US20120178813A1 - Lipid-lowering antidiabetic agent - Google Patents
Lipid-lowering antidiabetic agent Download PDFInfo
- Publication number
- US20120178813A1 US20120178813A1 US13/348,265 US201213348265A US2012178813A1 US 20120178813 A1 US20120178813 A1 US 20120178813A1 US 201213348265 A US201213348265 A US 201213348265A US 2012178813 A1 US2012178813 A1 US 2012178813A1
- Authority
- US
- United States
- Prior art keywords
- mammal
- administering
- effective amount
- therapeutically effective
- composition according
- 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.)
- Abandoned
Links
- XZWYZXLIPXDOLR-UHFFFAOYSA-N *.[H]/N=C(/N=C(N([H])[H])N([H])[H])N(C)C Chemical compound *.[H]/N=C(/N=C(N([H])[H])N([H])[H])N(C)C XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 2
- HOVSYXSAFRWKPO-UHFFFAOYSA-N Cl.[H]/N=C(/NC(N([H])[H])N([H])[H])N(C)C Chemical compound Cl.[H]/N=C(/NC(N([H])[H])N([H])[H])N(C)C HOVSYXSAFRWKPO-UHFFFAOYSA-N 0.000 description 1
- KPOOEHKKVJXAEF-VPYKRRBTSA-N [H]OC(=O)CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC.[H]OC(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC Chemical compound [H]OC(=O)CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC.[H]OC(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC KPOOEHKKVJXAEF-VPYKRRBTSA-N 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
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/52—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing groups, e.g. carboxylic acid amidines
-
- 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
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
- C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/03—Monocarboxylic acids
Definitions
- the present invention relates to salts of poly unsaturated fatty acids with biguanides.
- Diabetes mellitus has become pandemic and according to a forecast by the World Health Organization, there will be a sharp increase in the number of diabetic patients by the year 2030. This is an ominous forecast, because managing the long-term complications of diabetes, which include nephropathy, neuropathy, retinopathy, and cardiovascular complications, will have a serious impact on public health budgets.
- the hallmark of diabetes is chronically elevated blood glucose levels. It is also known that abnormally elevated glucose levels have an adverse impact on glutathione levels in key diabetic tissues. Furthermore, increased oxidative stress and increased production of reactive oxygen species are implicated under hyperglycemic conditions.
- non-insulin dependent diabetes mellitus type 2 diabetes, NIDDM
- NIDDM non-insulin dependent diabetes mellitus
- the clinically available hypoglycemic agents can either have side effects limiting their use, or an agent may not be effective with a particular patient.
- insulin dependent diabetes mellitus Type I
- insulin administration usually constitutes the primary course of therapy.
- the biguanide metformin is a known compound approved by the U.S. Food & Drug Administration for the therapeutic treatment of diabetes.
- the compound and its preparation and use are disclosed, for example, in U.S. Pat. No. 3,174,901.
- Metformin is orally effective in the treatment of type 2 diabetes.
- Metformin N,N-dimethylimidodicarbonimidic diamide
- Metformin is a biguanide, anti-hyperglycemic agent currently marketed in the United States in the form of its hydrochloride salt 1,1-dimethylbiguanide hydrochloride (Formula 1a).
- Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc., 1922, 121, 1790.
- U.S. Pat. No. 7,973,073 B2 (Mylari) describes use of metformin R-(+) lipoate as being useful for treating diabetes or diabetic complications.
- U.S. Patent Publication 2005/0165102 describes complexes of drugs (metformin being mentioned) with transport moieties (fatty acids being mentioned) to enhance absorption and control delivery of the drugs being used.
- fatty acid complexing agents mentioned are caprate, laurate, palmitate and oleate.
- U.S. Patent Publication 2005/0182029 describes metformin salts of lipophilic acid salts (fatty acids being mentioned), their pharmaceutical formulations, and methods of administering the metformin salts for the treatment of hyperglycemia.
- UPDS United Kingdom Perspective Diabetes Study
- metformin therapy was cost-saving and increased quality-adjusted life expectancy.
- overweight and obese patients randomized to initial therapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths.
- Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with Type 2 diabetes.
- Prediabetes is a syndrome. Many patients with type 2 diabetes and with a prediabetic condition known as metabolic syndrome suffer from a variety of lipid disorders including elevated triglycerides.
- the body uses triglycerides to store fat but high (>200 mg/dl) and very high (>500 mg/dl) triglycerides are associated with atherosclerosis which increases the patients risk of heart attack and stroke.
- Incipient diabetes with impaired glucose tolerance is another prediabetic condition.
- type 2 diabetes and incipient diabetes with impaired glucose tolerance are intimately intertwined with obesity, hyperlipidemia, including hypertriglyceridemia, and cardiovascular complications including arrhythmia, cardiomyopathy, myocardial infarction, stroke and heart failure.
- pre-diabetes means that blood sugar level is higher than normal, but it's not yet increased enough to be classified as type 2 diabetes.
- prediabetes is likely to become type 2 diabetes over time
- diabetic patients have impaired circulation which manifests itself in the slow healing of wounds in the foot and lower leg and puts the patient at risk for amputation.
- Elevated triglycerides may be lowered by diet and exercise.
- Niacin and omega-3 fatty acids commonly known as fish oil, are frequently used in the management of hypertriglyceridemia.
- Omega-3 fatty acids are unsaturated carboxylic acids which have a terminal double bond three carbons from the methyl terminus, the 3 position.
- Omega-3 fatty acids are commonly extracted from oily fish like salmon, mackerel and menhaden. They are also extracted from other marine sources like squid and krill. Omega-3 fatty acids are commercially available.
- the omega-3 fatty acids most commonly extracted from fish are eicosapentaenoic acid and docosahexaenoic acid. These compounds have been shown to have beneficial effects in treating obesity, arrhythmia, and myocardial infarction and have the structures:
- Resolvins are a special class of polyhydroxylated omega-3 fatty acids which possess potent antinflammatory and immunoregulatory actions. These biological actions of resolvins are thought to play a significant role in cardiovascular and diabetic conditions.
- HR is an omega-3 polyunsaturated C 16-24 fatty acid optionally substituted with from 1-3 hydroxy groups.
- compositions are typically compounds in the form of salts of metformin and an omega-3 polyunsaturated fatty acid (RH) in which the biguanide moiety is protonated and the acid moiety is at least partially in ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of the biguanide and acid components.
- the invention also provides pharmaceutical compositions comprising compositions of formula I and pharmaceutically acceptable excipients.
- the invention further provides methods for treating diabetes (especially type 2 diabetes), obesity, cardiac arrhythmia, myocardial infarction and elevated triglycerides.
- the compounds and compositions of this invention may provide high blood levels of the compositions of structure 1, when administered to patients, preferably by oral administration.
- Particularly useful compounds are those wherein HR is a fatty acid of 20 or 22 carbon atoms with four or five unsaturated bonds in addition to the required omega-3 unsaturated bond such as 4,7,10,13,16,19 docoshexaenoic acid, 5,8,11,14 eicosopentanoic acid and resolvins derived from these acids such as the 5,12,18 trihydroxy eicosopentanoic acid known as resolvin E1, the 15,18 dihydroxy eicosopentanoic acid, known as resolvin E2, the 7,8,17 trihydroxy docosahexaenoic acid known as resolvin DE and its 7,16,17 trihydroxy eipmer known as resolvin D2, the 4,11,17 trihydroxy docosahexaenoic acid known as resolvin D3 and the 4,5,17 trihydroxy docosahexaenoic acid known as resolvin D4.
- HR is a fatty acid of 20 or 22 carbon
- the invention relates to a compound of formula I which is a salt of metformin and an omega-3 polyunsaturated fatty acid and is meant to include any polymorphs, solvates, and hydrates thereof.
- RH is a resolving. In the most preferred embodiment, RH is eicosapentaenoic acid or docosahexaenoic acid.
- Compounds of the present invention can be considered as designer dual-acting drugs and additionally possess a means for improving the bioavailability of their component moieties as a result of their high degree of water solubility.
