• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a pharmaceutical composition, characterized in that it comprises as active ingredient, a combination of beta-elemene, lupeol and a pharmaceutically active agent selected from 2-hydroxycinnamaldehyde, 2'-benzoyloxycinnalmaldehyde, beta-sitosterol, curcumin and their mixtures.
    公开号:FR3058059A1
    申请号:FR1670666
    申请日:2016-11-08
    公开日:2018-05-04
    发明作者:Guy Faustin Monkam Nitcheu
    申请人:Guy Faustin Monkam Nitcheu；
    IPC主号:
    专利说明:

    (57) The present invention relates to a pharmaceutical composition, characterized in that it comprises, as active ingredient, a combination of beta-elemene, lupeol and a pharmaceutically active agent chosen from 2-hydroxycinnamaldehyde, 2 ' benzoyloxycinnalmaldehyde, beta-sitosterol, curcumin and their mixtures.
    LUPEOL
    AND OR
    AND THE 2ND BETA-
    [Technical Field of the Invention]
    The present invention relates to a pharmaceutical composition which can be used as a medicament, in particular for the therapeutic treatment of cancers and in particular of hepatocellular carcinoma.
    [Prior Art]
    Effective palliative treatment for hepatocellular carcinoma (HCC) has long been considered difficult due to the usual resistance of this type of tumor to conventional cytotoxic chemotherapy. In addition, aggressive chemotherapy comprising several non-selective cytotoxic molecules often cannot be offered to cirrhotic patients with compromised liver function because of the high risk of systemic side effects.
    Improved knowledge of the molecular processes involved in oncogenesis has made it possible to identify new targets for the treatment of cancers. Thus, new so-called “targeted” therapies are currently available in the treatment of HCC and other tumors. They are mainly involved in the transduction of signals (signals which ask the cell to multiply). The so-called tyrosine kinase pathway is the best known to date. This pathway can be blocked by monoclonal antibodies (Mab) or enzyme inhibitors (inib). Among these drugs are VEGF inhibitors (Vascular Endothelium Growth Factor; VEGF is secreted by most tumor cells, partly due to lack of local oxygenation and it promotes angiogenesis), inhibitors of the EGFR receptor (epidermal growth factor receptor), inhibitors of several receptors with tyrosine kinase activity that target angiogenesis and cell proliferation in parallel, kinase inhibitors, IGF-1R receptor inhibitors, inhibitors of mTOR and inhibitors of the MEK-ERK signaling pathway.
    However, these targeted therapies for the most part give relatively modest results in terms of efficacy and survival in HCC and in particular in advanced HCC. On the other hand, the effectiveness of targeted therapies in HCC is still limited by the phenomena of resistance. Certain cancer cells possess or acquire the possibility of circumventing the mechanisms of action of drugs, others on the other hand are initially sensitive but develop capacities of resistance during treatment.
    It should also be emphasized that with these targeted therapies, significant side effects can lead to discomfort, and therefore do not offer patients a better quality of life: myelosuppression (blood samples are taken regularly to check for red blood cells, white blood cells and platelets), alopecia (which can be difficult for patients to live with because it is a concrete and visible sign of the disease), skin disorder and hand-foot syndrome, diarrhea, increased blood pressure, proteinuria, hyperglycemia, hypercholesterolemia, allergic reactions, cytokine release syndrome, tumor lysis syndrome that can self-maintain the tumor, etc.
    On the other hand, several observations point to the existence of a close link between chronic inflammation and the risk of developing cancer. One of the best examples of this correlation is perhaps the dramatic increase (20 times) in the risk of colon cancer in people affected by inflammatory bowel disease, especially ulcerative colitis. This is also the case with stomach cancer, which develops as a result of inflammation caused by the presence of a bacterium, Helicobacter pylori. Prostate cancer is caused by an inflammation of the prostate (prostatitis). In HCC, the assumption is that chronic inflammation increases DNA mutations and that increased proliferation of hepatocytes in regenerative nodules increases the likelihood of binding oncogenic mutations. In addition, pre and postperfusion medication combining a corticosteroid and an antihistamine is strongly recommended in order to reduce the risk of allergic reactions linked to certain targeted therapies.
    While biomarkers have been validated for breast cancer (number of HER copies), lung cancer (EGFR mutations) or colon cancer (Kras mutations), there are currently no biomarkers prognoses validated for HCC under targeted therapy.
