WO2011025269A2 - Taurate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant - Google Patents

Taurate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant Download PDF

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WO2011025269A2
WO2011025269A2 PCT/KR2010/005711 KR2010005711W WO2011025269A2 WO 2011025269 A2 WO2011025269 A2 WO 2011025269A2 KR 2010005711 W KR2010005711 W KR 2010005711W WO 2011025269 A2 WO2011025269 A2 WO 2011025269A2
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metformin
cancer
taurine salt
composition
diabetes
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PCT/KR2010/005711
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Korean (ko)
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WO2011025269A3 (fr
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김성욱
전성수
민창희
구자성
강민석
김용은
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한올바이오파마주식회사
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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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton

Definitions

  • the present invention relates to a novel salt of metformin, a method for preparing the same, a pharmaceutical composition comprising the same, and a combination formulation comprising the same.
  • N, N-dimethyl imidodicarbonimidic diamide (N, N-dimethyl imidodicarbonimidic diamide), commonly known as metformin, is an insulin-independent diabetes treatment drug. Is a biguanide-based drug that has the best hypoglycemic action and is most effective in preventing complications and worsening of symptoms.
  • metformin alone has been characterized as the first choice in many papers.
  • metformin's efficacy activates AMP-activated protein kinase (AMPK) has justified its clinical effectiveness.
  • AMPK is a key enzyme that physiologically regulates carbohydrate and lipid metabolism. Metformin activates this enzyme to normalize hyperglycemia, improve lipid status, normalize menstrual irregularities, ovulation and pregnancy, and at the same time treat fatty liver and gene p53 (Tumor). protein p53) has been reported to prevent and treat cancer.
  • metformin an AMPK enzyme activator
  • metformin is a drug that activates AMPK enzymes to normalize sugar and lipid metabolism
  • metformin administration in cancers lacking the p53 gene alters the energy metabolic pathways of cancer cells and increases anticancer activity in proportion to the dose of metformin.
  • Metformin has been shown to be effective in treating cancer at normal doses for treating diabetes.
  • Josie MM Evans published a study showing that patients with type 2 diabetes have a lower incidence of cancer than those who do not receive metformin [Josie MM, Evans et al. BMJ. 2005 , 330, 1304-1305], Samantha L. Bowker reported that patients with type 2 diabetes who take metformin have a lower mortality associated with cancer than patients who take sulfonylureas or take insulin [Samantha L et al. Diabetes Care. 2006, 29, 254-258.
  • metformin has been reported to improve cardiovascular disease, lower triglycerides, low-density lipoprotein, and cholesterol levels in diabetics due to its antioxidant effects [UKPDS group. Effect of intensive blood-glucose control with metformin on complications in overweight Patients with type 2 diabetes (UKPDS 34) Lancet 1998: 352: 854-865].
  • metformin is useful in the free base form, but it is administered in the form of a pharmaceutically acceptable acid addition salt because of the disadvantage of poor stability.
  • metformin is sold in the form of hydrochloride, and other metformin salts are metformin folate in Chinese Patent Publication No. CN 1962661A, metformin 1,2,6,7,8,8a-hexahydro- in WO 2005/033067.
  • Beta gamma, 6-trihydroxy-2-methyl-8-[(2s) -2-methyl-1-oxobutoxy]-, (beta R, gamma R, 1S, 2S, 6S, 8S, 8aS) -1-naphthaleneheptarate, metformin acetylsalicylate in US Pat. No. 3,957,853, metformin clofibrate salt in US Pat. No.
  • One technical problem to be solved by the present invention is to provide a metformin novel salt excellent in pharmacological effect.
  • Another technical problem to be solved by the present invention is to provide a method for producing a metformin novel salt.
  • Another technical problem to be solved by the present invention is diabetes, diabetes, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome
  • the present invention provides a pharmaceutical composition for preventing, alleviating, or treating a disease or condition selected from cancer, myalgia, muscle cytotoxicity, menopausal syndrome, and rhabdomyolysis.
  • Another technical problem to be solved by the present invention is to provide an antioxidant pharmaceutical composition comprising a metformin novel salt as an active ingredient.
  • Another technical problem to be solved by the present invention is to provide a combination formulation comprising a metformin novel salt and a second drug.
  • the present invention provides metformin taurine salt.
  • the binding molar ratio of metformin and taurine salt is preferably 2: 1 to 1: 2, and more preferably the 1: 1 molar ratio metformin taurine salt of the following formula (1).
  • metformin taurine salt is meant to include all anhydrides, hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, etc.), solvates, and the like of metformin taurine salts.
  • the metformin taurine salt may be in crystalline form.
  • the present invention comprises the steps of 1) reacting the metformin hydrochloride with an inorganic base to obtain a metformin free base; And 2) reacting the metformin free base obtained in step 1 with taurine to prepare a metformin taurine salt.
  • metformin hydrochloride used as starting material can be purchased commercially or prepared by a known method.
  • the inorganic base of step 1 means a conventional inorganic base used in the field of organic chemical manufacturing, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium hydrogen carbonate, or potassium hydrogen carbonate, but examples thereof are not limited to the inorganic base usable in the present invention.
  • the use equivalent weight of the inorganic base is preferably 0.7 to 4 molar equivalents, more preferably 0.9 to 4 molar equivalents, and even more preferably 0.9 to 1.5 molar equivalents, relative to 1 molar equivalent of metformin hydrochloride. .
  • the reaction temperature is preferably 0 to 60 ° C, more preferably 15 to 50 ° C.
  • the reaction time is preferably 30 minutes to 3 hours, but may vary depending on the reaction temperature.
  • Taurine used in the production method of the present invention can be purchased commercially available.
  • the use equivalent of taurine is preferably 0.7 to 4 molar equivalents, more preferably 0.9 to 4 molar equivalents, and even more preferably 0.9 to 1.5 molar equivalents, relative to 1 molar equivalent of metformin free base.
  • the reaction temperature is preferably 0 to 80 °C, the reaction temperature may vary depending on the type of reaction solvent.
  • the reaction solvent is water, it is preferable to react at room temperature (15 to 30 °C), and in the case of isopropanol, it is preferred to react by heating to 50 to 65 °C.
  • the reaction solvent is water or methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetra
  • methanol is preferred in step 1 and water or isopropanol is preferred in step 2.
  • metformin taurine salt represented by Chemical Formula 1 may be prepared by the steps represented by Schemes 1 and 2.
  • the present invention is diabetes, diabetes, metabolic syndrome, diabetic complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, containing metformin taurine salt as an active ingredient
  • a pharmaceutical composition for preventing, alleviating or treating one or more diseases or symptoms selected from symptoms, menopausal syndrome or rhabdomyolysis may be due to the activating action of AMPK ⁇ .
  • the composition may be for the prevention, alleviation or treatment of cancer and diabetes.
  • the cancer may be a cancer lacking the p53 gene.
  • the cancer may be cancer selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, colon cancer, lung cancer, skin cancer, blood cancer, liver cancer, pancreatic cancer, prostate cancer and thyroid cancer, preferably breast cancer Can be.
  • diabetes includes not only diabetes but also diabetes of those with metabolic syndrome, which means that diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis or polycystic ovary syndrome are combined.
  • metabolic syndrome means that diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis or polycystic ovary syndrome are combined.
  • the complications of diabetes are the same as the disease or condition referred to as metabolic syndrome.
  • composition may be for the prevention, alleviation or treatment of metabolic syndrome or diabetes.
  • composition of the present invention may be for co-administration with a second drug.
  • the second drug means another pharmaceutically effective ingredient other than metformin taurine salt of the present invention.
  • the metformin taurine salt of the present invention can be used for the treatment of various diseases as described above.
  • the metformin taurine salt of the present invention can be used in combination with a second drug for more efficient treatment of each disease.
  • the second drug may be an anticancer agent, an antihyperglycemic agent, an antiobesity agent, or the like.
  • the antihyperglycemic agent may be for prevention, alleviation or treatment of diabetes mellitus, diabetes, metabolic syndrome, and / or diabetes complications due to hyperglycemia
  • the antiobesity agent may be for prevention, alleviation or treatment of obesity.
  • the antihyperglycemic agent may be at least one drug selected from the group consisting of biguanide-based drugs, sulfonylurea-based drugs, thiazolidione-based drugs, and alpha-glocosidase inhibitors.
  • the anticancer agent is not limited as long as it can be used in combination with metformin taurine salt, but may be a biological agent such as a gene therapy agent in addition to known chemotherapeutic agents such as alkylating agents, metabolic antagonists, natural agents, hormones, and / or antagonists, and / or immunotherapy agents. Can be.
  • the antihyperglycemic agent is not limited as long as it can be used in combination with metformin ascorbate, but is not limited to acarbose, miglitol, bogliose, pramlinted, buformin, metformin, phenformin, allogliptin, sasagliptin, cytagliptin , Stammagliptin, Exenatide, Reroglutide, Insulin, Mytiglinide, Nateglinide, Repaglinide, Setohexamide, Carbutamide, Chlorpropamide, Glibenclamide, Glyborneuride, Glyclagit, glymepiride, glyphigit, glyquidone, glycentide, glysolamide, glycyclamide, tol azamide, tolbutamide, pioglitazone, rosiglitazone, and / or troglitazone.
