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WO2014008374A2 - Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie - Google Patents

Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie Download PDF

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Publication number
WO2014008374A2
WO2014008374A2 PCT/US2013/049285 US2013049285W WO2014008374A2 WO 2014008374 A2 WO2014008374 A2 WO 2014008374A2 US 2013049285 W US2013049285 W US 2013049285W WO 2014008374 A2 WO2014008374 A2 WO 2014008374A2
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pharmaceutically
prodrug
acceptable salt
metformin
pharmaceutical composition
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PCT/US2013/049285
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English (en)
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WO2014008374A3 (fr
Inventor
Banavara L. Mylari
Frank C. SCIAVOLINO
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Thetis Pharmaceuticals Llc
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Publication of WO2014008374A3 publication Critical patent/WO2014008374A3/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • 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

Definitions

  • the present invention is directed to a combination therapy comprising metformin eicosapentaenoate or metformin docosahexaenoate, or a mixture thereof, and an
  • the present invention also is directed to a combination therapy comprising metformin eicosapentaenoate or metformin
  • docosahexaenoate or a mixture thereof, and an antihyperlipidemic agent, or a
  • the invention further relates to methods of treating a metabolic disorder selected from the group consisting of type 2 diabetes (T2D), pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in diabetic patients.
  • T2D type 2 diabetes
  • pre-diabetes obesity
  • metabolic syndrome e.g., obesity
  • hypertriglyceridemia e.g., pre-diabetes
  • T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in diabetic patients.
  • 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.
  • the treatment of diabetes remains less than satisfactory 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.
  • Non-insulin dependent diabetes mellitus Type II diabetes, NIDDM
  • NIDDM non-insulin dependent diabetes mellitus
  • hypoglycemic agents e.g., thiazolidenediones
  • insulin dependent diabetes mellitus Type I, IDDM or "juvenile diabetes”
  • insulin administration usually constitutes the primary course of therapy.
  • Co -morbidities in patients with long-term diabetes include lipid metabolism disorders, such as elevated levels of total cholesterol, elevated levels of low density (LDL) and very low density (VLDL) cholesterol, decreased levels of high density cholesterol (HDL), and elevated levels of triglycerides (TGs).
  • LDL low density
  • VLDL very low density
  • HDL high density cholesterol
  • TGs triglycerides
  • cardiovascular complications such as cardiac arrhythmia, atrial fibrillation, myocardial ischemia, stroke, and cardiomyopathy.
  • T1D type 1 diabetes
  • T2D type 2 diabetes
  • pre-diabetes as well as related conditions, such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in diabetic patients.
  • agents to treat lipid metabolism disorders to more effectively control diabetes complications in diabetic patients.
  • the present invention relates to a combination therapy comprising metformin eicosapentaenoate, metformin docosahexaenoate or a mixture thereof, and an
  • an antihyperglycemic agent or an antihyperlipidemic agent to treat a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome,
  • hypertriglyceridemia as well as T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals (e.g., diabetic patients).
  • T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals (e.g., diabetic patients).
  • the invention relates to a combination therapy comprising metformin eicosapentaenoate, metformin docosahexaenoate, or a mixture thereof, and an
  • a pharmaceutical composition comprising metformin eicosapentaenoate, metformin docosahexaenoate or a combination thereof, an antihyperglycemic agent and a
  • the two compounds are present in x and y% with the proviso that x and y are not zero, but the sum of x and y is 100%.
  • the antihyperglycemic agent is about 1-20% by weight of the pharmaceutical composition.
  • docosahexaenoate or a mixture of the two is present in unit dosage strength of 250, 500, 750, 1000, or 1250 mg, and the said antihyperglycemic agent is present in a unit dosage strength of 1, 2.5, 5, 10, 20, 25, 50, 100, 150, or 200 mg. In another embodiment, the said antihyperglycemic agent is present in a unit dosage strength between 5 and 100 mg.
  • the invention relates to a combination therapy comprising metformin eicosapentaenoate, metformin docosahexaenoate, or a mixture thereof, and an antihyperlipidemic agent and a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • a pharmaceutical composition comprising metformin eicosapentaenoate, metformin docosahexaenoate or a combination thereof, an antihyperlipidemic agent and a pharmaceutically-acceptable carrier.
  • the two compounds are present in x and y% with the proviso that x and y are not zero, but the sum of x and y is 100%.
  • the antihyperlipidemic agent is about 0.1-1 % by weight of the pharmaceutical composition.
