WO2002012177A1 - Composition of metformin with succinic acid or salts thereof and method for treating diabetes - Google Patents
Composition of metformin with succinic acid or salts thereof and method for treating diabetes Download PDFInfo
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- WO2002012177A1 WO2002012177A1 PCT/RU2000/000322 RU0000322W WO0212177A1 WO 2002012177 A1 WO2002012177 A1 WO 2002012177A1 RU 0000322 W RU0000322 W RU 0000322W WO 0212177 A1 WO0212177 A1 WO 0212177A1
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- Prior art keywords
- metformin
- succinic acid
- pharmaceutically acceptable
- acceptable salt
- mammal
- Prior art date
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 title claims abstract description 84
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960003105 metformin Drugs 0.000 title claims abstract description 45
- 239000001384 succinic acid Substances 0.000 title claims abstract description 41
- 150000003839 salts Chemical class 0.000 title claims abstract description 32
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 241000124008 Mammalia Species 0.000 claims abstract description 15
- 230000002195 synergetic effect Effects 0.000 claims abstract description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 6
- UFKWZZBTOYMVIC-UHFFFAOYSA-N butanedioic acid;3-(diaminomethylidene)-1,1-dimethylguanidine Chemical compound OC(=O)CCC(O)=O.CN(C)C(=N)N=C(N)N UFKWZZBTOYMVIC-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- -1 metformin succinates Chemical class 0.000 abstract description 7
- 230000002641 glycemic effect Effects 0.000 abstract 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 14
- 239000008103 glucose Substances 0.000 description 14
- 241000700159 Rattus Species 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108010023302 HDL Cholesterol Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000010030 glucose lowering effect Effects 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 229960004329 metformin hydrochloride Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
Definitions
- This invention relates to combinations of metformin with succinic acid or a pharmaceutically acceptable salt thereof, and to a method for treating diabetes mellitus employing such combinations.
- Diabetes mellitus is a metabolic disorder of multiple aetiology characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Clinically, diabetes mellitus manifesting itself in pathologically elevated plasma glucose levels and can be assessed by measurement of glucose concentration in blood.
- Metformin has long been known as an antidiabetic compound, which is useful in lowering the sugar content in blood and treating insulin resistance, especially under type 2 diabetes, obesity and aging.
- metformin has a relatively short duration in respect of its activity and therefore it is required to administer metformin to the patient frequently. Hence it has become desirable to provide a hypoglycemic which is characterized by an improved duration of activity.
- Metformin is used as such in the form of salts such as the hydrochloride, the sulfate, the phosphate, the adamantanoate, the dichloroacetate, or the citrate. Until the invention described herein, there was no report of use of metformin in the form of salts such as the succinate.
- Succinic acid or salts thereof were described in JP patent 61171417 as antidiabetics useful for stimulating insulin secretion. Contrary to JP 61171417, MacDonald et al. found that succinic acid and salts thereof did not stimulate insulin secretion from pancreas, and only esters of succinic acid are potent insulin secretagogues. MacDonald, M.J. and Fahien, L.A. Diabetes 37(7): 997-999 (1988). Also, succinic acid was described in JP patent 6062798 as a component of food for person with poor glucose-tolerance in combination with acetic, lactic, and gluconic acid.
- Disodium succinate was described as a component of the composition for decreasing blood glucose in rabbits with alloxan diabetes in combination with citric and acetic acid. Dzvonkevich, N.D. et al, Ukr. Biokhim. Zh.. 46(5):547-552(1974).
- compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof. More specifically, this invention relates to compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects for the treatment of diabetes, particularly for synergistic improvement in giycemic control. Further, the invention relates to new salts of metformin, more specifically to metformin succinates and process for producing the same. Further, this invention relates to methods of treating diabetes in mammal in need thereof, which methods comprise administering to said mammal, either stepwise or in combination, synergistically effective amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION
- the present invention provides a pharmaceutical composition, which comprises from about 0.05 to 2000 mg of metformin and from about 0.05 to 2000 mg of succinic acid or a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition which comprises from about 0.05 to 2000 mg of metformin and from about 0.05 to 2000 mg of succinic acid or a pharmaceutically acceptable salt thereof.
- said amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof are synergistic for the treatment of diabetes mellitus in a mammal in need thereof.