  • the anti-obesity agent is not limited if it can be used in combination with metformin ascorbate, but not limited to dexamphetamine, caffeine, dexfenfluramine, diethylpropion, ephedrine, fenfluramine, fluoxetine, leptin, liraglutide, magdol, metformin, methylcellulose, oligo Start, penmetrazine, phentermine, phenylpropanolamine, limonabant, sibutramine, stuculia, sucrose, polyester, tefenfencin, topiramate, and / or zonamide.
  • the present invention also provides an antioxidant pharmaceutical composition containing metformin taurine salt as an active ingredient.
  • Metformin taurine salt may exhibit antioxidant activity by increasing the activity of AMPK ⁇ and inhibiting the activity of NAD (P) H oxidase which produces superoxide anion.
  • P NAD
  • prevention means any action that inhibits or delays the onset of a disease or condition by administration of a composition of the present invention.
  • treatment means any action that improves or beneficially changes the symptoms of the disease by administration of the composition of the present invention
  • laxation means that the disease or symptom is no longer worsened by administration of the composition of the present invention. It means all actions.
  • compositions of the present invention may be in the form of conventional formulations that are acceptable and commonly used in the medical arts and may be, for example, tablets, soft capsules, hard capsules, pills, granules, powders, injections or solutions.
  • the composition may be selected from sustained or immediate release.
  • the sustained release means that the release of the active ingredient occurs slowly, including the base used for the purpose of sustained release in addition to the active ingredient, the immediate release means that the active ingredient is released immediately.
  • the tablet may be a sustained release tablet or an immediate release tablet.
  • compositions of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient.
  • a component selected from an enteric polymer, a hydrophobic substance, a hydrophilic polymer, and the like may be used as the matrix base used for sustained release.
  • the enteric polymer include polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, (methacrylic acid and methyl methacrylate) copolymers, and poly (methacrylic acid, ethylacrylic). Rate) copolymers and the like can be used one or more selected, preferably hydroxypropyl methyl cellulose phthalate is used.
  • the hydrophobic materials are pharmaceutically acceptable polyvinyl acetate, poly (methacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate as polymethacrylate copolymers).
  • Acrylates copolymers, ethyl cellulose and cellulose acetate, fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances, and the like, specifically, glyceryl palmitostearate, Fatty acid alcohols such as glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid, such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol, as waxes, carnauba wax, beeswax Talc, sedimentation as an inorganic material, such as microcrystalline wax Selecting an acid, calcium hydrogen phosphate, calcium oxide, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and one or two or more selected from such bigeom and the like can be used.
  • glyceryl palmitostearate Fatty acid alcohols such as glyceryl stearate, glyceryl
  • the hydrophilic polymer may be selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers, and specifically, as the sugars, dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin and the like can be selected and used as cellulose derivatives.
  • Hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose and the like can be selected and used as a gum , Locker Soybean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, etc. can be selected and used, and gelatin, casein, zein, etc.
  • polyvinyl derivative as a polyvinyl derivative Alcohol
  • polyvinyl pyrrolidone polyvinyl acetal diethylamino acetate, and the like
  • polymethacrylate copolymer and poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate Rate) copolymer, etc.
  • polyethylene glycol, polyethylene oxide, etc. can be selected and used as a polyethylene derivative
  • a carbomer can be used as a carboxyvinyl polymer.
  • Starch microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and / or dicalcium phosphate may be used as a pharmaceutically acceptable diluent without impairing the effects of the present invention. have.
  • starch starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone and / or gelatin, etc. Can be used.
  • Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinks such as crospovidone A polymer and boiling agents, such as sodium bicarbonate and a citric acid, can be selected and used.
  • clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and
  • Lubricants include talc, magnesium stearate and alkaline earth metal stearate type calcium, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol 4000 and / or polyethylene glycol 6000 and the like can be used.
  • metformin taurine salt can be utilized as a preparation for oral administration in various forms.
  • the dosage is preferably 50 to 3,000 mg of metformin taurine salt (based on metformin free base), but may vary according to the patient's age, sex, weight, nationality, health condition, and degree of disease. Depending on the judgment, divided doses may be given once or twice a day.
