007-2011) and in mice (Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823; Albini et al. (2006), FASEB J., 20, 527-529; Monteiro et al. (2008), Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts, J. Cell Biochem., e-pub), which is achieved at a dose of about 1 mg / kg per day orally (Albini et al. (2006), FASEB J., 20, 527-529). J., 20, 527-529) for 3 days, or 4-6 mg / kg daily in drinking water for 60 days (Monteiro et al. (2008), J. Cell Biochem., e-pub) or after subcutaneous administration of 1000 mg / kg (Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823).

[0015] In further studies on the molecular mechanism of the protective effect of xanthohumol, an effect on NF-κB (nuclear factor κB) was noted. NF-κB is a cellular transcription factor that plays a role in the stimulation and production of pro-inflammatory target genes and has a decisive influence on the progression and duration of inflammation, such as interleukins, tumor necrosis factor α, inducible nitric oxide synthase (iNOS), and inducible cyclooxygenase (Cox-2). Diseases characterized by NF-κB-regulated genes include inflammatory events such as glomerulonephritis, arteriosclerosis, septic shock or pulmonary fibrosis, as well as chronic diseases such as asthma and rheumatoid arthritis. Inhibition of NF-кB in cell culture and in vivo is described in Albini et al. (2006), FASEB J., 20, 527-529; Colgate (2007), Cancer Lett., 246, 201-209; Dell'Eva et al. (2007), Cancer, 110, 2007-2011 and Monteiro et al. (2008), J. Cell Biochem., e-pub.

[0016] In animal studies, xanthohumol has been studied for its cancer prevention effects. It can be confirmed that xanthohumol inhibits tumor formation in three different tumor models. Human breast tumor cells (MX-1 cells, studied in Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823; MXF7 cells, studied in Monteiro et al. (2008), Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts, J. Cell Biochem., e-pub) were transfected into immunodeficient mice and the growth of tumors was measured. As described in Gerhauser and Frank (2005), Mol. Nutr. Food Res., 49, 821823, after daily subcutaneous administration of 1000 mg / kg xanthohumol, tumor growth was inhibited by 46% within one week and by 83% within two weeks. As described in Monteiro et al. (2008), Xanthohumol inhibitsinflammatory factor production and angiogenesis in breast cancer xenografts, J. Cell Biochem., e-pub, after daily administration of 4-6 mg / kg xanthohumol in drinking water, tumor growth was inhibited by 35%, however this result could not be statistically verified at the 95% level. As described in Albini et al. (2006), FASEB J., 20, 527-529, cells of human Kaposi's sarcoma (KS-IMM) were transfected into immunodeficient mice and treated with about 1.2 mg / kg xanthohumol for 23 days; tumor growth was inhibited by 68%.

[0017] Antimutagenic / antigenotoxic studies by Miranda et al. (2000), Cancer Lett., 149, 21-29; Dietz et al. (2005), Chem Res. Taxeal., 18, 1296-1305; Plazar et al. (2007), Mutat Res., 632, 1-8; Kac et al. (2008), Phytomedicine., 15, 216-220 and Plazar et al. (2008), Toxicol In Vitro, 22, 318-327 describe the antimutagenic and antigenotoxic activity of xanthohumol. Cells in culture or in rat liver were pre-incubated with xanthohumol and subsequently treated with free radical-forming genotoxic or cancer-producing substances. Both in the so-called Ames test (a test for mutagenic damage in bacterial cultures) and in the Comet test (a test describing DNA damage caused by genotoxic substances), xanthohumol inhibits the damage by 100%, depending on the dose between 0.01 and 10 μM.