- the invention relates to a mixture of metformin or a pharmaceutically acceptable salt thereof, (e.g., hydrochloride, succinate, fumarate) with an omega-3 polyunsaturated fatty acid (RH), or a pharmaceutically acceptable salt thereof.
- RH is a resolvin.
- RH is eicosapentaenoic acid or docosahexaenoic acid.
- the present invention provides a pharmaceutical composition of the invention comprising compound of formula I and a pharmaceutically-acceptable carrier, vehicle or diluent.
- the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion.
- Such compositions and methods for their preparation may be found, for example, in ‘Remington's Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).
- the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
- the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and an active compound.
- Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
- Tablet dosage forms typically also include a disintegrant (such as sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate) a binder (such as microcrystalline cellulose, gelatin, a sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose) and a lubricant (such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate).
- a disintegrant such as sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline
- compositions of the invention may also be present.
- Compositions of the invention may also be administered for example as capsules made, for example, from gelatin or hydroxypropylmethylcellulose.
- Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
- the compositions of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
- the invention further provides methods for treatment or lowering the risk of developing conditions such as diabetes, especially type 2 diabetes, prediabetes, obesity, arrhythmia, myocardial infarction and stroke by administering therapeutically effective amounts of compositions of formula I.
- Such compositions may also be used to lower triglyceride levels in a subject and so have a role in treatment of diabetes exacerbated with high triglyceride levels.
- Suitable dosages may be determined by conventional means.
- the triglyceride lowering efficacy of the compounds of the present invention can be determined in animal models according to the procedure described by Sidika et al in Journal of Lipid Research, 1992, 33, 1-7.
- the following example describes a diabetic rat model that may be used for determination of conditions leading to a method for treatment and prevention of post-ischemic damage of the heart and heart tissue.
- BB/W rats Spontaneously diabetic Bio-Bred (BB/W) rats from the colony maintained at the University of Massachusetts Medical Center, Worcester, were used in this study.
- BB/W rats were chosen for the current study because the BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes DM).
- BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes DM.
- DM autoimmune human insulin-dependent diabetes DM
- Like human IDDM spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria.
- pathological changes in retina, myocardium, liver, kidney, bone metabolism and peripheral nerves have all been well documented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992).
- the BB/W rats were 3 to 4 months old and weighed about 300 to 350 g.
- the BB/W rats received daily insulin, which was discontinued 24 h prior to performing the isolated heart perfusion studies, leading to a hyperglycemic state.
- the rats were acutely diabetic, receiving 2.02 ⁇ 0.04 units of insulin daily, and had been diabetic for at least 12 ⁇ 3 days.
- the mean blood glucose levels in these diabetic rats were 386 ⁇ 24 mg/dL.
- the age-matched non-diabetic controls had mean blood glucose levels of 92 ⁇ 12 mg/dL.
- This example describes an isolated perfused rat heart model used in development of the invention. Studies are performed using an isovolumic isolated rat heart preparation. Acutely diabetic male BB/W rats and non-diabetic age-matched (3 to 4 months old) control are pretreated with heparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP). After deep anaesthesia is achieved as determined by the absence of a foot reflex, the hearts are rapidly excised and placed into iced saline. The arrested hearts are retrograde perfused in a non-recirculating model through the aorta within 2 minutes following their excision.
- LVDP Left ventricular developed pressure
- Perfusion pressure is monitored using high pressure tubing off the perfusion line. Hemodynamic measurements are recorded on a 4-channel Gould recorder.
- the system has two parallel perfusion lines with separate oxygenators, pumps and bubble traps, but common temperature control allows rapid change perfusion media.
- the hearts are perfused using an accurate roller pump.
- the perfusate consists of 118 mM NaCl, 0.47 mM KCl, 12 mM CaCl 2 , 12 mM MgCl2, 25 mM NaHCO 3 , and the substrate 11 mM glucose.
- the perfusion apparatus is tightly temperature-controlled, with heated baths being used for the perfusate and for the water jacketing around the perfusion tubing to maintain heart temperature at 37 ⁇ 0.5° C. under all conditions.
- the oxygenated perfusate in the room temperature reservoir is passed through 25 ft. of thin-walled silicone tubing surrounded by distilled water at 37° C. saturated with 95% oxygen.
- the perfusate then enters the water-jacketed (37° C.) tubing leading to the heart through a water jacketed bubble trap. This preparation provides excellent oxygenation that routinely has been stable for 3 to 4 hours.
- Diabetic control (DC) diabetic treated (DZ) normal (C) control and normal treated (CZ) hearts are subjected to 20 minutes of normoxic perfusion followed by 20 minutes of zero-flow ischemia where the perfusate flow is completely shut off, followed by 60 minutes of reperfusion.
- Hearts are treated with 10 ⁇ M metformin eicosapentaenoate.
- metformin eicosapentaenoate treated diabetic group DZ
- hearts are subjected to 10 minutes of normoxic perfusion with normal Krebs-Henseleit buffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffer containing 10 ⁇ M metformin eicosapentaenoate.
- the hearts are then subjected to 20 minutes of zero-flow ischemia followed by 60 minutes of reperfusion.
- both DC and DZ hearts are reperfused with normal Krebs-Henseleit buffer.
- Diabetic control hearts are subjected to 20 minutes of normoxic perfusion at a flow rate of 12.5 mL/minute followed by 30 minutes of low-flow ischemia where the perfusate flow is slowed down to 1.25 mL/min, that is about 10% of normal perfusion, followed by 30 minutes of reperfusion at a normal flow rate (12.5 mL/min).
- metformin eicosapentaenoate treated diabetic or non-diabetic groups DZ or CZ
- hearts are subjected to 10 minutes of normoxic perfusion (flow rate 12.5 mL/min) with normal Krebs-Henseleit buffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffer containing 10 ⁇ M metformin eicosapentaenoate.
- the hearts are subjected to 30 minutes of low-flow ischemia (flow rate 1.25 mL/min) and 30 minutes of reperfusion at normal flow rate (12.5 mL/min).
- the present invention is exemplified by the following non-limiting examples.
- N,N-dimethylimidodicarbonimidic diamide N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.01 g, 24.3 mmol) was dissolved in 1N sodium hydroxide (24.2 mL, 24.2 mmol) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and to the residue was added ethanol (80 mL). The mixture was carefully concentrated to azeotropically remove water. To the resulting solid was added EtOH (60 mL) and the suspension was filtered to remove precipitated NaCl. The filtrate was concentrated and the resulting solid was placed on high vacuum overnight to yield 3.18 g (102%) of metformin as a white solid.
- Metformin free base (2.67 g, 20.7 mmol) was dissolved in acetonitrile (100 mL) and the resulting solution was filtered through a medium frit to remove a small amount of NaCl that precipitated.
- To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (5.40 g, 17.8 mmol) in acetonitrile (30 mL). A white solid precipitated immediately upon addition of the acid.
- the reaction flask was covered in foil to protect it from light. The mixture was stirred for one hour at room temperature and was then chilled to 0° C.
- Example 1 was a light tan solid; MP 121-124° C.
- N,N-dimethylimidodicarbonimidic diamide N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.06 g, 24.5 mmol) was dissolved in IN sodium hydroxide (24.5 mL, 24.5 mmol) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuum and to the residue was added ethanol (80 mL). The mixture was carefully concentrated to azeotropically remove water. To the resulting solid was added (60 mL) and the suspension was filtered to remove precipitated sodium chloride. The filtrate was concentrated and the resulting solid was placed on high vaccum overnight to yield 3.22 g (102%) of N,N-dimethylimidodicarbonimidic diamide as a white solid.
- N,N-Dimethylimidodicarbonimidic diamide (968 mg, 7.61 mmol) was dissolved in acetonitrile (36 mL) and the resulting solution was filtered through a medium frit to remove a small amount of sodium chloride that precipitated.
- To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16, 19-hexaenoic acid (2.00 g, 6.09 mmol) in acetonitrile (35 mL). A white solid precipitated immediately upon addition of the acid.
- the reaction flask was covered in foil to protect it from light.