  • the present invention is diabetic, diabetes, metabolic syndrome, diabetic complications, dysmenorrhea, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, menopausal syndrome or rhabdomyosis of metformin taurine salt Prophylactic, alleviating or treating use of one or more diseases or symptoms selected from fusion and antioxidant use.
  • the present invention is an effective amount of metformin taurine salt diabetes, diabetes mellitus, metabolic syndrome, diabetes complications, menstrual disorders, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, menopausal syndrome Or administering to a mammal, including a human, in need of prophylaxis, symptom relief or treatment of at least one disease selected from rhabdomyolysis.
  • the present invention also provides an antioxidant method comprising administering to a mammal, including a human, in need of an effective amount of metformin taurine salt.
  • an antioxidant method comprising administering to a mammal, including a human, in need of an effective amount of metformin taurine salt.
  • the term "administration" refers to introducing the metformin taurine salt and / or pharmaceutical composition of the present invention to a patient in any suitable manner, wherein the route of administration of the metformin taurine salt and / or pharmaceutical composition of the present invention is a target tissue.
  • Administration can be by any general route as long as it can be reached. Oral administration, intravenous administration, intramuscular administration, subcutaneous administration, endothelial administration, intranasal administration, pulmonary administration, rectal administration, intraperitoneal administration, intradural administration, but is not limited thereto.
  • the present invention is selected from diabetes, diabetes, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, myococytosis, menopause syndrome or rhabdomyolysis Metformin taurine salt is provided for the prevention, alleviation or treatment of one or more diseases or conditions.
  • the present invention also provides a metformin taurine salt for antioxidant.
  • the present invention also provides a pharmaceutical formulation comprising the metformin taurine salt of the present invention and a second drug.
  • the active ingredient in the composition or formulation of the present invention may be included in 10 to 95% by weight based on the total weight.
  • Metformin taurine salt and the composition of the present invention exhibits excellent AMPK ⁇ activation action, diabetes, diabetes, metabolic syndrome, diabetes complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia It is effective in the treatment or prevention of muscle cell toxicosis, menopausal syndrome and rhabdomyolysis, and has antioxidant activity.
  • the present invention provides a crystalline acid addition salt suitable for the preparation of pharmaceutical formulations, by using a taurine salt having a relatively low toxicity compared to conventional metformin hydrochloride prepared using hydrochloric acid, as well as low solubility, stability, It has the effect of increasing the pharmaceutical and physical advantages such as non-hygroscopicity and ease of processing of tablet formulations.
  • metformin taurine salt can be manufactured easily by the manufacturing method of this invention.
  • the co-formulation of the present invention is excellent in pharmacological effects and can promote the convenience of the patient's medication.
  • Figure 1 shows the IR spectrum for metformin taurine salt according to an embodiment of the present invention.
  • Figure 2 is a graph confirming the activation effect of AMPK ⁇ of metformin taurine salt according to an embodiment of the present invention.
  • the reagents and solvents mentioned below were purchased from Aldrich, USA and Daejin, Korea.
  • the 1 H-NMR and 13 C-NMR data are measured by Innova 600 MHz FT-NMR from Verian, USA, and the melting point (mp) is No. 1 of Electrothermal, UK.
  • the metformin taurine salt is a crystalline acid addition salt suitable for the preparation of pharmaceutical formulations, using a taurine salt having a relatively low toxicity compared to conventional metformin hydrochloride prepared using hydrochloric acid, as well as low toxicity, solubility, stability, and non-hygroscopicity. And pharmaceutical and physical advantages such as ease of processing of tablet formulations.
  • the final mixture was compressed into tablets containing 383.87 mg of metformin taurine salt in one tablet.Opadry O3B28796 (hydroxypropylmethylcellulose 62.50%, titanium oxide) using a high coater (SFC-30N, Sejong Machinery, Korea) 31.25% polyethylene glycol 400 6.25%; Colorcon; USA) as a coating base to form a 10 mg film coating layer per tablet to prepare a tablet containing metformin taurine salt.
  • a high coater SFC-30N, Sejong Machinery, Korea
  • the final mixture was compressed into tablets containing 767.75 mg of metformin taurine salt in one tablet, and a 20 mg film coating layer per tablet was used as a coating agent based on Opadry O3B28796 as a high coater (SFC-30N, Sejong Machinery, Korea).
  • a high coater SFC-30N, Sejong Machinery, Korea.
  • the final mixture was compressed into tablets to prepare a sustained-release tablet containing 383.87 mg of metformin taurine salt in one tablet.
  • a coating layer was formed to prepare metformin tablets containing metformin taurine salt.
  • the final mixture was compressed into tablets to prepare a sustained-release tablet containing 383.87 mg of metformin taurine salt in one tablet.