    Numerous studies have shown that reptin and / or pontine are overexpressed during carcinogenesis; their nucleo-cytoplasmic location was variable according to the type of cancer and was not necessarily a factor of poor prognosis. On the other hand, the overexpression of reptin and pontine is a factor of poor prognosis in HCC and a high level of pontine mRNA is correlated with a poor prognosis [(Haurie et al., 2009). Hepatology. 2009 Dec; 50 (6): 1871-83. doi: 10.1002 / hep.23215],
    Furthermore, it is known that reptin is overexpressed in prostate cancer, hepatocellular carcinoma (HCC), gastric cancer, kidney cancer and breast cancer.
    Pontine is also known to be overexpressed in hepatocellular carcinoma, lung cancer and colorectal cancer.
    Reptin and / or pontine dysfunction has also been demonstrated in other cancers such as chronic leukemias, mesotheliomas and multiple myelomas, high grade lymphomas, Burkitt lymphomas, brain tumors such as gliomas and bladder tumors.
    Survivin is also known as a therapeutic target in the case of cancer. The majority of solid tumors (breast cancer, prostate, lung, kidney, ... etc) or hematopoietic (multiple myeloma, leukemia, ... etc) expresses it in an aberrant way. It is also known that cells from cancerous breast, lung and kidney tumors overexpress survivin.
    Furthermore, it is known that beta-elemene can be used as an anti-cancer. It also has a broad antineoplastic spectrum, including tumors resistant to the anticancer drugs conventionally used. It is also known to be non-cytotoxic and well tolerated by patients. It can pass the blood-brain barrier and has immunostimulatory properties. Its anti-inflammatory activity is also known. It is also known that beta-elemene inhibits survivin. It is also known to reduce or even eliminate the resistance of cancer cells to anti-cancer drugs.
    It is also known that beta-elemene also reduces the resistance of cancer cells to certain drugs. Thus, it significantly inhibits MDR1, MRP and GST-. Chen et al., (2006) (Journal of Medicinal Plants Research Vol. 6 (46), pp. 5720-5729, December 3, 2012) have shown that β-Elemene inevitably increases the intracellular accumulation of AMD (Adriamycin, Methotrexate, Daunorubicin) in U251 / AMD cells (cells that have developed resistance to AMD) in human glioblastoma, reduces the IC50 of U251 / AMD cells from 0.915 to 0.051 mg / 1.
    In addition, it is also known that lupeol (also known as Fagarsterol or Clerodol), is a pharmacologically active compound having anti-inflammatory and anticancer properties, in particular by its antiproliferative activity, by regulating the cell cycle, and apoptosis. , angiogenesis and its effect on the epithelio-mesenchymal transition. It also boosts the immune system of cancer patients. It should be noted that lupéol at an effective therapeutic dose shows no toxicity on normal cells and tissues.
    In the case of HCC, it is known that lupeol inhibits the protein BDNF (BrainDerived Neurotrophic Factor-Neurotrophic Factor Derived from the Brain). Lupeol inhibits the cellular proliferation of HCCLM3 cells of CHC as a function of concentration and time, this through the activation of Caspase-3 and the cleavage of PARP [oly (ADPribose) polymerase]. However, Zhang L et al. (European Journal of Pharmacology, volume 762, September 5, 2015, Pages 55-62) also found that lupeol-induced cell death was associated with a marked decrease in expression of the protein BDNF and a ser-9- phosphorylation of GSK-3B (Glycogen Synthase Kinase 3 Beta), with a concomitant suppression of the expression of Aktl, PI3K (phosphatidyl inositol 3-kinase), B-catenin, cMyc and mRNA of Cycline Dl. The inhibition of overexpression of BDNF results from the decrease in the expression of the proteins Akt and PI3k, as well as the reactivation of the function of GSK-3B in HepG2 cells.
    Furthermore, oral administration of lupeol at a dose of 50 mg / kg for 18 consecutive days produced no mortality or systemic toxicity in rats.
    It is also known that 2-hydroxycinnamaldehyde (HCA) and its metabolite or synthetic derivative, BCA (2-benzoyloxycinnamaldehyde), each have anti-inflammatory, anti-proliferative, anti-angiogenic, anti-metastatic activity via the inhibition of TEM (epithelio-mesenchymal transition) and pro-apoptotic on many human cancer cells such as melanoma, breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, myeloma and leukemia.
    HCA is also known to have an effect on HCC. Thus, 25 Moon EY., (EunYi Moon et al., (2005) European Journal of Pharmacology 530 (2006) 270 - 275.) studied the inhibitory effect of HCA on famesyl transferase. In a model mouse having developed hepatocellular carcinoma following a transgenic mutation H-rasl2V and under the control of a specific promoter such as albumin. It was found that administration of HCA / BCA for 10 weeks delayed development of liver cancer compared to the control group. HCA / BCA significantly reduces the number and size of liver damage. HCA / BCA increases the number of splenocytes and the infiltration of lymphocytes into the liver. These data suggest that the delay in the onset of liver cancer may be caused by an immunostimulatory effect of HCA / BCA on T cells.
