EP1272171A1 - Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes - Google Patents

Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes

Info

Publication number
EP1272171A1
EP1272171A1 EP00950127A EP00950127A EP1272171A1 EP 1272171 A1 EP1272171 A1 EP 1272171A1 EP 00950127 A EP00950127 A EP 00950127A EP 00950127 A EP00950127 A EP 00950127A EP 1272171 A1 EP1272171 A1 EP 1272171A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
acceptable salt
succinic acid
mammal
choline
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00950127A
Other languages
German (de)
English (en)
French (fr)
Inventor
Igor Anatolievich Pomytkin
Olga Evgenievna Kolesova
Tatiyana Jurievna Ukhanova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
VERTELETSKY, PAVEL VASILIEVICH
Original Assignee
Verteletsky Pavel Vasilievich
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 Verteletsky Pavel Vasilievich filed Critical Verteletsky Pavel Vasilievich
Publication of EP1272171A1 publication Critical patent/EP1272171A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic 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
    • A61P3/06—Antihyperlipidemics
    • 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 compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal.
  • this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof. Further, this invention relates to a novel derivative of choline.
  • this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar ratio 2: 1 , a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
  • Insulin is the major anabolic hormone in the body and has multiple effects on a variety of tissues. Insulin stimulates the glucose uptake in muscle and fat and inhibits the glucose release from the liver. In addition, insulin regulates both plasma and tissue lipid metabolism, protein synthesis, cell growth and electrolyte balance. 0 Insulin resistance is defined as an impaired biological response to either exogenous or endogenous insulin. The measured biological responses could reflect metabolic processes such as changes in carbohydrate, lipid or protein metabolism as well as mitogenic processes such as alterations in growth, differentiation, DNA synthesis, and regulation of gene transcription.
  • Insulin resistance has clearly emerged as an important cause of glucose intolerance leading to type 2 diabetes and a cluster of abnormalities, including hyperlipidemia and dyslipidemia, high blood pressure, hyperuricemia, and a decrease in plasma fibrinolytic activity. Reaven, G. M. Physiol-Rev. 75(3): 473-86 (1995); "Consensus development conference on insulin resistance", Diabetes Care. 21 (2) 1998.
  • Insulin resistance can be associated with a variety of disease states such as gestational diabetes mellitus, obesity, ageing, atherosclerosis, cardiovascular syndrome X, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition, lupus and other autoimmune diseases, endocrine diseases, polycystic ovary syndrome, or complications arising from athletic activity.
  • disease states such as gestational diabetes mellitus, obesity, ageing, atherosclerosis, cardiovascular syndrome X, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition, lupus and other autoimmune diseases, endocrine diseases, polycystic ovary syndrome, or complications arising from athletic activity.
  • insulin resistance manifesting itself in pathologically elevated fasting plasma insulin levels and can be assessed by measurement of insulin concentration in plasma.
  • diabetes mellitus describes 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.
  • 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).
  • Monocholine succinate the acid salt formed by choline base and succinic acid in the molar ratio 1 :1 , was described in US patent 5,124,061 as a component of plant cryoprotectant composition.
  • this salt has not been obtained as the product with reproducible properties and was defined only by reference to process in which choline base and succinic acid were entered in molar ratio 1 :1. Acidity of monocholine succinate and absence of reproducible properties restricts the use of the described monocholine succinate in medicine.
  • This invention relates to compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal. Further, this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof.
  • this invention relates to a novel derivative of choline. More specifically, this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar ratio 2:1 , a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
  • treating means the management and care of a mammal for the purpose of combating the disease, condition, or disorder and includes the administration of choline base or a pharmaceutically acceptable salt thereof 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 insulin resistance includes increasing insulin sensitivity in a mammal and other effects, which are resulted from increasing insulin sensitivity in a mammal Such effects include, but are not limited to improving in carbohydrate, lipid, or protein metabolism, alterations in growth, differentiation, DNA synthesis, and regulation of gene transcription
  • the present invention provides a method for achieving a synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises administering to said mammal an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof Preferred effect achieved according to this invention in treating insulin resistance is lowering pathologically elevated plasma insulin levels
  • Insulin resistance in the mammal can be associated with disorders such as diabetes mellitus and its chronic complications, gestational diabetes mellitus, impaired glucose tolerance, obesity, ageing, atherosclerosis, syndrome X, cardiovascular disease, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition, lupus and other autoimmune diseases, endocrine diseases, hyperu ⁇ cemia, hyperlipidemia, dyslipidemia, polycystic ovary syndrome, or complications arising from athletic activity