  • docosahexaenoate or a mixture of the two is present in unit dosage strength of 250, 500, 750, 1000, or 1250 mg, and the said antihyperlipidemic agent is present in a unit dosage strength of 1, 2.5, 5, 10, 20, 30, 40, or 50 mg. In another embodiment, the said antihyperlipidemic agent is present in a unit dosage strength of 5-100 mg.
  • the present invention provides a method of treating a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and diabetes complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, and cardiomyopathy in mammals (e.g., diabetic patients) comprising administering to a subject in need thereof the combination therapy described herein.
  • a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, hypertriglyceridemia and diabetes complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, and cardiomyopathy in mammals (e.g., diabetic patients) comprising administering to a subject in need thereof the combination therapy described herein.
  • the components of the antihyperlipidemic combination therapy can be used to treat obesity,
  • cardiovascular disease and related indications, in a subject in need thereof.
  • a method of treating hyperlipidemia comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating hypertriglyceridemia comprising administering to a subject in need thereof an effective amount of the
  • a method of treating dyslipidemia comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating cardiovascular disease comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • the cardiovascular disease can be cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.
  • the arrhythmia is an atrial fibrillation.
  • a method of treating obesity comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • the subject is human.
  • the components of the combination therapy can be administered in a variety of ways.
  • the components are in separate formulations or unit dosage forms.
  • the components are administered with a pharmaceutically acceptable carrier.
  • the components can be administered separately, at substantially the same time, or administered at different times. When administered separately, they can be administered in any order.
  • the present invention is directed to pharmaceutical compositions comprising metformin eicosapentaenoate, metformin docosahexaenoate, or a mixture of the two and an antihyperglycemic agent, or a pharmaceutically- acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and a pharmaceutically- acceptable carrier, vehicle or diluent.
  • Antihyperglycemic agents that can be used in accordance with the invention can include, for example, sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP IV inhibitors, and SGLT-2 inhibitors and pharmaceutically-acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.
  • the antihyperglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP IV inhibitor, and SGLT-2 inhibitors or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • the antihyperglycemic agent is a sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP IV inhibitor, and SGLT-2 inhibitors or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • pharmaceutically acceptable salt is selected from the group consisting of a propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1 ,4-dioate, hexyne-1 ,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathal ate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, p- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate,
  • Preferred agents among thiazolidinediones are pioglitazone, pharmaceutically- acceptable salts or a prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • Preferred alpha- glucosidase inhibitors include, but are not limited to, acarbose, vaglibose, and miglitol, pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • Preferred DPP-IV inhibitors include, but are not limited to, sitagliptin, linagliptin, vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, melogliptin and dutogliptin, and pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • Preferred SGLT-2 inhibitors include, but are not limited to, dapagliflozin
  • the present invention is directed to pharmaceutical compositions comprising metformin eicosapentaenoate, metformin docosahexaenoate, or a mixture of the two and an antihyperlipidemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug; and a pharmaceutically- acceptable carrier, vehicle or diluent.
  • Antihyperlipidemic agents that can be used in accordance with the invention can include, for example, statins, which are HMG CoA enzyme inhibitors, cholesterol absorption inhibitors, and cholesterol esterase transfer protein (CETP) inhibitors and pharmaceutically- acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.
  • statins which are HMG CoA enzyme inhibitors, cholesterol absorption inhibitors, and cholesterol esterase transfer protein (CETP) inhibitors and pharmaceutically- acceptable salts and prodrug thereof, and pharmaceutically-acceptable salts of said prodrug, and others.
  • the antihyperlipidemic agent is a statin, cholesterol absorption inhibitor, and CETP inhibitor or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • the pharmaceutically acceptable salt is selected from the group consisting of a propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathal ate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, p- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate,
  • statins are atorvastatin, risuvo statin, simvastatin, or pravastatin, pharmaceutically-acceptable salts or a prodrugs thereof, and pharmaceutically- acceptable salts of said prodrugs.
  • Preferred agents among cholesterol absorption inhibitors include ezetimibe, also known as Zetia.
  • Preferred agents among CETP inhibitors include anacetrapib.
  • CETP inhibitors include, but are not limited to anacetrapib or a hydrate, and solvate thereof.
  • metformin salts of EPA, DHA, or a combination thereof are present in the combination therapy an amount ranging from 1000 mg to 6000 mg.
  • the pravastatin is present in the amount ranging from 10 mg to 100 mg.
  • the ezetimibe is present 5 mg to 50 mg.
  • kits comprising a first unit dosage form comprising metformin salts of EPA, DHA or a combination thereof; a second unit dosage form comprising an antiglycemic agent or a hydrate, and solvate thereof; and a container.
  • kits comprising a first unit dosage form comprising metformin salts of EPA, DHA or a combination thereof; a second unit dosage form comprising an antihyperlipidemic agent or a hydrate, and solvate thereof; and a container.
  • Figure 1 shows a graph summarizing data acquired from a single dose
  • Metabolic syndrome is intricately intertwined with T2D, which has become pandemic.
  • Clinical presentation of this syndrome is patient-dependent and the co-morbidities in patients with diabetes (chronic hyperglycemia) include high blood pressure, hyperlipidemia and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy.
  • the long-term consequences of these co-morbidities also include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic cataracts.
  • Metformin eicosapentaenoate, metformin docosahexaenoate, and a mixture of the two have been described and claimed as dual action treatment for T2D and elevated triglycerides in a pending application (U.S. Provisional Application Serial No. 13/348,265). It is also stated that the composition of metformin eicosapentaenoate, metformin docosahexaenoate and a composition of a mixture of two can provide high blood levels.
  • T2D is a heterogeneous disease with multiple causes that are responsible for chronic hyperglycemia and its attendant complications.
  • the principal target of metformin eicosapentaenoate is believed to be the liver, where metformin eicosapentaenoate acts to control excess glucose and triglycerides (hypertriglyceridemia) production.
  • Antidiabetic agents such as sulfonylureas, meglitinides, thiazolidinediones, alpha- glucosidase inhibitors, dipeptidylpeptidase IV (DPP IV) inhibitors and sodium-glucose transporter-2 (SGLT-2) inhibitors control hyperglycemia by different mechanisms.
  • DPP IV dipeptidylpeptidase IV
  • SGLT-2 sodium-glucose transporter-2
  • Antidiabetic agents such as sulfonylureas, meglitinides, thiazolidinediones, alpha- glucosidase inhibitors, dipeptidylpeptidase IV (DPP IV) inhibitors and sodium-glucose transporter-2 (SGLT-2) inhibitors control hyperglycemia by different mechanisms.
  • DPP IV inhibitors prevent glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP) inactivation and hence, are able
  • Antihyperlipidemic agents such as HMG CoA inhibitors, cholesterol absorption inhibitors and CETP inhibitors control hyperlipidemia by different mechanisms.
  • HMG CoA inhibitors control cholesterol biosynthesis by the liver
  • cholesterol absorption inhibitors control the entry of cholesterol from the digestive track into systemic circulation
  • CETP inhibitors enhance the blood levels of high density or the so called good cholesterol.
  • eicosapentaenoic acid shows enhanced benefit in impaired glucose metabolism and shows cardiovascular benefits in reducing coronary events in humans, including stroke [Y. Saito et al. Atherosclerosis. 200: 135-140 (2008); S. Oikawa et al. Atherosclerosis. 206: 535-539, (2009)].
  • hypercholesterolaemic patients a randomized open-label, blinded endpoint analysis Lancet. 369: 1090-8, (2007)] found that treatment with 1.8g of eicosapentaenoic acid as an ester derivative per day reduced the risk of major coronary events by 19% over statin-therapy alone in patients being treated for hypercholesterolemia with statins.
  • the study followed 18,645 patients in Japan for five years.
  • the study also found that EPA reduced the risk of unstable angina and non-fatal coronary events in the population. Multiple sub-analyses have been performed on the data from the JELIS study as well.
  • docosahexaenoic acid is a component of Lovaza® (marketed by Glaxo), which is prescribed for controlling hypertriglyceridemia.
  • docosahexaenoic acid plays an important role in the retina. Additional studies confirmed DHA benefits for other nervous system functions, cardiovascular health, and potentially other organs. In one study, men who took DHA supplements for 6-12 weeks decreased the concentrations of several inflammatory markers in their blood by approximately 20% [Kelley et al. J. Nutr. 139: 495-501 (2009)]. It is now considered so important to brain and eye development that DHA is included in most infant formulas. Moreover, in preliminary research, it was found that a diet rich in DHA might protect stroke victims from brain damage and disability and aid in a speedier recovery.
  • combination therapies comprising metformin eicosapentaenoate, metformin docosahexaenoate or a mixture thereof, and an antihyperglycemic agent or an antihyperlipidemic agent, to treat a metabolic disorder selected from the group consisting of T2D, pre-diabetes, obesity, metabolic syndrome, and, respectively, hyperglycemia or hyperlipidemia.
  • T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including atrial fibrillation, cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in mammals (e.g., diabetic patients).
  • the methods, compositions, and kits of disclosure are useful in treating diabetes and cardiovascular complications, including, but not limited to, atrial fibrillation, arrhythmia, myocardial infarction, stroke and cardiomyopathy.
  • treating refers to retarding, arresting, or reversing the progress of, or alleviating or preventing either the disorder or condition to which the term “treating” applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a disorder, symptom, or condition, as the term “treating” is defined above.
  • Metformin eicosapentaenoate is represented below:
  • Metformin docosahexaenoate is represented below:
  • metformin EPA and metformin DHA have a water solubility of at least 50 mg/mL.
  • metformin EPA and metformin DHA comprise a triglyceride lowering effective amount of eicosapentaenoic acid or docosahexaenoic acid.
  • metformin EPA and metformin DHA are in solid form.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.
  • administration encompasses co -administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate containers (e.g., capsules) for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • single formulation refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient.
  • the single vehicle is designed to deliver an effective amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • unit dose is used herein to mean simultaneous administration of both agents together, in one dosage form, to the patient being treated.
  • the unit dose is a single formulation.
  • the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the agents along with pharmaceutically acceptable carriers and excipients.
  • the unit dose is one or more tablets, capsules, pills, or patches administered to the patient at the same time.
  • test substance refers to metformin eicosapentaenoate, metformin docosahexaenoate, or a combination thereof, and an antihyperglycemic agent or an antihyperlipidemic agent.
  • oral dosage form includes a unit dosage form prescribed or intended for oral administration.
  • a "mixture of metformin eicosapentaenoate and metformin docosahexaenoate” refers to a mixture of the two compounds present in x and y%, wherein x and y are not zero, but the sum of x and y is 100 %. For example, when metformin eicosapentaenoate is present at 50%, then metformin docosahexaenoate will be present at 50%.
  • a combination therapy comprising an effective amount of metformin eicosapentaenoate, metformin docosahexaenoate, or a combination thereof, and an antihyperglycemic agent or an antihyperlipidemic agent.
  • An "effective amount" of a combination of agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorders treated with the combination.
  • the combination of metformin eicosapentaenoate, metformin docosahexaenoate, or a combination thereof, and an antihyperglycemic agent or an antihyperlipidemic agent described herein displays a synergistic effect.
  • the term "synergistic effect" as used herein refers to action of two agents producing an effect, for example, slowing the symptomatic progression of diabetes or symptoms thereof, which is greater than the simple addition of the effects of each drug administered alone.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation
  • a combination therapy comprising a combination of metformin eicosapentaenoate or metformin docosahexaenoate, or a mixture thereof, and an
  • This therapy is effective for the treatment of T2D, pre-diabetes, obesity, metabolic syndrome,
  • hypertriglyceridemia and T2D complications such as neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including cardiac arrhythmia, myocardial infarction, stroke, and cardiomyopathy in diabetic patients.
  • Diabetes mellitus commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia (see, e.g., LeRoith, D. et al., (eds.), Diabetes Mellitus (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996)).
  • hyperglycemia Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for macrovascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease.
  • type 1 diabetes (formerly referred to as insulin-dependent diabetes or IDEM); and type 2 diabetes (formerly referred to as noninsulin dependent diabetes or NIDDM).
  • IDEM insulin-dependent diabetes
  • NIDDM noninsulin dependent diabetes
  • Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type 2 diabetes can range from
  • Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of insulin to compensate for this defect.
  • inadequate amounts of insulin are present to compensate for insulin resistance and adequate control of glucose, a state of impaired glucose tolerance develops.
  • insulin secretion declines further and the plasma glucose level rises, resulting in the clinical state of diabetes.
  • Type 2 diabetes can be due to a profound resistance to insulin stimulating regulatory effects on glucose and lipid metabolism in the main insulin-sensitive tissues: muscle, liver and adipose tissue.
  • obesity is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m 2 .
  • the term obesity can be categorized as follows: the term “class I obesity” is the condition wherein the BMI is equal to or greater than 30 kg/m 2 but lower than 35 kg/m 2 ; the term “class II obesity” is the condition
  • the term "class III obesity" is the condition wherein the BMI is equal to or greater than 40 kg/m 2 .
  • visceral obesity is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
  • hypoglycemia is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L).