- Metformin hydrochloride (331.25 g, 2 moles) was weighed into a 4000 mL beaker containing a stir bar. 1N KOH (1980 mL, 1.998 moles) was added, the beaker was covered, and the mixture was stirred for 2 h. The solids were collected by vacuum filtration, and the filtrate was concentrated to a damp solid. Isopropanol (500 mL) was added and after brief swirling, the mixture was concentrated. The residual white solid was dried for 16 h in a vacuum oven (yield: 269.08 g).
- Metformin free base 50.10 g, 0.366 mole was weighed into a 4000 mL beaker containing a stir bar. CH 3 CN (2000 mL) was added and the mixture was rapidly stirred until all metformin had dissolved. A fine white solid was removed by vacuum filtration. After ⁇ 30 min, the hazy filtrate was vacuum filtered through the same medium, and the clear filtrate was transferred to a 5000 mL 3-necked round bottom flask, which was fitted with a complete stir shaft assembly, N 2 inlet and addition funnel and bubbler.
- the funnel was charged with a solution of eicosapentaenoic acid (100.01 g, 0.324 mole) in acetonitrile (500 mL) which was added drop-wise over 70 min. After stirring for 2 h, the flask was fitted with a N 2 balloon, sealed, and placed in the refrigerator over-night. The off-white solid was collected by vacuum filtration and washed with acetonitrile (500 mL). The damp solid was transferred to a pyrex dish, which was stored in a vacuum oven for 24 h. The oven was vented with nitrogen gas, and the beige solid was coarsely ground in a mortar with pestle then transferred to an amber jar that had been flushed with N 2 to obtain the compound of Example 3 (yield: 130.49 g).
- Measurement of the water solubility of the test compounds is accomplished by using methods well known to those skilled in the art. Specifically, to a weighed amount of the test compound of Example 1 distilled water is added in small portions until a clear solution is obtained. The total-volume of the solution is measured. The water solubility is calculated by dividing the weight of the salt, in mg, by the volume of the solution, in mL. The water solubility of the compound of Example 1 when measured using the above technique, was determined to be 50 mg/ml. Likewise, the water solubility of EPA was found to be ⁇ 0.2 mg/mL. The compound of Example 1 is therefore, at least, 250 times more soluble in water than EPA itself.
Abstract
A composition which includes a salt of metformin and the use of the composition for treatment of or use in prediabetes, diabetes, lowering triglycerides and/or other conditions in mammals.
Description
- The present application claims priority from U.S. provisional patent application 61/461,113 filed on Jan. 12, 2011, the contents of which are herein incorporated by reference.
- 1. Field of the Invention
- The present invention relates to salts of poly unsaturated fatty acids with biguanides.
- 2. Technical Background
- Diabetes mellitus has become pandemic and according to a forecast by the World Health Organization, there will be a sharp increase in the number of diabetic patients by the year 2030. This is an ominous forecast, because managing the long-term complications of diabetes, which include nephropathy, neuropathy, retinopathy, and cardiovascular complications, will have a serious impact on public health budgets. The hallmark of diabetes is chronically elevated blood glucose levels. It is also known that abnormally elevated glucose levels have an adverse impact on glutathione levels in key diabetic tissues. Furthermore, increased oxidative stress and increased production of reactive oxygen species are implicated under hyperglycemic conditions.
- In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
- The use of insulin requires multiple daily doses, usually by self-injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. Treatment of non-insulin dependent diabetes mellitus (type 2 diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and, in more severe cases, insulin. However, the clinically available hypoglycemic agents can either have side effects limiting their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin administration usually constitutes the primary course of therapy.
- The biguanide metformin is a known compound approved by the U.S. Food & Drug Administration for the therapeutic treatment of diabetes. The compound and its preparation and use are disclosed, for example, in U.S. Pat. No. 3,174,901. Metformin is orally effective in the treatment of type 2 diabetes. Metformin (N,N-dimethylimidodicarbonimidic diamide) is a biguanide, anti-hyperglycemic agent currently marketed in the United States in the form of its hydrochloride salt 1,1-dimethylbiguanide hydrochloride (Formula 1a).
- Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc., 1922, 121, 1790.
- U.S. Pat. No. 7,973,073 B2 (Mylari) describes use of metformin R-(+) lipoate as being useful for treating diabetes or diabetic complications.
- U.S. Patent Publication 2005/0165102 describes complexes of drugs (metformin being mentioned) with transport moieties (fatty acids being mentioned) to enhance absorption and control delivery of the drugs being used. Among the fatty acid complexing agents mentioned are caprate, laurate, palmitate and oleate.
- U.S. Patent Publication 2005/0182029 describes metformin salts of lipophilic acid salts (fatty acids being mentioned), their pharmaceutical formulations, and methods of administering the metformin salts for the treatment of hyperglycemia.
- According to United Kingdom Perspective Diabetes Study (UKPDS) (Clarke et al. Diabetologia, 2005, 48, 868-877), metformin therapy was cost-saving and increased quality-adjusted life expectancy. In the UKPDS, overweight and obese patients randomized to initial therapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with Type 2 diabetes.
- Prediabetes is a syndrome. Many patients with type 2 diabetes and with a prediabetic condition known as metabolic syndrome suffer from a variety of lipid disorders including elevated triglycerides. The body uses triglycerides to store fat but high (>200 mg/dl) and very high (>500 mg/dl) triglycerides are associated with atherosclerosis which increases the patients risk of heart attack and stroke.
- Incipient diabetes with impaired glucose tolerance is another prediabetic condition. Overall, type 2 diabetes and incipient diabetes with impaired glucose tolerance, are intimately intertwined with obesity, hyperlipidemia, including hypertriglyceridemia, and cardiovascular complications including arrhythmia, cardiomyopathy, myocardial infarction, stroke and heart failure. Clinically, pre-diabetes means that blood sugar level is higher than normal, but it's not yet increased enough to be classified as type 2 diabetes. Still, without intervention, prediabetes is likely to become type 2 diabetes over time
- Also diabetic patients have impaired circulation which manifests itself in the slow healing of wounds in the foot and lower leg and puts the patient at risk for amputation.
- Elevated triglycerides may be lowered by diet and exercise. Niacin and omega-3 fatty acids, commonly known as fish oil, are frequently used in the management of hypertriglyceridemia. Omega-3 fatty acids are unsaturated carboxylic acids which have a terminal double bond three carbons from the methyl terminus, the 3 position. Omega-3 fatty acids are commonly extracted from oily fish like salmon, mackerel and menhaden. They are also extracted from other marine sources like squid and krill. Omega-3 fatty acids are commercially available. The omega-3 fatty acids most commonly extracted from fish are eicosapentaenoic acid and docosahexaenoic acid. These compounds have been shown to have beneficial effects in treating obesity, arrhythmia, and myocardial infarction and have the structures:
- Resolvins are a special class of polyhydroxylated omega-3 fatty acids which possess potent antinflammatory and immunoregulatory actions. These biological actions of resolvins are thought to play a significant role in cardiovascular and diabetic conditions.
- This present invention provides compositions of the formula I:
- Wherein HR is an omega-3 polyunsaturated C16-24 fatty acid optionally substituted with from 1-3 hydroxy groups.
- The compositions are typically compounds in the form of salts of metformin and an omega-3 polyunsaturated fatty acid (RH) in which the biguanide moiety is protonated and the acid moiety is at least partially in ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of the biguanide and acid components. The invention also provides pharmaceutical compositions comprising compositions of formula I and pharmaceutically acceptable excipients. The invention further provides methods for treating diabetes (especially type 2 diabetes), obesity, cardiac arrhythmia, myocardial infarction and elevated triglycerides. The compounds and compositions of this invention may provide high blood levels of the compositions of structure 1, when administered to patients, preferably by oral administration.
- Particularly useful compounds are those wherein HR is a fatty acid of 20 or 22 carbon atoms with four or five unsaturated bonds in addition to the required omega-3 unsaturated bond such as 4,7,10,13,16,19 docoshexaenoic acid, 5,8,11,14 eicosopentanoic acid and resolvins derived from these acids such as the 5,12,18 trihydroxy eicosopentanoic acid known as resolvin E1, the 15,18 dihydroxy eicosopentanoic acid, known as resolvin E2, the 7,8,17 trihydroxy docosahexaenoic acid known as resolvin DE and its 7,16,17 trihydroxy eipmer known as resolvin D2, the 4,11,17 trihydroxy docosahexaenoic acid known as resolvin D3 and the 4,5,17 trihydroxy docosahexaenoic acid known as resolvin D4.