[0018] Xanthohumol exerts antimicrobial effects (Herath (2003), Chem Pharm. Bull. (Tokyo), 51, 1237-1240; Buckwold et al. (2004), Antiviral Res., 61, 57-62; Wang (2004), Antiviral Res., 64, 189-194; Frolich (2005), J. Antimicrob. Chemother., 55, 883-887; Allen (2007), Avian Dis., 51, 21-26). Studies by Miranda et al. (2000), Drug Metab Dispos., 28, 1297-1302 and Frolich et al. (2005), J. Antimicrob. Chemother., 55, 883-887 describe effects against four different strains of Plasmodium that cause malaria, and studies by Allen (2007), Avian Dis., 51, 21-26 give a description of an effect against coccidia, parasites that mainly inhabit the gastrointestinal tract of livestock. Xanthohumol is used in vitro as an antiviral agent against HIV-1 (human immunodeficiency virus) (Wang et al. (2004), Antiviral Res., 64, 189-194), against BVDV (bovine viral diarrhea virus), HSV-1 and 2 (herpes simplex virus) and against CMV (cytomegalovirus) (Buckwold et al. (2004), Antiviral Res., 61, 57-62).

[0019] The stability of bones depends on the balance between bone-forming cells (osteoblasts) and bone-resorbing cells (osteoclasts). If the activity of osteoclasts is proportionally increased, osteoporosis occurs. It is possible that in vitro, 1 μM concentration of xanthohumol inhibited bone resorption by 35%, and 10 μM concentration inhibited bone resorption by 94% (Tobe et al. (1997), Biosci. Biotechnol. Biochern., 61, 158-159). Another study (Effenberger et al. (2005), J. Steroid Biochem. Mol. Biol., 96, 387-399) described the activity of osteoclasts.

[0020] Diacylglycerol acetyltransferase (DGAT) represents an enzyme that is important for the formation and accumulation of triglycerides in cells in the context of metabolic syndrome. Studies conducted by Tabata et al. (1997), Phytochemistry, 46, 683-687 and Casaschi et al. (2004), J Nutr., 134, 13401346 showed the inhibition of this enzyme by xanthohumol in vitro; studies reported by Nozawa et al. (2005) Biochem. Biophys. Res. Commun., 336, 754-761 were able to detect a reduction in triglyceride and plasma glucose levels in mice.

[0021] Xanthohumol is poorly absorbed after oral application in rats, remaining largely unchanged in feces (Avula et al. (2004), J Chromatogr. Sci., 42, 378-382; Stevens (2004), Phytochemistry, 65, 1317-1330; Hanske (2005), Mol. Nutr. Food Res., 49, 868-873); in vitro it binds to cytosolic proteins (Pang et al. (2007), Mol. Nutr. Food Res., 51, 872-879) leading to in vitro (Yilmazer (2001), FEBS Lett., 491, 252-256; Ruefer et al. (2005), Mol. Nutr. Food Res., 49, 851-856; Kim et al. (2006), J Nat Prod., 69, 1522-1524) and in vivo (Stevens (2004), Phytochemistry, 65, 1317-1330) glucuronidation. However, feces, characterized by a wide diversity of metabolites (Nookandeh et al. (2004), Phytochemistry, 65, 561-570), can also be produced from intestinal microbial activity. In rats, the intestinal flora itself was not affected (Hanske et al. (2005), Mol. Nutr. Food Res., 49, 868-873).

[0022] Oral application of xanthohumol in drinking water for 4 weeks (5 x 10 -4M, ad libitum, corresponding to approximately 28 mg / kg / day) showed no adverse effects on the health of female C3H-mice. The development of body weight and the appearance of organs, hematological clinical parameters, liver enzyme values ​​and parameters of glucose metabolism remained unaffected by xanthohumol (Vanhoecke et al. (2005), In Vivo, 19, 103-107). In a study on rats, 100 mg / kg of xanthohumol was administered daily in drinking water for 4 weeks, 500 mg / kg was mixed into the feed, and 1000 mg / kg was administered via a pharyngeal tube. Except for the reduction in liver weight due to the decomposition of glycogen in the high-dose groups (500 mg / kg / day and 1000 mg / kg / day), no toxic effects were detected (Hussong et al. (2005), Mol. Nutr. Food Res., 49, 861-867). Because xanthohumol is characterized by anti-estrogenic activity, the study focused on whether rat fertility was impaired. The animals were treated with 100 mg / kg / day xanthohumol in drinking water for 4 weeks and then mated. Neither female nor male pretreatment had any effect on fertility or lactation (Hussong et al. (2005), Mol. Nutr. Food Res., 49, 861-867).

[0023] The extremely multifaceted spectrum of xanthohumol's activity is striking. For example, it inhibits carcinogenic mechanisms both at the initiation stage and at the pro- and progression stages. Antioxidant and anti-inflammatory properties are just as important as antiestrogenic activity, inhibition of cell proliferation, induction of apoptosis and inhibition of angiogenesis. All these properties, originally discovered in vitro, have now also been detected in vivo in animal experiments.

[0024] Acute and subchronic toxicity (4 weeks) studies in mice and rats with oral doses up to 100 mg / kg / day showed no signs of toxicity. Glycogenolysis in rat liver following daily administration of more than 500 mg / kg xanthohumol can be easily explained by the significantly increased energy requirements peaking in the metabolism of a large amount of exogenous substances. It should be emphasized that the high concentrations were given only to test for possible toxicity. Recent studies have shown cancer prevention effects obtained with single-digit mg / kg doses.

[0025] Because the mechanisms of carcinogenesis are comparable in rodents and humans (due to very similar metabolism in both), many studies have been performed with recombinant human enzymes, human cells in culture, or human cells in immunodeficient mice, and similar results can be expected in humans. Summary of the invention

[0026] The invention described herein is based on the main object of providing a method by which one, several or all health-promoting effects of xanthohumol on humans and / or animals can be enhanced.

[0027] Xanthohumol (hereinafter also referred to as XN), a prenylflavonoid compound (polyphenol) of hop, is found in the lupulin glands of hop cones. The content of XN in hop varies between 0.1 and 1% depending on the hop species. Hop species with a high content of XN generally contain a high proportion of bitter substances.

[0028] Hop products can be divided into raw hops, hop pellets and hop extracts. Since XN is found in the lupulin glands of hop cones, hop pellets generally show a high content of XN corresponding to alpha-acid aggregation. Hop extracts can be obtained by extraction with CO2 and / or ethanol. Conventionally, products enriched in XN are produced by combining two extraction methods. Depending on the production method, the XN content reached is between 8 and 99%. The production of hop extracts enriched in XN and beverages containing XN is described in, for example, patents DE 19939350, DE 10256031, DE 10240065 and EP1431385.

[0029] XN is relatively unstable during the brewing process and, due to its limited solubility, is precipitated mainly via trub, yeast, by filtration and stabilization. In addition, XN is isomerized to iso-XN, which also has a positive effect, but to a much lower degree than XN. In most cases, less than 0.2 mg / l XN is obtained in the final beer using conventional methods. In some strong beers or porter type dark beers, XN contents of up to 1.2 mg / l XN are found (Walker et al., Brauwelt 2003). With specific brewing methods, which use late hopping and rapid cooling of the wort, the XN content in unfiltered pale beers can be increased (DE 102 56 166).

[0030] Early internal studies conducted on behalf of the applicant (which focused on a technical field different from the subject matter described in the present application) have shown that soluble roasted substances seem to be able to absorb or bind XN, thus apparently keeping it in solution, which leads to a much higher yield of XN in hop extracts. In this context, a method for producing a roasted extract containing XN from a roasted product of cereals, cereal malt, coffee or cocoa and a hop extract containing XN is provided. The hop extract containing XN is characterized by a particularly high content of XN. Due to the use of the roasted extract, beer with a significantly increased content of XN compared to the prior art according to, for example, the German Beer Purity Act can be obtained (reference EP 1 761 245B1). In addition, due to improvements in brewing methods, the isomerization of XN to iso-XN is suppressed to a large extent. Therefore, the amount of XN can be increased without causing the beer to become, for example, unpleasant bitter. In addition, it is possible to add stabilizers that usually result in a relative reduction in the XN content.

[0031] High levels of XN are also desirable in order to exploit the health promoting effects of XN, it being first expected that binding and / or absorption of XN into the baked material would be detrimental to the beneficial activities of XN.

[0032] However, further subsequent studies, directly comparing the activity of toasted extracts containing XN with that of pure XN, now surprisingly show that compositions containing toasted extracts and XN are even more effective than pure XN. Thus, the interaction of the toasted substances with XN appears not only to promote a higher yield of XN in the extract, but in addition they appear to enhance the beneficial activity of XN.

[0033] Therefore, the above main objects are met by a composition, preferably a pharmaceutical composition, comprising xanthohumol (XN), wherein the xanthohumol is preferably present in a therapeutically effective amount,

[0034] (i) for the treatment and / or prevention of cancer, and / or

[0035] (ii) for the treatment and / or prevention of osteoporosis, and / or

[0036] (iii) for the treatment and / or prevention of metabolic syndrome, and / or

[0037] (iv) for the treatment and / or prevention of diabetes, and / or

[0038] (v) for the treatment and / or prevention of cardiovascular disease, and / or

[0039] (vi) act as an antioxidant, and / or

[0040] (vii) as a detoxifying agent, preferably as an inducer of carcinogen detoxifying enzymes, and / or

[0041] (viii) inhibiting metabolic activation of procarcinogens, and / or

[0042] (ix) for use as antimutagenic and / or antigenotoxic agents, and / or

[0043] (x) for use as an antiestrogen and / or estrogenic agent, and / or

[0044] (xi) inducing apoptosis, and / or

[0045] (xii) for use as an anti-angiogenic agent, and / or

[0046] (xiii) as an anti-inflammatory agent, and / or

[0047] (xiv) inhibiting NF-κB, and / or

[0048] (xv) use as an antimicrobial agent, and / or

[0049] wherein the composition comprises or consists of: (a) a toasted extract and (b) xanthohumol, preferably a hop extract comprising xanthohumol, and / or wherein the composition is obtainable by or is obtainable by mixing: (a) a toasted extract and (b) XN, or preferably a hop extract comprising xanthohumol.

[0050] "Roasted extract" preferably means a cold or hot extract from coarsely ground or unground roasted malt or grains, including hot or cold extracts from coffee or cocoa; "cereal malt" means grains that have been artificially or controllably germinated.

[0051] "Hop extract comprising XN" preferably means an extract from hops which is obtained with the aid of a solvent and which exhibits a preferably increased content of XN.

[0052] The above studies indicate that the beneficial effects of XN on human and / or animal health are synergistically enhanced when combined with toasted substances.

[0053] Without wishing to be bound by theory, it is currently hypothesized that the interaction between the roasted material and XN enhances the bioavailability of XN. On the one hand this means that more XN is available for absorption by the body or cells. On the other hand, the increased stability against metabolic degradation may play a role in the observed effects. Therefore, the smaller amount of XN in the roasted extract shows a higher activity compared to pure XN.

[0054] The compositions of the present invention are therefore ideally suited for the treatment and prevention of a diverse range of diseases.

[0055] For example, in the treatment and / or prevention of cancer, the compositions of the present invention can interfere with tumorigenesis, growth and / or proliferation through a variety of interactions (including antioxidant, anti-estrogen or apoptosis induction and anti-angiogenic activity). The enhanced detoxification of carcinogens and the inhibition of metabolic activation of pro-carcinogens by the compositions of the present invention and anti-mutagenic and / or anti-genotoxic activity can be advantageously used to effectively prevent cancer.

[0056] Any of the above mentioned effects may simultaneously be related to the treatment and / or prevention of other disorders such as osteoporosis or metabolic syndrome.

[0057] Metabolic syndrome includes a wide range of conditions that lead to serious diseases such as cardiovascular disease and / or diabetes. Therefore preventive measures as well as early treatment of metabolic syndrome are highly desirable.

[0058] The composition of the invention can also be used for its anti-inflammatory effect. Among the beneficial effects in this context, an effective inhibition of NF-κB is observed, allowing for use in the treatment and / or prevention of inflammatory events in glomerulonephritis, arteriosclerosis, septic shock, pulmonary fibrosis, asthma and / or rheumatoid arthritis.

[0059] Further advantages of the compositions of the present invention are provided by antimicrobial activity, including antiviral, antibacterial and antiparasitic effects.

[0060] In a preferred embodiment, the XN content in the composition of the invention is at least 10 mg / kg, preferably at least 20 mg / kg, preferably at least 50 mg / kg, in particular at least 200 mg / kg.

[0061] Preferably, the amount of roasted extract is sufficient to enhance, preferably synergistically enhance, the therapeutic effects of XN as described above.

[0062] Due to the synergistic enhancement of XN activity in the composition of the present invention, already lower amounts of XN in the composition show beneficial effects, but said content can be increased if desired, since the above-mentioned toxicity tests indicate safe use.

[0063] The roasted extract in the composition of the invention is preferably chosen from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

[0064] Preferably, for the production of roasted extracts, a hot aqueous extract of ground roasted products, such as roasted products of barley, wheat, rye and the corresponding malt, coffee beans or cocoa beans, is prepared.

[0065] The composition of the invention is preferably obtainable or obtainable by a process comprising the step of mixing XN or a hop extract comprising XN with a roasted extract selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

[0066] XN in the composition of the invention may be provided synthetically, for example as described by Khupse and Erhardt in "Total synthesis of xanthohumol", J Nat. Prod., 2007, 70(9), 1507-9, or it may be provided as an extract from hops.

[0067] Preferably, when preparing a toasted extract, the hop extract containing XN is added at the beginning of the heating phase, since the presence of the toasted products results in an XN content well above the solubility limit of XN in typical aqueous solutions.

[0068] In a preferred embodiment of the composition of the present invention, the XN-containing hop extract used has a content of XN ranging from 0.5 to 99% w / w (weight / weight percentage).

[0069] The XN content in the composition of the invention may be lower, since the beneficial effects are synergistically enhanced by the roasted substances in the roasted extract. Alternatively, a hop extract highly enriched in XN may be used and may be strongly diluted in the resulting composition, if convenient for the intended application.

[0070] In another preferred embodiment, after mixing the XN-containing hop extract with the roasted extract, the resulting mixture is concentrated, preferably by evaporation, freeze drying or concentration under reduced pressure, to obtain a dry matter of 40-50% w / w (weight / weight percentage), in particular 47 to 48% w / w (weight / weight percentage).

[0071] Depending on the intended use, the mixture can be concentrated and subsequently diluted in a suitable medium.

[0072] The process for obtaining or obtaining the composition of the invention may further comprise a step of (pre)dissolving the hop extract in ethanol in order to dissolve XN, preferably by heating, stirring, mixing, shaking, sonicating, applying alternating current and / or treating in a dispersing manner.

[0073] Any of the above mentioned treatments may be used to increase the amount of XN in solution, facilitating further processing and ensuring sufficient interaction of the maximum amount of XN with the roasted material when subsequently mixed with the roasted extract.

[0074] The present invention also relates to the use of the roasted extract for enhancing, preferably synergistically enhancing, one or more therapeutic effects of XN.

[0075] The therapeutic effects that can be enhanced by the use of the present invention are preferably selected from one, several or all of the following effects: tumor prevention effect, antioxidant effect, anti-tumor proliferation effect, carcinogen detoxification effect, anti-mutagenic effect, anti-genotoxic effect, inhibition of metabolic activation of pro-carcinogens, anti-estrogen effect, estrogen effect, induction of cell apoptosis, anti-angiogenesis effect, anti-osteoporosis effect, anti-metabolic syndrome effect, anti-inflammatory effect, inhibition of NF-κB, antiviral effect, anti-bacterial effect, and anti-parasitic effect.

[0076] In a preferred embodiment of the use according to the invention, XN is present in the form of a hop extract or as a component of a hop extract.

[0077] In another preferred embodiment of the use according to the invention, the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

[0078] In a particularly preferred embodiment of the use according to the invention, both the roasted extract and the XN or hop extract are components of a pharmaceutical composition.

[0079] For the use in which the roasted extract and XN or hop extract are components of a pharmaceutical composition, the effects and advantages in the context of the use of the invention as described above are preferably achieved.

[0080] The present invention also relates to a method for enhancing, preferably synergistically enhancing, one or more therapeutic effects of XN, wherein the method comprises the following steps:

[0081] - mixing XN with a roasted extract, preferably chosen from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa,

[0082] Provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

[0083] Pure XN can be either produced synthetically or purified from hop extracts, thereby excluding any potentially undesirable components that may interfere with the enhanced beneficial effects described herein, and it can be used to avoid undesirable side effects due to the presence of other ingredients.