  • fasting has the usual meaning as a medical term.
  • Insulin-sensitizing Asperger's trademark for a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to a wide range of materials, including but not limited to insulin resistance-improving", or “insulin resistance- lowering” are synonymous and used interchangeably.
  • insulin resistance is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state
  • a method of determining insulin resistance is the euglycaemic/hyperinsulinaemic clamp test.
  • the ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique.
  • There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition).
  • WHO definition 25th percentile of the background population investigated.
  • Rather less laborious than the clamp test are so called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and from these the insulin resistance is calculated. With this method, it is not possible to distinguish between hepatic and peripheral insulin resistance.
  • insulin resistance the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia can be quantified by assessing the "homeostasis model assessment to insulin resistance (HOMA- IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care. 24: 362-5 (2001)). Further reference is made to methods for the determination of the HOMA- index for insulin sensitivity (Matthews et al. Diabetologia. 28:412-19 (1985)), of the ratio of intact proinsulin to insulin (Forst et al. Diabetes. 52(Suppl .l): A459 (2003)) and to an euglycemic clamp study.
  • HOMA- IR homeostasis model assessment to insulin resistance
  • HOMA-IR homeostasis assessment model
  • the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.
  • HbAlc refers to the product of a non-enzymatic glycation of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbAlc value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbAlc in the sense of a "blood sugar memory” reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbAlc value is consistently well adjusted by intensive diabetes treatment (i.e. ⁇ 6.5% of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy.
  • metformin on its own achieves an average improvement in the HbAlc value in the diabetic of the order of 1.0-1.5%. This reduction of the HbAlc value is not sufficient in all diabetics to achieve the desired target range of ⁇ 6.5% and preferably ⁇ 6% HbAlc.
  • the "metabolic syndrome”, also called “syndrome X” (when used in the context of a metabolic disorder), also called the “dysmetabolic syndrome” is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen D E, et al. Am J Epidemiol. 156: 1070-7 (2002)).
  • diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present:
  • Abdominal obesity defined as waist circumference >40 inches (or 102 cm) in men, and >35 inches (or 94 cm) in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumference85 cm in men and 90 cm in women;
  • Patients with a predisposition for the development of IGT or IFG or T2D are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant.
  • a typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre -diabetes.
  • pancreatic beta-cells The methods to investigate the function of pancreatic beta-cells are similar to the above methods with regard to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement of beta-cell function can be measured for example by determining a HOMA- index for beta-cell function (Matthews et al. Diabetologia. 28:412-19 (1985)), the ratio of intact proinsulin to insulin (Forst et al., Diabetes.
  • Pre -diabetes is the condition wherein an individual is pre-disposed to the development of type 2 diabetes.
  • Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with a fasting blood glucose within the high normal range 100 mg/dL (J. B. Meigs, et al. Diabetes. 52:1475-1484 (2003)) and fasting hyperinsulinemia (elevated plasma insulin concentration).
  • the scientific and medical basis for identifying prediabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes” issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases ⁇ Diabetes Care. 25:742- 749 (2002)).
  • insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score>4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.
  • type 2 diabetes is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/ L).
  • the measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/L) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it.
  • the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.
  • late stage T2D mellitus includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and macrovascular complications, e.g. diabetic nephropathy, or coronary heart disease (CHD).
  • CHD coronary heart disease
  • the methods, compositions, and kits of the invention are useful in treating diabetic complications, including, but not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy.
  • treating refers to retarding, arresting or reversing the progress of, or alleviating or preventing either the disorder or condition to which the term “treating”, applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a disorder, symptom or condition, as the term “treating”, is defined above.
  • a combination therapy comprising metformin eicosapentaenoate or metformin docosahexaenoate, or a mixture thereof, and an antihyperglycemic agent, or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug.
  • antihyperglycemic agents that can be used in accordance with the invention are members of different classes of antihyperglycemic agents (e.g., sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors, SGLT-2 inhibitors and others), pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • antihyperglycemic agents e.g., sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors, SGLT-2 inhibitors and others
  • pharmaceutically-acceptable salts and prodrugs e.g., sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors
  • sulfonylureas refers to a class of compounds that stimulate insulin release by binding to the sulfonylurea receptor, a subunit of the ICATP channel complex. This binding leads to closure of the channel, resulting in voltage change in the beta-cell membrane and, in turn, influx of Ca 2+ ions causing exocytosis of insulin granules.
  • sulfonylureas see, for example, Metabolism. 55: 20 (2006) and references cited therein, and Lancet. 358: 1709 (2001) and references cited therein.
  • thiazolidinediones refers to a class of compounds that are selective agonists for the peroxisome proliferator- activated receptor gamma (PPARy), a member of family of nuclear hormone receptors that function as ligand-activated transcription factors.
  • PPARy peroxisome proliferator- activated receptor gamma
  • thiazolidinediones see, for example, Trends Endocrin. Met. 10: 9 (1999) and references cited therein.
  • alpha-glucosidase inhibitors refers to a class of compounds having the ability to competitively inhibit brush border enzyme alpha-glucosidase in the GI tract, which has the ability to cleave complex carbohydrates into sugars.
  • alpha-glucosidase inhibitors see, for example, Diabetes Res. Clin. Pr. 40: S51 (1998) and references cited therein.
  • DPP IV inhibitors refers to a class of compounds that have the ability to selectively inactivate the enzyme DPP-IV, and those which have the ability to rapidly inactivate incretin hormones (e.g., glucagon-like peptide-1 (GLP-1) and insulinotropic polypeptide (GIP)), that are released by the intestine throughout the day, and whose levels are increased after a meal.
  • GLP-1 glucagon-like peptide-1
  • GIP insulinotropic polypeptide
  • the DPP-IV inhibitor sitagliptin can be prepared according to procedure described by Kim et al. in J. Med. Chem. 48: 141-151 (2005) and in J. Med. Chem. 51 : 589-602 (2008).
  • SGLT-2 inhibitors refers to a class of compounds that have the ability to selectively inhibit renal sodium-glucose co -transporter 2 and prevent renal glucose reabsorption from the glomerular filtrate and provide an insulin-independent means of controlling hyperglycemia.
  • SGLT-2 inhibitors see, for example, J. Med. Chem. 52: 1785 1794 (2009) and references cited therein.
  • any sulfonylurea, meglitinide, thiazolidinedione, alpha-glucosidase inhibitor, DPP-IV inhibitor, or a SGLT-2 inhibitor or a pharmaceutically- acceptable salt or a prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug, or any combination thereof, can be employed.
  • Sulfonylureas that can be used in accordance with the invention include, but are not limited to, acetohexamide, which can be prepared as described in U.S. Patent No. 3,013,072;
  • glibornuride which can be prepared as described in U.S. Patent No. 4,153,710
  • gliclazide which can be prepared as described in U.S. Patent No. 6,733,782
  • glipizide which can be prepared and its use as oral administration as described in U.S. Patent No. 5,545,413 ;
  • pioglitazone refers to pioglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the hydrochloride salt.
  • DPP- IV inhibitors that can be used in accordance with the invention include, but are not limited to, linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, denagliptin, carmegliptin, melogliptin, and dutogliptin, or a pharmaceutically-acceptable salt of one of the beforementioned DPP IV inhibitors, or a prodrug thereof.
  • linagliptin refers to linagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. Crystalline forms are described in WO 2007/128721. Methods for the manufacture of linagliptin are described in the patent applications WO 2004/018468 and WO 2006/ 048427 for example. Linagliptin is distinguished from structurally comparable DPP IV inhibitors, as it combines exceptional potency and a long- lasting effect with favorable pharmacological properties, receptor selectivity and a favorable side-effect profile or bring about unexpected therapeutic advantages or improvements when used in combination with an SGLT2 inhibitor and a third antidiabetic agent according to this invention.
  • sitagliptin refers to sitagliptin (or MK-0431) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. In one embodiment, sitagliptin is in the form of its
  • sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate.
  • a class of this embodiment refers to sitagliptin phosphate monohydrate.
  • Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Patent No. 6,699,871 and in Example 7 of WO 03/004498.
  • Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and in WO 2007/050485. For details, e.g. on a process to manufacture or to formulate this compound or a salt thereof, reference is thus made to these documents.
  • a tablet formulation for sitagliptin is commercially available under the trade name Januvia®.
  • vildagliptin refers to vildagliptin (or LAF-237) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. Specific salts of vildagliptin are disclosed in WO 2007/019255. A crystalline form of vildagliptin as well as a vildagliptin tablet formulation are disclosed in
  • a modified release vildagliptin formulation is described in WO 2006/135723.
  • a tablet formulation for vildagliptin is expected to be commercially available under the trade name Galvus.
  • saxagliptin refers to saxagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof
  • saxagliptin is in the form of the free base or a HC1 salt (for example as mono- or dihydrochloride, including hydrates thereof), or a mono-benzoate salt as disclosed in WO 2004/052850 and WO 2008/131149.