  • a coating layer was formed to prepare a metformin sustained-release tablet containing metformin taurine salt.
  • the final mixture was then filled into capsules to prepare capsules containing 191.93 mg of metformin taurine salt in one capsule.
  • the final mixture was compressed into tablets containing 383.78 mg of metformin taurine salt and 75 mg of capecitabine in one tablet, and was coated with Opadry O3B28796 as a coating agent (SFC-30F, Sejong Machinery, Korea).
  • the film coating layer was formed to prepare a film-coated tablet containing metformin taurine salt and capecitabine.
  • Metformin taurine salt synthesized in the manner described in Example 1 of the present invention was treated with cancer cells to determine the effect of inhibiting cancer cell proliferation.
  • the experimental method is as follows.
  • MTT (3- (4,5-dimethylthiazole-2-yl) -2,5-ditetrazoliumbromide) assay
  • GAC50 metformin taurine salt
  • MCF7 cell line (Korea Cell Line Bank) was incubated for 24 hours in a 96 well plate so that each cell number was approximately 5000 in Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum. Then, to see the cell viability, metformin taurine salt synthesized in Example 1 2mM and 10mM were respectively treated in the culture solution and incubated for 72 hours. In addition, in order to obtain GIC50, the culture solution was treated with metformin taurine salt 10 mM, 2 mM, 0.4 mM, 0.08 mM and 0.016 mM, respectively, and cultured for 72 hours.
  • DMEM Dulbecco's modified Eagle's medium
  • MTT was added to the culture medium to identify living cells, and further cultured for 3 hours.
  • the resulting formazan crystal was dissolved using dimethyl sulfoxide (DMSO), and then the absorbance of the solution was measured at 560 nm.
  • DMSO dimethyl sulfoxide
  • the number of cells surviving in the well plate treated with metformin taurine compared to the number of cells cultured in the well plate not treated with metformin taurine after incubation for 72 hours is expressed as% cell viability.
  • concentration of metformin taurine salt (GIC 50) in which growth was inhibited to 50% using the cell viability curve was calculated to confirm the effect of inhibiting cancer cell proliferation of metformin taurine salt, and the results are shown in Table 1 and Table 2, respectively.
  • metformin hydrochloride or taurine instead of metformin taurine salt was used to obtain the cell viability (%) and GIC 50 values, and the results are shown in Table 1 and Table 2, respectively.
  • metformin taurine salt could effectively inhibit the growth of cancer cells derived from breast cancer than metformin hydrochloride.
  • Metformin taurine salt synthesized in the manner described in Example 1 of the present invention was treated with cells to determine the effect of activating AMPK ⁇ .
  • the experimental method is as follows.
  • AMPK ⁇ (5′-AMP-activated protein kinase alpha) activation of metformin taurine salt was confirmed in MCF 7 cell line derived from human breast cancer cells using AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651).
  • MCF 7 cells were cultured in DMEM medium containing 10% calf serum and placed in a 6 well plate such that the number of cells was about 5 ⁇ 10 5 , followed by culturing the cells in an incubator supplied with 5% CO 2. .
  • the culture solution was treated with 10 mM metformin taurine salt, and then cultured for 24 hours.
  • threonine 172 residue (T172) of AMPK ⁇ in cells cultured in the presence of metformin taurine and cells cultured without metformin taurine salt was confirmed using an AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651). After lysing cells in the manner suggested by the AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651), the method was described in the instructions for use of the AMPK ⁇ immunoassay kit. The degree of phosphorylation of threonine 172 residue of AMPK ⁇ from the cell lysate was used and the results are shown in Table 3 and FIG. 2. The ratio of the degree of phosphorylation of cells cultured in the presence of metformin taurine salts to the degree of phosphorylation of cells cultured in medium without metformin taurine salt is shown in Table 3.
  • metformin taurine salt activates AMPK ⁇ more effectively than metformin hydrochloride.
  • metformin taurine is thus linked to diabetes, diabetes mellitus, metabolic syndrome, diabetic complications, menstrual irregularities, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity, menopausal syndrome and rhabdomyolysis It can be shown that it can show an excellent effect on diseases such as lysis and can prevent heart disease and slow aging through antioxidant activity.
  • the present invention provides metformin taurine salt, a preparation method thereof, a pharmaceutical composition comprising the same, and a combination formulation comprising the same.
  • Metformin taurine salt of the present invention has excellent stability and ease of processing of tablets, low toxicity, and exhibits excellent AMPK ⁇ activating action, diabetes, diabetes, metabolic syndrome, diabetic complications, menstrual irregularity, hypertension, hyperlipidemia, fatty liver, coronary artery It is effective in diseases, osteoporosis, polycystic ovary syndrome, cancer, myalgia, myocyte cytotoxicity, menopausal syndrome and rhabdomyolysis, and has industrial applicability because it shows antioxidant activity.

