WO2014086379A1 - Compositions à base de lignanes - Google Patents

Compositions à base de lignanes Download PDF

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Publication number
WO2014086379A1
WO2014086379A1 PCT/EP2012/004978 EP2012004978W WO2014086379A1 WO 2014086379 A1 WO2014086379 A1 WO 2014086379A1 EP 2012004978 W EP2012004978 W EP 2012004978W WO 2014086379 A1 WO2014086379 A1 WO 2014086379A1
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lignan
pharmaceutical composition
concentration
cancer
present
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PCT/EP2012/004978
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English (en)
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Jianying Yam
Matthias H. Kreuter
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Alpinia Laudanum Institute Of Phytopharmaceutical Sciences Ag
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Priority to PCT/EP2012/004978 priority Critical patent/WO2014086379A1/fr
Priority to PCT/EP2013/003646 priority patent/WO2014086480A1/fr
Publication of WO2014086379A1 publication Critical patent/WO2014086379A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to secondary plant metabolites, in particular to lignan compounds and compositions in the medical field.
  • the present invention relates to lignan compounds and compositions which are useful in tumour and cancer therapy.
  • Lignan compounds are secondary plant metabolites, which are produced from shikimic acid via the phenylpropanoid pathway. They develop from flavonoid precursors and are responsible for conferring resistance to plants against pathogens and predators. Since lignan compounds are natural products found in various plants, said compounds may be purified from lignan-containing plant material. Furthermore, synthesis processes for the preparation of synthetic lignans are also known for a variety of lignan compounds. Lignan compounds belong to the group of phytohormones, which have attracted much attention in recent years by the pharmaceutical industry. Phytochemical and biological investigations have been carried out in order to explore the use of lignan compounds in medicine. The use of medicinal plants for therapeutic purposes is well known throughout many cultures and dates back to the beginning of civilization.
  • a medicinal plant which is rich in lignans, is Piper cubeba L. of the genus Piperaceae, which is distributed throughout Indonesia in particular the Greater Sunda islands including Borneo, Java and Sumatra. Cultivations of the plant are found in Indonesia, Sri Lanka and India (Assam, Mysore) but also in some African countries such as Sierra Leone and Kongo. To date, twenty four lignans have been reported for Piper cubeba. The berries of Piper cubeba are commonly known as cubeb and used in Indonesian traditional medicine to treat a variety of conditions, such as gonorrhoea, dysentery, syphilis, abdominal pain, diarrhoea, enteritis and asthma.
  • Cubebs consist of sugars (20 %), proteins (9 %), free amino acids (26.5 %), oils (18.2 %) and several inorganic compounds, above all sulphur (275.9 ppm) and manganese (1 16.6 ppm).
  • cubebs contain essential oil compounds, various lignans and fatty oil with palmitinic, oleic, linolic and linolenic acid being the major components.
  • cubebic acid as well as acidic and neutral resins (3.0 to 3.7 %) were found in cubebs.
  • WO 03/080600 A1 and for the treatment and prevention of liver disease (cf. JP 1 180824A). Furthermore, analgesic and anti-inflammatory activities and their usefulness for the treatment of pain and inflammatory diseases, such as arthritis, have been suggested for cubebin derivatives and hinokinin (cf. WO 2006/1 13981 A2).
  • Pusztai et al. investigated a range of lignans as potential cancer chemopreventive agents by evaluating their ability to inhibit HCMV immediate early (IE) antigen expression in A549 cells. While hinokinin was able to reduce IE-antigen expression, dihydrocubebin even resulted in an increase in IE-antigen expression, which renders dihydrocubebin unsuitable as chemopreventive agent in this model system.
  • IE immediate early
  • Mansoor et al. (Mansoor et al., 2912, Phytotherapy Res. 26: 292-696) evaluated seven lignans obtained from Pycnanthus angolensis or by derivatrsation for their ability to induce apoptosis in human HuH-7 hepatoma cells. The results indicated that among others hinokinin appeared to be an inducer of apoptosis in HuH-7 cells. Furthermore, hinokinin appeared to possess cytotoxic activity against the P-388 and HT-29 cell lines in the study of Lin et al. (cf. Lin et al., 2004, Planta Med 70: 234-238), however, according to a study of Chang et al.
  • hinokinin does not show any significant cytotoxic effects on the A-549, MCF-7 and HT- 29 cell lines.
  • compositions based on secondary plant metabolites are preferably useful in the prevention or treatment of tumour diseases, preferably in the prevention or treatment of hormone-dependent tumour diseases, e.g. in the prevention or treatment of prostate cancer.
  • pharmaceutical compositions based on secondary plant metabolites, in particular based on lignan compounds which exhibit good bioavailability, in particular good oral bioavailability.
  • the present inventors were able to show that a particular subset of lignan compounds, e.g. present in Piper cubeba, i.e. clusin, dihydrocubebin, hinokinin, yatein and cubebin, exhibit, each individually, a surprisingly effective therapeutic activity, in particular in the prevention and treatment of tumour diseases, such as prostate cancer, breast cancer and pancreatic cancer, which is even superior if the lignan compounds are used in a combination of at least two of the lignans of the identified subset of lignan compounds.
  • tumour diseases such as prostate cancer, breast cancer and pancreatic cancer
  • a pharmaceutical composition comprising at least one of the compounds, preferably at least two of the compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents, preferably for use as a medicament.
  • compositions according to the present invention are useful for the treatment or prevention of a variety of conditions and diseases
  • the pharmaceutical compositions according to the present invention are particularly useful in the treatment of tumour diseases, such as tumour diseases and cancers, which are influenced by hormones in their growth and phenotype, such as, e.g. hormone-dependent breast cancer, hormone-dependent endometrial cancer, hormone-dependent prostate cancer, hormone- dependent testicular cancer, hormone-dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone-dependent bladder cancer.
  • the pharmaceutical compositions according to the present invention are for use in the treatment or prevention of tumour diseases, preferably for use in the treatment or prevention of cancer diseases, more preferably for use in the treatment or prevention of hormone-dependent cancer diseases, such as in the treatment or prevention of prostate cancer.
  • the present invention provides clusin, dihydrocubebin and/or hinokinin for use in the treatment or prevention of a tumour disease, such as prostate cancer.
  • Dihydrocubebin and clusin were shown by the present inventors to exhibit a particularly effective therapeutic activity.
  • the present invention provides dihydrocubebin and/or clusin for use as a medicament, in particular for use in the treatment or prevention of tumour diseases, preferably in the treatment or prevention of cancer diseases, more preferably for use in the treatment or prevention of hormone- dependent cancer diseases, such as in the treatment or prevention of prostate cancer.
  • Fig. 1 Anti-proliferative effects of cubebin, clusin, dihydrocubebin, hinokinin and yatein were assessed on the human prostate cancer cell line LNCaP. A solvent control was used at 1 % (v/v) ethanol final concentration.
  • Fig. 2 Anti-proliferative effects of 10 g/ml of the lignan fraction (Pip.cub.40p2.001 .E03.S04; cf. Example 1 1 ) and the five individual lignans on cells of the LNCaP cell line were assessed. A solvent control was used at 1 % (v/v) ethanol final concentration. The dose response curves and the IC 50 values of the lignans are presented in the graph.
  • Fig. 3 Anti-proliferative effects of lignan-spiked compositions according to Example 20 were assessed on cells of the human prostate cancer cell line LNCaP. 1 % (v/v) ethanol final concentration was used as solvent control; 3A: cubebin and dihydrocubebin, 3 B: clusin and hinokinin, 3C: yatein.
  • Fig. 4 Effect of 1 0 g/ml of the indicated lignan compositions on LNCaP cell growth.
  • the individual lignans and the lignan fraction (Pip.cub.40p2.001 .E03.S04; cf. Example 1 1 ) were tested alone and in combination with various lignans (lignan-spiked fractions) as indicated. All data points are expressed as % of the solvent controls.
  • Fig. 5 Pharmacokinetics of hinokinin and lignan fraction pip.cub.40p2.001 .E03.S04 (Example 1 1 ) in the plasma of male SCID-beige mice.
  • Fig. 6 Tissue distribution of lignans in murine organs of male SCID-beige mice analyzed by HPLC following oral administration.
  • Fig. 7 Anti-proliferative effects of 1 0pg ml of the lignan fraction (Pip.cub.40p2.001 .E03.S04; cf. Example 1 1 ) and the five individual lignans on cells of the HPAFII cell line were assessed. A solvent control was used at 1 % (v/v) ethanol final concentration. The dose response curves and the IC 50 values of the lignans are presented in the graph. DETAILED DESCRIPTION OF THE INVENTION
  • the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin provide individually excellent therapeutic potential, in particular for the treatment or prevention of tumour diseases, and that the combination of two or more of said lignan compounds provides even superior therapeutic efficiency, e.g. in tumour therapy, and unexpectedly high bioavailability of individual lignan compounds when administered in combination, in particular excellent oral bioavailability.
  • the lignan compounds of the subset of lignan compounds according to the present invention preferably exhibit chemical structures according to Formulas I to V below: In the context of the present invention, any stereochemical variant or a mixture of stereochemical variants of the lignan compounds used in the present invention are encompassed.
  • lignan compound "clusin” includes (-)-clusin, (+)-clusin, and mixtures of (-)- and (+)-clusin
  • lignan compound "dihydrocubebin” includes (-)- dihydrocubebin, (+)-dihydrocubebin, and mixtures of (-)- and (+)-dihydrocubebin
  • lignan compound "hinokinin” includes (-)-hinokinin, (+)-hinokinin, and mixtures of (-)- and (+)-hinokinin
  • lignan compound "yatein” includes (-)-yatein, (+)-yatein, and mixtures of (-)- and (+)-yatein
  • lignan compound "cubebin” includes (-)-cubebin, (+)- cubebin, and mixtures of (-)- and (+)-cubebin.
  • the lignan compound is the (-)-lignan, i.e. (-)-clusin, (-)-dihydrocubebin, (-)-hinokinin, (-)-yatein, (-)-cubebin.
  • the lignan compounds used in the present invention may be obtained by isolation and purification from natural sources or by de novo synthesis or semi synthesis from suitable starting materials.
  • the lignan compounds may be obtained by purification from plant extracts, e.g. extracts of defatted powder of Piper cubeba L. or Piper clusii Cass., by filtration and direct application of ethanolic extracts on preparative reversed phase chromatography employing RP-C18 silica and elution under isocratic conditions using 70% methanol aq. as eluent and subsequent further purification by high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the lignan compounds used in the present invention are obtainable by synthesis.
  • hinokinin or dihydrocubebin are obtainable by oxidative homocoupling of chiral 3-arylpropanoic acid derivates as, e.g. described by Kise et al.
  • the lignan compounds used in the present invention are individually suitable for use in medicine, in particular for use in the treatment or prevention of tumour diseases. Accordingly, preferably the lignan compounds used in the present invention as well as the pharmaceutical compositions according to the present invention and the lignan compositions according to the present invention are preferably for use in tumour therapy, i.e. for use in the treatment or prevention of tumour diseases, wherein "treatment” refers to a therapy of an existing tumour disease and "prevention” refers to preventive therapy for prevention of the occurrence of a tumour disease.
  • tumor refers to a swelling or lesion formed by an abnormal growth of cells (called neoplastic cells or tumour cells).
  • tumor cell an abnormal cell that grows by a rapid, uncontrolled cellular proliferation and continues to grow after the stimuli that initiated the new growth cease. Tumours show partial or complete lack of structural organization and functional coordination with the normal tissue, and usually form a distinct mass of tissue, which may be benign, pre-malignant, or malignant.
  • a tumour disease in the context of the invention is a cancer disease, i.e. a malignant disease, and a tumour cell is a cancer cell.
  • a tumour disease according to the invention is cancer, wherein the term "cancer” according to the invention preferably comprises leukaemias, seminomas, melanomas, teratomas, lymphomas, neuroblastomas, glioblastomas, rectal cancer, endometrial cancer, kidney cancer, adrenal cancer, thyroid cancer, blood cancer, skin cancer, cancer of the brain, cervical cancer, intestinal cancer, liver cancer, colon cancer, stomach cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophagus cancer, colorectal cancer, pancreatic cancer, ear, nose and throat (ENT) cancer, breast cancer, prostate cancer, cancer of the uterus, ovarian cancer and lung cancer and the metastases thereof.
  • cancer preferably comprises leukaemias, seminomas, melanomas, teratomas, lymphomas, neuroblast
  • tumour disease in the context of the present invention is selected from the group consisting of prostate cancer, breast cancer, and pancreatic cancer, most preferably the tumour disease in the context of the present invention is prostate cancer, such as hormone-dependent prostate cancer.
  • tumour disease and cancer in the context of the present invention may be hormone-dependent or hormone-independent.
  • tumor disease and cancer in the context of the present invention is hormone-dependent.
  • hormone-dependent tumour diseases and cancers relates to tumour diseases and cancer types, which are influenced by hormones in their growth and phenotype, such as, e.g. hormone-dependent breast cancer, hormone-dependent endometrial cancer, hormone-dependent prostate cancer, hormone-dependent testicular cancer, hormone- dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone- dependent bladder cancer.
  • said term refers to any tumour disease or cancer, in which cellular functions, such as cell division of the respective cancer or tumour cells, are hormone-dependent.
  • hormone in the context of the invention preferably refers to sex hormones, such as e.g. androgens and estrogens, but also includes steroid hormones and peptide hormones.
  • hormone-dependent refers to androgen- or estrogen-dependency.
  • a particularly preferred hormone-dependent cancer in the context of the present invention is hormone-dependent prostate cancer.
  • androgen in the context of the invention refers, for example, to dehydroepiandrosterone, androstenedione, androstenediol, dihydrotestosterone and teststosterone.
  • estrogen in the context of the invention refers, for example, to estrone, estradiol and estriol.
  • tumour disease or cancer in the context of the present invention refers to any tumour disease or cancer, which is not hormone- dependent for its growth or respective phenotype, such as e.g. retinoblastoma etc..
  • the lignan compounds used in the present invention are particularly superior in their therapeutic activity, e.g. for treating or preventing tumour diseases, if at least two of the lignan compounds according to the present invention, i.e. two, three, four or five lignan compounds according to the present invention are used in combination.
  • the bioavailability of the single lignans is improved if at least two lignans of the subset of lignans used in the present invention, i.e. clusin, dihydrocubebin, hinokinin, yatein and cubebin, are used in combination.
  • combinations of clusin and dihydrocubebin, clusin and hinokinin, clusin and yatein, clusin and cubebin, dihydrocubebin and hinokinin, dihydrocubebin and yatein, dihydrocubebin and cubebin, hinokinin and yatein, hinokinin and cubebin, and yatein and cubebin are combinations of two lignan compounds according to the present invention, combinations of clusin, dihydrocubebin and hinokinin, clusin, dihydrocubebin and yatein, clusin, dihydrocubebin and cubebin, clusin, hinokinin and yatein, clusin, hinokinin and cubebin, clusin, yatein and cubebin, dihydrocubebin, hinokinin and yatein, dihydrocubebin, hinokinin and cubebin, dihydrocube
  • the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • the at least one compound is preferably selected from the group consisting of clusin, dihydrocubebin and hinokinin, more preferably from the group consisting of clusin and dihydrocubebin.
  • the pharmaceutical composition according to the present invention is preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein.
  • the tumour disease is preferably cancer, which may be hormone-dependent or hormone-independent.
  • the cancer or tumour disease is hormone-dependent, such as estrogen- or androgen-dependent.
  • the cancer or tumour disease is selected from the group consisting of hormone- dependent breast cancer, hormone-dependent endometrial cancer, hormone- dependent prostate cancer, hormone-dependent testicular cancer, hormone-dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone-dependent bladder cancer.
  • the pharmaceutical composition according to the present invention is for use in the treatment or prevention of prostate cancer, breast cancer or pancreatic cancer, preferably for use in the treatment of prostate cancer, such as hormone-dependent prostate cancer.
  • the present invention provides a pharmaceutical composition comprising clusin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone- dependent prostate cancer.
  • the pharmaceutical composition comprising clusin according to the present invention further comprises at least one compound selected from the group consisting of dihydrocubebin, hinokinin, yatein and cubebin.
  • the pharmaceutical composition according to the present invention comprises clusin as the only pharmaceutically active ingredient.
  • the pharmaceutical composition consists of clusin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin is preferably present in the pharmaceutical composition according to the present invention in a concentration of at least 10% (w/w), preferably at least 20% (w/w), more preferably at least 30% (w/w), such as at least 40% (w/w), at least 50% (w/w), or at least 60% (w/w), and may be present in a concentration of up to 100%, such as in a concentration of 90% (w/w), 95% (w/w), 99% (w/w) or 100%.
  • clusin is preferably present in the pharmaceutical composition according to the present invention in a concentration of between about 10% and 100% (w/w), such as in a concentration of between about 10% and 99% (w/w), 10% and 95% (w/w), 10% and 90% (w/w), 10% and 60% (w/w), or 10% and 30% (w/w).
  • the present invention further provides a pharmaceutical composition comprising dihydrocubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone- dependent prostate cancer.
  • the pharmaceutical composition comprising dihydrocubebin according to the present invention further comprises at least one compound selected from the group consisting of clusin, hinokinin, yatein and cubebin.
  • the pharmaceutical composition comprises dihydrocubebin as the only pharmaceutically active ingredient.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Dihydrocubebin is preferably present in the pharmaceutical composition according to the present invention in a concentration of at least 5% (w/w), preferably at least 10% (w/w), more preferably at least 15% (w/w), such as at least 20% (w/w), at least 25% (w/w), or at least 30% (w/w), and may be present in a concentration of up to 100%, such as in a concentration of 90% (w/w), 95% (w/w), 99% (w/w) or 100%.
  • dihydrocubebin is preferably present in the pharmaceutical composition according to the present invention in a concentration of between about 5% and 100% (w/w), such as in a concentration of between about 5% and 99% (w/w), 5% and 95% (w/w), 5% and 90% (w/w), 5% and 50% (w/w), or 5% and 25% (w/w).
  • the present invention further provides a pharmaceutical composition comprising hinokinin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising hinokinin according to the present invention further comprises at least one compound selected from the group consisting of clusin, dihydrocubebin, yatein and cubebin.
  • the pharmaceutical composition comprises hinokinin as the only pharmaceutically active ingredient.
  • the pharmaceutical composition according to the present invention consists of hinokinin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Hinokinin is preferably present in the pharmaceutical composition according to the present invention in a concentration of at least 15% (w/w), preferably at least 20% (w/w), more preferably at least 30% (w/w), such as at least 40% (w/w), at least 50% (w/w), or at least 60% (w/w), and may be present in a concentration of up to 100%, such as in a concentration of 90% (w/w), 95% (w/w), 99% (w/w) or 100%.
  • hinokinin is preferably present in the pharmaceutical composition according to the present invention in a concentration of between about 1 5% and 100% (w/w), such as in a concentration of between about 15% and 99% (w/w), 15% and 95% (w/w), 15% and 90% (w/w), 15% and 70% (w/w), or 15% and 50% (w/w).
  • the present invention further provides a pharmaceutical composition comprising yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising yatein according to the present invention further comprises at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin and cubebin.
  • the pharmaceutical composition comprises yatein as the only pharmaceutically active ingredient.
  • the pharmaceutical composition according the present invention consists of yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Yatein is preferably present in the pharmaceutical composition according to the present invention in a concentration of at least 2% (w/w), preferably at least 4% (w/w), more preferably at least 8% (w/w), such as at least 15% (w/w), at least 30% (w/w), or at least 50% (w/w), and may be present in a concentration of up to 100%, such as in a concentration of 90% (w/w), 95% (w/w), 99% (w/w) or 100%.
  • yatein is preferably present in the pharmaceutical composition according to the present invention in a concentration of between 2% and 100% (w/w), such as in a concentration of between about 2% and 99% (w/w), 2% and 95% (w/w), 2% and 90% (w/w), 2% and 50% (w/w), or 2% and 15% (w/w).
  • the present invention further provides a pharmaceutical composition comprising cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising cubebin according to the present invention further comprises at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin and yatein.
  • the pharmaceutical composition comprises cubebin as the only pharmaceutically active ingredient.
  • the pharmaceutical composition according the present invention consists of cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Cubebin is preferably present in the pharmaceutical composition according to the present invention in a concentration of at least 25% (w/w), preferably at least 35% (w/w), more preferably at least 45% (w/w), such as at least 55% (w/w), at least 65% (w/w), or at least 75% (w/w), and may be present in a concentration of up to 100%, such as in a concentration of 90% (w/w), 95% (w/w), 99% (w/w) or 100%.
  • cubebin is preferably present in the pharmaceutical composition according to the present invention in a concentration of between 25% and 100% (w/w), such as in a concentration of between about 25% and 99% (w/w), 25% and 95% (w/w), 25% and 90% (w/w), 25% and 80% (w/w), or 25% and 60% (w/w).
  • compositions according to the present invention are those comprising clusin and/or dihydrocubebin, preferably for use as a medicament, more preferably for use in the treatment of a tumour disease as disclosed herein.
  • the pharmaceutical composition according to the present invention comprises at least two compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, preferably from the group consisting of clusin, dihydrocubebin and hinokinin. Any combination of the lignan compounds as disclosed herein may be comprised in the pharmaceutical composition according to the present invention.
  • the present invention provides, for example, a pharmaceutical composition comprising clusin and dihydrocubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising clusin and dihydrocubebin further comprises a compound selected from the group consisting of hinokinin, yatein and cubebin.
  • the pharmaceutical composition comprises clusin and dihydrocubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • One or both of clusin and dihydrocubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin in a concentration of between 10% and 30% (w/w), and/or dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w), such as in a concentration of between 5% and 20% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising clusin and hinokinin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising clusin and hinokinin further comprises a compound selected from the group consisting of dihydrocubebin, yatein and cubebin.
  • the pharmaceutical composition comprises clusin and hinokinin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, hinokinin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • One or both of clusin and hinokinin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • hinokinin in a concentration of between 10% and 30% (w/w), and/or hinokinin may be present in a concentration of, e.g. at least 1 5% (w/w), such as in a concentration of between 15% and 50% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising ciusin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone- dependent prostate cancer.
  • the pharmaceutical composition comprising ciusin and yatein further comprises a compound selected from the group consisting of dihydrocubebin, hinokinin and cubebin.
