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 PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
metformin
succinic acid
pharmaceutically acceptable
acceptable salt
mammal
Prior art date
Application number
PCT/RU2000/000322
Other languages
French (fr)
Inventor
Igor Anatolievich Pomytkin
Olga Evgenievna Kolesova
Tatyana Jurievna Ukhanova
Pavel Vasilievich Verteletsky
Valentin Georgievich Nenajdenko
Original Assignee
Igor Anatolievich Pomytkin
Olga Evgenievna Kolesova
Tatyana Jurievna Ukhanova
Pavel Vasilievich Verteletsky
Nenajdenko Valentin Georgievic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Igor Anatolievich Pomytkin, Olga Evgenievna Kolesova, Tatyana Jurievna Ukhanova, Pavel Vasilievich Verteletsky, Nenajdenko Valentin Georgievic filed Critical Igor Anatolievich Pomytkin
Priority to PCT/RU2000/000322 priority Critical patent/WO2002012177A1/en
Priority to AU2001213150A priority patent/AU2001213150A1/en
Publication of WO2002012177A1 publication Critical patent/WO2002012177A1/en

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic 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)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (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
Figure imgf000004_0001
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
Figure imgf000005_0001
The present invention provides bis(N,N-dimethylimidodicarbonimidic diamide) succinate, a metformin succinate salt (2:1), which has a chemical formula
2 • HOOCCH2CH2COOH
Figure imgf000005_0002
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.
Figure imgf000007_0001
*)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.
Figure imgf000008_0001
*) 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

WE CLAIM:
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.
PCT/RU2000/000322 2000-08-03 2000-08-03 Composition of metformin with succinic acid or salts thereof and method for treating diabetes WO2002012177A1 (en)

Priority Applications (2)

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
AU2001213150A AU2001213150A1 (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
WO2002012177A1 true WO2002012177A1 (en) 2002-02-14

Family

ID=20129537

Family Applications (1)

Application Number Title Priority Date Filing Date
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

Country Status (2)

Country Link
AU (1) AU2001213150A1 (en)
WO (1) WO2002012177A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053090A2 (en) * 2000-12-29 2002-07-11 Dospharma Medicinal association of a biguanine (metformin) and arginine
WO2009038396A2 (en) * 2007-09-21 2009-03-26 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

Citations (3)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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 (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053090A2 (en) * 2000-12-29 2002-07-11 Dospharma Medicinal association of a biguanine (metformin) and arginine
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
WO2009038396A2 (en) * 2007-09-21 2009-03-26 Hanall Pharmaceutical Company. Ltd N,n-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same
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

Also Published As

Publication number Publication date
AU2001213150A1 (en) 2002-02-18

Similar Documents

Publication Publication Date Title
US6548481B1 (en) Effectors of dipeptidyl peptidase IV
EP1377278B1 (en) Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase iv
JP2006507303A5 (en)
US6482858B1 (en) (−)-hydroxycitric acid for wound healing and immunomodulation
JP2002154967A (en) Therapeutic agent for diabetes mellitus
WO2002012177A1 (en) Composition of metformin with succinic acid or salts thereof and method for treating diabetes
EP2992888B1 (en) Use of pentacyclic triterpenoid saponin compound from szechuan melandium root for preparing hypoglycemic drug
EP3158995B1 (en) Meglumine for reducing high triglyceride levels
JP3944393B2 (en) Synergistic composition comprising choline base and succinic acid for insulin resistance and diabetes
JP2006508995A (en) Use of a PPARα agonist and metformin to lower serum triglyceride levels
US6521665B1 (en) Method of treating insulin resistance
KR101311534B1 (en) A composition for treating or preventing diabetes comprising 4-hydroxy tamoxifen analog or pharmaceutically acceptable salts thereof as an effective ingredient
US6358999B2 (en) Use of zinc tranexamate in the treatment of diabetes
RU2228174C2 (en) Bis-(2=hydroxy-n,n,n-trimethylethaneaminium) succinate for treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia
EP4316486A1 (en) Novel use of 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative
CS208752B2 (en) Method of making the r-n-(2-fenyl-2-hydroxyethyl)-3-fenyl propylamines
WO2008118946A1 (en) Methods and compositions using certain phenolic derivatives for the treatment of diabetes
JPH072867A (en) Production of biotin amide derivatives, and remedies against diabetes and diabetic complication containing them
WO2013057422A1 (en) Anti-diabetic aminosteroid derivatives
CZ20004427A3 (en) Novel effectors of IV dipeptidyl peptidase
AU2003262286A2 (en) Novel Effectors of Dipeptidyl Peptidase IV
AU2006202684A1 (en) Novel effectors of dipeptidyl peptidase IV

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 69(1) EPC

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase