WO2011008053A2 - Propionate de n,n-diméthyl diamide imidocarbonimidique, son procédé de préparation ainsi que compositions et combinaisons pharmaceutiques le contenant - Google Patents

Propionate de n,n-diméthyl diamide imidocarbonimidique, son procédé de préparation ainsi que compositions et combinaisons pharmaceutiques le contenant Download PDF

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WO2011008053A2
WO2011008053A2 PCT/KR2010/004673 KR2010004673W WO2011008053A2 WO 2011008053 A2 WO2011008053 A2 WO 2011008053A2 KR 2010004673 W KR2010004673 W KR 2010004673W WO 2011008053 A2 WO2011008053 A2 WO 2011008053A2
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metformin
propionate
cancer
formula
pharmaceutical composition
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PCT/KR2010/004673
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Korean (ko)
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WO2011008053A3 (fr
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김성욱
전성수
민창희
강민석
김용은
구자성
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한올바이오파마주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/122—Propionic acid
    • 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
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • 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

Definitions

  • the present invention relates to propionate of N, N-dimethyl imidodicarbonimidic diamide, a method for preparing the same, a pharmaceutical composition comprising the same, and a combination formulation comprising the same.
  • N, N-dimethyl imidodicarbonimidic diamide commonly known as metformin, is the most insulin-dependent diabetic medication and has the highest hypoglycemic effect among all oral diabetes medications and the most effective prevention of complications and worsening. It is an excellent biguanide drug.
  • metformin is the only first-choice drug that has been shown in several papers.
  • AMPK AMP-activated protein kinase
  • metformin has been shown to be effective in treating cancer at normal doses to treat diabetes, such as altering the energy metabolic pathways of cancer cells and increasing anticancer activity in proportion to the dose of metformin when administered to cancer patients lacking the P53 gene.
  • Josie M M Evans found that patients with type 2 diabetes had a lower incidence of cancer than those who did not receive metformin treatment [Josie MM, Evans .; Louise A, Donnelly .; Alistair M, Emslie-Smith .; Dario R, Alessi .; Andrew D, Morris. BMJ. 2005, 330, 1304-1305], Samantha L. Bowker reported that type 2 diabetics taking metformin have lower cancer-related mortality than patients taking sulfonylureas or insulin (Samantha L, Bowker .; Sumit R, Majumdar .; Paul, Veugelers .; Jeffrey A, Johnson. Diabetes Care. 2006, 29, 254-258.
  • metformin is useful in the free base form, but is administered in the form of a pharmaceutically acceptable salt because of the disadvantage of poor stability.
  • Korean Patent No. 90,479 discloses a pharmaceutically acceptable salt comprising (1) good solubility; (2) good stability; (3) nonhygroscopic; It states that physicochemical criteria such as (4) anti-sticking properties and (5) processability into formulations must be met.
  • metformin hydrochloride has poor physicochemical properties such as solubility, stability, non-hygroscopicity, anti-adhesion properties, and processability as a formulation, which may lower the pharmacological effect when processed into a formulation and may also cause toxicity due to hydrochloride.
  • An object of the present invention is to provide a metformin propionate having excellent solubility, stability, non-hygroscopicity and anti-adhesion properties, having excellent processability and good efficacy as a formulation.
  • Another object of the present invention is metformin, which is very effective for the prevention or treatment of at least one disease of diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity and rhabdomyolysis It is to provide a pharmaceutical composition comprising a propionate.
  • Yet another object of the present invention is to provide a combination formulation comprising metformin propionate and a second drug.
  • the present invention provides metformin propionate represented by the following formula (1).
  • metformin propionate is interpreted to include all metformin propionate present in crystalline form or in anhydride or hydrate form.
  • Metformin propionate represented by the formula (1) of the present invention has a superior survival and growth inhibitory effect of cancer cells as compared to metformin hydrochloride, and also has an excellent effect of AMPK ⁇ activation. Therefore, it exhibits a better pharmacological effect than metformin hydrochloride for various diseases including diabetes or cancer.
  • pharmaceutical physicochemical advantages, such as stability, non-hygroscopicity and processability as formulations, have been increased, making them suitable for the preparation of pharmaceutical formulations over merformin hydrochloride.
  • the present invention also comprises the step of reacting the metformin hydrochloride represented by the formula (2) with a base in an organic solvent to produce a metformin free base represented by the formula (3) and the reaction of the metformin free base with propionic acid It provides a method for producing metformin propionate represented by.