  • the pharmaceutical composition comprises ciusin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of ciusin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • ciusin and yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of ciusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • ciusin may be present in a concentration of at least 10% (w/w), e.g.
  • yatein in a concentration of between 10% and 30% (w/w), and/or yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising ciusin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising clusin and cubebin further comprises a compound selected from the group consisting of dihydrocubebin, hinokinin and yatein.
  • the pharmaceutical composition comprises clusin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • One or both of clusin and cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • cubebin in a concentration of between 10% and 30% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising dihydrocubebin and hinokinin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising dihydrocubebin and hinokinin further comprises a compound selected from the group consisting of clusin, yatein and cubebin.
  • the pharmaceutical composition comprises dihydrocubebin and hinokinin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, hinokinin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • dihydrocubebin and hinokinin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • hinokinin in a concentration of between 5% and 20% (w/w), and/or hinokinin may be present in a concentration of, e.g. at least 15% (w/w), such as in a concentration of between 1 5% and 50% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising dihydrocubebin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising dihydrocubebin and yatein further comprises a compound selected from the group consisting of clusin, hinokinin and cubebin.
  • the pharmaceutical composition comprises dihydrocubebin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • dihydrocubebin and yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • yatein in a concentration of between 5% and 20% (w/w), and/or yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising dihydrocubebin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising dihydrocubebin and cubebin further comprises a compound selected from the group consisting of clusin, hinokinin and yatein.
  • the pharmaceutical composition comprises dihydrocubebin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • dihydrocubebin and cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • cubebin in a concentration of between 5% and 20% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising hinokinin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising hinokinin and yatein further comprises a compound selected from the group consisting of clusin, dihydrocubebin and cubebin.
  • the pharmaceutical composition comprises hinokinin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of hinokinin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • One or both of hinokinin and yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • hinokinin may be present in a concentration of at least 15% (w/w), e.g.
  • yatein in a concentration of between 15% and 50% (w/w), and/or yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition comprising hinokinin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising hinokinin and cubebin further comprises a compound selected from the group consisting of clusin, dihydrocubebin and yatein.
  • the pharmaceutical composition comprises hinokinin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of hinokinin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • One or both of hinokinin and cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • hinokinin may be present in a concentration of at least 10% (w/w), e.g.
  • cubebin in a concentration of between 15% and 50% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprising yatein and cubebin further comprises a compound selected from the group consisting of ciusin, dihydrocubebin and hinokinin.
  • the pharmaceutical composition comprises yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of yatein, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • yatein and cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of ciusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • yatein may be present in a concentration of at least 2% (w/w), e.g.
  • the pharmaceutical composition according to the present invention comprises at least three compounds selected from the group consisting of ciusin, dihydrocubebin, hinokinin, yatein and cubebin, preferably the pharmaceutical composition comprises ciusin, dihydrocubebin and hinokinin. Any combination of the lignan compounds as disclosed herein may be comprised in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising ciusin, dihydrocubebin and hinokinin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, dihydrocubebin and hinokinin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin, hinokinin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, dihydrocubebin and/or hinokinin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin in a concentration of between 10% and 30% (w/w)
  • dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w), such as in a concentration of between 5% and 20% (w/w)
  • hinokinin may be present in a concentration of, e.g. at least 15%, such as in a concentration of between 1 5% and 50% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, dihydrocubebin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, dihydrocubebin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, dihydrocubebin and/or yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin in a concentration of between 10% and 30% (w/w)
  • dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w), such as in a concentration of between 5% and 20% (w/w)
  • yatein may be present in a concentration of, e.g. at least 2%, such as in a concentration of between 2% and 1 5% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, dihydrocubebin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, dihydrocubebin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, dihydrocubebin and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin in a concentration of between 10% and 30% (w/w)
  • dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w), such as in a concentration of between 5% and 20% (w/w)
  • cubebin may be present in a concentration of, e.g. at least 25%, such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, hinokinin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, hinokinin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, hinokinin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, hinokinin and/or yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, hinokinin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, hinokinin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, hinokinin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, hinokinin and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • w/w a concentration of between 10% and 30% (w/w)
  • hinokinin may be present in a concentration of at least 1 5%, e.g. in a concentration of between 15% and 50% (w/w)
  • cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, yatein and cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, yatein and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 1 5% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25%, such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising dihydrocubebin, hinokinin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises dihydrocubebin, hinokinin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, hinokinin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Dihydrocubebin, hinokinin and/or yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising dihydrocubebin, hinokinin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises dihydrocubebin, hinokinin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, hinokinin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Dihydrocubebin, hinokinin and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • hinokinin may be present in a concentration of, e.g. at least 1 5% (w/w), such as in a concentration of between 15% and 50% (w/w)
  • cubebin may be present in a concentration of, e.g. at least 25%, such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising dihydrocubebin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises dihydrocubebin, yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, yatein, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Dihydrocubebin, yatein and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25%, such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising hinokinin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises hinokinin, yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of hinokinin, yatein, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Hinokinin, yatein and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • hinokinin may be present in a concentration of at least 1 5% (w/w), e.g.
  • the pharmaceutical composition according to the present invention comprises at least four compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin. Any combination of the lignan compounds as disclosed herein may be comprised in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, dihydrocubebin, hinokinin and yatein and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, dihydrocubebin, hinokinin and yatein as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin, hinokinin, yatein and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, dihydrocubebin, hinokinin and/or yatein may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin in a concentration of between 10% and 30% (w/w)
  • dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w), such as in a concentration of between 5% and 20% (w/w)
  • hinokinin may be present in a concentration of, e.g. at least 15%, such as in a concentration of between 15% and 50% (w/w)
  • yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, dihydrocubebin, hinokinin and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, dihydrocubebin, hinokinin and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin, hinokinin, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, dihydrocubebin, hinokinin and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w), such as in a concentration of between 5% and 20% (w/w), and/or hinokinin may be present in a concentration of, e.g. at least 15%, such as in a concentration of between 15% and 50% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, hinokinin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, hinokinin, yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, hinokinin, yatein, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, hinokinin, yatein and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • ⁇ in a concentration of between 10% and 30% (w/w)
  • hinokinin may be present in a concentration of, e.g. at least 15%, such as in a concentration of between 15% and 50% (w/w)
  • yatein may be present in a concentration of, e.g. at least 2% (w/w), such as in a concentration of between 2% and 15% (w/w)
  • cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, dihydrocubebin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises clusin, dihydrocubebin, yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of clusin, dihydrocubebin, yatein, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Clusin, dihydrocubebin, yatein and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w), e.g.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g. in a concentration of between 5% and 20% (w/w), and/or yatein may be present in a concentration of, e.g. at least 2%, such as in a concentration of between 2% and 15% (w/w), and/or cubebin may be present in a concentration of, e.g. at least 25% (w/w), such as in a concentration of between 25% and 60% (w/w), in the pharmaceutical composition according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising dihydrocubebin, hinokinin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers, and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition comprises dihydrocubebin, hinokinin, yatein and cubebin as the only pharmaceutically active ingredients.
  • the pharmaceutical composition according the present invention consists of dihydrocubebin, hinokinin, yatein, cubebin and one or more pharmaceutically acceptable excipients, carriers, and/or diluents.
  • Dihydrocubebin, hinokinin, yatein and/or cubebin may be present in the pharmaceutical composition according to the present invention, e.g. in a concentration as disclosed above for the pharmaceutical composition comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • dihydrocubebin may be present in a concentration of at least 5% (w/w), e.g.
  • the pharmaceutical composition according to the present invention comprises at least one, preferably at least two, but not more than four, i.e.
  • the present invention provides, a pharmaceutical composition comprising at least two, but not more than four, i.e.
  • clusin may be absent from the pharmaceutical composition according to the present invention
  • dihydrocubebin may be absent from the pharmaceutical composition according to the present invention
  • hinokinin may be absent from the pharmaceutical composition according to the present invention
  • yatein may be absent from the pharmaceutical composition according to the present invention
  • cubebin may be absent from the pharmaceutical composition according to the present invention.
  • Any combination of the lignan compounds as disclosed herein may be comprised in the pharmaceutical composition according to this embodiment of the present invention, except of the combination clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • the pharmaceutical composition comprising at least two, but not more than four compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin may comprise or consist of the combinations of lignan compounds, including the preferred concentrations of the lignan compounds, as defined above for pharmaceutical compositions comprising or consisting of two, three or four lignan compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • the pharmaceutical composition according the present invention comprises clusin, dihydrocubebin, hinokinin, yatein and cubebin, and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, such as hormone-dependent cancer, e.g.
  • concentrations of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin are concentrations, e.g. as defined above for the pharmaceutical compositions comprising at least one compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • clusin may be present in a concentration of at least 10% (w/w) as described above, e.g. in a concentration of between 10% and 30% (w/w), and/or dihydrocubebin may be present in a concentration of, e.g. at least 5% (w/w) as described above, e.g. in a concentration of between 5% and 20% (w/w), and/or hinokinin may be present in a concentration of, e.g. at least 15% (w/w) as described above, e.g. in a concentration of between 15% and 50% (w/w), and/or yatein may be present in a concentration of, e.g.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin, dihydrocubebin, hinokinin, yatein and cubebin, and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer, wherein
  • clusin is present in a concentration of at least 10% (w/w), such as at least 10% (w/w), at least 20% (w/w), at least 30% (w/w), at least 40% (w/w), at least 50% (w/w), or at least 60% (w/w), e.g. in a concentration of between about 10% and 60% (w/w), such as in a concentration of between about 10% and 30% (w/w),
  • dihydrocubebin is present in a concentration of at least 5% (w/w), such as at least 5% (w/w), at least 10% (w/w), at least 15% (w/w), at least 20% (w/w), at least 25% (w/w), or at least 30% (w/w), more preferably in a concentration of between about 5% and 50% (w/w), most preferably in a concentration of between about 5% and 25% (w/w), hinokinin is present in a concentration of at least 15% (w/w), such as at least 1 5% (w/w), at least 20% (w/w), at least 30% (w/w), at least 40% (w/w), at least 50% (w/w), or at least 60% (w/w), more preferably in a concentration of between about 15% and 70% (w/w), most preferably in a concentration of between about 1 5% and 50% (w/w), yatein is present in a concentration of at least 2% (w/w), such as at least 2% (w/w), at
  • cubebin is present in a concentration of at least 25% (w/w), such as at least 25% (w/w), at least 35% (w/w), at least 45% (w/w), at least 55% (w/w), at least 65% (w/w), or at least 75% (w/w), e.g. in a concentration of between about 25% and 80% (w/w), such as in a concentration of between about 25% and 60% (w/w).