    In addition, beta-sitosterol is known to have anti5 inflammatory, antipyretic, antineoplastic and immunomodulatory properties.
    [Technical problem to be solved]
    An object of the present invention is to provide a new pharmaceutical composition which can be used as a medicament and more particularly which can be used in the treatment of cancer.
    Another object of the invention is to propose a new pharmaceutical composition which can be used as a medicament and more particularly which can be used in the treatment of cancer which remedies all or part of the drawbacks linked to the compositions of the above-mentioned prior art.
    Another object of the invention is to provide a pharmaceutical composition which proves to be particularly advantageous in the treatment of HCC.
    Another object of the present invention is to provide a pharmaceutical composition which can be used as a medicament, in particular for the therapeutic treatment of HCC, hepatocellular insufficiency and in particular liver cirrhosis.
    Another object of the present invention is to provide a pharmaceutical composition for use in the treatment of breast cancer and / or prostate cancer.
    Another object of the present invention is to provide a pharmaceutical composition, in particular as mentioned above, which has reduced toxicity and / or which is well tolerated by patients.
    Another object of the present invention is to provide a pharmaceutical composition which makes it possible to reduce drug resistance and in particular drug resistance to anticancer agents.
    Another object of the present invention is to provide a pharmaceutical composition which acts specifically on cancer cells which overexpress at least one protein chosen from reptin, pontine and survivin and in particular which acts on cancer cells which overexpress reptin and pontine and possibly survivin.
    Another object of the present invention is to provide a pharmaceutical composition which inhibits the activity of stromal cells in the overexpression by cancer cells of at least one protein chosen from reptin, pontine and survivin.
    Another object of the present invention is to provide a pharmaceutical composition which makes it possible to inhibit the formation of the tumor stroma and the metastatic process, to reduce the risk of tumor recurrence.
    Another object of the present invention is to provide a pharmaceutical composition which makes it possible to reduce or inhibit chemoresistance.
    [Brief Description of the Invention]
    To solve at least one of the abovementioned technical problems, the present invention provides a pharmaceutical composition which, in a characteristic manner according to the invention, comprises as active ingredient, a combination of beta-elemene, lupeol and a pharmaceutically active agent. chosen from 2-hydroxycinnamaldehyde, 2'benzoyloxycinnalmaldehyde, beta-sitosterol, curcumin and their mixtures.
    The Applicant has in fact found that such a pharmaceutical composition is found to be active in the treatment of cancer, in particular in the case of HCC, breast and prostate cancer.
    The Applicant has also demonstrated a synergistic effect of at least three of the constituents which provides an enhanced action of the composition of the invention on at least one mechanism involved in the phenomenon of cancer, namely a mechanism chosen from the formation of the tumor stroma, cell growth, inflammation, apoptosis, angiogenesis, metastatic process.
    The Applicant has also demonstrated that the composition according to the invention had an effect on cells overexpressing reptin and / or pontine, which is the case for cancer cells of the majority of cancers, including CHC, breast cancer. and prostate.
    [Detailed description]
    The pharmaceutical composition according to the invention can be used as a medicament and in particular for its use in the therapeutic treatment of cancer.
    According to a particular embodiment of the present invention, the composition of the invention may further comprise a mixture of beta-sitosterol and 23058059 hydroxycinnamaldehyde or a mixture of beta-sitosterol and 2'-benzoyloxycinnamaldehyde or a mixture of 2 -hydroxycinnamaldehyde and 2'-benzoyloxycinnameldehyde.
    Preferably, whatever the embodiment, the composition does not contain curcumin.
    Preferably, it does not comprise a mixture of 2-hydroxycinnamaldehyde, 2'benzoyloxycinnalmaldehyde and beta-sitosterol.
    By way of example, it may comprise as a percentage by mass of the total mass of the active ingredients, a mass percentage of lupeol substantially equal to or greater than 15% and substantially equal to or less than 55, and in particular substantially equal to or greater than 30% and substantially equal to or less than 50%, a percentage of beta-elemene substantially equal to or greater than 10% and substantially equal to or less than 55%, and in particular substantially equal to or greater than 20% and substantially equal to or less than 40%, a percentage of 2hydroxycinnamaldehyde substantially equal to or greater than 10% and substantially equal to or less than 45%, and in particular substantially equal to or greater than 20% and substantially equal to or less than 40%, a percentage of 2'-benzoyloxycinnalmaldehyde substantially equal to or greater than 10% and substantially equal to or less than 45%, and in particular substantially equal to or greater than 20% and substantially equal to or less than 40%, one for beta-sitosterol concentration, when said composition contains this ingredient, substantially equal to or greater than 10% and substantially equal to or less than 45%, and in particular substantially equal to or greater than 20% and substantially equal to or less than 40%. When the composition comprises 2hydroxycinnamaldehyde and 2'-benzoyloxycinnalmaldehyde, their mass percentage relative to the total mass of the active ingredients is in particular equal and in particular substantially equal to 20%.
    The composition according to the invention also comprises at least one pharmaceutically acceptable excipient. This excipient can be solid or liquid. It can be chosen, for example, from purified water, ethyl alcohol, propylene glycol, glycerin, vegetable oils, animal oils, hydrocarbons, silicones, sugars such as glucose, levulose, wheat starch, corn starch, potato starch, xanthan gum, arabic gum, tragacanth, sterculia gum, Guar or Guaranates gum, pectins, alginates, carrageenans, agar or Agar-Agar, gelatin, cellulose and its derivatives.
    The composition of the invention can be administered by any suitable route, for example by the oral, rectal, local (topical, for example), intraperitoneal, systemic, intravenous, intramuscular, subcutaneous or mucosal, in particular sublingual, route. , or using a patch, or alternatively in a form encapsulated in, or immobilized on, liposomes, microparticles, microcapsules, associated with nanoparticles and the like. Mention may in particular be made, by way of nonlimiting examples of excipients suitable for oral administration, talc, lactose, starch and its derivatives, cellulose and its derivatives, polyethylene glycols, polymers of acrylic acid, gelatin, magnesium stearate, animal, vegetable or synthetic fats, paraffin derivatives, glycols, stabilizers, preservatives, antioxidants, wetting agents, anti-caking agents, dispersants, emulsifiers , taste modifiers, penetrants, solubilizers. The techniques for formulating and administering drugs and pharmaceutical compositions are well known in the art considered here, those skilled in the art may in particular refer to the work Remington's Pharmaceutical Sciences, latest edition.
    According to the invention, the composition can be advantageously administered orally, by intravenous injection.
    Advantageously, the composition according to the invention is suitable for being administered orally or intravenously at a dose equal to or greater than 40 mg / kg / 24h and equal to or less than 200 mg / kg / 24h in one or more doses to a mammal. presenting such a need.
    By way of examples, the composition of the invention can be used in the therapeutic treatment of a cancer chosen from hepatocellular carcinoma, colon cancer, rectal cancer, stomach cancer, cancers of the mouth, including tongue cancer, prostate cancer, metastatic prostate cancer, kidney cancer, breast cancer, drug-resistant breast cancer, bladder cancer, chronic leukemia or acute, multiple myeloma, lymphoma, brain tumors, lung cancer, especially lung adenocarcinoma, uterine cancer, ovarian cancer, bone tumors, pancreatic cancer, gallbladder cancer and liver cancer.
    The composition according to the invention can advantageously be used in patients suffering from a chronic inflammatory disease and in particular, chronic inflammatory diseases of the intestine, more particularly ulcerative colitis, patients carrying a pathogenic agent capable of causing inflammation, in particular, Helicobacter pylori, patients with diabetes, patients with dyslipidemia, patients with hepatocellular insufficiency, osteoarticular disorders, patients with hepatocellular insufficiency and patients with bacterial or viral infections, in particular those affected by the hepatitis B or hepatitis C virus.
    In the case of HCC, the Applicant has demonstrated that the composition according to the invention gives good results at least in vitro and does not present any toxicity for the patient's liver cells.
    The mode of action of the composition of the invention is not fully understood. It is more than likely to act simultaneously on different mechanisms of cancer. Thus, the composition of the invention can be used in the therapeutic treatment of cancer as an agent inhibiting the formation of the tumor stroma and / or as an agent inhibiting the overexpression of at least one protein chosen from reptin, pontine and survivin, and preferably reptin and pontine and / or anti-inflammatory agent and / or agent inhibiting cell proliferation and / or agent causing apoptosis of cancer cells and / or inhibiting agent angiogenesis and / or anti-metastatic agent.
    The present invention also relates to a pharmaceutical preparation which comprises the composition according to the invention, and, in addition, as a mixture or separately packaged, at least one anticancer agent for their use in the therapeutic treatment of cancer simultaneously, sequenced or spaced in time.
    For example, the anti-cancer agent can be chosen from VEGF inhibitors, EGFR receptor inhibitors, inhibitors of several receptors with tyrosine kinase activity which target angiogenesis and cell proliferation in parallel, inhibitors kinases, IGF-1R receptor inhibitors, mTOR inhibitors, MEK-ERK signaling pathway inhibitors, paclitaxel, As4S4, tamoxifen, curcumin, vincristine, adriamycin, raclarubicin, oxaliplatin , calcium folinate, 5-fluorouracil, capecitabine, cisplatin, tetramethylpyrazine, methotrexate, daunorubicin and their mixtures and in particular mixtures of two of said anticancer agents, radioactive agents usable in brachytherapy and / or injectable radioactive metabolites or unmanageable.
    The present invention also relates to a pharmaceutical preparation which comprises in combination beta-elemene, lupeol and / or beta-sitosterol and 2hydroxycinnamaldehyde and / or 2'-benzoyloxycinnamaldehyde and optionally curcumin.
    The present invention also relates to a food supplement which comprises in combination beta-elemene, lupeol and / or beta-sitosterol and a pharmaceutically active agent chosen from 2-hydroxycinnamaldehyde, 2'benzoyloxycinnalmaldehyde and their mixtures and optionally curcumin.
    [Definitions]
    The terms "therapeutic treatment" refer to curative treatment and prophylactic treatment; within the meaning of the present invention, a therapeutic treatment makes it possible to restore at least partially, at least partially correct or at least partially modify physiological functions by exerting a pharmacological, immunological or metabolic action.
    The term "patient" refers to an animal or human mammal. The composition according to the invention can also be used in veterinary medicine.
    Within the meaning of the present invention, an "anticancer agent" is an element which exhibits at least in vitro an action against cancer cells, independently of its mechanism of action. By “action” is meant, within the meaning of the present invention, the destruction or at least partial modification of cancer cells which in particular makes it possible to limit the proliferation of cancer cells and / or their spread.
    The term "diabetes patients" refers to patients with type 1 diabetes, patients with type 2 diabetes, patients with gestational diabetes, patients with diabetes insipidus and patients with renal diabetes.
    The term "dyslipidaemia" refers to hyperlipidaemia and hypolipidaemia determined according to the criteria in force.
    The term "patients with osteoarticular disorders" refers to patients who have at least two signs chosen from inflammatory signs, fistulas and the proven presence of bacteria detected by a puncture or a blood culture.
    The term "patients with hepatocellular insufficiency" refers to patients with hepatitis, whatever its cause (viral, toxic, drug or ischemic) and patients with cirrhosis of the liver.
    For the purposes of the present invention, a "food supplement" is a foodstuff whose purpose is to supplement the normal diet and which constitutes a concentrated source of nutrients or other substances having a nutritional or physiological effect alone or in combination.
    With regard to the anti-cancer agents mentioned, the terms used include, unless otherwise indicated, the isomers of constitution, the stereoisomers of conformation, the enantiomers and the diastereoisomers of the chemical compound under consideration.
    [Examples]
    The percentage of the compositions below is a percentage by mass relative to the total mass of the active ingredients.
    Composition la: beta-elemene (30%), lupeol (30%) and 2-hydroxy cinnamaldehyde (40%).
    Composition 1b: beta-elemene (30%), lupeol (30%) and 2'-benzoyloxycinnamaldehyde (40%).
    Composition 2: beta-elemene (30%), lupeol (30%), 2-hydroxycinnamaldehyde (20%) and 2'benzoyloxycinnamaldehyde (20%).
    Composition 3a: beta-elemene (50%), lupeol (30%), and 2-hydroxycinnamaldehyde (20%).
    Composition 3b: beta-elemene (50%), lupeol (30%), and 2'-benzoyloxycinnamaldehyde (20%).
    Composition 4a: beta-elemene (15%), lupeol (50%), beta-sitosterol (25%) and 2 hydroxycinnamaldehyde (10%).
    Composition 4b: beta-elemene (15%), lupeol (50%), beta-sitosterol (25%) and 2’benzoyloxycinnamaldehyde (10%).
    Composition 5a: beta-elemene (20%), lupeol (20%), beta-sitosterol (40%) and 2 hydroxycinnamaldehyde (20%).
    Composition 5b: beta-elemene (20%), lupeol (20%), beta-sitosterol (40%) and 2’benzoyloxycinnamaldehyde (20%).
    Composition 6a: beta-elemene (25%), lupeol (35%), beta-sitosterol (15%) and 2 hydroxycinnamaldehyde (25%).
    Composition 6b: beta-elemene (25%), lupeol (35%), beta-sitosterol (15%) and 2’benzoyloxycinnamaldehyde (25%).
    Composition 7a: beta-elemene (40%), lupeol (20%), beta-sitosterol (20%) and 2hydroxycinnamaldehyde (20%).