  • the process for manufacturing the metformin free base was established to allow a simple and without special equipment.
  • US Pat. No. 4,080,472 uses an ion exchange resin column, or introduces harsh production conditions such as heating US reflux of a solvent and filtering a hot solution, as in US Pat. No. 4,028,402.
  • the synthesis of free bases can be used for the reaction with various acids used to prepare pharmaceutically acceptable salts.
  • the metformin propionate represented by Chemical Formula 1 may be prepared by the steps represented by the following Schemes 1 and 2.
  • the metformin free base represented by Chemical Formula 3 may be prepared by reacting metformin hydrochloride represented by Chemical Formula 2 with a base in an organic solvent to remove the hydrochloride.
  • the metformin free base represented by Formula 3 prepared by the reaction represented by Scheme 1 may be obtained in crystalline form.
  • the reaction equivalent of the base to the metformin hydrochloride can be appropriately adjusted depending on whether the base is monovalent, divalent or trivalent.
  • the base when the base is a monovalent base, the base may be used in the amount of 1 to 4 equivalents based on 1 equivalent of the metformin hydrochloride, preferably 1 to 2 equivalents.
  • an organic solvent may be used as the solvent, and preferably no water.
  • the solvent is methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (ACN), acetone, dimethylformamide (DMF), N-methylpi Rollidinone (NMP), dimethylacetamide (DMA) or mixtures thereof, preferably isopropanol.
  • the inorganic base used to form the free base may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. And preferably sodium hydroxide or potassium hydroxide.
  • the metformin propionate represented by Formula 1 may be prepared by reacting the metformin free base represented by Formula 3 with propionic acid in a solvent.
  • the propionic acid is added to the metformin free base represented by Formula 3 under a solvent to prepare a mixture, and the mixture is stirred to filter, wash, and dry the resulting solid to Formula 1
  • the metformin propionate represented can be prepared.
  • the stirring may be performed at a temperature of about ⁇ 10 ° C. to 90 ° C., preferably at room temperature.
  • Metformin propionate prepared by the reaction represented by Scheme 2 may be obtained in crystalline form.
  • the solvent is water, methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (ACN), acetone, Dimethylformamide (DMF), N-methylpyrrolidinone (NMP), dimethylacetamide (DMA) or mixtures thereof, preferably acetone.
  • metformin propionate of the present invention it is possible to easily prepare metformin propionate without an ion exchange resin column or a high temperature heating step.
  • the reaction proceeds using a relatively acidic propionic acid rather than a strong acid such as hydrochloric acid to produce metformin propionate under mild reaction conditions, thereby producing metformin propionate with economical and high efficiency.
  • the present invention also relates to diseases of diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, cancer, myalgia, muscle cell toxicity or rhabdomyolysis, including metformin propionate represented by the following formula (1):
  • Prophylactic or therapeutic pharmaceutical compositions are provided.
  • Metformin propionate represented by the formula (1) of the present invention has a superior survival and growth inhibitory effect of cancer cells as compared to metformin hydrochloride, and also has an excellent effect of AMPK ⁇ activation. Therefore, while using propionic acid, which is less toxic than hydrochloric acid, it has better blood sugar strengthening effect than metformin hydrochloride, especially on fasting as well as lowering postprandial blood sugar, and can effectively suppress cancer cells, thereby preventing metformin against various diseases including diabetes or cancer. It shows better pharmacological effect than hydrochloride. Therefore, the pharmaceutical composition comprising metformin propionate represented by Chemical Formula 1 may be used as an anticancer agent because it shows an excellent effect not only for treating diabetes but also for treating cancer.
  • the cancer may be one selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer, liver cancer, pancreatic cancer, prostate cancer and thyroid cancer, and particularly as an anticancer agent for breast cancer. It can be very useful.
  • metformin propionate represented by Chemical Formula 1 has excellent stability, excellent solubility in various solvents, non-hygroscopicity, low adhesion, and excellent physicochemical properties such as processability to formulation. Therefore, when formulated in the form of tablets or capsules, it is possible to produce a tablet or capsule with excellent dispersibility and uniform pharmacological effect, and does not cause a problem that the pharmacological effect is lowered during the formulation process. Therefore, it is possible to produce formulations such as tablets or capsules which have good pharmacological effects and have a uniform pharmacological effect.