[0084] The therapeutic effects enhanced by the methods of the present invention are the same as those mentioned in the context of the above uses.

[0085] Furthermore, the present invention also relates to a method for producing a composition, preferably a pharmaceutical composition, wherein the method comprises the following steps:

[0086] - mixing XN with a roasted extract, preferably chosen from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa,

[0087] Provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

[0088] For the method of producing the composition, the effects and advantages as described in detail above preferably apply.

[0089] Finally, the invention also relates to a composition, preferably a pharmaceutical composition, consisting of or comprising the following components: a roasted extract, preferably chosen from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa, and XN, with the proviso that XN is pure XN, or synthetically produced XN and / or is not derived from hops.

[0090] For the composition of the invention, preferably the same effects and advantages apply as in the context of the composition, use and method described in detail above.

[0091] Obviously, the composition described herein, in particular the pharmaceutical composition described herein may - depending on the intended use - contain one or more other components, such as conventional pharmaceutical additives, preferably one, two, three or more pharmaceutically acceptable carriers and / or diluents, and / or other ingredients, in particular one, two, three or more pharmaceutically acceptable excipients.

[0092] The pharmaceutically acceptable ingredients may be, for example, binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants, sweeteners and other flavoring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents and carriers for various types of preparations.

[0093] Preferred pharmaceutical compositions of the present invention are oral preparations, which may be solid preparations such as capsules, tablets, pills and troches, or liquid suspension preparations; particularly preferred are gel tablets.

[0094] The pharmaceutical composition of the present invention can be used directly in the form of a syrup or gel, or it can be combined with other pharmaceutically acceptable ingredients by mixing the components and optionally finely distributing and / or filling them into capsules, for example, consisting of hard gelatin or soft gelatin, and / or compressing them into tablets, pills or lozenges, and / or suspending them in a liquid medium. A coating may be applied after compression into pellets.

[0095] The present invention also relates to a method for treating and / or preventing one, two or all of the diseases selected from cancer, metabolic syndrome, diabetes, cardiovascular disease and osteoporosis, comprising the step of administering an effective amount of the pharmaceutical composition as described above to a subject in need thereof.

[0096] Specifically, the present invention relates to a method for conferring one or more effects selected from the following to a subject in need: tumor prevention effect, antioxidant effect, anti-tumor proliferation effect, detoxification effect, anti-mutagenic effect, anti-genotoxic effect, inhibition of metabolic activation of pro-carcinogens, anti-estrogen effect, estrogen effect, induction of apoptosis, anti-angiogenesis effect, anti-osteoporosis effect, anti-metabolic syndrome effect, anti-inflammatory effect, inhibition of NF-κB, antiviral effect, antibacterial effect, anti-parasitic effect, the method comprising the step of administering to the subject an effective amount of the pharmaceutical composition as described above.

[0097] For methods of treatment and / or prevention and methods of conferring the effects listed above, preferably the same effects and advantages as described in the context of the compositions, uses and methods described in detail above apply.

[0098] Embodiment 1: Preparation of the pharmaceutical composition for medical purposes described in the present application

[0099] After mashing and separation of mash according to the beer association method, 25 g / l of hop extract (XanthoExtrakt, Simon H.Steiner Hopfen GmbH, XN 2.0%) rich in XN was added during boiling of the roasted malt. After separation of the hot residue and separation with diatomaceous earth, the roasted malt containing XN was vacuum concentrated (200 mbar, about 55° C.) to obtain an extract content of about 50% w / w. The syrupy extract ("density 1.25" kg / l) has an XN content of about 1320 mg / kg. The roasted malt extract containing XN can be directly mixed with any conventional pharmaceutical carriers and additives as required.

[0100] The present invention includes the following embodiments:

[0101] 1. A composition, preferably a pharmaceutical composition, comprising xanthohumol (XN), preferably in a therapeutically effective amount, wherein the composition

[0102] (i) for the treatment and / or prevention of cancer, and / or

[0103] (ii) for the treatment and / or prevention of osteoporosis, and / or

[0104] (iii) for the treatment and / or prevention of metabolic syndrome, and / or

[0105] (iv) for the treatment and / or prevention of diabetes, and / or

[0106] (v) for the treatment and / or prevention of cardiovascular disease, and / or

[0107] (vi) act as an antioxidant, and / or

[0108] (vii) used as an antidote, and / or

[0109] (viii) inhibiting metabolic activation of procarcinogens, and / or

[0110] (ix) for use as antimutagenic and / or antigenotoxic agents, and / or

[0111] (x) for use as an antiestrogen and / or estrogenic agent, and / or

[0112] (xi) inducing apoptosis, and / or

[0113] (xii) for use as an anti-angiogenic agent, and / or

[0114] (xiii) as an anti-inflammatory agent, and / or

[0115] (xiv) inhibiting NF-κB, and / or

[0116] (xv) for use in the treatment and / or prevention of infections, in particular as an antimicrobial agent,

[0117] wherein the composition comprises or consists of: (a) a roasted extract and (b) XN, preferably a hop extract comprising XN, and / or wherein the composition is obtainable or is obtainable by mixing: (a) a roasted extract and (b) XN, preferably a hop extract comprising XN.

[0118] 2. The composition of embodiment 1, wherein the content of XN in the composition is at least 10 mg / kg, preferably at least 20 mg / kg, preferably at least 50 mg / kg, preferably at least 200 mg / kg, and / or wherein the amount of the toasted extract is sufficient to enhance, preferably synergistically enhance, one or more therapeutic effects of XN.

[0119] 3. The composition of embodiment 1 or 2, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

[0120] 4. The composition according to any one of the preceding embodiments, wherein the composition is obtainable or obtained by a process comprising the step of mixing XN or a hop extract preferably comprising XN with a roasted extract selected from a cold or hot extract of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

[0121] 5. The composition of embodiment 4, wherein the hop extract containing XN used has a content of XN ranging from 0.5 to 99% w / w (weight / weight percentage).

[0122] 6. The composition of embodiment 4 or 5, wherein after mixing the hop extract comprising XN with the roasted extract, the resulting mixture is concentrated, preferably by evaporation, freeze drying or concentration under reduced pressure, to a dry matter of 40-50% w / w (weight / weight percentage), in particular 47 to 48% w / w (weight / weight percentage).

[0123] 7. The composition according to any one of embodiments 4 to 6, wherein the method further comprises the step of (pre)dissolving the hop extract in ethanol in order to dissolve XN, preferably by heating, stirring, mixing, shaking, sonicating, applying alternating current and / or treating in a dispersing manner.

[0124] 8. Use of the roasted extract for enhancing, preferably synergistically enhancing, one or more therapeutic effects of XN, preferably one, several or all of the therapeutic effects as described in embodiment 1.

[0125] 9. The use according to embodiment 8, wherein XN is present in the form of a hop extract or as a component of a hop extract.

[0126] 10. The use according to embodiment 8 or 9, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

[0127] 11. The use according to any one of embodiments 8 to 10, wherein both the roasted extract and XN or preferably the hop extract are components of a pharmaceutical composition.

[0128] 12. A method for enhancing, preferably synergistically enhancing, one or more therapeutic effects of XN, wherein the method comprises the following steps:

[0129] - mixing XN with a roasted extract, preferably chosen from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa,

[0130] Provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

[0131] 13. A method for producing a composition, preferably a pharmaceutical composition, wherein the method comprises the following steps:

[0132] - mixing XN with a roasted extract, preferably chosen from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa,

[0133] Provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

[0134] 14. A composition, preferably a pharmaceutical composition, consisting of or comprising: a roasted extract, preferably selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa, and XN, with the proviso that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

Claims

1. Use of a composition comprising xanthohumol (XN) in the preparation of a medicament for: (i) for the treatment and / or prevention of cancer, and / or (ii) for the treatment and / or prevention of osteoporosis, and / or (iii) for the treatment and / or prevention of metabolic syndrome, and / or (iv) for the treatment and / or prevention of diabetes, and / or (v) for the treatment and / or prevention of cardiovascular disease, and / or (vi) act as an antioxidant, and / or (xiv) inhibiting NF-κB, The composition comprises or consists of the following ingredients: (a) toasted extract and (b) XN, and / or wherein the composition is obtainable by or is obtainable by mixing: (a) toasted extract and (b) XN.

2. The use according to claim 1, wherein the xanthohumol is in a therapeutically effective amount.

3. The use of claim 1, wherein the composition is a pharmaceutical composition.

4. The method of claim 1, wherein the composition comprises or consists of the following ingredients: (a) roasted extract and (b) hop extract containing XN.

5. The use of claim 1, wherein the composition is obtained by mixing (a) a roasted extract and (b) a hop extract comprising XN.

6. The use according to any one of claims 1 to 5, wherein the content of XN in the composition is at least 10 mg / kg, and / or wherein the amount of the roasted extract is sufficient to enhance one or more therapeutic effects of XN.

7. The use according to claim 6, wherein the content of XN in the composition is at least 20 mg / kg.

8. The use according to claim 6, wherein the content of XN in the composition is at least 50 mg / kg.

9. The use according to claim 6, wherein the content of XN in the composition is at least 200 mg / kg.

10. The use of claim 6, wherein the amount of the toasted extract is sufficient to synergistically enhance one or more therapeutic effects of XN.

11. Use according to any one of claims 1 to 10, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

12. Use according to any of the preceding claims, wherein the composition is obtainable or obtained by a process comprising the step of mixing XN with a roasted extract selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

13. Use according to claim 12, wherein the composition is obtained by a process comprising the step of mixing a hop extract comprising XN with a roasted extract selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

14. Use according to claim 12 or 13, wherein the XN-containing hop extract used has a content of XN ranging from 0.5 to 99% w / w (weight / weight percentage).

15. Use according to any one of claims 12 to 14, wherein after mixing the hop extract comprising XN with the roasted extract, the resulting mixture is concentrated to obtain a dry matter of 40-50% w / w (weight / weight percentage).

16. The use according to claim 15, wherein the concentration is carried out by evaporation, freeze drying or reduced pressure.

17. The use according to claim 15, wherein the obtained mixture is concentrated to obtain a dry matter of 47 to 48% w / w (weight / weight percentage).

18. The use according to any one of claims 12 to 17, wherein the method further comprises the step of dissolving or pre-dissolving the hop extract in ethanol in order to dissolve the XN.

19. The use according to claim 18, wherein the step of dissolving or pre-dissolving is carried out by heating, stirring, mixing, shaking, ultrasonic treatment, application of alternating current and / or treatment in a dispersing manner.

20. Use of the roasted extract in the preparation of a medicament for enhancing one or more therapeutic effects of XN.

21. The use of claim 20, wherein the medicament is used to synergistically enhance one or more therapeutic effects of XN.

22. The use according to claim 20, wherein the one or more therapeutic effects of XN are one, several or all of the therapeutic effects described in claim 1.

23. The use according to any one of claims 20 to 22, wherein XN is present in the form of a hop extract or as a component of a hop extract.

24. Use according to any one of claims 20 to 23, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

25. The use according to any one of claims 20 to 24, wherein both the roasted extract and XN are components of a pharmaceutical composition.

26. The use of claim 25, wherein both the roasted extract and the hop extract are components of a pharmaceutical composition.

27. A method for producing a medicament for enhancing one or more therapeutic effects of XN, wherein the method comprises the steps of: - Mix XN with the roasted extract, Provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

28. The method of claim 27, wherein the drug is used to synergistically enhance one or more therapeutic effects of XN.

29. The method of claim 27, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, grains, coffee or cocoa.

30. The use of claim 1, wherein the composition is produced by a method comprising the steps of: - Mix XN with the roasted extract, Provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

31. The use according to claim 30, wherein the composition is a pharmaceutical composition.

32. Use according to claim 30, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.

33. The use of claim 1, wherein the composition consists of or comprises the following ingredients: a roasted extract and XN, provided that the XN is pure XN, or synthetically produced XN and / or is not derived from hops.

34. The use of claim 33, wherein the composition is a pharmaceutical composition.

35. Use according to claim 33, wherein the roasted extract is selected from cold or hot extracts of coarsely ground or unground roasted malt, cereals, coffee or cocoa.