    Composition 7b: beta-elemene (40%), lupeol (20%), beta-sitosterol (20%) and 2’benzoyloxycinnamaldehyde (20%).
    [Experimental results]
    Different human cell lines HuH7, Hep3B (CHC), MCF-7 (Breast cancer), PC-3, DU-145 (Prostate cancer) have been studied. They were selected on the basis of the overexpression of at least one protein chosen from reptin, pontine and survivin. Stromal cells have also been studied in order to determine the impact of the composition according to the invention in the tumor microenvironment. These cells were kept in DMEM, supplemented with 10% fetal bovine serum (FBS) and a 1% antibiotic-antimycotic solution (PSM), containing, penicillin, streptomycin and amphotericin B under standard growth conditions. (5% CO2, 37 ° C, a humidified atmosphere). The above compositions were dissolved and diluted in DMSO.
    The abovementioned cells were treated with the solutions (10-80 μM) for 48 h in complete cell media. All treatment and control protocols were prepared as described above.
    The aforementioned solutions have resulted in a selective inhibition of the proliferation of HuH7 and Hep3B cells of hepatocellular carcinoma which overexpress reptin, associated with an induction of apoptosis. The effect of this solution on the induction of apoptosis in HuH7 and Hep3B cells was then determined using annexin-V / propidium iodide after 48 hours of treatment. Increased staining of annexin-V has been observed in cells
    HuH7 and Hep3B while minimal staining was observed in untreated control cells.
    On PC-3 and DU-145 lines, derived from metastatic sites with a significantly high expression of survivin, this solution resulted in an inhibition of cell growth, a dose-dependent decrease in their viability. A similar result was observed with MCF-7 cells resistant to 5-FU.
    In a co-culture of cancer and stromal cells, treatment of the confluent cells (50% confluent) with any of the solutions prepared resulted in a decrease in their adhesion associated with the death of the cancer cells, inhibition of ia production by stromal cells of solubid factors found in the tumor microenvironment and involved in the metastatic process and chemoresistance.
    These results as a whole suggest that this pharmaceutical composition inhibits the formation of the tumor stroma and therefore, metastatic spread and chemoresistance. It can, rightly, be used in the treatment of hepatocellular carcinoma, ie breast cancer, prostate cancer even at advanced stages.
    权利要求:
    Claims (9)
    [1" id="c-fr-0001]
    Claims:
    1. Pharmaceutical composition, characterized in that it comprises, as active principle, a combination of beta-elemene, of lupeol and of a pharmaceutically active agent chosen from 2-hydroxycinnamaldehyde, 2'-benzoyloxycinnalmaldehyde, betasitosterol, curcumin and their mixtures.
    [2" id="c-fr-0002]
    2. Pharmaceutical composition according to claim 1, characterized in that it further comprises a mixture of beta-sitosterol and 2-hydroxycinnamaldehyde or a mixture of beta-sitosterol and 2'-benzoyloxycinnalmaldehyde or a mixture of 2hydroxycinnamaldehyde and 2'-benzoyloxycinnalmaldehyde.
    [3" id="c-fr-0003]
    3. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises as a percentage by mass of the total mass of the active ingredients, a mass percentage of lupeol substantially equal to or greater than 15% and substantially equal to or less than 55 , and in particular substantially equal to or greater than 30% and substantially equal to or less than 50%, a percentage of beta-elemene substantially equal to or greater than 10% and substantially equal to or less than 55%, and in particular substantially equal or greater than 20% and substantially equal to or less than 40%, a percentage of 2hydroxycinnamaldehyde substantially equal to or greater than 10% and substantially equal to or less than 45%, and in particular substantially equal to or greater than 20% and substantially equal to or less than 40%, a percentage of 2'- benzoyloxycinnalmaldehyde substantially equal to or greater than 10% and substantially equal to or less than 45%, and in particular meaning approximately 20% or more and substantially equal to or less than 40%, a percentage of beta-sitosterol, when said composition contains this ingredient, substantially equal to or greater than 10% and substantially equal to or less than 45%, and in particular substantially equal or greater than 20% and substantially equal to or less than 40%.
    [4" id="c-fr-0004]
    4. Pharmaceutical composition according to any one of the preceding claims, for its use in the therapeutic treatment of a cancer chosen from hepatocellular carcinoma, colon cancer, rectal cancer, stomach cancer, cancers of the mouth, including tongue cancer, prostate cancer, metastatic prostate cancer, kidney cancer, breast cancer, chemoresistant breast cancer, bladder cancer, chronic leukemia or acute, multiple myeloma, lymphoma, brain tumors, lung cancer, especially lung adenocarcinoma, uterine cancer, ovarian cancer, bone tumors, pancreatic cancer, gallbladder cancer and liver cancer.