  • compositions comprising the metformin propionate of the crystalline form of the present invention may further comprise a pharmaceutically acceptable carrier, diluent, binder, disintegrant, lubricant or other additive.
  • the pharmaceutically acceptable carrier may be used starch, microcrystalline cellulose, lactose, glucose, mannitol, light silicic anhydride, alkaline earth metal salt, polyethylene glycol and dicalcium phosphate.
  • starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, povidone, copovidone and gelatin, etc. Can be used.
  • talc As lubricants, talc, hard silicic anhydride, stearic acid, magnesium stearate, calcium stearate, zinc stearate, lauryl sulfate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostea Elate, polyethylene glycol 4000 and polyethyleneglycol 6000 may be used, and pharmaceutically acceptable additives may be selected and used as various additives selected from colorants and fragrances.
  • the pharmaceutical composition comprising the metformin propionate of the present invention may be preferably formulated according to each disease or component by a suitable method in the art.
  • the pharmaceutical composition may be formulated by additionally adding a pharmaceutically acceptable carrier, diluent, dispersant, surfactant, binder, lubricant and various additives.
  • the content of the added carrier, diluent, dispersant, surfactant, binder, lubricant and additive is not particularly limited, and the content range used in conventional formulation It can be adjusted appropriately within.
  • the pharmaceutical composition comprising metformin propionate may be sustained and rapid release tablets, soft capsules, hard capsules, pills, granules or powders, injections using carriers, diluents, dispersants, surfactants, binders, lubricants and additives. It may be formulated in the form of a liquid, or the like, and used for the prevention or treatment of a pathological condition of diabetes mellitus or its associated accompanying disease.
  • the pharmaceutical composition comprising the metformin propionate of the present invention may be formulated in a sustained release formulation, wherein an enteric polymer, a water insoluble polymer, a hydrophobic compound, or a hydrophilic polymer may be used as the matrix base.
  • the enteric polymer is insoluble or stable under acidic conditions of less than pH 5, refers to a polymer that is dissolved or decomposed under conditions of pH 5 or more, and the water-insoluble polymer is a pharmaceutically acceptable to control the release of the drug.
  • the enteric polymer is insoluble or stable under acidic conditions of less than pH 5
  • the water-insoluble polymer is a pharmaceutically acceptable to control the release of the drug.
  • hydrophobic compounds are substances that are not soluble in pharmaceutically acceptable water that controls the release of the drug
  • hydrophilic polymers are soluble in pharmaceutically acceptable water that controls the release of the drug.
  • a polymer material refers to a polymer material.
  • the pharmaceutical composition comprising metformin propionate of the present invention may be orally administered or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) in various forms according to the desired method, preferably It may be a preparation for oral administration.
  • the pharmaceutical composition may be for use in combination with a second drug.
  • the "second drug” means another pharmaceutically effective ingredient other than metformin propionate of the present invention.
  • Metformin propionate of the present invention can be used for the treatment of various diseases as described above.
  • the metformin propionate 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 second drug may be an anticancer agent.
  • the anticancer agent for use in combination with metformin propionate according to the present invention can be any known anticancer agent.
  • the anticancer agent may include known chemotherapeutic agents such as alkylating agents, metabolic antagonists, natural agents, hormones and antagonists, and biological agents such as immunotherapy agents and gene therapy agents.
  • the anticancer agent may be nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, zefitinib, vandetanib, nirotinib, semasanib, conservinib, axitinib, Cediranib, restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, biscumalboom, asparaginase, tretinoin, hydride Roxycarbamide, Dasatinib, Estramustine, Gemtuzuma
  • the present invention also provides a combination formulation comprising metformin propionate having a structure of Formula 1 and a second drug:
  • metformin propionate may be provided in the form of a combination formulation formulated with a second drug.
  • the second drug may be an antihyperglycemic agent.
  • the antihyperglycemic agent may be at least one drug selected from the group consisting of a biguanide drug, a sulfonylurea drug, a thiazolidione drug and an alpha-glucosidase inhibitor.
  • the second drug may be an anticancer agent, and the types of anticancer agents that can be used are as described above.
  • the dosage of the pharmaceutical composition or the combination formulation containing metformin propionate of the present invention is in the range according to the weight, age, sex, nationality, health condition, diet, time of administration, method of administration, excretion rate and severity of the patient, etc. There are a variety of, divided administration is possible depending on the judgment of the prescriber.