- The invention relates to a compound of formula I which is a salt of metformin and an omega-3 polyunsaturated fatty acid and is meant to include any polymorphs, solvates, and hydrates thereof.
- In one preferred embodiment, RH is a resolving. In the most preferred embodiment, RH is eicosapentaenoic acid or docosahexaenoic acid.
- Compounds of the present invention can be considered as designer dual-acting drugs and additionally possess a means for improving the bioavailability of their component moieties as a result of their high degree of water solubility.
- In certain embodiments, the invention relates to a mixture of metformin or a pharmaceutically acceptable salt thereof, (e.g., hydrochloride, succinate, fumarate) with an omega-3 polyunsaturated fatty acid (RH), or a pharmaceutically acceptable salt thereof. In one preferred embodiment, RH is a resolvin. In the most preferred embodiment, RH is eicosapentaenoic acid or docosahexaenoic acid.
- The present invention provides a pharmaceutical composition of the invention comprising compound of formula I and a pharmaceutically-acceptable carrier, vehicle or diluent.
- The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion. Such compositions and methods for their preparation may be found, for example, in ‘Remington's Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995). The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and an active compound.
- Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
- Tablet dosage forms typically also include a disintegrant (such as sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate) a binder (such as microcrystalline cellulose, gelatin, a sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose) and a lubricant (such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate). A diluent such as lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dehydrate) may also be present. Compositions of the invention may also be administered for example as capsules made, for example, from gelatin or hydroxypropylmethylcellulose.
- Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compositions of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
- Other formulations will be apparent to those skilled in the art.
- The invention further provides methods for treatment or lowering the risk of developing conditions such as diabetes, especially type 2 diabetes, prediabetes, obesity, arrhythmia, myocardial infarction and stroke by administering therapeutically effective amounts of compositions of formula I. Such compositions may also be used to lower triglyceride levels in a subject and so have a role in treatment of diabetes exacerbated with high triglyceride levels. Suitable dosages may be determined by conventional means.
- The triglyceride lowering efficacy of the compounds of the present invention can be determined in animal models according to the procedure described by Sidika et al in Journal of Lipid Research, 1992, 33, 1-7.
- The following example describes a diabetic rat model that may be used for determination of conditions leading to a method for treatment and prevention of post-ischemic damage of the heart and heart tissue.
- Spontaneously diabetic Bio-Bred (BB/W) rats from the colony maintained at the University of Massachusetts Medical Center, Worcester, were used in this study. BB/W rats were chosen for the current study because the BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes DM).Like human IDDM, spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria. As in the case of human diabetics, pathological changes in retina, myocardium, liver, kidney, bone metabolism and peripheral nerves have all been well documented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992). The BB/W rats were 3 to 4 months old and weighed about 300 to 350 g. The BB/W rats received daily insulin, which was discontinued 24 h prior to performing the isolated heart perfusion studies, leading to a hyperglycemic state. The rats were acutely diabetic, receiving 2.02±0.04 units of insulin daily, and had been diabetic for at least 12±3 days. The mean blood glucose levels in these diabetic rats were 386±24 mg/dL. The age-matched non-diabetic controls had mean blood glucose levels of 92±12 mg/dL.
- This example describes an isolated perfused rat heart model used in development of the invention. Studies are performed using an isovolumic isolated rat heart preparation. Acutely diabetic male BB/W rats and non-diabetic age-matched (3 to 4 months old) control are pretreated with heparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP). After deep anaesthesia is achieved as determined by the absence of a foot reflex, the hearts are rapidly excised and placed into iced saline. The arrested hearts are retrograde perfused in a non-recirculating model through the aorta within 2 minutes following their excision. Left ventricular developed pressure (LVDP) is determined using a latex balloon in the left ventricle with high pressure tubing connected to a pressure transducer. Perfusion pressure is monitored using high pressure tubing off the perfusion line. Hemodynamic measurements are recorded on a 4-channel Gould recorder. The system has two parallel perfusion lines with separate oxygenators, pumps and bubble traps, but common temperature control allows rapid change perfusion media. The hearts are perfused using an accurate roller pump. The perfusate consists of 118 mM NaCl, 0.47 mM KCl, 12 mM CaCl2, 12 mM MgCl2, 25 mM NaHCO3, and the substrate 11 mM glucose. The perfusion apparatus is tightly temperature-controlled, with heated baths being used for the perfusate and for the water jacketing around the perfusion tubing to maintain heart temperature at 37±0.5° C. under all conditions. The oxygenated perfusate in the room temperature reservoir is passed through 25 ft. of thin-walled silicone tubing surrounded by distilled water at 37° C. saturated with 95% oxygen. The perfusate then enters the water-jacketed (37° C.) tubing leading to the heart through a water jacketed bubble trap. This preparation provides excellent oxygenation that routinely has been stable for 3 to 4 hours.
- This example describes a procedure used for study of zero-flow ischemia in diabetic control, diabetic treated, non-diabetic treated and control isolated hearts. Diabetic control (DC) diabetic treated (DZ) normal (C) control and normal treated (CZ) hearts are subjected to 20 minutes of normoxic perfusion followed by 20 minutes of zero-flow ischemia where the perfusate flow is completely shut off, followed by 60 minutes of reperfusion. Hearts are treated with 10 μM metformin eicosapentaenoate. In the metformin eicosapentaenoate treated diabetic group (DZ), hearts are subjected to 10 minutes of normoxic perfusion with normal Krebs-Henseleit buffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffer containing 10 μM metformin eicosapentaenoate. The hearts are then subjected to 20 minutes of zero-flow ischemia followed by 60 minutes of reperfusion. In order to avoid any variability in reperfusion conditions, both DC and DZ hearts are reperfused with normal Krebs-Henseleit buffer.
- This example describes a procedure used for study of low-flow ischemia in diabetic controls, diabetic treated, non-diabetic treated and non-diabetic control isolated hearts. Diabetic control hearts (DC) are subjected to 20 minutes of normoxic perfusion at a flow rate of 12.5 mL/minute followed by 30 minutes of low-flow ischemia where the perfusate flow is slowed down to 1.25 mL/min, that is about 10% of normal perfusion, followed by 30 minutes of reperfusion at a normal flow rate (12.5 mL/min). In the metformin eicosapentaenoate treated diabetic or non-diabetic groups (DZ or CZ), hearts are subjected to 10 minutes of normoxic perfusion (flow rate 12.5 mL/min) with normal Krebs-Henseleit buffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffer containing 10 μM metformin eicosapentaenoate. The hearts are subjected to 30 minutes of low-flow ischemia (flow rate 1.25 mL/min) and 30 minutes of reperfusion at normal flow rate (12.5 mL/min).
- Animal models to determine the effects of compounds of the invention on diabetes and complications of diabetes have been reviewed by Tirabassi et al., ILAR Journal, 2004, 45, 292-302. Antidiabetic activity may also be tested according to protocols described in the following patents: U.S. Pat. Nos. 4,340,605; 4,342,771; 4,367,234; 4,617,312; 4,687,777 and 4,703,052. Additional references relevant to this application include the following: French Patent 2796551 and United States Published Patent Application No. 20030220301.
- The present invention is exemplified by the following non-limiting examples.
- N,N-dimethylimidodicarbonimidic diamide. N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.01 g, 24.3 mmol) was dissolved in 1N sodium hydroxide (24.2 mL, 24.2 mmol) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and to the residue was added ethanol (80 mL). The mixture was carefully concentrated to azeotropically remove water. To the resulting solid was added EtOH (60 mL) and the suspension was filtered to remove precipitated NaCl. The filtrate was concentrated and the resulting solid was placed on high vacuum overnight to yield 3.18 g (102%) of metformin as a white solid.