  • the concentration of lignan compounds together preferably the concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w), and even more preferably at least 80%, and may be up to 100%, such as 90% (w/w), 95% (w/w), 99% (w/w) or 100%.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one, preferably at least two, such as two, three, four or five compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, preferably selected from the group consisting of clusin, dihydrocubebin and hinokinin, more preferably selected from the group consisting of clusin and dihydrocubebin, and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents as disclosed herein, wherein the concentration of lignan compounds together, preferably the concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w), and even more preferably at least 80% or higher, preferably for
  • hormone-dependent breast cancer hormone-dependent endometrial cancer
  • hormone-dependent prostate cancer hormone-dependent testicular cancer
  • hormone-dependent ovarian cancer hormone-dependent colorectal cancer
  • hormone-dependent bladder cancer preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone- dependent prostate cancer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one, preferably at least two, but not more than four, i.e. two, three or four compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents as disclosed above, wherein preferably the concentration of lignan compounds together, preferably the concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), and even more preferably at least 75% (w/w) and may be up to 100%, preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, such as hormone-dependent
  • hormone-dependent breast cancer hormone-dependent endometrial cancer
  • hormone-dependent prostate cancer hormone-dependent testicular cancer
  • hormone-dependent ovarian cancer hormone-dependent colorectal cancer
  • hormone-dependent bladder cancer preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition according to the present invention may comprise clusin in a concentration of at least 10% as described above and may comprise a total lignan concentration, preferably a lignan concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together, of at least 60%, preferably at least 65% (w/w), more preferably at least 70% (w/w), and even more preferably at least 75% (w/w), and/or the pharmaceutical composition according to the present invention may comprise dihydrocubebin in a concentration of at least 5% as described above and may comprise a total lignan concentration, preferably a lignan concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together, of at least 60%, preferably at least 65% (w/w), more preferably at least 70% (w/w), and even more preferably at least 75% (w/w), and/or the
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising clusin and dihydrocubebin, preferably comprising clusin, dihydrocubebin and hinokinin, more preferably comprising clusin, dihydrocubebin, hinokinin, yatein and cubebin, and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents, wherein the concentration of lignan compounds together, preferably the concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together, is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), and even more preferably at least 75% (w/w), preferably for use as a medicament, more preferably for use in the treatment or prevention of a tumour disease as described herein, even more preferably for use in the treatment or prevention of cancer, such as hormone-dependent cancer, e.g
  • hormone-dependent breast cancer hormone-dependent endometrial cancer
  • hormone-dependent prostate cancer hormone-dependent testicular cancer
  • hormone-dependent ovarian cancer hormone-dependent colorectal cancer
  • hormone-dependent bladder cancer preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone- dependent prostate cancer, such as hormone-dependent prostate cancer.
  • the pharmaceutical composition according to the present invention comprises at least two compounds selected from the group consisting of clusin, cubebin, dihydrocubebin, hinokinin and yatein, wherein at least one of the compounds is present in the following concentrations: - clusin in a concentration of at least 10% (w/w), such as at least 10% (w/w), at least 20% (w/w), at least 30% (w/w), at least 40% (w/w), at least 50% (w/w), or at least 60% (w/w), e.g. in a concentration of between about 10% and 60% (w/w), such as in a concentration of between about 10% and 30% (w/w),
  • dihydrocubebin in a concentration of at least 5% (w/w), such as at least 5% (w/w), at least 10% (w/w), at least 1 5% (w/w), at least 20% (w/w), at least 25% (w/w), or at least 30% (w/w), e.g. in a concentration of between about 5% and 50% (w/w), such as in a concentration of between about 5% and 25% (w/w), hinokinin in a concentration of at least 15% (w/w), such as at least 15% (w/w), at least 20% (w/w), at least 30% (w/w), at least 40% (w/w), at least 50% (w/w), or at least 60% (w/w), e.g. in a concentration of between about 15% and 70% (w/w), such as in a concentration of between about 15% and 50% (w/w),
  • - yatein in a concentration of at least 2% (w/w), such as at least 2% (w/w), at least 4% (w/w), at least 8% (w/w), at least 15% (w/w), at least 30% (w/w), or at least 50% (w/w), e.g. in a concentration of between about 2% and 50% (w/w), such as in a concentration of between about 2% and 15% (w/w),
  • cubebin in a concentration of at least 25% (w/w), such as at least 25% (w/w), at least 35% (w/w), at least 45% (w/w), at least 55% (w/w), at least 65% (w/w), or at least 75% (w/w), more preferably in a concentration of between about 25% and 80% (w/w), most preferably in a concentration of between about 25% and 60% (w/w).
  • the pharmaceutical composition according to the present invention comprises clusin, wherein clusin is present in a concentration of at least 10% (w/w) as described above, preferably for the use as described above.
  • the pharmaceutical composition comprising clusin, wherein clusin is present in a concentration of at least 10% (w/w) further comprises at least one further compound selected from the group consisting of dihydrocubebin, cubebin, hinokinin and yatein, preferably at least two further compounds selected from the group consisting of dihydrocubebin, cubebin, hinokinin and yatein, preferably at least three further compounds selected from the group consisting of dihydrocubebin, cubebin, hinokinin and yatein.
  • the pharmaceutical composition comprising clusin further comprises dihydrocubebin, preferably in a concentration of at least 5% (w/w), more preferably in a concentration of between 5% and 20% (w/w), and/or hinokinin, preferably in a concentration of at least 15% (w/w), more preferably in a concentration of between 1 5% and 50% (w/w), and/or yatein, preferably in a concentration of at least 2% (w/w), more preferably in a concentration of between 2% and 15% (w/w), and/or cubebin, preferably in a concentration of at least 25% (w/w), more preferably in a concentration of between 25% and 60% (w/w).
  • dihydrocubebin preferably in a concentration of at least 5% (w/w), more preferably in a concentration of between 5% and 20% (w/w), and/or hinokinin, preferably in a concentration of at least 15% (w/w), more preferably in a concentration of between 1 5% and 50%
  • the pharmaceutical composition according to the present invention comprises dihydrocubebin, wherein dihydrocubebin is present in a concentration of at least 5% (w/w) as described above, preferably for the use as described above.
  • the pharmaceutical composition comprising dihydrocubebin, wherein dihydrocubebin is present in a concentration of at least 5% (w/w) further comprises at least one further compound selected from the group consisting of clusin, cubebin, hinokinin and yatein, preferably at least two further compounds selected from the group consisting of clusin, cubebin, hinokinin and yatein, preferably at least three further compounds selected from the group consisting of clusin, cubebin, hinokinin and yatein.
  • the pharmaceutical composition comprising dihydrocubebin further comprises clusin, preferably in a concentration of at least 10% (w/w), more preferably in a concentration of between 10% and 30% (w/w), and/or hinokinin, preferably in a concentration of at least 1 5% (w/w), more preferably in a concentration of between 1 5% and 50% (w/w), and/or yatein, preferably in a concentration of at least 2% (w/w), more preferably in a concentration of between 2% and 1 5% (w/w), and/or cubebin, preferably in a concentration of at least 25% (w/w), more preferably in a concentration of between 25% and 60% (w/w).
  • the pharmaceutical composition according to the present invention comprises hinokinin, wherein hinokinin is present in a concentration of at least 1 5% (w/w) as described above, preferably for the use as described above.
  • the pharmaceutical composition comprising hinokinin, wherein hinokinin is present in a concentration of at least 1 5% (w/w) further comprises at least one further compound selected from the group consisting of clusin, cubebin, dihydrocubebin and yatein, preferably at least two further compounds selected from the group consisting of clusin, cubebin, dihydrocubebin and yatein, preferably at least three further compounds selected from the group consisting of clusin, cubebin, dihydrocubebin and yatein.
  • the pharmaceutical composition comprising hinokinin further comprises clusin, preferably in a concentration of at least 10% (w/w), more preferably in a concentration of between 10% and 30% (w/w), and/or dihydrocubebin, preferably in a concentration of at least 5% (w/w), more preferably in a concentration of between 5% and 20% (w/w), and/or yatein, preferably in a concentration of at least 2% (w/w), more preferably in a concentration of between 2% and 1 5% (w/w), and/or cubebin, preferably in a concentration of at least 25% (w/w), more preferably in a concentration of between 25% and 60% (w/w).
  • clusin preferably in a concentration of at least 10% (w/w), more preferably in a concentration of between 10% and 30% (w/w), and/or dihydrocubebin, preferably in a concentration of at least 5% (w/w), more preferably in a concentration of between 5% and 20% (w
  • the pharmaceutical composition according to the present invention comprises yatein, wherein yatein is present in a concentration of at least 2% (w/w) as described above, preferably for the use as described above.
  • the pharmaceutical composition comprising yatein, wherein yatein is present in a concentration of at least 2% (w/w) further comprises at least one further compound selected from the group consisting of clusin, cubebin, hinokinin and dihydrocubebin, preferably at least two further compounds selected from the group consisting of clusin, cubebin, hinokinin and dihydrocubebin, preferably at least three further compounds selected from the group consisting of clusin, cubebin, hinokinin and dihydrocubebin.
  • the pharmaceutical composition comprising yatein further comprises clusin, preferably in a concentration of at least 10% (w/w), more preferably in a concentration of between 10% and 30% (w/w), and/or hinokinin, preferably in a concentration of at least 15% (w/w), more preferably in a concentration of between 15% and 50% (w/w), and/or dihydrocubebin, preferably in a concentration of at least 5% (w/w), more preferably in a concentration of between 5% and 20% (w/w), and/or cubebin, preferably in a concentration of at least 25% (w/w), more preferably in a concentration of between 25% and 60% (w/w).
  • the pharmaceutical composition according to the present invention comprises cubebin, wherein cubebin is present in a concentration of at least 25% (w/w) as described above, preferably for the use as described above.
  • the pharmaceutical composition comprising cubebin, wherein cubebin is present in a concentration of at least 25% (w/w) further comprises at least one further compound selected from the group consisting of clusin, dihydrocubebin, hinokinin and yatein, preferably at least two further compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin and yatein, preferably at least three further compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin and yatein.
  • the pharmaceutical composition comprising cubebin further comprises clusin, preferably in a concentration of at least 10% (w/w), more preferably in a concentration of between 10% and 30% (w/w), and/or hinokinin, preferably in a concentration of at least 15% (w/w), more preferably in a concentration of between 15% and 50% (w/w), and/or yatein, preferably in a concentration of at least 2% (w/w), more preferably in a concentration of between 2% and 1 5% (w/w), and/or dihydrocubebin, preferably in a concentration of at least 5% (w/w), more preferably in a concentration of between 5% and 20% (w/w).
  • the pharmaceutical composition according to the present invention does not comprise proteins in a significant amount, preferably the pharmaceutical composition according to the present invention is free of proteins.
  • the pharmaceutical composition according to the present invention does not comprise amino acids in a significant amount, preferably the pharmaceutical composition according to the present invention is free of amino acids.
  • the pharmaceutical composition according to the present invention is essentially free from proteins and/or amino acids, preferably the pharmaceutical composition according to the present invention does not comprise proteins and/or amino acids.
  • the term "significant amount” preferably means in the context of the present invention an amount of more than 0.5% (w/w).
  • the pharmaceutical composition according to the present invention preferably does not comprise more than 0.5% (w/w) proteins and/or preferably does not comprise more than 0.5% (w/w) amino acids.
  • the term "essentially free” preferably refers to an amount of at most 0.5% (w/w), more preferably of at most 0.3% (w/w), even more preferably of at most 0.1 % (w/w), and most preferably to an amount of below the detection limit (using state of the art detection methods for the respective compounds).
  • the pharmaceutical composition according to the present invention is not an extract type of Piper cubeba as disclosed in WO 2009/021 347.