- Metformin is widely employed to treat diabetes, for example as described in USP Dispensing Information. It typically is used clinically as a pharmaceutically acceptable salt, preferably the hydrochloride salt.
- a commercial form of metformin hydrochloride is available, and its chemical name is N,N-dimethylimidodicarbonimidic diamide hydrochloride.
- Metformin hydrochloride has the chemical formula
- metalformin means the base compound as well as its pharmaceutically acceptable salts.
- Succinic acid has the chemical formula
- the pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases.
- bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, and triethanolamine.
- compositions of the invention can be administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous solutions, elixirs, syrups and the like.
- composition of the invention is metformin succinates, a salts of metformin base with succinic acid.
- the present invention provides N,N-dimethylimidodicarbonimidic diamide succinate, a metformin succinate salt (1 :1), which has a chemical formula
- the present invention provides bis(N,N-dimethylimidodicarbonimidic diamide) succinate, a metformin succinate salt (2:1), which has a chemical formula
- the present invention provides a process for producing N,N- dimethylimidodicarbonimidic diamide succinate, which comprises reacting N,N- dimethylimidodicarbonimidic diamide with succinic acid, wherein the mole ratio of
- N,N-dimethylimidodicarbonimidic diamide to succinic acid entered in reaction is about
- the present invention provides a process for producing bis(N,N- dimethylimidodicarbonimidic diamide) succinate, which comprises reacting N,N- dimethylimidodicarbonimidic diamide with succinic acid, wherein the mole ratio of N,N-dimethylimidodicarbonimidic diamide to succinic acid entered in reaction is about 2:1.
- the reactions of the invention take place at ambient temperatures in a solvent such as water, alcohol, or mixture thereof and the desired product is obtained as a white crystalline powder with reproducible properties.
- the present invention provides a method of treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal from about
- Metformin and succinic acid or a pharmaceutically acceptable salt thereof can be administered enterally or parenterally in the methods of the invention.
- each agent will vary depending upon the severity of the disease, the frequency of administration, the particular agents and combinations utilized, and other factors routinely considered by an attending medical practitioner.
- treating means the management and care of a mammal for the purpose of combating the disease, condition, or disorder and includes the administration of metformin and succinic acid or a pharmaceutically acceptable salt thereof to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
- Treating diabetes mellitus includes, but is not limited to, improving giycemic control in mammal in need thereof.
- Plasma insulin concentrations were determined using a kit ("Dako", Dutch) with a rat insulin standard (Novo Research Institute, Bagsvard, Denmark). Plasma glucose concentrations were determined by glucose oxidase method using a kit ("Agat”, Russia). Plasma triglycerides and cholesterol concentrations were determined with reagents FS, "DiaSys", Germany; HDL cholesterol with reagents “Cormay”, Tru; and LDL cholesterol with reagents "Boehringer Mannheim", Germany. Animals. Male Wistar rats 8-10 weeks of age 210-230g of body weight were used. The rats were housed at the temperature of 18 ⁇ 21°C on a 12 hour light-dark cycle.
- Rats were fed on a stock laboratory diet (59 % carbohydrates; 17 % protein; 3 % fat; 21 % minerals, water, and cellulose) and allowed water ad libitum. Diabetes mellitus was induced in Wistar male rats by twice i.v. injection (tail vein) of alloxan (40 mg/kg body wt) with break of 48 hours. The rats were used in experiments 6 days after the first alloxan injection. Fasting plasma glucose, insulin, total cholesterol (Ch), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels of these animals are presented in Table 1 as Mean ⁇ SD in comparison with healthy control. Insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, and dyslipidemia characterize the rats prepared by this means.
- Effect of the combination is 8.4 mmol/1 decreasing in glucose level from the control.
- N,N-dimethylimidodicarbonimidic diamide succinate and the process for producing same.
- the reaction mixture was stirred at ambient temperature for 1 hour and concentrated under vacuum to dryness at a temperature of 40-50°C.
- the desired product was obtained at a yield approximating 60 % as a solid white crystalline material: NMR 1H (D 2 O): ⁇ 2.24 (s, 4H), 2.87 (s, 6H); Anal. Calculated for C 8 H 17 N 5 O 4 : C, 38.86; H, 6.88. Found: C, 38.79; H 6.81.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention relates to compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof. More specifically, this invention relates to compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects for the treatment of diabetes, particularly for synergistic improvement in glycemic control. Further, the invention relates to new salts of metformin, more specifically to metformin succinates and process for producing the same. Further, this invention relates to methods of treating diabetes in mammal in need thereof, which methods comprise administering to said mammal, either sepwise or in combination, synergistically effective amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof.