- Metformin free base (2.67 g, 20.7 mmol) was dissolved in acetonitrile (100 mL) and the resulting solution was filtered through a medium frit to remove a small amount of NaCl that precipitated. To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (5.40 g, 17.8 mmol) in acetonitrile (30 mL). A white solid precipitated immediately upon addition of the acid. The reaction flask was covered in foil to protect it from light. The mixture was stirred for one hour at room temperature and was then chilled to 0° C. for 1 hour, and then filtered under an atmosphere of nitrogen. The resulting solid was washed with 50 mL acetonitrile and then quickly transferred to a foil-covered round bottom flask and placed under high vacuum. The material was left under high vacuum overnight to yield 6.5 (84%) of the title compound of Example 1 as a light tan solid; MP 121-124° C. (with decomposition); 1H NMR (400 MHz, MeOD) d 5.36 (m, 10 H), 3.03 (s, 6 H), 2.84 (m, 8 H), 2.18 (m, 2 H), 2.10 (m, 4 H), 1.66 (m, 2 H), 0.97 (t,J=7.57 Hz, 3 H); MS (ESI-) for C20H24O2 m/z 301.2 (M-H).
- N,N-dimethylimidodicarbonimidic diamide. N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.06 g, 24.5 mmol) was dissolved in IN sodium hydroxide (24.5 mL, 24.5 mmol) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuum and to the residue was added ethanol (80 mL). The mixture was carefully concentrated to azeotropically remove water. To the resulting solid was added (60 mL) and the suspension was filtered to remove precipitated sodium chloride. The filtrate was concentrated and the resulting solid was placed on high vaccum overnight to yield 3.22 g (102%) of N,N-dimethylimidodicarbonimidic diamide as a white solid.
- N,N-Dimethylimidodicarbonimidic diamide (968 mg, 7.61 mmol) was dissolved in acetonitrile (36 mL) and the resulting solution was filtered through a medium frit to remove a small amount of sodium chloride that precipitated. To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16, 19-hexaenoic acid (2.00 g, 6.09 mmol) in acetonitrile (35 mL). A white solid precipitated immediately upon addition of the acid. The reaction flask was covered in foil to protect it from light. After stirring for 1 h at room temperature, the mixture was chilled to 0° C. for 1 h, and then filtered under an atmosphere of nitrogen. The solid was washed with 50 mL ice-cold acetonitrile and then quickly transferred to a foil-covered round bottom flask and placed under high vac. The material was left under high vacuum overnight to yield 2.54 g (91%) of 1 as a light tan solid. The material was found to be air and light sensitive, and was therefore stored in an amber vial under nitrogen: MP 124-127° C. (turned brown); 1H NMR (400 MHz, MeOD) 5.36 (m, 12 H), 3.03 (s, 6 H), 2.85 (m, 10 H), 2.37 (m, 2 H), 2.19 (m, 2 H), 2.09 (m, 2 H), 0.97 (t, J=7.57 Hz, 3 H); MS (ESI-) for C22H32O2 m/z 327.3 (M-H).
- N,N-dimethylimidodicarbonimidic diamide.
- Metformin hydrochloride (331.25 g, 2 moles) was weighed into a 4000 mL beaker containing a stir bar. 1N KOH (1980 mL, 1.998 moles) was added, the beaker was covered, and the mixture was stirred for 2 h. The solids were collected by vacuum filtration, and the filtrate was concentrated to a damp solid. Isopropanol (500 mL) was added and after brief swirling, the mixture was concentrated. The residual white solid was dried for 16 h in a vacuum oven (yield: 269.08 g).
- Metformin free base (50.10 g, 0.366 mole) was weighed into a 4000 mL beaker containing a stir bar. CH3CN (2000 mL) was added and the mixture was rapidly stirred until all metformin had dissolved. A fine white solid was removed by vacuum filtration. After ˜30 min, the hazy filtrate was vacuum filtered through the same medium, and the clear filtrate was transferred to a 5000 mL 3-necked round bottom flask, which was fitted with a complete stir shaft assembly, N2 inlet and addition funnel and bubbler. The funnel was charged with a solution of eicosapentaenoic acid (100.01 g, 0.324 mole) in acetonitrile (500 mL) which was added drop-wise over 70 min. After stirring for 2 h, the flask was fitted with a N2 balloon, sealed, and placed in the refrigerator over-night. The off-white solid was collected by vacuum filtration and washed with acetonitrile (500 mL). The damp solid was transferred to a pyrex dish, which was stored in a vacuum oven for 24 h. The oven was vented with nitrogen gas, and the beige solid was coarsely ground in a mortar with pestle then transferred to an amber jar that had been flushed with N2 to obtain the compound of Example 3 (yield: 130.49 g).
- The solubility of the compound of Example 1 in water was compared with that of eicosapentaenoic acid (EPA).
- Measurement of the water solubility of the test compounds is accomplished by using methods well known to those skilled in the art. Specifically, to a weighed amount of the test compound of Example 1 distilled water is added in small portions until a clear solution is obtained. The total-volume of the solution is measured. The water solubility is calculated by dividing the weight of the salt, in mg, by the volume of the solution, in mL. The water solubility of the compound of Example 1 when measured using the above technique, was determined to be 50 mg/ml. Likewise, the water solubility of EPA was found to be <0.2 mg/mL. The compound of Example 1 is therefore, at least, 250 times more soluble in water than EPA itself. This is a clear indication of an unexpectedly high degree of bioavailability of the compositions of the invention. Highly water soluble medicinal preparations, when administered orally, result in efficient absorption of such preparations from the gastrointestinal tract into systemic circulation. Such preparations permit rapid absorption into the blood stream resulting in a high concentration of the active agent in the blood. Furthermore, water soluble preparations are especially suitable for parenteral administration, for example, intravenous administration.
Claims (44)
2. The composition of claim 1 in which the polyunsaturated fatty acid RH is an omega-3 fatty acid.
3. A composition of claim 1 wherein RH is an omega-3 polyunsaturated C16-24 fatty acid optionally substituted with from 1-3 hydroxy groups
4. A composition as claimed in claim 2 wherein RH is a fatty acid of 20 or 22 carbon atoms with a total of 4- or 5 unsaturated linkages in the fatty acid chain in addition to the omega-3 unsaturated bond.
5. A composition of claim 1 , wherein RH is selected from the group consisting of resolvins D1, D2, D3, D4, E1, and E2.
6. The composition of claim 1 in which the polyunsaturated fatty acid RH is eicosapentaenoic acid.
7. The composition of claim 1 in which the polyunsaturated fatty acid RH is docosahexaenoic acid.
8. A composition according to claim 1 , wherein R is a mixture of polyunsaturated fatty acids.
9. The mixture of claim 8 in which the polyunsaturated fatty acid comprises a mixture of eicosapentaenoic acid and docosahexaenoic acid.
10. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier, vehicle or diluent.
11. A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier, vehicle or diluent.
12. A pharmaceutical composition comprising a mixture according to claim 8 and a pharmaceutically acceptable carrier, vehicle or diluent.
13. A kit comprising a) a unit dosage form comprising the compound of claim 6 ; b) instructions on how to use the kit; and c) at least one container for holding the unit dosage forms.
14. A kit comprising a) a unit dosage form comprising the compound of claim 7 ; b) instructions on how to use the kit; and c) at least one container for holding the unit dosage forms.
15. A kit comprising a) a unit dosage form comprising the salts of claim 8 b) instructions on how to use the kit; and c) at least one container for holding the unit dosage forms.
16. A method for treating diabetes in a mammal, comprising administering a therapeutically effective amount of a compound according to claim 6 .
17. A method for treating diabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of a composition according to claim 7 .
18. A method for treating diabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of a composition according to claim 8 .
19. A method for treating diabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of a composition according to claim 9 .
20. A method of lowering triglycerides in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 6 .
21. A method of lowering triglycerides in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 7 .
22. A method of lowering triglycerides in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 8 .
23. A method of lowering triglycerides in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 9 .
24. A method of treating prediabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 6 .
25. A method of treating prediabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 7 .
26. A method of treating prediabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 8 .
27. A method of treating prediabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 9 .
28. A method of treating obesity in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 6 .
29. A method of treating obesity in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 7 .
30. A method of treating obesity in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 8 .
31. A method of treating obesity in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 9 .
32. A method of treating cardiac arrhythmia in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 6 .
33. A method of treating cardiac arrhythmia in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 7 .
34. A method of treating cardiac arrhythmia in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 8 .
35. A method of treating cardiac arrhythmia in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 9 .
36. A method of treating cardiomyopathy in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 6 .
37. A method of treating cardiomyopathy in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 7 .
38. A method of treating cardiomyopathy in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 8 .
39. A method of treating cardiomyopathy in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 9 .
40. A method of treating myocardial infarction in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 6 .
41. A method of treating myocardial infarction in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 7 .
42. A method of treating myocardial infarction in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 8 .
43. A method of treating myocardial infarction in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 9 .
44. A method for the manufacture of the composition of claim 1 comprising: a) freshly preparing the free base of metformin from a suitable metformin salt; and b) reacting the freshly prepared free base of metformin with eicosapentaenoic acid, docosahexaenoic acid or a mixture thereof at a temperature between about 1 degree C. and about 60 degree C.
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/348,265 US20120178813A1 (en) | 2011-01-12 | 2012-01-11 | Lipid-lowering antidiabetic agent |
JP2013549539A JP5911514B2 (en) | 2011-01-12 | 2012-01-12 | Lipid-lowering antidiabetic drugs |
CN201280005222.1A CN103533833B (en) | 2011-01-12 | 2012-01-12 | Blood fat reducing antidiabetic |
KR20137018679A KR20140092228A (en) | 2011-01-12 | 2012-01-12 | Lipid-Lowering Antidiabetic Agent |
EA201391028A EA201391028A1 (en) | 2011-01-12 | 2012-01-12 | HYPOLIPIDEMIC ANTI-DIABETIC MEANS |
EP12734013.1A EP2663186A4 (en) | 2011-01-12 | 2012-01-12 | Lipid-lowering antidiabetic agent |
CA2824192A CA2824192A1 (en) | 2011-01-12 | 2012-01-12 | Lipid-lowering antidiabetic agent |
AU2012205547A AU2012205547B2 (en) | 2011-01-12 | 2012-01-12 | Lipid-lowering antidiabetic agent |
PCT/US2012/021070 WO2012097144A1 (en) | 2011-01-12 | 2012-01-12 | Lipid-lowering antidiabetic agent |
MX2013008131A MX2013008131A (en) | 2011-01-12 | 2012-01-12 | Lipid-lowering antidiabetic agent. |
BR112013017845A BR112013017845A2 (en) | 2011-01-12 | 2012-01-12 | lipid lowering antidiabetic agent |
US13/923,829 US8901107B2 (en) | 2011-01-12 | 2013-06-21 | Lipid-lowering antidiabetic agent |
IL227346A IL227346A0 (en) | 2011-01-12 | 2013-07-04 | Lipid-lowering-lowering antidiabetic agent |
US14/136,843 US9012507B2 (en) | 2011-01-12 | 2013-12-20 | Lipid-lowering antidiabetic agent |
US14/524,721 US9216951B2 (en) | 2011-01-12 | 2014-10-27 | Lipid-lowering antidiabetic agent |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161461113P | 2011-01-12 | 2011-01-12 | |
US13/348,265 US20120178813A1 (en) | 2011-01-12 | 2012-01-11 | Lipid-lowering antidiabetic agent |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/923,829 Division US8901107B2 (en) | 2011-01-12 | 2013-06-21 | Lipid-lowering antidiabetic agent |
US14/136,843 Continuation US9012507B2 (en) | 2011-01-12 | 2013-12-20 | Lipid-lowering antidiabetic agent |
Publications (1)
Publication Number | Publication Date |
---|---|
US20120178813A1 true US20120178813A1 (en) | 2012-07-12 |
Family
ID=46455756
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/348,265 Abandoned US20120178813A1 (en) | 2011-01-12 | 2012-01-11 | Lipid-lowering antidiabetic agent |
US13/923,829 Expired - Fee Related US8901107B2 (en) | 2011-01-12 | 2013-06-21 | Lipid-lowering antidiabetic agent |
US14/136,843 Expired - Fee Related US9012507B2 (en) | 2011-01-12 | 2013-12-20 | Lipid-lowering antidiabetic agent |
US14/524,721 Expired - Fee Related US9216951B2 (en) | 2011-01-12 | 2014-10-27 | Lipid-lowering antidiabetic agent |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/923,829 Expired - Fee Related US8901107B2 (en) | 2011-01-12 | 2013-06-21 | Lipid-lowering antidiabetic agent |
US14/136,843 Expired - Fee Related US9012507B2 (en) | 2011-01-12 | 2013-12-20 | Lipid-lowering antidiabetic agent |
US14/524,721 Expired - Fee Related US9216951B2 (en) | 2011-01-12 | 2014-10-27 | Lipid-lowering antidiabetic agent |
Country Status (12)
Country | Link |
---|---|
US (4) | US20120178813A1 (en) |
EP (1) | EP2663186A4 (en) |
JP (1) | JP5911514B2 (en) |
KR (1) | KR20140092228A (en) |
CN (1) | CN103533833B (en) |
AU (1) | AU2012205547B2 (en) |
BR (1) | BR112013017845A2 (en) |
CA (1) | CA2824192A1 (en) |
EA (1) | EA201391028A1 (en) |
IL (1) | IL227346A0 (en) |
MX (1) | MX2013008131A (en) |
WO (1) | WO2012097144A1 (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014011814A1 (en) * | 2012-07-10 | 2014-01-16 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
WO2014080307A2 (en) * | 2012-11-21 | 2014-05-30 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
US8765811B2 (en) | 2012-07-10 | 2014-07-01 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
US8901107B2 (en) | 2011-01-12 | 2014-12-02 | Thetis Pharmaceuticals Llc | Lipid-lowering antidiabetic agent |
WO2014195961A1 (en) * | 2013-06-04 | 2014-12-11 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
WO2015022613A1 (en) * | 2013-08-11 | 2015-02-19 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
US9242008B2 (en) | 2014-06-18 | 2016-01-26 | Thetis Pharmaceuticals Llc | Mineral amino-acid complexes of fatty acids |
US20160107985A1 (en) * | 2014-05-05 | 2016-04-21 | Thetis Pharmaceuticals Llc | Compositions and Methods Relating to Ionic Salts of Peptides |
US9382187B2 (en) | 2012-07-10 | 2016-07-05 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
US20160244405A1 (en) * | 2015-02-20 | 2016-08-25 | Mohan Murali Alapati | Compositions and methods for the treatment of hyperglycemia and metabolic syndrome |
WO2014195810A3 (en) * | 2013-06-04 | 2017-03-09 | Cellixbio Private Limited | Compositions and methods for the treatment of diabetes and pre-diabetes |
US9999626B2 (en) | 2014-06-18 | 2018-06-19 | Thetis Pharmaceuticals Llc | Mineral amino-acid complexes of active agents |
US10130719B2 (en) | 2016-06-03 | 2018-11-20 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators |
WO2019008101A1 (en) | 2017-07-06 | 2019-01-10 | Evonik Technochemie Gmbh | Enteric coated solid dosage form comprising omega-3 fatty acid amino acid salts |
WO2019034698A1 (en) | 2017-08-15 | 2019-02-21 | Evonik Technochemie Gmbh | Tablets with high active ingredient content of omega-3 fatty acid amino acid salts |
WO2021023857A1 (en) | 2019-08-08 | 2021-02-11 | Evonik Operations Gmbh | Solubility enhancement of poorly soluble actives |
WO2021023849A1 (en) | 2019-08-08 | 2021-02-11 | Evonik Operations Gmbh | Down streaming process for the production of polyunsaturated fatty acid salts |
US11497722B2 (en) * | 2017-12-18 | 2022-11-15 | Soochow University | Use of metformin salt in the treatment of cerebral infarction |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9371276B1 (en) * | 2015-03-21 | 2016-06-21 | Mohan Murali Alapati | Compositions and methods for the treatment of hyperglycemia and metabolic syndrome |
CN113105367B (en) * | 2021-03-30 | 2022-08-02 | 广州大学 | Metformin salt and preparation method and application thereof |
CN115192625A (en) * | 2022-06-30 | 2022-10-18 | 山东海赜生物科技有限公司 | Oral composition |
Family Cites Families (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5795909A (en) | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
US6720001B2 (en) | 1999-10-18 | 2004-04-13 | Lipocine, Inc. | Emulsion compositions for polyfunctional active ingredients |
KR100784752B1 (en) | 2000-02-04 | 2007-12-13 | 다케다 야쿠힌 고교 가부시키가이샤 | Stable emulsion compositions |
US6491950B1 (en) | 2000-08-07 | 2002-12-10 | Kos Pharmaceuticals, Inc. | Controlled release pharmaceutical composition |
US6667064B2 (en) | 2000-08-30 | 2003-12-23 | Pilot Therapeutics, Inc. | Composition and method for treatment of hypertriglyceridemia |
US6689385B2 (en) * | 2000-11-03 | 2004-02-10 | Chronorx Llc | Formulations for the treatment of insulin resistance and type 2 diabetes mellitus |
FR2818906B1 (en) * | 2000-12-29 | 2004-04-02 | Dospharma | DRUG ASSOCIATION OF A BIGUANINE AND A CARRIER, FOR EXAMPLE OF METFORMIN AND ARGININE |
DE10102050A1 (en) | 2001-01-17 | 2002-07-18 | Basf Ag | Food, nutritional supplement, feed or medicament preparations containing conjugated cis/trans-octatrienoic acid, useful e.g. for reducing food intake, improving food utilization or treating cancer or diabetes |
EP1373182A1 (en) | 2001-03-29 | 2004-01-02 | Basf Aktiengesellschaft | Conjugated unsaturated glyceride mixtures and a method for producing the same |
DE60234780D1 (en) | 2001-08-31 | 2010-01-28 | Univ Rutgers | METHOD FOR THE TREATMENT OF DISEASES WITH PLANT EXTRACTS |
ITMI20012384A1 (en) | 2001-11-12 | 2003-05-12 | Quatex Nv | USE OF POLYUNSATURATED FATTY ACIDS FOR THE PRIMARY PREVENTION OF MAJOR CARDIOVASCULAR EVENTS |
US20030220301A1 (en) * | 2002-02-14 | 2003-11-27 | Sonus Pharmaceuticals, Inc. | Metformin salts of lipophilic acids |
US7670612B2 (en) | 2002-04-10 | 2010-03-02 | Innercap Technologies, Inc. | Multi-phase, multi-compartment capsular delivery apparatus and methods for using same |
JP4694207B2 (en) * | 2002-07-05 | 2011-06-08 | コルジウム ファーマシューティカル, インコーポレイテッド | Abuse deterrent pharmaceutical compositions for opioids and other drugs |
BR0314799A (en) * | 2002-09-27 | 2005-07-26 | Market Biosciences Corp | Enhanced glycemic control for pre-diabetes and / or type ii diabetes using docosahexaenoic acid |
ITMI20022394A1 (en) | 2002-11-13 | 2004-05-14 | Bracco Spa | USE OF 3-SULPHATE TRIODOTHYRONIN AS A THYROIMIMETIC ACTIVITY AND RELATED PHARMACEUTICAL FORMULATIONS. |
RU2356247C2 (en) * | 2003-03-18 | 2009-05-27 | Новартис Аг | Combinations and compositions containing fatty acids and amino acids, their application for prevention and delay of progressing or treatment of diabetes and diabetes associated diseases and conditions, method of weight reduction in mammal, kit |
EP1510208A1 (en) | 2003-08-22 | 2005-03-02 | Fournier Laboratories Ireland Limited | Pharmaceutical composition comprising a combination of metformin and statin |
US20080045559A1 (en) | 2003-10-29 | 2008-02-21 | Sonus Pharmaceuticals, Inc. | Tocopherol-modified therapeutic drug compounds |
TW200522978A (en) | 2003-10-29 | 2005-07-16 | Sonus Pharma Inc | Tocopherol-modified therapeutic drug compounds |
US20060094782A9 (en) | 2003-10-31 | 2006-05-04 | Wong Patrick S | Compositions and dosage forms for enhanced absorption |
WO2005070429A1 (en) | 2004-01-22 | 2005-08-04 | Neurosearch A/S | Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an n-methyl-d-aspartate (nmda) receptors antagonist |
WO2005118612A1 (en) | 2004-06-04 | 2005-12-15 | Sonus Pharmaceuticals, Inc. | Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs |
EP1833313A2 (en) * | 2004-10-15 | 2007-09-19 | Corporation Limited Photonz | Compositions containing high omega-3 and low saturated fatty acid levels |
EP1804815A2 (en) | 2004-10-29 | 2007-07-11 | Joan Campell-Tofte | Anti-diabetic extract isolated from rauvolfia vomitoria and citrus aurantium, and methods of using same |
CA2613875C (en) | 2005-07-04 | 2018-09-25 | Ramu Krishnan | Improved drug or pharmaceutical compounds and a preparation thereof |
JP2009514893A (en) | 2005-11-03 | 2009-04-09 | イリプサ, インコーポレイテッド | Multivalent indole compounds and their use as phospholipase A2 inhibitors |
AU2007213506A1 (en) * | 2006-02-07 | 2007-08-16 | Universitetet I Oslo | Omega 3 |
EP1984355A2 (en) | 2006-02-16 | 2008-10-29 | Takeda Pharmaceutical Company Limited | Cyclic amine compound and use thereof for the prophylaxis or treatment of hypertension |
US20090047340A1 (en) | 2006-03-29 | 2009-02-19 | Guilford F Timothy | Liposomal reduced glutathione and 1-arginine, including with other ingredient(s), capable of multipath administration for reversal and prevention of obesity and for mitochondrial biogenesis |
EP2046773A1 (en) | 2006-06-16 | 2009-04-15 | Indigene Pharmaceuticals Inc. | Metformin r-(+) lipoate as an antidiabetic agent for control of diabetic hyperglycemia and diabetic complications |
JP5552313B2 (en) | 2006-11-01 | 2014-07-16 | プロノヴァ・バイオファーマ・ノルゲ・アーエス | Lipid compounds |
WO2008053340A1 (en) * | 2006-11-03 | 2008-05-08 | Pronova Biopharma Norge As | A combination product comprising at least one lipid substituted in the alpha position and at least one hypoglycemic agent |
US20100105773A1 (en) * | 2006-11-09 | 2010-04-29 | The Children's Medical Center Corporation | Use of resolvins and docosatrienes and analogues thereof for the treatment of angiogenesis and ocular neovascularization |
JP4592818B2 (en) * | 2007-01-29 | 2010-12-08 | ハナル バイオファーマ カンパニー リミテッド | N, N-dimethylimidodicarbonimidic acid diamide acetate, process for producing the same, and pharmaceutical composition containing the same |
US20090227560A1 (en) | 2007-04-27 | 2009-09-10 | Takanobu Kuroita | Substituted imidazole compound and use thereof |
WO2008139941A1 (en) | 2007-04-27 | 2008-11-20 | Takeda Pharmaceutical Company Limited | Substituted imidazole compound and use thereof |
US20090054513A1 (en) * | 2007-08-22 | 2009-02-26 | Response Scientific, Inc. | Method of managing blood glucose levels, insulin levels and/or insulin receptor functionality in individuals with diabetes, polycystic ovarian syndrome and/or alzheimer's disease |
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 |
EP2202228B1 (en) | 2007-10-15 | 2014-12-10 | Takeda Pharmaceutical Company Limited | Amide compounds and use of the same |