  • the pharmaceutical composition or co-formulation comprising the metformin propionate of the present invention may be administered orally once to three times daily so that the content of metformin as an active ingredient is 50 mg to 3,000 mg.
  • Metformin propionate according to the present invention exhibits superior pharmacological effects against various diseases including diabetes and cancer than metformin hydrochloride, which has been used as a conventional diabetes treatment.
  • metformin propionate has excellent physicochemical properties such as solubility, stability, non-hygroscopicity and anti-adhesion properties.
  • the method for producing metformin propionate according to the present invention can synthesize a new salt of metformin at a lower cost by increasing the industrial availability by simply improving the process to be synthesized in a general production facility without special equipment.
  • the pharmaceutical composition comprising metformin propionate according to the present invention has excellent pharmacological effects.
  • the metformin propionate has excellent physicochemical properties, and thus the pharmaceutical composition including the same may be easily formulated into tablets or capsules.
  • the combination preparation containing both metformin propionate and the second drug according to the present invention has excellent pharmacological effect and can promote the convenience of the patient's medication.
  • FIG. 1 is a view showing the degree of activation of AMPK ⁇ of metformin propion hydrochloride according to the present invention.
  • the final mixture was compressed to prepare a tablet layer containing 306.79 mg of metformin propionate in one tablet, and was coated with Opadry OY-C-7000A as a coating agent as a high coater (SFC-30F, Sejong Machinery, Korea). A 10 mg film coating layer was formed to make tablets containing metformin propionate.
  • sustained-release tablet layer containing 306.58 mg of metformin propionate in one tablet, and was coated with Opadry OY-C-7000A as a high coater (SFC-30F, Sejong Machinery, Korea).
  • a sustained-release tablet containing metformin propionate was prepared by forming a 20 mg film coating layer.
  • metformin propionate 45.21 g of microcrystalline cellulose, and 270 g of polyethylene oxide (molecular weight 5 million, Dow Chemical, USA) were sieved through a No. 20 sieve and mixed in a double cone mixer for 60 minutes.
  • 20 g of collidone VA64 and 4 g of hard silicic anhydride were sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes.
  • 4 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.
  • sustained-release tablet layer containing 306.58 mg of metformin propionate in one tablet, and was coated with Opadry OY-C-7000A as a high coater (SFC-30F, Sejong Machinery, Korea).
  • a sustained-release tablet containing metformin propionate was prepared by forming a 20 mg film coating layer.
  • metformin propionate and 54.11 g of microcrystalline cellulose were sieved through a No. 20 sieve, respectively, and mixed in a V-type mixer for 60 minutes.
  • 1.5 g of hard silicic anhydride was sieved through a No. 35 sieve, added to the mixture, and mixed for 60 minutes.
  • 1 g of stearic acid was sieved through a No. 35 sieve, added to the mixture, and mixed for 3 minutes.
  • the final mixture was compressed to prepare a tablet layer containing 306.79 mg of metformin propionate and 50 mg of bicalutamide in 1 tablet, and Opadry OY-C-7000A was used as a high coater (SFC-30F, Sejong Machinery, Korea). 20 mg of a film coating layer was formed on the basis of the coating to prepare a tablet containing metformin propionate and bicalutamide.
  • Metformin propionate synthesized in the manner described in Example 2 of the present invention was treated with cancer cells to determine the effect of inhibiting cancer cell proliferation.
  • a brief experimental method is as follows.
  • MCF7 cells derived from human breast cancer were used as a test system, and the survival rate (%) and cell growth were 50% using MTT (3- (4,5-dimethylthiazole-2-yl) -2,5-ditetrazoliumbromide) assay.
  • MTT 3- (4,5-dimethylthiazole-2-yl) -2,5-ditetrazoliumbromide) assay.
  • the concentration of metformin propionate inhibited by% was measured to determine the cancer cell proliferation inhibitory effect of metformin propionate.
  • MCF7 cells were incubated for about 24 hours in a 96 well plate so that each cell number was about 5000 in DMEM medium containing 10% calf serum. Thereafter, 2mM and 10mM of metformin propionate synthesized in Example 2 were treated in the culture solution and cultured for 72 hours. In addition, in order to obtain GIC50, the culture solution was treated with metformin propionate 10 mM, 2 mM, 0.4 mM, 0.08 mM and 0.016 mM, and incubated for 72 hours.