Abstract

La présente invention concerne du taurate de metformine, un procédé de préparation correspondant, une composition pharmaceutique le comprenant et une formulation combinée le comprenant. Le taurate de metformine selon l'inventin a une stabilité supérieure, il est facile à comprimer, il a une faible toxicité et il présente d'excellents effets d'activation de AMPKα, et ainsi, il peut être efficacement utilisé pour traiter une glycosurie, un diabète, un syndrome métabolique, des complications du diabète, des irrégularités menstruelles, une hypertension, une hyperlipidémie, une stéatose hépatique, une coronaropathie, une ostéoporose, un syndrome des ovaires polykystiques, un cancer, une myalgie, des symptômes liés à la cytotoxicité dans la cellule musculaire, un climatère et une rhabdomyolose, etc., et il permet d'obtenir une activité anti-oxydante.
PCT/KR2010/005711 2009-08-25 2010-08-25 Taurate de metformine, procédé de préparation correspondant, composition pharmaceutique le comprenant et formulation combinée le comprenant WO2011025269A2 (fr)

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US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9211264B2 (en) 2009-11-09 2015-12-15 Wyeth Llc Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272

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KR101532944B1 (ko) * 2014-06-12 2015-07-02 서울대학교산학협력단 골수유래 세포의 이식성과를 향상시키는 세포감작방법
US20170340584A1 (en) * 2014-12-16 2017-11-30 Jonghyun BYUN Modified taurine, and pharmaceutical composition for preventing or treating metabolic diseases containing same
WO2017217757A1 (fr) * 2016-06-15 2017-12-21 변종현 Taurine modifiée et son procédé de préparation

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EP1591114A1 (fr) * 2004-03-12 2005-11-02 Fournier Laboratories Ireland Limited Utilisation de la metformine et de l'Orlistat pour le traitement ou la prévention de l'obésité
AR065669A1 (es) * 2007-03-09 2009-06-24 Indigene Pharmaceuticals Inc Combinacion de metformina r-(+) lipoato y agentes antihipertensivos para el tratamiento de hiperglucemia diabetica y las complicaciones diabeticas

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US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10603314B2 (en) 2005-02-03 2020-03-31 The General Hospital Corporation Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9630946B2 (en) 2007-10-17 2017-04-25 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10035788B2 (en) 2007-10-17 2018-07-31 Wyeth Llc Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US10111868B2 (en) 2008-06-17 2018-10-30 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9211264B2 (en) 2009-11-09 2015-12-15 Wyeth Llc Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea

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WO2011025269A3 (fr) 2011-07-21
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