  • the pharmaceutical composition according to the present invention is not an extract from Piper cubeba prepared by ethanol extraction of C0 2 defatted powder of Piper cubeba using ethanol absolute or a dilution of ethanol, such as 90% ethanol aq. (w/w), stirring for 2 hours at room temperature, and removing solid plant material from the obtained extract, such as by filtration, e.g. using a cellulose filter AF6, without any further purification steps.
  • the present invention provides clusin, dihydrocubebin and/or hinokinin for use in the treatment or prevention of a tumour disease as disclosed above, preferably for use in the treatment or prevention of cancer, more preferably for use in the treatment or prevention of a hormone-dependent cancer, such as hormone- dependent breast cancer, hormone-dependent endometrial cancer, hormone- dependent prostate cancer, hormone-dependent testicular cancer, hormone-dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone-dependent bladder cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • a hormone-dependent cancer such as hormone- dependent breast cancer, hormone-dependent endometrial cancer, hormone- dependent prostate cancer, hormone-dependent testicular cancer, hormone-dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone-dependent bladder cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • Preferred tumour diseases are selected from prostate cancer, breast cancer and pancreatic cancer.
  • the compounds clusin, dihydrocubebin and/or hinokinin may be used alone or in combination. If used in combination, the compounds may be used together in a pharmaceutical composition as disclosed above or separately, for example, in separate pharmaceutical compositions, e.g. for concurrent or sequential administration and/or for the same or different administration routes.
  • the present invention provides clusin for use in the treatment or prevention of a tumour disease as disclosed above, preferably for use in the treatment or prevention of cancer, more preferably for use in the treatment or prevention of a hormone-dependent cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the present invention provides dihydrocubebin for the treatment of a tumour disease as disclosed above, preferably for use in the treatment or prevention of cancer, more preferably for use in the treatment or prevention of a hormone-dependent cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • the present invention provides hinokinin for use in the treatment of a tumour disease as disclosed above, preferably for use in the treatment or prevention of cancer, more preferably for use in the treatment or prevention of a hormone-dependent cancer, most preferably for use in the treatment or prevention of prostate cancer, such as hormone-dependent prostate cancer.
  • clusin, dihydrocubebin and hinokinin are as described throughout the specification of the present invention.
  • the disclosure provided for the pharmaceutical composition according to the present invention e.g. the concentrations and combinations of two or three lignan compounds selected from clusin, dihydrocubebin and hinokinin also applies to this aspect of the present invention.
  • the present invention provides a process for preparing a lignan composition
  • the lignan composition prepared according to the process according to the present invention may have a lignan concentration of up to 100%, such as about 90% (w/w), about 95% (w/w), about 99% (w/w) or 100%.
  • the lignan composition obtainable according to the process according to the present invention comprises clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • the lignan concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w) and may be up to 100%, such as about 90% (w/w), about 95% (w/w), about 99% (w/w) or 100%, in the lignan composition obtainable by the process according to the present invention.
  • the lignan concentration in the lignan composition may be determined by HPLC technology.
  • concentrations of the single lignan compounds of the lignan composition obtainable according to the process according to the present invention are preferably as follows:
  • clusin is preferably present in a concentration of at least 10% (w/w), preferably between 10% and 30% (w/w),
  • dihydrocubebin is preferably present in a concentration of at least 5% (w/w), preferably between 5% and 20% (w/w),
  • hinokinin is preferably present in a concentration of at least 15% (w/w), preferably between 15% and 50% (w/w),
  • yatein is preferably present in a concentration of at least 2% (w/w), preferably between 2% and 15% (w/w), and
  • cubebin is preferably present in a concentration of at least 25% (w/w), preferably between 25% and 60% (w/w).
  • the lignan concentrations of the single lignan compounds in the lignan composition may be determined by HPLC technology.
  • the process according to the present invention comprises the steps of: (a) contacting lignan-containing plant material with an extraction solvent to obtain an extraction solution,
  • lignan concentration preferably the lignan concentration of the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin together, in the lignan composition is at least 60% (w/w), preferably at least 70% (w/w), more preferably at least 75% (w/w).
  • Steps (d) to (f) may optionally be repeated for further purification.
  • the term "contacting" with an extraction solvent in the context of the process according to the present invention preferably refers to wetting, submerging, bathing or any other type of incubation of the plant material with an extraction solution.
  • extraction solvent in the context of the present invention refers to any solvent or liquid, which is suitable for the process disclosed herein.
  • Suitable extraction solvents are known to a person skilled in the art and may include, but are not limited to water, supercritical gases, such as supercritical C0 2 , organic solvents, alcohols, such as e.g. methanol, ethanol, isopropanol, aromatic alcohols and their aqueous dilutions, wherein the alcohol is present in an amount of e.g.
  • the extraction solvent may also be any of the organic solvents, such as for example diethyl ether, chloroform, 1 ,4-dioxane, toluene, benzene, cyclohexane, hexane, pentane, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, or any combination thereof.
  • the extraction solvent can also be a mixture of alcohol and another organic solvent, or a water-saturated alcohol/organic solvent solution.
  • the extraction solvent is ethanol or an aqueous dilution of ethanol, such as absolute ethanol or e.g. 80% to 99% ethanol aq. (v/v), such as 90% ethanol aq. (v/v).
  • supercritical gases such as supercritical C0 2 , are possible and preferred extraction solvents.
  • lignan composition refers to a composition comprising one or more lignan compounds, such as clusin, dihydrocubebin, hinokinin, yatein and/or cubebin.
  • the lignan composition obtainable by the process according to the present invention comprises lignan compounds, preferably the lignan compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin, in a total concentration of at least 60% (w/w), preferably in a total concentration of at least 65% (w/w), more preferably in a total concentration of at least 70% (w/w), even more preferably in a total concentration of at least 75% (w/w) and may comprise a total lignan concentration of up to 100%, such as about 90% (w/w), about 95% (w/w), about 99% (w/w) or 100%.
  • the separation step (b) of the process according to the present invention may comprise filtration or centrifugation.
  • filtration refers to the mechanical or physical operation which is used for the separation of solids from fluids by interposing a medium through which only the fluid can pass.
  • centrifugation as used herein also refers to differential centrifugation, isopycnic centrifugation, and ultracentrifugation. Various methods of centrifugation are known in prior art and are readily available.
  • the optional concentration step (c) of the process according to the invention preferably comprises evaporation or precipitation, more preferably evaporation. In a preferred embodiment of the present invention, step (c) involves or comprises evaporation. It will be evident to the skilled person that evaporation can be facilitated by elevated temperatures of, e.g.
  • the evaporation process may also be facilitated when carried out under reduced pressure of, e.g. 1 mbar to 500mbar, preferably 10mbar to 250mbar, preferably 20 to l OOmbar, preferably 24 to 70mbar, preferably 25mbar to 80mbar, preferably 30mbar to 90mbar, preferably at 10 to 10Ombar, preferably at 1 Smbar to 70mbar, preferably at 1 5mbar to SOmbar.
  • 1 mbar to 500mbar preferably 10mbar to 250mbar, preferably 20 to l OOmbar, preferably 24 to 70mbar, preferably 25mbar to 80mbar, preferably 30mbar to 90mbar, preferably at 10 to 10Ombar, preferably at 1 Smbar to 70mbar, preferably at 1 5mbar to SOmbar.
  • the degree of concentration may be, for example, a concentration to 1/5, preferably to 1/10 of the volume of the extraction solution obtained in step (a) or (b).
  • the concentration in step (c) may also be, for example, up to dryness.
  • Methods for concentrating extraction solutions are known to the skilled person and include evaporation on a rotary evaporator, thin film evaporator, vaccum centrifugal evaporator, vacuum band evaporator etc..
  • Fractionation step (d) preferably comprises filtration, centrifugation or chromatography, preferably chromatography.
  • chromatography comprises techniques such as, e.g. column chromatography, planar chromatography, paper chromatography, thin layer chromatography, affinity chromatography, adsorption chromatography, liquid/liquid extraction etc..
  • chromatography involves column chromatography, e.g. using polymeric resins, such as polystyrene, silica gels, aluminium oxides, dextrans etc., most preferably medium pressure liquid chromatography.
  • a particularly preferred chromatography material is RP-C18 or RP-C8 silica (50 ⁇ ), e.g.
  • chromatography is performed under reverse phase conditions, preferably using isocratic conditions for elution.
  • isocratic elution is effected using an alcohol/water solution, such as a methano l/water solution at a ratio of e.g. 80:20 (v/v), 70:30 (v/v) or 60:40 (v/v), preferably at a ratio of 70:30 (v/v).
  • step (e) of the process according to the present invention means “combining”.
  • fractions containing lignan compounds are combined.
  • Such fractions containing lignan compounds may be readily identified by the skilled person, for example, by applying diode array detection at 218 nm and/or HPLC methodology using, for example, a Phenomenex R Luna RP-C18 stationary phase column.
  • the optional concentration step (f) of the process for preparing a lignan composition according to the present invention may, for example, comprise freeze-drying, vacuum evaporation, vacuum band drying, spray drying etc. of the pooled lignan-containing fractions obtained in step (e).
  • a particularly preferred concentration step comprises freeze drying.
  • the degree of concentration in concentration step (f) is preferably at least 1/10, more preferably at least 1/20 of the volume of the pooled lignan fractions.
  • the concentration may be, for example, up to dryness.
  • the process according to the present invention comprises the steps of:
  • extraction solvent is preferably a supercritical gas, such as supercritical C0 2 , an organic solvent or an aqueous solution of an organic solvent, preferably alcohol or an aqueous solution of an alcohol, more preferably ethanol or an aqueous solution of ethanol, such as 90% ethanol aq. (v/v) or ethanol absolute,
  • a supercritical gas such as supercritical C0 2
  • an organic solvent or an aqueous solution of an organic solvent preferably alcohol or an aqueous solution of an alcohol, more preferably ethanol or an aqueous solution of ethanol, such as 90% ethanol aq. (v/v) or ethanol absolute
  • step (c) optionally concentrating said extraction solution, preferably by evaporation or precipitation, preferably evaporation, e.g. to at least 1/5, preferably to at least 1/10 of the volume of the extraction solution obtained in step (b),
  • the lignan concentration in the lignan composition is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w).
  • the lignan-containing plant material used in the process according to the present invention comprises at least one lignan compound selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, preferably comprises at least two lignan compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, more preferably comprises at least three lignan compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, even more preferably comprises at least four lignan compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, and most preferably comprises clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • the lignan-containing plant material used in the process according to the present invention is preferably derived from plant species selected from the group consisting of Piper cubeba, such as Piper cubeba L, Tarenna madagascariensis, Piper ribesioides, Piper clusii, Juniperus phoenicea, such as Imagine Juniperus phoenicea, Juniperus thurifera, such as Juniperus thurifera var. Africana, Chamaecyparis obtuse, and Lychnophora ericoides.
  • the plant material, which is derived from Piper cubeba is Piper cubeba L. fruits, preferably unripe Piper cubeba L. fruits, most preferably Fructus Cubebae as defined in " Deutsches Arzneibuch 6" (DAB6).
  • plant material derived from plant species preferably means that the plant material may be any part of the plant or a mixture of plant parts of the particular plant species it is derived from, such as the leaves, the flowers, the seeds, the fruits, unripe fruits, buds, stems, stalks, roots etc., or the entire plant. Particularly preferred plant parts may vary between the different applicable plants. For example, particularly preferred plant parts for Piper cubeba are the fruits, particularly preferred plant parts for Piper ribesioides are the fruits and/or stems, particularly preferred plant parts for Chamaecyparis obtusa are the leaves, particularly preferred plant parts for Lychnophora ericoides are the roots and/or stems.