  • 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 propionate compared to the number of cells cultured in the well plate not treated with metformin propionate after 72 hours of cultivation is expressed as% cell viability.
  • concentration of metformin propionate (GIC 50) in which growth was inhibited to 50% using a cell viability curve was calculated, and the effect of inhibiting cancer cell proliferation of metformin propionate was shown in Table 1 and Table 2, respectively.
  • metformin hydrochloride or propionic acid in place of metformin propionate was used to obtain the cell viability (%) and GIC 50 values, and the results are shown in Table 1 and Table 2, respectively.
  • metformin propionate can effectively inhibit the growth of cancer cells derived from breast cancer than metformin hydrochloride.
  • MCF 7 cells derived from human breast cancer cells were used as a test system, and the AMPK ⁇ (5′-AMP-activated protein kinase alpha) activation effect of metformin propionate was confirmed using an AMPK ⁇ immunoassay kit (Invitrogen, catalog No. KHO0651).
  • MCF 7 cells were cultured in DMEM medium containing 10% calf serum, placed in a 6 well plate with a cell number of about 5 ⁇ 10 5 , and then cultured in an incubator fed with 5% CO 2. .
  • the culture solution was treated with 0.4 mM, 2 mM and 10 mM metformin propionate, respectively, and then cultured for 24 hours.
  • threonine 172 residue (T172) of AMPK ⁇ in cells cultured in the presence of metformin propionate and cells cultured without metformin propionate 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 the threonine 172 residue of AMPK ⁇ from the cell lysate was used and the results are shown in Table 3 and FIG. 1. The ratio of the degree of phosphorylation of cells cultured in the presence of metformin propionate to the degree of phosphorylation of cells cultured in medium without metformin propionate is shown in Table 3.
  • metformin propionate phosphorylated more threonine 172 residues of AMPK ⁇ than metformin hydrochloride at the same concentration.
  • metformin propionate activates AMPK ⁇ more efficiently than metformin hydrochloride, whereby pharmaceutical compositions comprising metformin propionate can be used for diabetes, obesity, hypertension, hyperlipidemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, It can be seen that it can have an excellent effect on diseases such as cancer, myalgia, myocyte cytotoxicity and rhabdomyolysis.
  • metformin propionate of the present invention not only has a better pharmacological effect than metformin hydrochloride, but also can be administered at a lower dose than metformin hydrochloride to achieve a therapeutic purpose.
  • it has excellent physicochemical properties such as solubility, stability, hygroscopicity, anti-adhesion properties, and the like as a formulation, and thus may be usefully used as a pharmaceutically acceptable salt of metformin.
  • the metformin propionate may be prepared in the form of a combination formulation to be co-administered with additional drugs.

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Abstract

La présente invention concerne du propionate de metformine, un procédé de préparation de ce dernier, ainsi que des compositions et des combinaisons pharmaceutiques le contenant. Le propionate de metformine selon la présente invention présente un excellent effet pharmacologique comparé à l'hydrochlorure de metformine et permet d'obtenir un effet thérapeutique par administration d'une quantité inférieure à celle de l'hydrochlorure de metformine. En outre, le propionate de metformine présente d'excellentes propriétés physico-chimiques, telles qu'une solubilité, une stabilité, une hygroscopicité et une propriété de prévention d'adsorption, utilisées pour le traitement de formulations et peut par conséquent être efficacement utilisée en tant que sel pharmaceutiquement acceptable de la metformine.
PCT/KR2010/004673 2009-07-17 2010-07-16 Propionate de n,n-diméthyl diamide imidocarbonimidique, son procédé de préparation ainsi que compositions et combinaisons pharmaceutiques le contenant WO2011008053A2 (fr)

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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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WO1999047128A1 (fr) * 1998-03-19 1999-09-23 Bristol-Myers Squibb Company Systeme d'apport a liberation lente biphasique destine a des medicaments a solubilite elevee et procede associe
KR100760430B1 (ko) * 2004-12-31 2007-10-04 한미약품 주식회사 당뇨병 치료제의 경구 투여용 서방성 복합 제제 및 이의제조 방법
KR20090013736A (ko) * 2007-08-02 2009-02-05 주식회사 한독약품 메트포르민 산 부가염을 포함하는 서방성 제제

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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
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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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