  • insulin resistance is associated with diabetes mellitus in the mammal
  • the present invention provides a method for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels
  • choline base or a pharmaceutically acceptable salt thereof of the invention is choline chloride
  • succinic acid or a pharmaceutically acceptable salt thereof of the invention is disodium succinate
  • choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof can be stepwise in time or simultaneous with the simultaneous method being preferred.
  • Choline base or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, topically, or rectally.
  • choline base or a pharmaceutically acceptable salt thereof is administered parenterally.
  • Succinic acid or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, topically, or rectally.
  • succinic acid or a pharmaceutically acceptable salt thereof is administered parenterally.
  • the choline base or a pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer, more preferably for a period of 3 to 7 days.
  • the succinic acid or pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer, more preferably for a period of 3 to 7 days.
  • the present invention provides a composition for achieving a synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • Preferred effect achieved according to this invention in treating insulin resistance is lowering pathologically elevated plasma insulin levels.
  • the present invention provides a composition for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
  • the pharmaceutically acceptable salt of the choline base is prepared by known methods from nontoxic organic and inorganic acids.
  • Such acids include, but are not limited to, hydrogen chloride, hydrogen bromide, citric acid, tarta c acid, and succinic acid.
  • choline base or a pharmaceutically acceptable salt thereof of the invention is choline chloride.
  • 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, triethanolamine, and choline base.
  • succinic acid or a pharmaceutically acceptable salt thereof of the invention is disodium succinate.
  • suitable carriers and diluents include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl- and propylhydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil.
  • the compositions of the invention can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • 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 effective amount of choline base or a pharmaceutically acceptable salt thereof for use in the methods and compositions of this invention is preferably from 3 to 300 mg per day per kg of body weight of the mammal.
  • the effective amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the methods and compositions of this invention is preferably from 1 to 250 mg per day per kg of body weight of the mammal.
  • the present invention provides bis(2-hydroxy-N,N,N- thmethylethanaminium) succinate, which has the chemical formula given below:
  • N,N,N-trimethylethanaminium) succinate which comprises reacting choline base with succinic acid in the presence of water, alcohol, or mixture thereof.
  • bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is prepared by reacting the choline base and succinic acid, wherein the mole ratio of choline base to succinic acid entered in reaction is about 2:1 , but no lower than 1.9:1 and no higher than 2.1 :1.
  • the reaction take place at ambient temperatures and the reaction is quantitative.
  • the desired product is obtained as a white crystalline powder with reproducible properties.
  • bis(2- hydroxy-N,N,N-trimethylethanaminium) succinate in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, and diabetes mellitus in a mammal in need thereof.
  • Preferred effect achieved according to this invention in treating insulin resistance is lowering pathologically elevated plasma insulin levels.
  • Preferred effects achieved according to this invention in treating hyperlipidemia are lowering pathologically elevated plasma triglycerides and cholesterol levels.
  • Preferred effects achieved according to this invention in treating dyslipidemia are lowering low-density lipoprotein cholesterol levels and increasing high- density lipoprotein cholesterol levels.
  • Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
  • This example shows the synergistic effects in treating insulin resistance and diabetes mellitus achieved by co-administration of effective amounts of choline chloride and disodium succinate to diabetic rats.
  • 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 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.
  • mice 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 at 6 th day from the first alloxan injection.
  • Effect of the combination is 7.8 mmol/l decreasing in fasting plasma glucose level from the control.
  • Effect of the combination is 4.1 ⁇ U/l decreasing in fasting plasma insulin level from the control.
  • Bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is effective in treating insulin resistance, hyperlipidemia, dyslipidemia, and diabetes mellitus in diabetic rats.
  • Diabetic rats were prepared as described in Example 1 of the invention.
  • the animals were divided into two groups: a diabetic control group
  • EXAMPLE 3 The process for producing bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP00950127A 2000-04-10 2000-04-10 Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes Withdrawn EP1272171A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2000/000122 WO2001076583A1 (en) 2000-04-10 2000-04-10 Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes

Publications (1)

Publication Number Publication Date
EP1272171A1 true EP1272171A1 (en) 2003-01-08

Family

ID=20129496

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00950127A Withdrawn EP1272171A1 (en) 2000-04-10 2000-04-10 Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes

Country Status (8)

Country Link
EP (1) EP1272171A1 (enrdf_load_stackoverflow)
JP (1) JP3944393B2 (enrdf_load_stackoverflow)
KR (1) KR20020089444A (enrdf_load_stackoverflow)
CN (1) CN1452482A (enrdf_load_stackoverflow)
AU (1) AU2000263274A1 (enrdf_load_stackoverflow)
BR (1) BR0017206A (enrdf_load_stackoverflow)
CA (1) CA2404864A1 (enrdf_load_stackoverflow)
WO (1) WO2001076583A1 (enrdf_load_stackoverflow)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004112773A1 (fr) * 2003-04-24 2004-12-29 Shin-Jen Shiao Compositions pharmaceutiques utilisees pour le traitement de maladie immune et amelioration
KR20100031760A (ko) * 2007-08-02 2010-03-24 부다 바이오파마 오와이 리미티드 숙신산의 콜린염을 포함하는 비강내 투여용 약학 조성물
KR101360569B1 (ko) 2008-11-26 2014-02-10 이고르 아나토리에비치 포밋트킨 우울증, 불안증, 정신분열증, 수면장애 및 간질의 치료를 위한 숙신산의 콜린염
US8314080B2 (en) 2010-04-06 2012-11-20 Kuwait University Method of treating type I diabetes
CN106727476A (zh) * 2016-12-09 2017-05-31 杨远志 一种组合物及其在改善动物肌纤维类型中的应用
WO2024231663A1 (en) 2023-05-05 2024-11-14 Mitocholine Ltd Method of synthesis
WO2025163212A2 (en) 2024-08-09 2025-08-07 Jantar Gmbh Succinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of chronic rhinosinusitis
WO2025120626A2 (en) 2025-04-14 2025-06-12 Mitocholine Ltd Synthetic method

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03169498A (ja) * 1989-11-28 1991-07-23 Yotsukaichi Gosei Kk 水溶性はんだフラックス
JPH0586319A (ja) * 1991-09-27 1993-04-06 Pentel Kk 水性インキ組成物
EP0652012A1 (en) * 1989-03-27 1995-05-10 Albert Naito Combination of sugars with animo acids and other drugs
US5895652A (en) * 1996-07-29 1999-04-20 Longevity Institute International Method of metabolic adjuvanation and cellular repair

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR6346669D0 (pt) * 1962-02-12 1973-06-14 Squibb & Sons Inc Processo de preparacao de uma composicao farmaceutica estavel de sais de esteres de colina
JPS61171417A (ja) * 1985-01-23 1986-08-02 Wakunaga Seiyaku Kk 抗糖尿病剤
WO2000051594A1 (en) * 1999-03-01 2000-09-08 Verteletsky, Pavel Vasilievich Use of succinic acid or salts thereof and method of treating insulin resistance
AU4937699A (en) * 1999-04-05 2000-10-23 Olga Evgenievna Kolesova Use of succinic acid or salts thereof for the treatment of diabetes mellitus andwound healing

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0652012A1 (en) * 1989-03-27 1995-05-10 Albert Naito Combination of sugars with animo acids and other drugs
JPH03169498A (ja) * 1989-11-28 1991-07-23 Yotsukaichi Gosei Kk 水溶性はんだフラックス
JPH0586319A (ja) * 1991-09-27 1993-04-06 Pentel Kk 水性インキ組成物
US5895652A (en) * 1996-07-29 1999-04-20 Longevity Institute International Method of metabolic adjuvanation and cellular repair

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0176583A1 *

Also Published As

Publication number Publication date
WO2001076583A1 (en) 2001-10-18
CN1452482A (zh) 2003-10-29
AU2000263274A1 (en) 2001-10-23
JP3944393B2 (ja) 2007-07-11
JP2004506605A (ja) 2004-03-04
BR0017206A (pt) 2003-01-14
KR20020089444A (ko) 2002-11-29
CA2404864A1 (en) 2001-10-18

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