US20110046053A1 (en) | 2008-05-05 | 2011-02-24 | Oramed Ltd. | Methods and compositions for oral administration of exenatide |
CN102123990B (en) | 2008-06-19 | 2014-07-09 | 武田药品工业株式会社 | Heterocyclic compound and use thereof |
NZ624963A (en) * | 2009-04-29 | 2016-07-29 | Amarin Pharmaceuticals Ie Ltd | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
US20110052678A1 (en) | 2010-11-05 | 2011-03-03 | Shantha Totada R | Method for treating age related macular degeneration |
US20120178813A1 (en) | 2011-01-12 | 2012-07-12 | Thetis Pharmaceuticals Llc | Lipid-lowering antidiabetic agent |
WO2013192109A1 (en) | 2012-06-17 | 2013-12-27 | Matinas Biopharma, Inc. | Omega-3 pentaenoic acid compositions and methods of use |
-
2012
- 2012-01-11 US US13/348,265 patent/US20120178813A1/en not_active Abandoned
- 2012-01-12 JP JP2013549539A patent/JP5911514B2/en not_active Expired - Fee Related
- 2012-01-12 WO PCT/US2012/021070 patent/WO2012097144A1/en active Application Filing
- 2012-01-12 CA CA2824192A patent/CA2824192A1/en not_active Abandoned
- 2012-01-12 BR BR112013017845A patent/BR112013017845A2/en not_active IP Right Cessation
- 2012-01-12 EA EA201391028A patent/EA201391028A1/en unknown
- 2012-01-12 KR KR20137018679A patent/KR20140092228A/en not_active Application Discontinuation
- 2012-01-12 EP EP12734013.1A patent/EP2663186A4/en not_active Withdrawn
- 2012-01-12 AU AU2012205547A patent/AU2012205547B2/en not_active Ceased
- 2012-01-12 CN CN201280005222.1A patent/CN103533833B/en not_active Expired - Fee Related
- 2012-01-12 MX MX2013008131A patent/MX2013008131A/en not_active Application Discontinuation
-
2013
- 2013-06-21 US US13/923,829 patent/US8901107B2/en not_active Expired - Fee Related
- 2013-07-04 IL IL227346A patent/IL227346A0/en unknown
- 2013-12-20 US US14/136,843 patent/US9012507B2/en not_active Expired - Fee Related
-
2014
- 2014-10-27 US US14/524,721 patent/US9216951B2/en not_active Expired - Fee Related
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8901107B2 (en) | 2011-01-12 | 2014-12-02 | Thetis Pharmaceuticals Llc | Lipid-lowering antidiabetic agent |
US9216951B2 (en) | 2011-01-12 | 2015-12-22 | Thetis Pharmaceuticals Llc | Lipid-lowering antidiabetic agent |
US9012507B2 (en) | 2011-01-12 | 2015-04-21 | Thetis Pharmaceuticals Llc | Lipid-lowering antidiabetic agent |
US8933124B2 (en) | 2012-07-10 | 2015-01-13 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
US9382187B2 (en) | 2012-07-10 | 2016-07-05 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
US8765811B2 (en) | 2012-07-10 | 2014-07-01 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
JP2015523382A (en) * | 2012-07-10 | 2015-08-13 | テティス・ファーマシューティカルズ・エルエルシー | The trisalt form of metformin |
WO2014011814A1 (en) * | 2012-07-10 | 2014-01-16 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
WO2014080307A3 (en) * | 2012-11-21 | 2014-12-24 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
WO2014080307A2 (en) * | 2012-11-21 | 2014-05-30 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
WO2014195961A1 (en) * | 2013-06-04 | 2014-12-11 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
WO2014195810A3 (en) * | 2013-06-04 | 2017-03-09 | Cellixbio Private Limited | Compositions and methods for the treatment of diabetes and pre-diabetes |
WO2015022613A1 (en) * | 2013-08-11 | 2015-02-19 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
US20160107985A1 (en) * | 2014-05-05 | 2016-04-21 | Thetis Pharmaceuticals Llc | Compositions and Methods Relating to Ionic Salts of Peptides |
US9505709B2 (en) * | 2014-05-05 | 2016-11-29 | Thetis Pharmaceuticals Llc | Compositions and methods relating to ionic salts of peptides |
US9242008B2 (en) | 2014-06-18 | 2016-01-26 | Thetis Pharmaceuticals Llc | Mineral amino-acid complexes of fatty acids |
US9999626B2 (en) | 2014-06-18 | 2018-06-19 | Thetis Pharmaceuticals Llc | Mineral amino-acid complexes of active agents |
US20160244405A1 (en) * | 2015-02-20 | 2016-08-25 | Mohan Murali Alapati | Compositions and methods for the treatment of hyperglycemia and metabolic syndrome |
US11135298B2 (en) | 2016-06-03 | 2021-10-05 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators |
US10130719B2 (en) | 2016-06-03 | 2018-11-20 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators |
US11191840B2 (en) | 2016-06-03 | 2021-12-07 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators |
US11925688B2 (en) | 2016-06-03 | 2024-03-12 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators |
WO2019008101A1 (en) | 2017-07-06 | 2019-01-10 | Evonik Technochemie Gmbh | Enteric coated solid dosage form comprising omega-3 fatty acid amino acid salts |
WO2019034698A1 (en) | 2017-08-15 | 2019-02-21 | Evonik Technochemie Gmbh | Tablets with high active ingredient content of omega-3 fatty acid amino acid salts |
US11497722B2 (en) * | 2017-12-18 | 2022-11-15 | Soochow University | Use of metformin salt in the treatment of cerebral infarction |
WO2021023857A1 (en) | 2019-08-08 | 2021-02-11 | Evonik Operations Gmbh | Solubility enhancement of poorly soluble actives |
WO2021023849A1 (en) | 2019-08-08 | 2021-02-11 | Evonik Operations Gmbh | Down streaming process for the production of polyunsaturated fatty acid salts |
Also Published As
Publication number | Publication date |
---|---|
EA201391028A1 (en) | 2013-12-30 |
CA2824192A1 (en) | 2012-07-19 |
BR112013017845A2 (en) | 2019-09-24 |
AU2012205547A1 (en) | 2013-08-01 |
JP5911514B2 (en) | 2016-04-27 |
KR20140092228A (en) | 2014-07-23 |
US20130281535A1 (en) | 2013-10-24 |
WO2012097144A1 (en) | 2012-07-19 |
JP2014512333A (en) | 2014-05-22 |
US8901107B2 (en) | 2014-12-02 |
CN103533833B (en) | 2016-08-31 |
AU2012205547B2 (en) | 2015-08-27 |
US20150051284A1 (en) | 2015-02-19 |
US9012507B2 (en) | 2015-04-21 |
EP2663186A1 (en) | 2013-11-20 |
MX2013008131A (en) | 2014-01-08 |
US20140107360A1 (en) | 2014-04-17 |
EP2663186A4 (en) | 2014-09-24 |
IL227346A0 (en) | 2013-09-30 |
US9216951B2 (en) | 2015-12-22 |
CN103533833A (en) | 2014-01-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9216951B2 (en) | Lipid-lowering antidiabetic agent | |
US7973073B2 (en) | Antidiabetic agent for control of diabetic hyperglycemia and diabetic complications | |
US8933124B2 (en) | Tri-salt form of metformin | |
US8853259B2 (en) | Metformin derivatives for treating diabetes and diabetes complications | |
KR20130069704A (en) | Biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same | |
US20220249463A1 (en) | Methods of altering cardiac remodeling using compounds that promote glucose oxidation | |
US20140024708A1 (en) | Ursolic acid salts for treating diabetes and obesity | |
EP2872483A1 (en) | Tri-salt form of metformin | |
TW516959B (en) | Composition containing ascorbic acid | |
US8440723B2 (en) | Metformin salts of salicylic acid and its congeners | |
US9382187B2 (en) | Tri-salt form of metformin | |
JP2954989B2 (en) | Treatment of diabetes mellitus with bisphenol derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: THETIS PHARMACEUTICALS LLC, CONNECTICUT Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MYLARI, BANAVARA L.;SCIAVOLINO, FRANK C.;SIGNING DATES FROM 20120110 TO 20120111;REEL/FRAME:027543/0106 |
|
AS | Assignment |
Owner name: THETIS PHARMACEUTICALS LLC, CONNECTICUT Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MYLARI, BANAVARA L.;SCIAVOLINO, FRANK C.;REEL/FRAME:031098/0717 Effective date: 20130826 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |