• 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:
    "combination of regorafenib and acetylsalicylic acid for cancer treatment". The present invention relates to pharmaceutical compositions and combinations comprising regorafenib and acetylsalicylic acid, or a pharmaceutically acceptable hydrate, solvate, metabolite or salt thereof or a polymorph thereof, for the treatment, prevention or management of diseases and conditions, including hyperproliferative disorders such as like cancer in humans and other mammals.
    公开号:BR112015006686A2
    申请号:R112015006686
    申请日:2013-09-23
    公开日:2019-08-27
    发明作者:Ziegelbauer Karl；Weber Olaf
    申请人:Bayer Ag；Bayer Pharma Aktiengellschaft；
    IPC主号:
    专利说明:

    Invention Patent Report For: COMBINATION OF REGORAFENIB AND ACETYLSAUCYLIC ACID FOR CANCER TREATMENT.
    [001] The present invention relates to pharmaceutical compositions and combinations comprising regorafenib and aeethylsalicylic acid, or a pharmaceutically acceptable hydrate, solvate, metabolite or salt thereof, or a polymorph thereof, for the treatment, prevention or management of diseases and pathologies, including hyperproliferative disorders, such as cancer in human sares and other mammals.
    [002] Regorafenib, which is 4- {443 (4-chloro-3tnfluoromethylphenyl) ~ ureido] ~ 3fluorophencxi} ~ pindine-2 ~ carboxylic acid methylamide, a compound of formula (I) [003] is a potent anti-cancer and anti-anigenogenic agent that has several activities, including inhibitory activity on the signaling molecules of VEGFR, PDGFR, raf, p38 and / or flt-3 and can be used for the treatment of several diseases and pathologies, such as hyperproliferative disorders, such as cancer, tumors, lymphomas, sarcomas and leukemias, as described in WO 2005/009961. It is currently developed for the treatment of colorectal cancer and gastrointestinal stromal tumors. In addition, the salts of the compound of structural formula (I), such as its cicndratc, mesylate and phenylsulfonate, are mentioned in WO 2005/009981. The monohydrate of the compound of formula (I) is mentioned in WO 2008/043446. WO 2011/128281 describes an improved process for the preparation of regorafenib with high purity.
    [004] Acetylsalicylic acid is a well-known drug which can be
    2/22 used not only to treat or reduce the risk of developing an event or cardiovascular disease, but there are also suggestions for its use to reduce the development of cancer diseases (Rothwell PM et a / (2012) Short-term effects of daily acetylsalicylic acid on cancer incidence, mortality and non-vascular death: analysis of the time course of risks and benefits in 51 randomized controlled trials. Lancet. 379: 1602-1612).
    (005] In addition, acetylsalicylic acid was able to reduce tumor metastases, providing a reduction in mortality, particularly in patients with odo-rectal cancer (Rothwell PM et at <(2012) Effect of daily acetylsalicylic acid on risk of cancer metastasis : a study of incident cancers during randomized controlled trials (Lancet, 379: 1591-1601).
    (006] The object of the present invention is to improve cancer therapy by administering regorafenib and acetylsalicylic acid in combination.
    [0Ô7] Surprisingly, the combination of regorafeoib and acetylsalicylic acid shows a significant improvement in terms of effectiveness in relation to the sum of monotherapy. In addition, the side effect profile (eg, hand-foot syndrome, high blood pressure, fatigue, diarrhea and inflammation of the mucous membranes) can be improved.
    [90S] The present invention relates to a combination comprising regorafenib, which is the compound of structural formula (0
    (60S] and acetylsalicylic acid, or a hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, or a polymorph thereof.
    [010] The expression “compound of structural formula (1) or“ regorafenib ”
    3/22 with respect to 4- {44 (([[4-chloro-3 ~ (trifluuromethyl) -phenyl] -aminu} -oaFbonyl) -amino] -3flucrophenoxy} -N-methylpindine-2 ~ carbuxamide, as illustrated in the structural formula (I), (011] The savages, for the purpose of the invention, are those forms of compounds or their salts in which the solvent molecules form a stoichiometric complex in the solid state and include, but without any limitation, for example , water, ethanol and methanol, [Ô12] Hydrates are a specific form of solvates, in which the solvent molecule is water.The hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds or salts with water, such as, for example, semi-, mono- or dihydrates. Regorafenib monohydrate is preferred, (013] The salts, for the purpose of the present invention, are preferably pharmaceutically acceptable salts of the compounds according to the invention Suitable pharmaceutically acceptable salts are c known to those skilled in the art and comprise salts of inorganic and organic acids, such as hydrochloric acid, bremidrioo acid, sulfuric acid, phosphoric acid, methanesulfonic acid, thfluoromethane-sulfonic acid, bemmno-sulphonic acid, p-toluene-sulphonic acid ( salt tosiiato), 1-naphthalenesulfene acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malty acid, tartaric acid, citric acid, lactic acid, oxalic acid, suoGinaceous acid, thematic acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts include salts of inorganic bases, such as salts containing alkali cations (v, g ', Li' *, Na * or K *), alkaline earth cations ( eg, Mg * 2 , Ca * : or Ba ' 2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic or aromatically substituted ammonia, and quaternary ammonium cations, such as those formed from the desecration or peralkylation of triethylamine, N, N- diethylamine, Ν, Ν-dteyclohexylamine, lysine, pindine, Ν, Ν-dimethylaminopyridine (DMAP), 1,4 ~ diazabiclo- [2,2,2] octane
    4/22 (DABCO), 1, o-dtobicylic [4.3.0] non-5 ~ ene (DBN) and 1,8-diaza ~ bicycles (5.4.0] undec7-ene (DBU). Sass hydrochloride is preferred , regorafenib mesiiate or phenylsulfonate.