Description
COMPOSITION OF METFORMIN WITH SUCCINIC ACID OR SALTS THEREOF AND METHOD FOR TREATING DIABETES
FIELD OF THE INVENTION
This invention relates to combinations of metformin with succinic acid or a pharmaceutically acceptable salt thereof, and to a method for treating diabetes mellitus employing such combinations.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a metabolic disorder of multiple aetiology characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Clinically, diabetes mellitus manifesting itself in pathologically elevated plasma glucose levels and can be assessed by measurement of glucose concentration in blood. Metformin has long been known as an antidiabetic compound, which is useful in lowering the sugar content in blood and treating insulin resistance, especially under type 2 diabetes, obesity and aging. However, there is a particular disadvantage in its use, i.e., metformin has a relatively short duration in respect of its activity and therefore it is required to administer metformin to the patient frequently. Hence it has become desirable to provide a hypoglycemic which is characterized by an improved duration of activity.
Metformin is used as such in the form of salts such as the hydrochloride, the sulfate, the phosphate, the adamantanoate, the dichloroacetate, or the citrate. Until the invention described herein, there was no report of use of metformin in the form of salts such as the succinate.
Succinic acid or salts thereof were described in JP patent 61171417 as antidiabetics useful for stimulating insulin secretion. Contrary to JP 61171417, MacDonald et al. found that succinic acid and salts thereof did not stimulate insulin secretion from pancreas, and only esters of succinic acid are potent insulin
secretagogues. MacDonald, M.J. and Fahien, L.A. Diabetes 37(7): 997-999 (1988). Also, succinic acid was described in JP patent 6062798 as a component of food for person with poor glucose-tolerance in combination with acetic, lactic, and gluconic acid. Disodium succinate was described as a component of the composition for decreasing blood glucose in rabbits with alloxan diabetes in combination with citric and acetic acid. Dzvonkevich, N.D. et al, Ukr. Biokhim. Zh.. 46(5):547-552(1974).
Until the invention described herein, there was no report of use of metformin together with succinic acid or a pharmaceutically acceptable salt thereof.
It has now been discovered that combination therapy with metformin and succinic acid or a pharmaceutically salts thereof results in synergistic improvement in giycemic control. Accordingly, such combinations are especially useful in treating diabetes.
It is an object of the present invention to provide the pharmaceutical composition comprising an effective amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof, preferably for synergistic treatment of diabetes. It is an object of the present invention to provide a method of treating diabetes in a mammal, comprising administering to the mammal in need thereof an effective amount of metformin stepwise or in combination with an effective amount of succinic acid or a pharmaceutically acceptable salt thereof.
SUMMARY OF THE INVENTION
This invention relates to compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof. More specifically, this invention relates to compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects for the treatment of diabetes, particularly for synergistic improvement in giycemic control. Further, the invention relates to new salts of metformin, more specifically to metformin succinates and process for producing the same. Further, this invention relates to methods of treating diabetes in mammal in need thereof, which methods comprise administering to said mammal, either stepwise or in combination, synergistically effective amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The term "synergistic", as used herein, means that the effect achieved with the methods and compositions of this invention is greater than the sum of the effects that result from methods and compositions comprising metformin and succinic acid or a pharmaceutically acceptable salt thereof separately and in the amounts employed in the methods and compositions hereof.
Accordingly to this invention, it is now possible to achieve a synergistic effect in treating diabetes in a mammal with amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof which, if administered in said amounts singly, are not capable of achieving said effect and which effect is greater than the sum of the effects achieved for metformin and succinic acid or a pharmaceutically acceptable salt thereof separately .
The present invention provides a pharmaceutical composition, which comprises from about 0.05 to 2000 mg of metformin and from about 0.05 to 2000 mg of succinic acid or a pharmaceutically acceptable salt thereof. Preferably, said amounts of metformin and succinic acid or a pharmaceutically acceptable salt thereof are synergistic for the treatment of diabetes mellitus in a mammal in need thereof.
Metformin is widely employed to treat diabetes, for example as described in USP Dispensing Information. It typically is used clinically as a pharmaceutically acceptable salt, preferably the hydrochloride salt. A commercial form of metformin hydrochloride is available, and its chemical name is N,N-dimethylimidodicarbonimidic diamide hydrochloride. Metformin hydrochloride has the chemical formula
As used herein, "metformin" means the base compound as well as its pharmaceutically acceptable salts.
Succinic acid has the chemical formula
HOOCCH2CH2COOH
The pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases. Such bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, and triethanolamine.
Compositions of the invention can be administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous solutions, elixirs, syrups and the like.
The particular embodiment of the composition of the invention is metformin succinates, a salts of metformin base with succinic acid.
The present invention provides N,N-dimethylimidodicarbonimidic diamide succinate, a metformin succinate salt (1 :1), which has a chemical formula
• HOOCCH2CH2COOH
The present invention provides bis(N,N-dimethylimidodicarbonimidic diamide) succinate, a metformin succinate salt (2:1), which has a chemical formula
2 • HOOCCH2CH2COOH
Further, the present invention provides a process for producing N,N- dimethylimidodicarbonimidic diamide succinate, which comprises reacting N,N- dimethylimidodicarbonimidic diamide with succinic acid, wherein the mole ratio of
N,N-dimethylimidodicarbonimidic diamide to succinic acid entered in reaction is about
1:1.
Further, the present invention provides a process for producing bis(N,N- dimethylimidodicarbonimidic diamide) succinate, which comprises reacting N,N- dimethylimidodicarbonimidic diamide with succinic acid, wherein the mole ratio of
N,N-dimethylimidodicarbonimidic diamide to succinic acid entered in reaction is about 2:1.
The reactions of the invention take place at ambient temperatures in a solvent such as water, alcohol, or mixture thereof and the desired product is obtained as a white crystalline powder with reproducible properties.
Further, the present invention provides a method of treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal from about
0.05 to 2000 mg of metformin stepwise or in combination with from about 0.05 to 2000 mg of succinic acid or a pharmaceutically acceptable salt thereof, wherein said amounts are synergistic for the treatment of diabetes.
Metformin and succinic acid or a pharmaceutically acceptable salt thereof can be administered enterally or parenterally in the methods of the invention.
The dosage of each agent will vary depending upon the severity of the disease, the frequency of administration, the particular agents and combinations utilized, and other factors routinely considered by an attending medical practitioner.
The term "treating" as used herein means the management and care of a mammal for the purpose of combating the disease, condition, or disorder and includes the administration of metformin and succinic acid or a pharmaceutically acceptable salt thereof to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder. Treating diabetes mellitus includes, but is not limited to, improving giycemic control in mammal in need thereof.
The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
EXAMPLE 1
Combination of metformin with succinic acid is synergistically effective for treating diabetes mellitus.
Assay. Plasma insulin concentrations were determined using a kit ("Dako", Dutch) with a rat insulin standard (Novo Research Institute, Bagsvard, Denmark). Plasma glucose concentrations were determined by glucose oxidase method using a kit ("Agat", Russia). Plasma triglycerides and cholesterol concentrations were determined with
reagents FS, "DiaSys", Germany; HDL cholesterol with reagents "Cormay", Poland; and LDL cholesterol with reagents "Boehringer Mannheim", Germany. Animals. Male Wistar rats 8-10 weeks of age 210-230g of body weight were used. The rats were housed at the temperature of 18 ± 21°C on a 12 hour light-dark cycle. Rats were fed on a stock laboratory diet (59 % carbohydrates; 17 % protein; 3 % fat; 21 % minerals, water, and cellulose) and allowed water ad libitum. Diabetes mellitus was induced in Wistar male rats by twice i.v. injection (tail vein) of alloxan (40 mg/kg body wt) with break of 48 hours. The rats were used in experiments 6 days after the first alloxan injection. Fasting plasma glucose, insulin, total cholesterol (Ch), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels of these animals are presented in Table 1 as Mean±SD in comparison with healthy control. Insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, and dyslipidemia characterize the rats prepared by this means.
Table 1. Fasting plasma parameters in rats at 6 th day since the first alloxan injection.