  • the skilled person is readily able to determine which plant parts are particularly useful for the process according the to the present invention, i.e. such plant parts comprising lignan compounds, by routine methods known in the art, such as by HPLC technology.
  • Piper cubeba comprises clusin, dihydrocubebin, hinokinin, yatein and cubebin
  • Tarenna madagascariensis comprises hinokinin, cubebin and dihydrocubebin
  • Piper ribesioides comprises cubebin and hinokinin
  • Piper clusii comprises clusin
  • Juniperus phoenicea such as Imagine Juniperus phoenicea
  • Juniperus thurifera such as Juniperus thurifera var.
  • Africana comprises yatein
  • Chamaecyparis obtusa comprises yatein
  • Lychnophora ericoides comprises hinokinin, cubebin and dihydrocubebin.
  • the plant material in the context of the present invention may be derived from one or more plant species.
  • the plant material may be derived from a mixture of plant species, preferably a mixture of plant species comprising clusin, dihydrocubebin, hinokinin, yatein and cubebin.
  • the process for preparing a lignan composition according to the present invention preferably results in a lignan composition comprising clusin, dihydrocubebin, hinokinin, yatein and cubebin as described herein.
  • the plant material is selected such that all five lignan compounds are present in the plant material.
  • the plant material is preferably derived from:
  • Juniperus phoenicea such as Moroccan Juniperus phoenicea
  • Juniperus thurifera such as Juniperus thurifera var. Africana
  • Chamaecyparis obtuse
  • the process according to the present invention may comprise the step of adding lignan compound(s), e.g. as purified or synthesized lignan compounds, to the lignan composition, e.g. obtained in step (e) or (f).
  • lignan compound(s) e.g. as purified or synthesized lignan compounds
  • the missing lignan may be added, e.g. as purified or synthesized lignan.
  • the lignan-containing plant material for preparing the lignan composition are fruits, preferably unripe fruits, from a Piper cubeba L plant, and the process comprises the steps of:
  • step (c) concentrating the extract by evaporation, preferably on a rotary evaporator, e.g. to at least 1/10 of the volume of the extraction solution obtained from step (b), (d) fractionating the extraction solution comprising the steps:
  • step (d2) subjecting the solution obtained in step (d1 ) to medium pressure liquid chromatography using reverse phase conditions, e.g. using polymeric resins, such as polystyrene, silica gels, aluminium oxides, dextrans etc, preferably using silica material, such as RP-C18 silica (e.g. 50 pm), (d3) eluting under isocratic conditions, preferably using a methanol/water solution, preferably at a ratio of methanol : water of 70:30 (v/v),
  • the lignan concentration in the lignan composition preferably the lignan concentration of the lignans clusin, dihydrocubebin, hinokinin, yatein and cubebin together, is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w).
  • the lignan concentration may, for example, be determined using HPLC technology.
  • the process according to the present invention further comprises the steps of:
  • step (g) adding one or more pharmaceutically acceptable excipients, diluents and/or carriers to the lignan composition obtained in step (e) or (f),
  • step (h) optionally formulating the lignan composition obtained in step (f) or step (g) to obtain a pharmaceutical formulation, preferably a parenteral or non-parenteral formulation.
  • a pharmaceutical formulation preferably a parenteral or non-parenteral formulation.
  • the present invention provides a lignan composition obtainable by the process according to the present invention.
  • the present invention provides, for example, a lignan composition obtainable by a process comprising the steps of:
  • the lignan concentration in the lignan composition preferably the lignan concentration of the lignans clusin, dihydrocubebin, hinokinin, yatein and cubebin together, is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w),
  • step(e) or (f) optionally adding one or more pharmaceutically acceptable excipients, diluents and/or carriers to the lignan composition obtained in step(e) or (f), and
  • step (h) optionally formulating the lignan composition obtained in step (e), (f) or (g) to obtain a pharmaceutical formulation, preferably a parenteral or non-parenteral formulation,
  • the present invention provides a lignan composition obtainable by a process comprising the steps of:
  • extraction solvent is preferably a supercritical gas, such as supercritical C0 2 , an organic solvent or an aqueous solution of an organic solvent, preferably alcohol or an aqueous solution of an alcohol, more preferably ethanol or an aqueous solution of ethanol,
  • step (b) separating the plant material solids from said extraction solution, preferably comprising filtration or centrifugation, preferably by filtration, (c) optionally concentrating said extraction solution, preferably by evaporation or precipitation, preferably by evaporation, e.g. to at least 1/5, preferably to at least 1/10 of the volume of the extraction solution obtained in step (b),
  • the lignan concentration in the lignan composition preferably the lignan concentration of the lignans clusin, dihydrocubebin, hinokinin, yatein and cubebin together, is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w),
  • step (g) optionally adding one or more pharmaceutically acceptable excipients, diluents and/or carriers to the lignan composition obtained in step (e) or (f), and
  • step (h) optionally formulating the lignan composition obtained in step (e), (f) or (g) to obtain a pharmaceutical formulation, preferably a parenteral or non-parenteral formulation
  • the present invention provides a lignan composition obtainable by a process comprising the steps of:
  • step (c) concentrating the extract by evaporation, preferably on a rotary evaporator, e.g. to at least 1/10 of the volume of the extraction solution obtained from step (b), (d) fractionating the extraction solution comprising the steps:
  • step (d1 ) dissolving the concentrated extract in alcohol, preferably in ethanol, preferably in absolute ethanol, preferably in a ratio of 1 :4 (weight of extract : volume of solvent)
  • step (d2) subjecting the solution obtained in step (d1 ) to medium pressure liquid chromatography using reverse phase conditions, e.g. using polymeric resins, such as polystyrene, silica gels, aluminium oxides, dextrans etc, preferably using silica material, such as P-C18 silica (e.g. 50 pm),
  • (d3) eluting under isocratic conditions preferably using a methanol/water solution, preferably at a ratio of methanol : water of 70:30 (v/v),
  • the lignan concentration in the lignan composition preferably the lignan concentration of the lignans clusin, dihydrocubebin, hinokinin, yatein and cubebin together, is at least 60% (w/w), preferably at least 65% (w/w), more preferably at least 70% (w/w), even more preferably at least 75% (w/w),
  • step (g) optionally adding one or more pharmaceutically acceptable excipients, diluents and/or carriers to the lignan composition obtained in step (e) or (f), and
  • step (h) optionally formulating the lignan composition obtained in step (f) or step (g) to obtain a pharmaceutical formulation, preferably a parenteral or non-parenteral formulation
  • the present invention provides, for example, a lignan composition obtainable by a process comprising or consisting of the method steps of Example 1 or 2 in combination with the method steps of Example 1 1 .
  • the present invention also provides the lignan composition obtainable by a process according to the present invention for use as a medicament, for example for use in the treatment or prevention of a tumour disease as defined herein, such as for use in the treatment or prevention of a hormone-dependent cancer, e.g. hormone-dependent breast cancer, hormone-dependent endometrial cancer, hormone-dependent prostate cancer, hormone-dependent testicular cancer, hormone-dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone-dependent bladder cancer.
  • a hormone-dependent cancer e.g. hormone-dependent breast cancer, hormone-dependent endometrial cancer, hormone-dependent prostate cancer, hormone-dependent testicular cancer, hormone-dependent ovarian cancer, hormone-dependent colorectal cancer, and hormone-dependent bladder cancer.
  • the present invention provides a lignan composition obtainable by the process according to the present invention for use in the treatment or prevention of prostate cancer, breast cancer, pancreatic cancer, preferably for use in the treatment of prostate cancer, such as hormone-dependent prostate cancer.
  • the present invention provides a pharmaceutical composition, a pharmaceutical formulation, and a medicament comprising the lignan composition according to the present invention and optionally one or more pharmaceutically acceptable excipients, carriers and/or diluents.
  • the present invention provides a method of treating or preventing a tumour disease as described above comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to the present invention, a therapeutically effective amount of a lignan composition according to the present invention, a therapeutically effective amount of a pharmaceutical composition, a pharmaceutical formulation or a medicament comprising the lignan composition according to the present invention, or a therapeutically effective amount of one or more compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, preferably selected from the group consisting of clusin, dihydrocubebin and hinokinin, more preferably selected from the group consisting of clusin and dihydrocubebin.
  • the tumour disease is preferably cancer, such as a hormone-dependent or hormone- independent cancer, preferably a hormone-dependent cancer, such as an androgen- or estrogen-dependent cancer as described herein.
  • the method is for treating or preventing prostate cancer, such as hormone-dependent prostate cancer, breast cancer, such as hormone-dependent breast cancer, or pancreatic cancer.
  • the present invention provides, for example, a method of treating or preventing a tumour disease as described herein, preferably cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, more preferably prostate cancer, such as hormone-dependent prostate cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one, preferably at least two, such as two, three, or four compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin and optionally one or more pharmaceutically active excipients, carriers and/or diluents, e.g. in a combination and/or in concentrations as disclosed herein.
  • a pharmaceutical composition comprising at least one, preferably at least two, such as two, three, or four compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin and optionally one or more pharmaceutically active excipient
  • the present invention provides a method of treating or preventing a tumour disease as described herein, preferably cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, more preferably prostate cancer, such as hormone-dependent prostate cancer, comprising administering to a subject in need thereof a therapeutically effective amount of one or more, preferably of at least two, such as two, three, or four compounds selected from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, preferably selected from the group consisting of clusin, dihydrocubebin and hinokinin, more preferably selected from the group consisting of clusin and dihydrocubebin, e.g.
  • the compounds clusin, dihydrocubebin, hinokinin, yatein and cubebin may be used alone or in combination. If used in combination, the compounds may be used together in a pharmaceutical composition as disclosed above or separately, for example, in separate pharmaceutical compositions, e.g. for concurrent or sequential administration and/or for the same or different administration routes.
  • the present invention provides a method of treating or preventing a tumour disease as described herein, preferably cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, more preferably prostate cancer, such as hormone-dependent prostate cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a lignan composition obtainable by a process according to the present invention as described above, a pharmaceutical composition comprising a lignan composition according to the present invention, a pharmaceutical formulation comprising a lignan composition according to the present invention, or a medicament comprising a lignan composition according to the present invention.
  • a tumour disease as described herein, preferably cancer, preferably selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer, more preferably prostate cancer, such as hormone-dependent prostate cancer
  • the term “subject” preferably relates to a "patient", an "individual”, or an “animal”, which terms preferably relate to a mammal.
  • mammals in the context of the present invention are humans, non-human primates, domesticated animals such as dogs, cats, sheep, cattle, goats, pigs, horses etc., laboratory animals such as mice, rats, rabbits, guinea pigs, etc. as well as animals in captivity such as animals of zoos.
  • the term “animal” as used herein also includes humans.
  • a preferred "subject” in the context of the present invention is a human.
  • excipient when used herein is intended to indicate all substances in a pharmaceutical formulation or pharmaceutical composition which are not pharmaceutically active ingredients such as, e.g. carriers, binders, lubricants, thickeners, disintegrants, surface active agents, preservatives, emulsifiers, buffers, flavouring agents, colorants, glidants, coatings or protective matrices etc.
  • pharmaceutically active ingredients such as, e.g. carriers, binders, lubricants, thickeners, disintegrants, surface active agents, preservatives, emulsifiers, buffers, flavouring agents, colorants, glidants, coatings or protective matrices etc.
  • Binders may be, for example, acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, magnesium aluminium silicate, methyl cellulose, povidone, prege latinized starch, sodium alginate, starch, dextrin, gelatine, hydrogenated vegetable oils, polymethacrylates, zein and the like.
  • compositions according to the present invention may comprise one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier in the context of the present invention relates to one or more compatible solid or liquid fillers or diluents, which are suitable for an administration to an animal, such as a mammal, e.g. a human.
  • carrier relates to a natural or synthetic organic or inorganic component which is combined with a pharmaceutically active component in order to facilitate the application of the pharmaceutically active component.
  • carrier components are sterile liquids such as water or oils, including those which are derived from mineral oil, animals or plants, such as peanut oil, soy bean oil, sesame oil, sunflower oil, etc. Salt solutions, aqueous dextrose and glycerin solutions, as well as a Ringer's solution may also be used as aqueous carrier compounds.
  • Particularly useful pharmaceutically acceptable carriers in the context of the present invention are emulsifying or solubilising substances, such as transcutol and/or Span20. Further useful pharmaceutically acceptable carriers are, for example, polyglycerins, polyoxyethylene glycols and their fatty acid esters like Macrogol glycerol hydroxystearate.
  • “Pharmaceutically acceptable diluents” may, for example, be lactose, mannitol, sucrose, dextrose, cellulose, such as microcrystalline cellulose or powdered cellulose, starches, sorbitol, dibasic calcium phosphate, calcium carbonate and mixtures thereof.
  • compositions according to the present invention may, in some embodiments, comprise further pharmaceutically active agents, for example, a therapeutically active component such as an anti-tumour and/or anti-cancer agent.
  • a therapeutically active component such as an anti-tumour and/or anti-cancer agent.
  • optional further active agents are gemcitabine, irinotecan, 5- flurouracil, cisplatin etc.
  • the pharmaceutical composition may further comprise one or more agents which facilitate the uptake of the compounds used according to the present invention, e.g. which improve the bioavailability of the compounds, for example, if the compound or the composition is applied.
  • agents are for example PGP inhibitors like e.g. Macrogol glycerol hydrostearate.
  • a “pharmaceutically active agent” in the context of the present invention refers to a "pharmaceutically active ingredient", i.e. a compound which possesses therapeutic or preventive potential.
  • said therapeutic or preventive potential preferably relates to therapeutic or preventive activity against a tumour disease as described herein, e.g. against prostate cancer, such as against hormone-dependent prostate cancer.
  • clusin, dihydrocubebin, hinokinin, yatein and cubebin are pharmaceutically active agents.
  • the lignan compounds used in the present invention, the pharmaceutical composition according to the present invention, and the lignan composition according to the present invention may be formulated in any suitable way, e.g. depending on the intended administration route.
  • the lignan compounds used in the present invention, the pharmaceutical composition, and the lignan composition according to the present invention may be formulated as tablet, pill, capsule, suppository, powder, granules, solution, suspension etc.
  • the pharmaceutical composition is formulated in a solid formulation form, such as a tablet, pill, powder, granule, such as encapsulated granules etc.
  • the pharmaceutical composition is formulated in liquid form, such as in a solution or suspension.
  • the pharmaceutically active ingredient(s) is/are mixed with a pharmaceutical excipient or carrier, e.g. conventional tabieting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and optionally pharmaceutical diluents to form a solid preformulation composition containing a homogenous mixture of the compound according to the present invention.
  • the solid preformulation composition may then be subdivided into unit dosage forms. Tablets or pills may be coated or otherwise compounded to provide a dosage form affording the advantage of, e.g. prolonged action or improved delivery.
  • liquid forms of the pharmaceutical compositions according to the present invention include, for example, aqueous solutions, liposomal preparations, micro- or nano-emulsions, alcoholic solutions, optionally flavoured syrups, aqueous, alcoholic or oil suspensions, and optionally flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil etc..
  • lignan compounds used in the present invention, the pharmaceutical compositions according to the present invention, or the lignan composition according to the present invention may be administered to an individual in need thereof, for example, a patient, by any suitable administration route, such as by oral, topical, rectal, vaginal, dermal, intra-tumoural, nasal, lingual, parenteral administration or administration by inhalation, insufflation, injection, infusion or by enema.
  • suitable administration route such as by oral, topical, rectal, vaginal, dermal, intra-tumoural, nasal, lingual, parenteral administration or administration by inhalation, insufflation, injection, infusion or by enema.
  • the lignan compound used in the present invention, the pharmaceutical composition according to the present invention, or the lignan composition according to the present invention may be adapted, for example, for oral, topical, rectal, vaginal, dermal, intra-tumoural, nasal, lingual, parenteral administration or administration by inhalation, insufflation, injection, infusion or by enema.
  • the method according to the present invention may comprise oral, topical, rectal, vaginal, dermal, intra-tumoural, nasal, lingual, parenteral administration or administration by inhalation, insufflation, injection, infusion or by enema.
  • Preferred administration routes are oral and parenteral administration, such as intravenous, intramuscular, subcutaneous, intranodal, intralymphatic, intra-tumoural or intraperitoneal injection, most preferable is oral administration.
  • the lignan compound used in the present invention, the pharmaceutical composition according to the present invention, or the lignan composition according to the present invention may also be directly applied to the tumour cells, e.g. the tumour tissue, for example, by injection into the tumour or cancer tissue.
  • the lignan compound used in the present invention, the pharmaceutical composition according to the present invention, or the lignan composition according to the present invention is adapted for parenteral administration, such as for intra- tumoural administration.
  • the method according to the present invention comprises administering the lignan compound used in the present invention, the pharmaceutical composition according to the present invention, or the lignan composition according to the present invention by a parenteral route, e.g.
  • the method according to the present invention comprises oral administration of the lignan compound used in the present invention, of the pharmaceutical composition according to the present invention, or the lignan composition according to the present invention.
  • the compounds and compositions according to the present invention are administered in a therapeutically effective amount.
  • a "therapeutically effective amount” relates to an amount which - alone or in combination with further dosages - results in a desired reaction or a desired effect.
  • the desired reaction relates to the inhibition of the progress of the disease and/or the cure from the disease.
  • An effective amount of the composition according to the present invention is dependent on the condition or disease, the severity of the disease, the individual parameters of the patient, including age, physiological condition, height and weight, the duration of the treatment, the type of an optionally accompanying therapy, the specific administration route, and similar factors. In case the reaction of a patient is insufficient with an initial dosage, higher dosages (or higher effective dosages which may be achieved by a more localized administration route) may be applied.
  • the lignan compound, the pharmaceutical composition, or the lignan composition is administered repeatedly.
  • the present invention provides the lignan compound used in the present invention, the pharmaceutical composition according to the present invention, or the lignan composition according to the present invention for use in the treatment or prevention of a tumour disease and the method of treating or preventing a tumour disease according to the present invention, wherein the compound or composition is administered repeatedly, for example, two times, three times, four times, five times, etc.
  • the compound or the compositions according to the present invention may be administered two times, three times, four times, five times, etc., preferably three times, at time intervals of between about 24 hours to 48 hours.
  • Example 1 Preparation of an ethanolic liquid extract Pip.cub.40p2.001 .E03.F0l according to EP2182966A1
  • Example 2 Preparation of an ethanolic liquid extract Pip.cub.40p2.E02.F01 according to EP2182966A1
  • Example 4 Preparation of a lipophilic fraction Pip.cub.40p2.001 .E03.S03
  • Elution was achieved using a mixture of methanol/water 50:50 (v/v) as initial eluent (-500 ml), applying a flow rate of 40 ml / min and detecting with diode array at 218 nm. Subsequently the mobile phase was changed to methanol/water 73:27 (v/v) and elution was continued for another -1 .200 ml at which point the lignan fraction has been completely eluted. The solvent was then changed to ethanol absolute and elution was continued (-700 ml) thereby affording the unpolar extract constituents.
  • the obtained powders were kept in a desiccator over night to give 1 .85 gram of cubebin of a purity of 95.6 %, as determined by HPLC.
  • the material was shown to be identical to an authentic reference standard of cubebin (de Pascoli et al., 2006, Phytochemistry 67: 735-742).
  • Example 9 Preparation of Yatein 500 g of C0 2 extracted powder from Piper cubeba fruits were mixed with 2.5 kg of EtOH. The mixture was stirred during 2 hours at 40 °C and then filtered on a deep layer cellulose filter AF15 from Filtrox followed by a AF40 filter. The filtrate was kept at 4 °C over night. The filtrate was concentrated on the rotary evaporator at 40 °C, 70 mbar - 24 mbar. Yielding 57.8 g of a brown oil. A preparative column 800G (92 x 378 mm) Silica HC, 50 pm was preconditioned with toluene/ethyl acetate 90:10 (V/V). The fraction size was 50 ml.
  • the sample 1 5 g dissolved with 5 mL of mobile phase (V ⁇ 20 ml) was applied. Flow rate 80 ml/min., ⁇ 280 nm until the first peak (hinokinin) was eluted and the signal lower than 7 %. Then the mobile phase was changed to toluene/ethyl acetate 70:30 (v/v) and the second peak (yatein and cubebin) was collected. The relevant fractions of this section were analysed for yatein content by HPLC methodology and were then pooled and dried on a rotary evaporator applying 40 °C and 1 mbar to give a yellow oil.
  • Elution was achieved using a mixture of methanol/water 50:50 (v/v) as initial eluent (-500 ml), applying a flow rate of 40 ml / min and detecting with diode array at 218 nm. Subsequently the mobile phase was changed to methanol/water 70:30 (v/v) elution was continued for another -1 .800 ml at which point the lignans have been completely eluted. Suitable, lignan containing, fractions of the collected eluent were concentrated on a rotary evaporator at 80 mbar and 40 °C.
  • Example 1 Preparation of a lignan fraction Pip.cub.40p2.001 .E03.S04
  • a liquid extract, prepared as described in example 1 was concentrated on a rotary evaporator at 40 °C, 70 mbar - 24 mbar to yield a brown, viscous oil.
  • a portion of 5 g of this concentrated extract was dissolved in ethanol absolute to a total volume of ca. 20 mL and was then subjected to purification by medium pressure liquid chromatography using a reversed phase conditions (49 mm x 460 mm, 500 g of RP-C18 silica, 50 pm MN) and eluted at 40 ml /min using isocratic conditions of methanol/water 70:30 (v/v) applying diode array detection at 218 nm and a fraction size of 50 ml during collection.
  • Example 12 Preparation of a lignan fraction Pip.cub.05.1 .S1
  • This Lignan fraction was obtained by supercritical extraction of Piper cubeba fruits with carbon dioxide recycle and two step separation. Prior to processing, the dried raw material was carefully ground (and heat generation avoided) and placed into a high pressure extractor. The system was subsequently pressurized and C02 passed through the material at 300 bar and 85°C. The extracts were collected by two-step partial depressurisation in two separator (separator 1 with waxy/actives, separator 2 with volatile oil). From 431 g of powdered fruits 41 g of volatile oils have been removed and 39 g of the Lignan Fraction Pip.cub.05.1 .SI has been obtained while resulting in a remaining 329 g of residue. Analysis showed a Lignan content of 24.4% in Pip.cub.05.1 . S1 and -90% of the absolute Lignan content of the fruits has been extracted into the target extract Pip.cub.05.1 .SI .