    [014] Regorafenib nietabpiitgs, for the purpose of the present invention, include 4 '{4 - ({[4-chloro-3- (trifluoromethyl) -phenyl | -carbamoyl} amino 1-oxide] ~ 1-fluorophenoxy] ~ N ~ methylpyridine ~ 2 ~ carbuxarnide, 4 ~ [4 - ({[4 ~ chloro ~ 3 (tnfluoromethyl) -phenyl] -carbamoyl} -arnino) -3-fluorophenoxy] N- (hydroxymethyl) -pyridine2 ~ carboxamide, 4- [4 '({[4-chloro-3- (triorooromethyl) -phenyl] ~ oarbam0II} -amino) ~ 3fluorophenoxy] ~ pyridine-2 ~ carboxamide and 4' [4 - ({[4-chlorO ' 3 (trifluoromethyl) -phenyl] -carbamoyl!} - amino) ~ 3-fluorophenoxy] ~ pindine ~ 2Cart) uxamide.
    [015] As the compound of the present invention, regorafenib and regorafenib monohydrate are preferred, [010] The compounds according to the invention can be prepared using chemical reactions and known procedures.
    Treatment method:
    [017] The present invention also relates to a method for the use of the combination and its combinations, for the treatment of hyperprcliferative disorders in mammals. This method comprises the administration to a mammal that needs it, including a human being, of a amount of the combination that is effective for treating the disorder. Hyperproliferative disorders include, but are not limited to, solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin , head and neck, thyroid, parathyroid and distant metastases. Such disorders also include lymphomas, sarcomas and leukemias.
    [018] Examples of breast cancer include, but are not limited to, invasive dutch carcinoma, invasive lobular carcinoma, dutal carcinoma / r s / fe and lobular carcinoma m s7tu.
    [010] Examples of the respiratory tract include, but are not limited to,
    5/22 constitutes any limitation, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma, [020] Examples of brain cancer include, but are not limited to, any limitation. , brain stem and hypophthalmic glioma, cerebellar and cerebral astrocltoma, as well as neuroectalmic and pineal tumors [021] As tumors of the male reproductive organs it is referred, but without any limitation, prostate and testicular cancer, As tumors of the female reproductive organs refers, but without limitation, cancer of the endometrium, cervical, ovary, vaginal and vulvar, as well as sarcoma of the uterus.
    [022] As tumors of the digestive tract, anal, colon, colorectal, esophageal cancer refers, but without any limitation. of the biliary, gastric, pancreatic, rat vesicle, small intestine and salivary glands.
    [023] Colorectal cancer is preferred.
    [024] Tumors of the gastrointestinal tract (GIST) are also preferred, [026] As tumors of the urinary tract are referred to, but without limitation, cancer of the bladder, penile, kidney, kidney, kidney, ureter s urethra.
    [026] As garlic cancer refers, but without limitation, this constitutes any limitation, melanoma and retinoblastoma.
    [027] Examples of liver cancer include, but are not limited to, Imitation, hepatocellular carcinoma (hepatic cell carcinomas 100 or without fibrolamellar variant), cholangiocarcinema (carcinoma of the intra-hepatic bile duct) and mixed hepatocellular culangiocarcinoma, [028] Liver cell cancer is preferred, [020] As skin cancer refers, but without limiting it, squamous cell carcinoma, Kaposi's sarcoma,
    6/22 malignant melanoma, Merkel cell skin cancer and non-melanoma skin cancer.
    [030] As cancer of the head and neck refers, but without limiting it, cancer of the larynx / hypopharynx / nasopharynx / oropharynx and cancer of the lip and oral cavity, [031] As lymphomas it refers, but without that this constitutes any limitation, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease and central nervous system lymphoma.
    [032] Sarcomas are referred to, but without limitation, sarcoma of the motor tissues, osteosarcoma, malignant fibrous histooitoma, lymphosarcoma and rhabdomyosarcoma.
    [033] As leukemia refers, but without limitation, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell leukemia.
    [034] These disorders are well characterized in humans, but they also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
    [035] Based on conventional laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative disorders, through conventional toxicity tests and through conventional pharmacological tests for the determination of the treatment of the pathologies previously identified in mammals, and by comparison from these results with the results obtained by known drugs that are used to treat these pathologies, it is possible to easily determine the effective dosage of the compounds of the present invention for the treatment of each desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions can vary widely depending on such considerations, such as the particular compound and dosage unit used, the mode of administration, the period of treatment, age and sex
    7/22 of the treated patient, and the nature and extent of the pathology treated.
    [036] The present invention further provides the use of the compound of the invention for the preparation of pharmaceutical compositions for the treatment of the aforementioned disorders.
    Administration [037] The combinations of the present invention can be administered in any form and through any effective route, including, eg, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (eg using any conventional adhesive), ophthalmic, nasaí, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, ratal, vaginal, intra-arterial and intra-tecal etc. .. They can be administered per se sb or in combination with any ingredients, active or inactive.
    [033] Oral administration is preferred.
    [039] Alternatively, acetylsalicylic acid can be administered intravenously.
    [040] The combinations of the present invention can be converted in a known manner in usual formulations, which may be liquid formulations or solid, eg s but not limited to , normal coated tablets and entérioos, capsules, pilules, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols and emulsions.
    [041] Examples of solid formulations for oral administration are described in the provisional US patent application ró 60/605 752.
    [042] In general, the use of the combinations of the present invention mentioned above will serve to:
    (1) providing better efficacy in reducing the growth of a tumor or even eliminating the tumor, compared to the administration of any agent alone, (2) providing the administration of lesser amounts of
    8/22 administered chemotherapeutic agents, (3) providing a chemotherapeutic treatment that is well tolerated by the patient with fewer harmful pharmacological complications than those seen with chemotherapeutics with an individual agent and with certain therapies in combination, (4) providing the treatment of a broader spectrum of different types of cancer in mammals and, in particular, in humans.
    (5) providing a higher response rate among treated patients, (6) providing a longer survival time among treated patients, compared to conventional chemotherapy treatments, (7) providing a longer time for tumor progression and / or (8) provide results of efficacy and tolerability through the menus as good as those obtained with the agents used by themselves, in comparison with known cases in which other combinations of agents against cancer produced antagonistic effects.
    [043] The term "combination" designates, for the purpose of the invention, not only a dosage form that contains all the components (the so-called fixed combinations) and combination packs that contain the components separately from each other, but also the components that they are administered simultaneously or sequentially, as long as they are used for the prophylaxis or for the treatment of the same disease.
    [Ô44] The amount of active ingredient administered can vary widely according to considerations, such as the particular compound and dosage unit used, the mode and time of administration, the period of treatment, age, sex and status general health of the treated patient, and the nature and extent of the pathology treated, the rate of drug metabolism and excretion, potential drug combinations and interactions
    9/22 drug-drug and the like.
    [045] One particularly important aspect of the invention concerns a combination comprising regorafenib in an amount comprised between 4 and 400 mg, preferably between 10 and 200 mg and, more preferably, between 10 and 100 mg.
    [046] Another particularly important aspect of the invention concerns a combination comprising acetylsalicylic acid in an amount of between 50 and 100 mg, preferably between 60 and 500 mg and, more preferably, between 70 and 350 mg. Typical doses of aoethylsalicylic acid are 78 mg, 81 mg. 100 mg, 325 mg, 500 mg and 1000 mg.
    [047] The daily dose of regorafenih is between 10 and 1000 mg, preferably between 40 and 500 mg and, more preferably, between 80 and 320 mg. e.g. 160 mg.
    [048] The daily dose of acetylsalicylic acid is between 50 and 1000 mg, preferably between 60 and 500 mg and, more preferably, between 70 and 350 mg. Typical daily doses of acetylsalicylic acid are 78 mg. 81 mg, 100 mg, 325 mg, 500 mg and 1000 mg.
    [040] The pharmaceutical composition according to the invention is administered one or more times, preferably between one and three times and, more preferably, up to twice a day. Oral administration is preferred. With each administration, the number of tablets or capsules administered simultaneously should not exceed two.
    [050] However, in some cases, it may be advantageous to deviate from the specified amounts, depending on body weight, individual behavior towards the active ingredient, the type of preparation and the time or interval over which the administration has place. For example, in some cases, an amount lower than the minimum quantities mentioned above may be sufficient, while in other cases, the specified upper limit will have to be exceeded. In the case of administering relatively large quantities, it may be advisable to divide them into
    10/22 several individual doses throughout the day.
    [051] Examples of an administration schedule include the following: in the first cycle, daily doses of 160 mg of regorafenib and 81 mg of acetylsalicylic acid are administered over 3 weeks. In the fourth week, only 81 mg of acetylsalicylic acid are administered. After the cycle is repeated. Alternatively, the daily dose of acetylsalicylic acid may be less than or equal to 325 mg (e.g., 100 mg) or it may be greater than 325 mg (e.g., 500 mg).
    [052] The combination may comprise effective amounts of the compound of formula I and acetylsalicylic acid, which achieves greater therapeutic efficacy than any of the compounds when used alone.
    [053] The relative proportions of each compound in the combination can also be selected based on their respective mechanisms of action and the biology of the disease. The relative proportions of each compound can vary widely.
    [054] The release of one or more combination agents can also be controlled, where appropriate, to provide the desired therapeutic activity, when in an individual dosage form, combination pack, kit or when in separate independent dosage forms .
    [055] The present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compounds of the present invention. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and harmless to a patient at concentrations consistent with effective activity of the active ingredient, so that any side effects attributable to the carrier do not overcome the beneficial effects of the active ingredient. A pharmaceutically effective amount of the compound is an amount that produces a result or that has an influence on the particular pathology
    11/22 in treatment.
    [0S6] For oral administration, the compounds can be formulated in solid or liquid preparations, such as solid dispersion, capsules, pills, tablets, triskles, lozenges, molten materials, powders, solutions, suspensions or emulsions, and can be prepared according to methods known in the art for the production of pharmaceutical compositions. The solid unit dosage forms can be a capsule which can be of the type of gelatin with hard or soft shell that contains, for example, surfactants, lubricants and inert fillers, tats such as lactose, sucrose, calcium phosphate and corn starch.
    [057] According to another variant, the compounds of the present invention can be transformed into tablets with conventional tablet bases, such as lactose, sucrose and corn starch, in combination with binders, such as acacia gum, corn starch or gelatin, disintegrating agents to help break and dissolve the tablet after administration, such as potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia, lubricants to improve fluidity. granulation of the tablet and prevent the adhesion of the tablet material to the surfaces of the dyes and bags of the tablet, for example, tala, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and agents sweeteners, such as peppermint, gualteria oil, or cherry flavoring, used to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in liquid dosage forms include calcium phosphate and diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either in the presence or in the absence of the addition of a tensoatlvu, suspension with a pharmaceutically acceptable emulsifying agent Various other materials may be present with coatings or else to modify the physical form of the dosage unit. For example, tablets, pills or capsules can be
    12/22 coated with gomadaca, sugar or both.
    [058] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. These provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents are exemplified by those mentioned above. Additional excipients, for example, those sweetening, sweetening and coloring agents mentioned above, may also be present.
    [G59] The pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents can be (1) naturally occurring gums, such as acacia gum and tragacanth, (2) naturally occurring phosphatides, such as soy and iecithin, (3) esters or partial beings from fatty acids and anhydrides of hexitoi, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and sweetening agents, [000] Oily suspensions can be formulated to suspend the active ingredient in a vegetable oil, such as, for example, hot oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, such as, for example, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-prepite p-hydroxybenzoate; one or more dyes; one or more sweetening agents and one or more sweetening agents, such as sucrose or saccharin.
    [061J Syrups and elixirs can be formulated with sweetening agents, such as, for example, glycerol, propylene glycol, sorbitol or
    13/22 sucrose, Such formulations may also contain an emollient and a preservative, such as motile and propyl parabens, and sweetening and coloring agents.
    [062] The compounds of the present invention can also be administered parenterally, that is. subcutaneously, intravenously, intraocularly, intranasally, intramuscularly or intraperitoneally in the form of injectable dosages of the compound in a physiologically acceptable dilueate with a pharmaceutical carrier that may be a sterile liquid or mixture of liquids, such as water, saline, aqueous dextrose and associated sugar solutions, an alcohol, such as ethanol, isopropanol or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1 : 1-dioxolane ~ 4-methanul, ethers, such as poly (ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or a fatty acid glyceride or an acetylated fatty acid glyceride, with or without the addition of a surfactant pharmaceutically acceptable, such as a soap or detergent, suspending agent, such as pectin, oarbomers, methyl cellulose, hydroxypropylmethyl cellulose or carboxymethyl cellulose, or emulsifying agent and others pharmaceutical adjuvants.
    [083] As illustrative oils that can be used in the parenteral formulations of the present invention are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, sesame oil, cotton oil, corn oil, olive oil, petrolatum and mineral oil, Suitable fatty acids include oteic acid, stearic acid, isostary acid and myristic acid. Suitable fatty acid esters include, for example, ethyl oate and isopropyl myristate. Suitable soaps include alkali metal salts, ammonia and triethanolamine with fatty acids and suitable detergents include cationic detergents, for example, dimethyl-dialkyl-ammonium halide, alkyl-pyridine halogenates, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and ciefin sulfonates, alkyl sulfates, define, ether and monoglyceride, and sulfo14 / 22 succinates; non-ionic detergents, for example, oxides of amines gards, alkanamides of fatty acids, and poly (oxyethylene-oxypropylene) or copolymers of ethylene oxide or propylene oxide; and amphoteric detergents, for example, alkyl-beta-ammonium propionates and 2-alkylimidazole quaternary ammonium salts, as well as mixtures.
    [064] The parenteral compositions of the present invention will typically contain between about Q, 5% and about 25% by weight of the active ingredient in solution. Advantageously, it is also possible to use preservatives and buffers. To minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant that has a hydrophilic-lipophilic balance (HLB) between about 12 and about 17. The amount of surfactant in such formulation intervals is comprised between about 5% and about 15% by weight. The surfactant can be an individual component that has the previous HLB or it can be a mixture of two or more components that has the desired HLB.
    [065] As illustrative surfactants used in parenteral formulations, we refer to polyethylene-orbitan fatty acid esters, for example, scrbitan mono-cleate and high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by condensation of propylene oxide with propylene glycol.
    [666] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, such as, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia range; dispersing or wetting agents which can be a naturally occurring phosphatide, such as lecithin, an alkylene oxide condensation product with a fatty acid, for example, polyoxyethylene stearate, an ethylene oxide condensation product with an alcohol
    15/22 long-chain aliphatic, eg heptadeca-ethyleneoxyethanol, a condensation product of ethylene oxide with a partial ester from a fatty acid and a hexuol, such as polyoxyethylene sorbitol monooleate and a product of condensation of an ethylene oxide with a partial ester from a fatty acid and a hexitol anhydride, for example, polyoxyethylene sorbitan monooleate, [087] The sterile injectable preparation also claims to be a sterile solution for injection in a diluent or solvent non-toxic and parenterally acceptable. As diluents and solvents that can be used, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally used as solvents or as suspending media. For this purpose, any soft fixed oil can be used, including synthetic mono- or di-glioeddios. In addition, it is possible to use fatty acids, such as oleic acid, in the preparation of injectables.
    [068] The compositions of the invention can also be administered in the form of suppositories for rat administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at normal temperatures, but liquid at the rat temperature, thus melting into the rectum to release the drug. Such a material refers, for example, to cocoa butter and polyethylene glycol.
    [069] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations. which are known in the art ..
    [070] The pharmaceutical compositions of the present invention can also be in the form of a solid dispersion. The solid dispersion may be a solid solution, a glassy fragment, an amorphous precipitation in a crystalline vehicle, eutectic or monotectic compound or complex formation and combinations thereof.
    [071] A particularly important aspect of the invention concerns
    16/22 a pharmaceutical composition comprising a solid dispersion, in which the matrix comprises a pharmaceutically acceptable polymer, such a polyvinylplyrolidine copolymer, vinylpyrrolidone / vinyl acetate copolymer, polyalkylene glycol (i.e., polyethylene glycol), hydroxyalkyl (cellulose) i.e., hydroxypropyl-cellulose), hydroxyalkyl-methyl-cellulose (i.e., hydroxypropyl-methyl · cellulose), carboxylmethyl-cellulose, sodium carboxymethyl-ceulose, ethyl-cellulose, pclimethacrylates, polyvinyl alcohol, polyvinyl acetate, polyvinyl acetate, polyvinyl acetate polyvinyl / vinyl acetate, polyglycolated glycerides, xanthan gum, oanagenin, chitosan, chitin, polydextrin, dextrine, starch and proteins.
    [072] Another aspect of the invention concerns a pharmaceutical composition that comprises a solid dispersion, in which the matrix comprises a sugar and / or sugar alcohol and / or cyclodextrin, for example, sucrose, iactosis, fructose, maltose, raffinose, sorbitol, lactitoí, manítoí, maltitol, erythritol, inositol, trehaliosis, isomalt, inclines, maltodextrin, β-clclodextnna, hydroxypropyl-p-cyclodextrin or cyclodextrin sulfobutyl ether.
    [073] Supplementary suitable vehicles useful for the formation of the solid dispersion matrix include, but are not limited to, alcohols, organic acids, organic bases, amino acids, fluids, waxes, salts, fatty acid esters, esters of polyoxyethyl-sorbitan fatty acids and urea.
    [074] The solid dispersion of regorafenib in the matrix may contain certain additional pharmaceutically acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, anti-foaming agents, anti-oxidants, adhesion removal agents, pH modifiers , sliding agents and lubricants.
    [075] The solid dispersion of the invention is prepared according to methods known in the art for the production of solid dispersions, such as melt / melt technology, hot melt extrusion, solvent evaporation (ie, lyophilization, drying spraying or layer formation of granule powders), co-precipitation,
    17/22 supercritical fluids and electrostatic extrusion method.
    1076] The compositions of the invention may also contain other ingredients for the formation of conventional pharmaceutically acceptable compounds, generally designated as carriers or diluents, as needed or desired. It is possible to use conventional procedures for the preparation of such compositions in suitable dosage forms.
    [077] As commonly used pharmaceutical ingredients, usable as appropriate to formulate the composition for the intended route of administration, refer to:
    [073] acidifying agents (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
    [079] alkalizing agents (examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);
    [880] adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);
    [081] aerosol propellants (examples include, but are not limited to, carbon dioxide, CCI 2 F 2 , F2CIC-CCIF2 and CCIF3) [882] air displacement agents (as examples refer to if, but without limitation, nitrogen and argon);
    [083] antifungal preservatives (examples include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);
    [884] antimicrobial preservatives (examples include, but are not limited to, benzene chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, tenol, phenylethyl alcohol, phenyl mercury nitrate and thimerosal) ;
    18/22 [085] anti-oxidants (examples include, but are not limited to, ascorbic acid, ascorbyl papyrate, butylated hydroxyanisole, butylated hydroxyethylene, hydrophosphorous acid, monothioglucerol, propyl gallate, sodium ascorbate, bisulfide sodium, formaldehyde-sodium sulfoxylate, sodium metabisulfide);
    [086] bonding materials (examples include, but are not limited to, block polymers, natural rubber and natural synthetic, polyaclates, polyurethanes, silicones, polysiloxanes and styrene-bu tad ie copolymers at the);
    [087] buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate and sodium citrate dihydrate) [088] transport (some examples refer, but without limitation), acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil , sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) [089] chelating agents (as examples, but without limitation, disudic edetate and edetic acid) [090] dyes (as examples refers to, but is not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and red iron oxide);
    [091] eifying agents (examples include, but are not limited to, bentonite);
    [092] emulsifying agents (examples include, but are not limited to, acacia, ketomacmgol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan mono-oeate 50, polystyrene mono-stearate 50);
    19Z22 [093] encapsulating agents (examples include, but are not limited to, gelatin and gelatin acetate-phthalate) [094] sweeteners (examples refer to, but not limited to, oil anise, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanilla);
    [995] humectants (examples include, but are not limited to, glycerol, propylene glycol and sorbitol);
    [096] levigation agents (examples include, but are not limited to, mineral oil and glycerin);
    [097] oils (examples include, but are not limited to, arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);
    [093] bases for ointments (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment and rose water ointment);
    [099] penetration enhancers (transdermal administration) (examples include, but are not limited to, monohydroxy or polyhydroxy alcohols, mono- or poly-active alcohols, saturated or unsaturated fatty alcohols, saturated fatty esters or insaturated, saturated or unsaturated dicarbonic acids, essential oils, phosphatidyl derivatives, cephaline, terpenes, amides, ethers, catenas and ureas) [199] plasticizers (as examples refer, but without limitation, diethyl phthalate and glycerol);
    [191] solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerine, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation);
    [192] hardening agents (as examples refer, but without
    20/22 that this constitutes any limitation, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax);
    [103] suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycols (mixtures));
    [104] surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, pclisorbate 80, sodium lauryl sulfate and sorbitan mono-palmltate);
    [105] suspending agents (as examples refer, but not limited to, agar, bentonite, carberoses, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyprupyl-methylcellulose, kaolin, methyl -cellulose, tragacanth and gum V);
    [105] sweetening agents (examples include, but are not limited to, aspartame, dextrose, glycerol, manifol, propylene glycol, sodium saccharin, sorbitol and sucrose);
    [107] non-stick tablets (as examples refer, but without limitation, magnesium stearate and talc);
    [108] binders for tablets (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethyl cellulose, compressible sugar, ethiphoelulose, gelatin, liquid glucose, methylcalphosis, polyvinylpinolidone not re-filled with pregelatinized starch);
    [109] diluents for tablets and capsules (as examples, but without limitation), dibasic calcium phosphate, kaolin, lactose, manifol, micromoristaline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, phosphate of sodium, sorbitol and starch);
    [110] tablet coating agents (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate-phthalate and gum -lacquer);
    21/22 [111] excipients for direct tablet compression (as examples refer, even without limitation, dibasic calcium phosphate);
    [112] disintegrants for tablets (examples include, but are not limited to, alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose. Potassium pclacrillin, cross-linked polyvinylplrolidone, sodium alginate, sodium amide glycolate) ;
    [113] tablet gliders (examples include, but are not limited to, cololdal silica, corn starch and talc):
    [114] lubricants for tablets (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);
    [115] agents for opacifying tablets / capsules (examples include, but are not limited to, titanium dioxide);
    [119] tablet polishing agents (examples include, but are not limited to, carnauba wax and white wax);
    [117] thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol and paraffin);
    [113] tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);
    [119] agents for increasing viscosity (examples include, but are not limited to, albinic acid, bentonite, carbomers, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate and tragacanth); and [120] wetting agents (examples include, but are not limited to, heptadecaethylene-oxycethanol, lecithin, monooleate
    22/22 sorbitol, polyoxyethylene-sorbltol mono-oeate and polyoxyethylene stearate).
    [121] It is believed that one skilled in the art, using the above information, could use the present invention to its fullest extent.
    权利要求:
    Claims (10)
    [1]
    1. Pharmaceutical combination characterized by comprising regorafenib with acathylsalicylic acid, or a hydrate, solvate, metabolite or pharmaceutically acceptable salt or polymorph thereof.
    [2]
    Combination according to claim 1, characterized in that it is a pharmaceutical composition comprising regorafenib and acetylsalioyl acid, or a pharmaceutically acceptable hydrate, solvate, metabolite or salt thereof, or a polymorph thereof, in a single dosage form.
    [3]
    Combination according to claim 1, characterized in that it is a combination package containing the components separated from each other.
    [4]
    Combination according to claim 1, characterized in that the components are administered, in separate dosage forms, simultaneously or sequentially for the treatment of the same disease.
    [5]
    Combination according to any one of claims 1 to 4, characterized in that it is for use as a medicine for the treatment of hyperproliferative diseases.
    [6]
    6. Combination according to claim 5, characterized in that hyperproliferative disorders are selected from the group consisting of cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver , skin, head and neck, thyroid, parathyroid and distant metastases.
    [7]
    Combination according to any one of claims 5 to
    6, characterized in that hyperproliferative disorders are selected from a group consisting of colorectal cancer and gastrointestinal stromal tumors (GIST).
    [8]
    Combination according to any one of claims 1 to
    7, characterized by being administered in such a way that regorafenib and acetylsalicylic acid are administered daily during the first three
    2/2 weeks and the fourth week is only administered and regorafenib daily,
    [9]
    Combination according to any one of claims 1 to 8, characterized in that it contains regorafenib in an amount between 10 and 1000 mg and acetylsalicylic acid in an amount between 50 and 1000 mg,
    [10]
    10, Method for the treatment of hyperproliferative disorders in a subject who needs it, characterized by the administration of effective amounts of regorafenib and acephylsalicylic acid, or a pharmaceutically acceptable hydrate, solvate, metabolite or salt thereof or a polymorph.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112015006686A2|2019-08-27|combination of regorafenib and acetylsalicylic acid for cancer treatment.
    TWI428322B|2014-03-01|4-[4-|phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide monohydrate
    ES2391382T3|2012-11-23|Aryl urea compounds in combination with other cytostatic or cytotoxic agents for the treatment of human cancers
    JP2010509382A|2010-03-25|Polymorph II of 4- [4-| phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide II
    CA2668748A1|2008-05-15|Polymorph iii of 4-[4-|phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide
    CN101835747A|2010-09-15|Benzimidazole derivative
    KR20200080254A|2020-07-06|Compounds and compositions for treating hematologic disorders
    US20200155674A1|2020-05-21|Combination of regorafenib and pd-1/pd-l1| inhibitors for treating cancer
    ES2796276T3|2020-11-26|Compounds with antitumor activity
    JP2018538354A|2018-12-27|CFTR regulator and method of using the same
    WO2021160708A1|2021-08-19|Combination of regorafenib and msln-ttc for treating cancer
    WO2018102824A1|2018-06-07|Methods for treating neurodegenerative disease
    JP2017509617A|2017-04-06|Novel compounds with antiallodynic activity and antihyperalgesic activity
    同族专利:
    公开号 | 公开日
    RS57875B1|2018-12-31|
    US10898500B2|2021-01-26|
    KR20150060869A|2015-06-03|
    PH12015500587A1|2015-05-11|
    LT2900269T|2018-11-12|
    DK2900269T3|2018-10-01|
    CY1120939T1|2019-12-11|
    HRP20181462T1|2018-11-02|
    PT2900269T|2018-10-22|
    JP6294888B2|2018-03-14|
    JP2015529234A|2015-10-05|
    AU2013322854A1|2015-04-02|
    KR102210575B1|2021-02-02|
    EA032023B1|2019-03-29|
    CN104994876A|2015-10-21|
    NZ705860A|2018-07-27|
    CA2885688C|2021-03-02|
    AU2013322854B2|2018-07-19|
    IL237690D0|2015-05-31|
    EA201500365A1|2015-08-31|
    EP2900269A1|2015-08-05|
    HK1214169A1|2016-07-22|
    IL237690A|2019-07-31|
    ZA201502840B|2017-11-29|
    CL2015000744A1|2016-01-08|
    SI2900269T1|2018-10-30|
    HUE039878T2|2019-02-28|
    SG10201702356VA|2017-04-27|
    SG11201501963RA|2015-04-29|
    MX357035B|2018-06-25|
    US20150202214A1|2015-07-23|
    PL2900269T3|2019-02-28|
    WO2014048881A1|2014-04-03|
    CA2885688A1|2014-04-03|
    EP2900269B1|2018-08-01|
    MX2015003728A|2015-09-23|
    ES2687985T3|2018-10-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US6620834B1|1999-07-02|2003-09-16|Hisamitsu Pharmaceutical Co., Inc.|Medicinal compositions for treating colorectal cancer|
    US20040121004A1|2002-12-20|2004-06-24|Rajneesh Taneja|Dosage forms containing a PPI, NSAID, and buffer|
    JP4777887B2|2003-07-23|2011-09-21|バイエル、ファーマシューテイカルズ、コーポレイション|Fluoro-substituted omegacarboxyaryl diphenylureas for the treatment and prevention of diseases and conditions|
    WO2007054303A2|2005-11-10|2007-05-18|Bayer Healthcare Ag|Diaryl urea for treating diabetic neuropathy|
    AR062927A1|2006-10-11|2008-12-17|Bayer Healthcare Ag|4- [4- PHENYL) CARBAMOIL] AMINO] -3- FLUOROPHENOXY) -N- METHYLPIRIDIN-2-MONOHIDRATED CARBOXAMIDE|
    GB201002530D0|2010-02-15|2010-03-31|Univ Wolverhampton The|Di-aspirin derivatives|
    AR081060A1|2010-04-15|2012-06-06|Bayer Schering Pharma Ag|PROCEDURE TO PREPARE 4- {4 - [ PHENYL] AMINO} CARBONYL) AMINO] -3-FLUOROPHENOXY} -N-METHYLPIRIDIN-2-CARBOXAMIDE|CA2872213A1|2012-06-13|2013-12-19|F. Hoffmann-La Roche Ag|New diazaspirocycloalkane and azaspirocycloalkane|
    UA116547C2|2012-09-25|2018-04-10|Ф. Хоффманн-Ля Рош Аг|New bicyclic derivatives|
    AR095079A1|2013-03-12|2015-09-16|F Hoffmann-La Roche Ag|DERIVATIVES OF OCTAHIDRO-PIRROLO [3,4-C] -PIRROL AND PIRIDINA-FENILO|
    MA38982A1|2013-11-26|2017-09-29|F Hoffmann-La Roche Ag|Novel octahydro-cyclobuta [1,2-c; 3,4-c '] dipyrrol-2-yl|
    PE20161223A1|2014-03-26|2016-11-12|F Hoffmann-La Roche Ag|[1,4] DIAZEPINE CONDENSED COMPOUNDS AS INHIBITORS OF THE PRODUCTION OF AUTOTAXINAND LYSOPHOSPHATIDIC ACID |
    SI3122750T1|2014-03-26|2019-12-31|F. Hoffmann-La Roche Ag|Bicyclic compounds as autotaxinand lysophosphatidic acidproduction inhibitors|
    CN104829523B|2014-04-30|2017-10-31|药源药物化学（上海）有限公司|Rui Gefeini salt and its crystal formation, preparation method|
    MA41898A|2015-04-10|2018-02-13|Hoffmann La Roche|BICYCLIC QUINAZOLINONE DERIVATIVES|
    JP6886967B2|2015-09-04|2021-06-16|エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ|Phenoxymethyl derivative|
    CN105267167A|2015-09-11|2016-01-27|江苏嘉逸医药有限公司|Regorafenib oral solid pharmaceutical composition preparation method|
    PE20180461A1|2015-09-24|2018-03-06|Hoffmann La Roche|NEW BICYCLE COMPOUNDS AS ATX INHIBITORS|
    RU2725138C2|2015-09-24|2020-06-30|Ф. Хоффманн-Ля Рош Аг|New bicyclic compounds as double inhibitors of autotaxin /carbonic anhydrase |
    EP3353176B1|2015-09-24|2022-01-19|F. Hoffmann-La Roche AG|Bicyclic compounds as atx inhibitors|
    JP6877413B2|2015-09-24|2021-05-26|エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ|A novel bicyclic compound as a dual ATX / CA inhibitor|
    WO2018167113A1|2017-03-16|2018-09-20|F. Hoffmann-La Roche Ag|New bicyclic compounds as atx inhibitors|
    MX2019010772A|2017-03-16|2019-12-16|Hoffmann La Roche|Heterocyclic compounds useful as dual atx/ca inhibitors.|
    KR20200011971A|2017-06-02|2020-02-04|바이엘 악티엔게젤샤프트|Combination of legolafenib and PD-1 / PD-L1inhibitors to treat cancer|
    KR20210156389A|2020-06-17|2021-12-27|재단법인대구경북과학기술원|Pharmaceutical composition for the prevention or treatment of inflammatory disease comprising regorafenib an active ingredient|
    法律状态:
    2019-09-17| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-10-15| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |
    2021-09-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-10-05| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2022-02-15| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    EP12185852|2012-09-25|
    PCT/EP2013/069735|WO2014048881A1|2012-09-25|2013-09-23|Combination of regorafenib and acetylsalicylic acid for treating cancer|
    [返回顶部]