    [5" id="c-fr-0005]
    5. Pharmaceutical composition according to any one of the preceding claims, for its use in the therapeutic treatment of cancer in patients suffering from a chronic inflammatory disease and in particular, chronic inflammatory diseases of the intestine, more particularly ulcerative colitis , patients with a pathogen capable of causing inflammation, in particular, Helicobacter pylori, patients with diabetes, dyslipidemia, osteoarticular disorders, patients with hepatocellular insufficiency and patients with bacterial or viral infections, especially those affected by the hepatitis B virus or hepatitis C.
    [6" id="c-fr-0006]
    6. Pharmaceutical composition according to any one of the preceding claims for its use in the treatment of cancer as an agent inhibiting the formation of the tumor stroma and / or agent inhibiting the overexpression of at least one protein chosen from reptin. , pontine and survivin and preferably reptin and pontine.
    [7" id="c-fr-0007]
    7. Pharmaceutical composition according to any one of the preceding claims for its use in the treatment of cancer, in particular in patients according to claim 7, as an anti-inflammatory agent and / or agent inhibiting cell proliferation and / or agent causing apoptosis of cancer cells and / or angiogenesis inhibiting agent and / or anti-metastatic agent.
    [8" id="c-fr-0008]
    8. Pharmaceutical preparation characterized in that it comprises the composition according to any one of the preceding claims and, in addition, as a mixture or separately packaged at least one anti-cancer agent for their use in the therapeutic treatment of cancer.
    [9" id="c-fr-0009]
    9. Pharmaceutical preparation according to claim 9, characterized in that said anticancer agent is chosen from VEGF inhibitors, inhibitors of the EGFR receptor, inhibitors of several receptors with tyrosine kinase activity which target angiogenesis and cell proliferation, kinase inhibitors, IGF-1R receptor inhibitors, mTOR inhibitors, inhibitors of the MEK-ERK signaling pathway, paclitaxel, As4S4, tamoxifen, curcumin, vincristine, adriamycin, aclarubicin, oxaliplatin, calcium folinate, 5-fluorouracil, capecitabine, cisplatin, tetramethylpyrazine, methotrexate, daunorubicin and their mixtures and in particular mixtures of two of said anticancer agents, the radioactive agents which can be used in brachytherapy and / or injectable or ingestible radioactive metabolites.
    类似技术:
    公开号 | 公开日 | 专利标题
    FR3058059A1|2018-05-04|PHARMACEUTICAL COMPOSITION COMPRISING BETA-ELEMENE, LUPEOL AND 2-HYDROXYCINNAMALDEHYDE AND / OR 2'-BENZOYLOXYCINNALMALDEHYDE AND / OR BETA-SITOSTEROL AND / OR CURCUMIN.
    US10993949B2|2021-05-04|17α-monoesters and 17α,21-diesters of cortexolone for use in the treatment of tumors
    EP3565536A1|2019-11-13|Pharmaceutical composition used for treating metabolic syndrome disorders, infectious diseases, and complications thereof
    Baer-Dubowska et al.2020|Tannic acid: specific form of tannins in cancer chemoprevention and therapy-old and new applications
    EP3429582B1|2021-05-19|Combination therapy for proliferative diseases
    US20190117618A1|2019-04-25|Isoflavonoid composition with improved pharmacokinetics
    FR3056108B1|2019-09-27|USE OF HARRINGTONINS IN THE TREATMENT OF BREAST CANCER, IN PARTICULAR TRIPLE-NEGATIVE
    JP2020132625A|2020-08-31|Combination therapy of safranal and sorafenib for liver cancer
    JP2020026434A|2020-02-20|Cancer treatment agent
    FR3058060A1|2018-05-04|PHARMACEUTICAL COMPOSITION COMPRISING BETA-ELEMENE, LUPEOL, CINNAMALDEHYDE AND / OR 2-HYDROXYCINNAMALDEHYDE AND / OR 2'-BENZOYLOXYCINNALMALDEHYDE AND / OR BETA-SITOSTEROL AND / OR CURCUMIN.
    EP2362772B1|2013-01-23|Pharmaceutical association containing lipoic acid and hydroxycitric acid as active ingredients
    TW201609094A|2016-03-16|Novel methods for treating cancer
    EP3399969A1|2018-11-14|Method for prevention, treatment and alleviation of infectious diseases and disorders
    AU2010336256B2|2014-07-03|Antitumor Agent or Postoperative Adjuvant Chemotherapeutic Agent for Hepatocellular Carcinoma Treatment
    WO2022052055A1|2022-03-17|Use of composition comprising antrocinol in preparation of medications for inhibiting growth of liver cancer cells or liver cancer stem cells
    WO2020062951A1|2020-04-02|Compound and use thereof
    OA19197A|2020-03-09|Pharmaceutical composition for use in the theurapeutic treatment of cancer and complications of cancer.