  • Example 1 3 Preparation of a lignan fraction Pip. cub.05.2. SI This Lignan fraction was obtained by supercritical extraction of Piper cubeba fruits with carbon dioxide recycle and two step separation. Prior to processing, the dried raw material was carefully ground (and heat generation avoided) and placed into a high pressure extractor. The system was subsequently pressurized and CO2 passed through the material at 300 bar and 90°C. The extracts were collected by two-step partial depressurisation in two separator (separator 1 with waxy/actives, separator 2 with volatile oil).
  • This Lignan fraction was obtained by supercritical extraction of Piper cubeba fruits with carbon dioxide recycle and two step separation. Prior to processing, the dried raw material was carefully ground (and heat generation avoided) and placed into a high pressure extractor. The system was subsequently pressurized and C02 passed through the material at 800 bar and 85°C. The extracts were collected by two-step partial depressurisation in two separator (separator 1 with waxy/actives, separator 2 with volatile oil). From 434 g of powdered fruits 52 g of volatile oils have been removed and 46 g of the Lignan Fraction Pip.cub.05.3.S1 has been obtained while resulting in a remaining 329 g of residue.
  • This Lignan fraction was obtained by supercritical extraction of Piper cubeba fruits with carbon dioxide recycle and two step separation. Prior to processing, the dried raw material was carefully ground (and heat generation avoided) and placed into a high pressure extractor. The system was subsequently pressurized and C02 passed through the material at 800 bar and 85°C. The extracts were collected by two-step partial depressurisation in two separator (separator 1 with waxy/actives, separator 2 with volatile oil). From 41 Og of powdered fruits 64g of volatile oils have been removed and 28 g of the Lignan Fraction Pip.cub.05.4.S1 has been obtained while resulting in a remaining 304g of residue. Analysis showed a Lignan content of 44.0% in Pip.cub.05.4.S1 and -90% of the absolute Lignan content of the fruits has been extracted into the target extract Pip.cub.05.4.S1 .
  • Example 1 6 Preparation of a pre-formulation Pip.cub.40p2.001 .E03.C03-01
  • the 51 .57g native extract obtained was adjusted with 1 6.08g Span 20 and 1 .62-g Transcutol HP in respect of the 1 /2/0.2 ratio.
  • the mixture was mixed under reduced pressure (25 mbar) and a bath temperature of 40°C for 90 min. 1 63.78 g of a brownish encapsulatable mass was obtained.
  • the content of native extract was found to be 30.7% (w/w).
  • Example 1 7 Effect of the individual l ignan on LNCaP cel lular growth
  • the human prostate cancer cell l ine LNCaP was cultivated in culture medium containi ng 10% FBS and kept in a humidified incubator at 37°C and 5% C0 2 . Cultures used in subsequent experiments were passaged less than 20 times. The cells were seeded at 1 0,000 cells in 96-wel l plate and left to adhere overnight. The individual lignans, prepared according to examples 5 to 9 respectively, were serially diluted in ethanoi to the corresponding concentrations before being added to the cel ls for a total of 48 hours. The cel ls were pulsed with a tracer, bromoxyuridine, BrdU 1 8 hours before the end of the treatment.
  • the plates were then processed with the Cell Prol iferation ELISA, BrdU (colorimetric) assay kit (Roche; Mannheim, Germany) according to manufacturer's instructions. Actively proliferating cel ls incorporated the BrdU could then be detected. The anti- prol iferation effect observed on the treated cells was taken as a percentage to the solvent control treated cells.
  • BrdU colorimetric
  • Fig.l the results indicate that all the lignans were able to inhibit cel l prol iferation of the human prostate cancer cel l line LNCaP at relatively low concentrations.
  • the most potent lignan in reducing cellular growth of the LNCaP cell line was dihydrocubebin, followed by clusin, yatein, hinokinin and cubebin.
  • Example 18 Effects of lignans versus the lignan fraction on LNCaP and HPAFII cellular growth
  • the anti-proliferative assay was performed similar to the above example 1 7.
  • the lignan fraction (Pip cub.40p2.001 .E03.S04) and lignan compounds prepared according to examples 5,6,7,8,9 and 1 1 were tested on the LNCap cell line and the human pancreatic cell line HPAFII.
  • the lignan fraction appeared to inhibit LNCaP (Fig.2) and HPAFII (Fig.7) cellular growth similar or more effective than the individual lignans at the same dose of 10pg/ml.
  • the IC 50 values derived from the LNCaP and HPAFII anti-proliferative studies demonstrated that the single lignan compounds were inferior compared to the lignan fraction, with the exception of dihydrocubebin, which appeared to result in a greater inhibition of LNCaP cell growth than the lignan fraction. It must be noted that the corresponding concentration of the lignans in the lignan fraction were considerably lower than the IC 50 values of the individual lignans. (E.g. There is 0.49 g ml of dihydrocubebin in 5.227pg/ml of lignan fraction). This indicates that there are synergistic effects of the 5 lignans.
  • Example 19 Lignan composition in various lignan fraction preparations
  • the spiked fractions were prepared by spiking with the corresponding percentage of the lignan for every one of them (e.g. the cubebin content in 100pg/ml Pip.cub.40p2.001 .E03.S04 is 38.9pg/ml, the spiked fraction comprises 77.8pg/ml of percentage of 56% in the spiked
  • Example 20 Additive method of testing potential additive effect of combinations of lignans on LNCaP's cellular growth
  • the anti-proliferative assay was performed similar to the above example 1 7.
  • the lignan fraction (Pip.cub.40p2.001 .E03.S04) and lignans prepared according to examples 5 to 1 1 were tested.
  • the anti-proliferative assay was performed similar to the above example 1 7.
  • the samples were prepared according to examples 1 , 3, 4 and 1 1 were tested.
  • the extract was fractionated into three main components; hydrophilic, lignan and lipophilic fractions.
  • the lignan fraction appeared to retain most of the bioactivity whereas the other two fractions contribute minimally to the antiproliferative effects. This clearly indicates that the lignans are the main active moieties in the extract.
  • the potent effects of the lignan fraction were more significant in other cancer cell types (e.g. breast and pancreatic cancer) when compared to the extract.
  • Example 22 Effects of lignan fraction versus the plant extract on cancer cells colony formation
  • the samples prepared according to examples 2 and 1 1 were tested against cell suspensions of 5 human tumour xenografts of prostate cancer i.e. 22Rv1 , DU-145, MRI-1579, PC-3 and PC-3M to investigate their potential to inhibit ex vivo colony formation of cells with the ability to grow anchorage independently in semi-solid medium.
  • the clonogenic assay was performed in a 24-well format according to a modified two- layer soft agar assay introduced by Hamburger & Salmon (Hamburger & Salomon, Science 197, 461 -463 (1977)). Each test well contained three layers of equal volume: 2 layers of semi-solid medium (bottom and top layer), and one layer of medium supernatant, with or without test compound.
  • the bottom layer consisted of 0.2 ml/well IMDM (supplemented with 20% (v/v) fetal calf serum, 0.01 % (w/v) gentamicin) and 0.75% (w/v) agar. 8,000 to 20,000 cells were added to 0.2 ml of the same culture medium supplemented with 0.4% (w/v) agar and plated in 24-well plates onto the bottom layer. The test compounds were applied by continuous exposure (drug overlay) in 0.2 ml culture medium. The drug overlay was added to the culture as 3-fold concentrated solution repeatedly, i.e. 24 hours after seeding the cells for first time, and again on day 3 by replacement of the culture supernatant.
  • Every plate included six untreated control wells and drug-treated groups in triplicate at 6 concentrations. Cultures were incubated at 37°C and 7.5% C02 in a humidified atmosphere for up to 20 days and monitored closely for colony growth using an inverted microscope. Within this period, ex vivo tumour growth led to the formation of colonies with a diameter of > 50 ⁇ . At the time of maximum colony formation (based on internal historical data, range 4 - 21 days), counts were performed with an automatic image analysis system (BIOREADER 5000-W , Biosys GmbH).
  • Example 23 The pharmacokinetics of the Iignan fraction versus hinokinin, a single Iignan
  • the purpose of this study was to determine the pharmacokinetic behaviour of the Iignan fraction and hinokinin in the plasma over time after oral administration in mice. Hinokinin was also applied intravenously as a control.
  • mice bearing the LNCaP tumours were randomized into 3 groups.
  • Group 1 received Hinokinin (2.5mg/kg) administrated intravenously,
  • Group 2 received Hinokinin 35.5 mg/kg orally and
  • Group 3 was treated orally with the Iignan fraction, Pip.cub.40p2.001 .E03.C03; prepared according to example 1 1 (T56.7mg kg).
  • Group 2 and 3 were dosed with identical amounts of hinokinin.
  • Hinokinin and the Iignan fraction were dissolved in vehicle (Span20/Transcutol HP mix) before being orally given to Group 2 and 3, respectively.
  • animals were sacrificed after 5,10,30,60,120 and 240 minutes.
  • Fig. 5 The results as shown in Fig. 5 indicate that the oral administration of the lignan fraction resulted in substantially elevated levels of Hinokinin in the plasma as compared to oral intake of Hinokinin alone. This suggests a better bio-availability of Hinokinin (and any of the other 4 lignans individually) when administering the lignan in the form of a lignan fraction of at least two different lignans from the group consisting of clusin, dihydrocubebin, hinokinin, yatein and cubebin, if compared to administering a single lignan.
  • mice were orally treated with the extract (450mg/kg) versus a lignan content equivalence lignan fraction dose (157mg/kg); Pip.cub.40p2.001 .E03.C03; prepared according to example 1 6.
  • Male SCID-Beige mice were treated with the test samples at the above mentioned dosages 3 times daily for 5 days before sacrifice.
  • the prostates, adrenal glands and brains were harvested, processed and subsequently subjected to LC-MS analysis. The results are shown in Fig. 6.
  • the lignan fraction was able to deliver similar if not higher levels of the lignans especially hinokinin and yatein compared to the extract, PIPER VKM (Example 16). It appeared that the lignans were selectively accumulated in the prostate and adrenal glands, which are the target organs for the treatment of prostate cancer.

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Abstract

La présente invention concerne des compositions pharmaceutiques comportant des lignanes qui sont utiles pour le traitement ou la prévention des tumeurs et/ou des cancers, en particulier pour le traitement ou la prévention des tumeurs et/ou des cancers hormono-dépendants, tels que le cancer de la prostate. En outre, la présente invention concerne un procédé pour obtenir une composition à base de lignanes à partir d'une matière végétale contenant des lignanes, telle que le Piper cubeba L, ainsi que l'utilisation de la composition à base de lignanes pouvant être obtenue grâce à ce procédé en tant que médicament.
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US20140170250A1 (en) * 2012-12-19 2014-06-19 Industrial Technology Research Institute Pharmaceutical compositions and method for inhibiting angiogenesis
US9682062B2 (en) * 2012-12-19 2017-06-20 Industrial Technology Research Institute Pharmaceutical compositions and method for inhibiting angiogenesis

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