*)Differs significantly from healthy control (P< 0.01)
Treatment. The diabetic animals with average plasma glucose level 12.5+2.4 mmol/1 after overnight fasting were divided into four groups. Rats were treated at 9.00 am by a single i.p. injection of saline (control, n=5), metformin in the form of hydrochloride (0.05 mg, n=5), succinic acid (0.07 mg, n=5), or the combination of metformin (0.05 mg) with succinic acid (0.07 mg, n=6).
Plasma glucose levels were monitored during 10 hours after the injection. Data are presented in Table 2 as Mean±SD.
Table 2. Plasma glucose in diabetic rats treated by metformin in combination with succinic acid.
*) Differs significantly from the combination (P< 0.01)
In diabetic control, the mean of glucose level was found to be 14.0 mmol/1 to 10th hour after the injection. Glucose-lowering effect (Δ glucose), as used herein, is difference between means of plasma glucose in control and treated rats to 10th hour after the injection calculated by equation: Δ glucose = 14.0 - Mean (mmol/1).
Effect of the combination is 8.4 mmol/1 decreasing in glucose level from the control. The sum of effects of metformin and succinic acid administered individually is 4.7 mmol/1 (4.6 +0.1 =4.7) decreasing in glucose level of control. Since glucose- lowering effect of the combination is greater than the sum of glucose-lowering effects of metformin and succinic acid administered individually, the combination is synergistically effective in lowering pathologically elevated plasma glucose levels. Moreover, the combination is characterized by an improved duration of activity in comparison with metformin alone.
'EXAMPLE 2
N,N-dimethylimidodicarbonimidic diamide succinate and the process for producing same.
To a solution of N,N-dimethylimidodicarbonimidic diamide 1.29 g (0.01 mole) in ethanol was added 1.18 g (0.01 mole) of succinic acid. The reaction mixture was stirred at ambient temperature for 1 hour and concentrated under vacuum to dryness at a temperature of 40-50°C. The desired product was obtained at a yield approximating 60 % as a solid white crystalline material: NMR 1H (D2O):δ 2.24 (s, 4H), 2.87 (s, 6H); Anal. Calculated for C8H17N5O4: C, 38.86; H, 6.88. Found: C, 38.79; H 6.81.
EXAMPLE 3
Bis(N,N-dimethylimidodicarbonimidic diamide) succinate and the process for producing same.
To a solution of N,N-dimethylimidodicarbonimidic diamide hydrochloride 1.66 g (0.01 mole) and sodium hydroxide 0.4 g (0.01 mole) in water were added 1.18 g (0.01 mole) of succinic acid. The reaction mixture was stirred at ambient temperature for 1 hour and concentrated under vacuum to dryness at a temperature of 40-50°C. The desired product was obtained at a yield approximating 80 % as a solid white crystalline material after extraction by ethanol and crystallization: NMR 1H (D2O):δ 2.20 (s, 4H), 2.85 (s, 12H); Anal. Calculated for C12H28N10O4: C, 38.29; H, 7.44. Found: C, 38.17; H 7.40.
Claims
1. A pharmaceutical composition, which comprises from about 0.05 to 2000 mg of metformin and from about 0.05 to 2000 mg of succinic acid or a pharmaceutically acceptable salt thereof.
2. The composition as claimed in Claim 1, wherein said amounts are synergistic for the treatment of diabetes mellitus in a mammal in need thereof.
3. N,N-dimethylimidodicarbonimidic diamide succinate.
4. Bis(N,N-dimethylimidodicarbonimidic diamide) succinate.
5. A process for producing N,N-dimethylimidodicarbonimidic diamide succinate, which comprises reacting N,N-dimethylimidodicarbonimidic diamide with succinic acid in molar ratio about 1:1.
6. A process for producing bis(N,N-dimethylimidodicarbonimidic diamide) succinate, which comprises reacting N,N-dimethylimidodicarbonimidic diamide with succinic acid in molar ratio about 2:1.
7. A method of treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal from about 0.05 to 2000 mg of metformin stepwise or in combination with from about 0.05 to 2000 mg of succinic acid or a pharmaceutically acceptable salt thereof, wherein said amounts are synergistic for the treatment of diabetes.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001213150A AU2001213150A1 (en) | 2000-08-03 | 2000-08-03 | Composition of metformin with succinic acid or salts thereof and method for treating diabetes |
| PCT/RU2000/000322 WO2002012177A1 (en) | 2000-08-03 | 2000-08-03 | Composition of metformin with succinic acid or salts thereof and method for treating diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2000/000322 WO2002012177A1 (en) | 2000-08-03 | 2000-08-03 | Composition of metformin with succinic acid or salts thereof and method for treating diabetes |
Publications (1)
| Publication Number | Publication Date |
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| WO2002012177A1 true WO2002012177A1 (en) | 2002-02-14 |
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| PCT/RU2000/000322 WO2002012177A1 (en) | 2000-08-03 | 2000-08-03 | Composition of metformin with succinic acid or salts thereof and method for treating diabetes |
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| WO (1) | WO2002012177A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002053090A3 (en) * | 2000-12-29 | 2003-02-20 | Dospharma | Medicinal association of a biguanine (metformin) and arginine |
| WO2009038396A3 (en) * | 2007-09-21 | 2009-05-14 | Hanall Pharmaceutical Co Ltd | N,n-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same |
| CN104684889A (en) * | 2012-07-10 | 2015-06-03 | 西蒂斯制药有限责任公司 | Tri-salt form of metformin |
| US9382187B2 (en) | 2012-07-10 | 2016-07-05 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
| US9505709B2 (en) | 2014-05-05 | 2016-11-29 | Thetis Pharmaceuticals Llc | Compositions and methods relating to ionic salts of peptides |
| US10166246B2 (en) | 2014-05-27 | 2019-01-01 | City Of Hope | TGR5 agonist complexes for treating diabetes and cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0283369A2 (en) * | 1987-03-06 | 1988-09-21 | Lipha, Lyonnaise Industrielle Pharmaceutique | Use of Metformin in the preparation of medicaments |
| WO1999029314A1 (en) * | 1997-12-08 | 1999-06-17 | Bristol-Myers Squibb Company | Novel salts of metformin and method |
| WO1999047128A1 (en) * | 1998-03-19 | 1999-09-23 | Bristol-Myers Squibb Company | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
-
2000
- 2000-08-03 AU AU2001213150A patent/AU2001213150A1/en not_active Abandoned
- 2000-08-03 WO PCT/RU2000/000322 patent/WO2002012177A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0283369A2 (en) * | 1987-03-06 | 1988-09-21 | Lipha, Lyonnaise Industrielle Pharmaceutique | Use of Metformin in the preparation of medicaments |
| WO1999029314A1 (en) * | 1997-12-08 | 1999-06-17 | Bristol-Myers Squibb Company | Novel salts of metformin and method |
| WO1999047128A1 (en) * | 1998-03-19 | 1999-09-23 | Bristol-Myers Squibb Company | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002053090A3 (en) * | 2000-12-29 | 2003-02-20 | Dospharma | Medicinal association of a biguanine (metformin) and arginine |
| US7265156B2 (en) | 2000-12-29 | 2007-09-04 | Dospharma | Medicinal association of a biguanine and a carrier, for example metformin and arginine |
| WO2009038396A3 (en) * | 2007-09-21 | 2009-05-14 | Hanall Pharmaceutical Co Ltd | N,n-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same |
| CN101855204A (en) * | 2007-09-21 | 2010-10-06 | 韩兀生物制药株式会社 | N,N-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same |
| JP2010539229A (en) * | 2007-09-21 | 2010-12-16 | ハンオル バイオファーマ カンパニー，リミテッド | Dicarboxylate of N, N-dimethylimidodicarbonimidic acid diamide, process for producing the same, and pharmaceutical composition thereof |
| US8076377B2 (en) | 2007-09-21 | 2011-12-13 | Hanall Pharmaceutical Company, Ltd. | N,N-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same |
| CN104684889A (en) * | 2012-07-10 | 2015-06-03 | 西蒂斯制药有限责任公司 | Tri-salt form of metformin |
| US9382187B2 (en) | 2012-07-10 | 2016-07-05 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
| US9505709B2 (en) | 2014-05-05 | 2016-11-29 | Thetis Pharmaceuticals Llc | Compositions and methods relating to ionic salts of peptides |
| US10166246B2 (en) | 2014-05-27 | 2019-01-01 | City Of Hope | TGR5 agonist complexes for treating diabetes and cancer |
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| Publication number | Publication date |
|---|---|
| AU2001213150A1 (en) | 2002-02-18 |
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