    KR20160036490A|2016-04-04|Pharmaceutical composition for treating cancer comprising medium chain fatty acids as active ingredient
    CN114159427A|2022-03-11|Application of composition containing android alcohol in preparation of medicine for inhibiting growth of liver cancer cells or liver cancer stem cells
    OA18060A|2018-04-06|Use of "purebred" sheep serum in the treatment of diseases related to HIV viruses.
    同族专利:
    公开号 | 公开日
    KR20190077449A|2019-07-03|
    CA3043456A1|2018-05-03|
    WO2018078539A1|2018-05-03|
    MX2019003685A|2019-09-26|
    CN109562080A|2019-04-02|
    IL266623D0|2019-07-31|
    EP3429568A1|2019-01-23|
    FR3058059B1|2020-07-10|
    ZA201902910B|2020-06-24|
    MA44413A|2021-03-17|
    FR3058058A1|2018-05-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CN109438166A|2018-11-08|2019-03-08|石药集团远大制药有限公司|-beta-elemene and its preparation method and application|
    FR3100128B1|2019-08-30|2022-02-18|Nitcheu Guy Faustin Monkam|Pharmaceutical composition for inhibiting HIV infectivity, treating acquired immunodeficiency syndromeand its complications|
    CN112891312A|2019-12-03|2021-06-04|成都康弘药业集团股份有限公司|Elemene-containing pharmaceutical composition, preparation method and application thereof|
    CN111909897B|2020-08-14|2021-12-21|宜兴市人民医院|Application of Ruvbl2 in regulation of proliferation and/or differentiation of human umbilical mesenchymal stem cells|
    法律状态:
    2017-11-29| PLFP| Fee payment|Year of fee payment: 2 |
    2018-05-04| PLSC| Search report ready|Effective date: 20180504 |
    2019-09-25| PLFP| Fee payment|Year of fee payment: 4 |
    2021-08-06| ST| Notification of lapse|Effective date: 20210705 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1670645A|FR3058058A1|2016-10-31|2016-10-31|PHARMACEUTICAL COMPOSITION COMPRISING AS ACTIVE INGREDIENT A COMBINATION OF BETA-ELEMENE, LUPEOL AND 2-HYDROXYCINNAMALDEHYDE AND / OR 2-BENZOYLOXYCINNALMALDEHYDE AND / OR BETA-SITOSTEROL|
    FR1670645|2016-10-31|FR1771115A| FR3058060B1|2016-10-31|2017-10-23|PHARMACEUTICAL COMPOSITION COMPRISING BETA-ELEMENE, LUPEOL, CINNAMALDEHYDE AND / OR 2-HYDROXYCINNAMALDEHYDE AND / OR 2'-BENZOYLOXYCINNALMALDEHYDE AND / OR BETA-SITOSTEROL AND / OR CURCUMIN.|
    MX2019003685A| MX2019003685A|2016-10-31|2017-10-25|Pharmaceutical composition for use in the therapeutic treatment of cancer and complications of cancer.|
    EP17808579.1A| EP3429568A1|2016-10-31|2017-10-25|Pharmaceutical composition for use in the therapeutic treatment of cancer and complications of cancer|
    KR1020197015106A| KR20190077449A|2016-10-31|2017-10-25|Pharmaceutical compositions for use in the therapeutic treatment of cancer and cancer complications|
    CA3043456A| CA3043456A1|2016-10-31|2017-10-25|Pharmaceutical composition for use in the therapeutic treatment of cancer and complications of cancer|
    PCT/IB2017/056612| WO2018078539A1|2016-10-31|2017-10-25|Pharmaceutical composition for use in the therapeutic treatment of cancer and complications of cancer|
    MA044413A| MA44413A|2016-10-31|2017-10-25|PHARMACEUTICAL COMPOSITION USED FOR THE THERAPEUTIC TREATMENT OF CANCER AND ITS COMPLICATIONS|
    CN201780049274.1A| CN109562080A|2016-10-31|2017-10-25|Pharmaceutical composition for treating cancer and cancer complication|
    ZA2019/02910A| ZA201902910B|2016-10-31|2019-05-09|Pharmaceutical composition for use in the therapeutic treatment of cancer and complications of cancer|
    IL266623A| IL266623D0|2016-10-31|2019-05-14|Pharmaceutical composition for use in the therapeutic treatment of cancer and complications of cancer|
    [返回顶部]