  • saxagliptin is in the form of the free base.
  • saxagliptin is in the form of the monohydrate of the free base as disclosed in WO 2004/052850.
  • a process for preparing saxagliptin is also Sdisclosed in WO 2005/106011 and WO 2005/ 115982.
  • Saxagliptin can be formulated in a tablet as described in WO 2005/117841.
  • a process to manufacture, to formulate or to use this compound or a salt thereof reference is thus made to these documents and U.S. Patent No. 6,395,767 and WO 01/68603.
  • denagliptin refers to denagliptin (or GSK-823093) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof.
  • denagliptin is in the form of its hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its tosylate salt as disclosed in WO 2005/009956.
  • a class of this embodiment refers to denagliptin tosylate.
  • Crystalline anhydrous denagliptin tosylate is disclosed in WO 2005/009956.
  • alogliptin refers to alogliptin (or SYR-322) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof
  • alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt each as disclosed in WO 2007/035629.
  • a class of this embodiment refers to alogliptin benzoate.
  • Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372.
  • a process for preparing alogliptin is disclosed in WO 2007/ 112368 and, specifically, in WO 2007/035629.
  • Alogliptin (namely its benzoate salt) can be formulated in a tablet and administered as described in WO 2007/033266.
  • Alogliptin namely its benzoate salt
  • WO 2007/033266 for details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents and to US 2005/261271 , EP 1586571 and WO 2005/095381.
  • carmegliptin refers to carmegliptin
  • melogliptin refers to melogliptin
  • Specifically claimed salts include the methanesulfonate and p-toluenesulfonate.
  • methanesulfonate and p-toluenesulfonate.
  • dutogliptin refers to dutogliptin (or PHX-1149, PHX- 1149T) and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its preparation are inter alia disclosed in WO 2005/047297. Pharmaceutically acceptable salts include the tartrate. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
  • SGLT-2 inhibitors that can be used in accordance with the invention include, but are not limited to dapagliflozin, canagliflozin, atigliflozin, remogliflozin and sergliflozin.
  • dipagliflozin refers to dapagliflozin, including hydrates and solvates thereof, and crystalline forms thereof.
  • the compound and methods of its synthesis are described in WO 03/099836 for example.
  • Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/ 002824 for example.
  • canagliflozin refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
  • the compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example.
  • Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.
  • atigliflozin refers to atigliflozin, including hydrates and solvates thereof, and crystalline forms thereof.
  • the compound and the methods of its synthesis are described in WO 2004/007517 for example.
  • remogliflozin refers to remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.
  • sergliflozin refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.
  • pharmaceutically-acceptable salts includes both pharmaceutically- acceptable acid addition salts and pharmaceutically-acceptable cationic salts, where appropriate, such as aliphatic mono or dicarboxylic acids, hydro xyalkanoic or hydro xyl alkanedioic acids, e.g.
  • methanesulfonic, or ethanesulfonic acid or aromatic sulfonic acids, e.g. benzenesulfonic, or 4-methylbenzenesulfonic acid; or cyclohexanesulfamic acid.
  • Preferred acids include, but are not limited to, hydrobrornic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic, ethanesulfonic, laurylsulfonic, benzene sulfonic, and para-toluenesulfonic acids.
  • metformin docosahexaenoate metformin eicosapentaenoate, or a mixture thereof, in combination with a non-fatty acid salt form of metformin, e.g., metformin hydrochloride, succinate, or fumarate, or in combination with the free base of metformin.
  • This combination can further comprise any of the antihyperglycemia agents described above. Additionally, this combination can comprise eicosapentanoic acid, and/or docosahexaenoic acid.
  • Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc. 121 : 1790 (1922)...
  • combination therapies comprising, at least, the following combination of agents:
  • metformin docosahexaenoate and miglitol metformin docosahexaenoate and glipizide; metformin docosahexaenoate and glyburide; metformin docosahexaenoate and saxagliptin; and metformin docosahexaenoate and sitagliptin; metformin docosahexaenoate and vildagliptin; metformin docosahexaenoate and linagliptin; metformin docosahexaenoate and dutogliptin;
  • metformin eicosapentaenoate and miglitol metformin eicosapentaenoate and glipizide; metformin eicosapentaenoate and glyburide; metformin eicosapentaenoate and saxagliptin; metformin eicosapentaenoate and sitagliptin; metformin eicosapentaenoate and vildagliptin; metformin eicosapentaenoate and linagliptin; metformin eicosapentaenoate and dutogliptin.
  • the combination therapies of paragraphs 1 and 2, above can be further combined with additional metformin (e.g., metformin hydrochloride), eicosapentanoic acid, and/or docosahexaenoic acid.
  • additional metformin e.g., metformin hydrochloride
  • eicosapentanoic acid eicosapentanoic acid
  • docosahexaenoic acid e.g., metformin hydrochloride
  • One aspect herein provides a combination therapy comprising metformin
  • antihyperlipidemic agent or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug.
  • antihyperlipidemic agents that can be used in accordance with the invention are members of different classes of antihyperlipidemic agents (e.g., HMG-CoA reductase inhibitors (statins), CETP inhibitors, and cholesterol absorption inhibitors and others), pharmaceutically-acceptable salts and prodrugs thereof, and pharmaceutically-acceptable salts of said prodrugs.
  • provided herein is a method of treating hyperlipidemia, comprising administering to a subject in need thereof an effective amount of the
  • provided herein is a method of treating hypertriglyceridemia, comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating dyslipidemia comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating cardiovascular disease comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • the cardiovascular disease can be cardiac arrhythmia, cardiac ischemia, myocardial infarction, cardiomyopathy, or stroke.
  • the arrhythmia is an atrial fibrillation.
  • a method of treating obesity comprising administering to a subject in need thereof an effective amount of the antihyperlipidemic combination therapy of the invention.
  • a method of treating prediabetes comprising administering to a subject in need thereof an effective amount of the
  • provided herein is a method of treating atherosclerosis, comprising administering to a subject in need thereof an effective amount of the combination therapy of the invention. Also provided herein is a method of lowering triglycerides in a subject in need thereof, comprising administering to the subject an effective amount of the antihyperlipidemic combination therapy of the invention. In another embodiment, provided herein is a method of treating atrial fibrillation, or reducing the probability of an occurrence of an atrial fibrillation, comprising administering to a subject in need thereof an effective amount of the
  • provided herein is a method of lowering the cholesterol level and/or the triglyceride level in a mammal comprising administering to the subject an effective amount of the antihyperlipidemic combination therapy of the invention.
  • HMG-CoA reductase inhibitor refers to a compound that competitively blocks the enzyme 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA) reductase. By competitively blocking this enzyme, the HMG-CoA reductase inhibitors interfere with cholesterol formation (enzyme catalyzes the conversion of HMG-CoA to mevalonate). As a result, they decrease total cholesterol, low-density lipoprotein cholesterol
  • LDL-C low-density lipoprotein
  • VLDL very low-density lipoprotein
  • HMG-CoA reductase inhibitors that can be used in accordance with the disclosure include, but are not limited to: atorvastatin, which can be prepared as disclosed in U.S. Patent No. 7,030,151 ; pravastatin and related compounds, which can be prepared as disclosed in U.S. Patent Nos.4,346,227 and 4,448,979; rosuvastatin, which can be prepared as disclosed in U.S. Patent No.6, 858, 618; simvastatin and related compounds, which can be prepared as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171.
  • HMG-CoA reductase inhibitors also include atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pravastatin, nisvastatin, itavastatin, velostatin and fluindo statin.
  • CETP inhibitor refers to a compound which catalyses the transfer of cholesteryl ester from HDL to apolipoprotein B containing lipoproteins in exchange for triglyceride and thereby plays a major role in lipoprotein metabolism.
  • CETP inhibitors see, for example, Curr. Opin. Pharmacol. 6:162 (2006) and references cited therein.
  • CETP inhibitors which can be used in accordance with the disclosure are not limited by any structure or group of CETP inhibitors.
  • CETP inhibitors which can be used in accordance with the disclosure include, but are not limited to: anacetrapib, which can be prepared as disclosed in WO 2007005572. The disclosure thereof is incorporated herein by reference.
  • cholesterol absorption inhibitors refers to a compound that inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids.
  • cholesterol absorption inhibitors see, for example, Nutr. Metab. Cardiovasc. Dis.13:42 (2004) and references cited therein.
  • Cholesterol absorption inhibitors which can be used in accordance with the disclosure include, but are not limited to ezetimibe (Zetia), which can be prepared as disclosed in U.S. Patent Nos. 5,767,115 and 5, 846,966. The disclosures thereof are incorporated herein by reference. In the practice of the compositions and methods of the disclosure, any HMG Co-A reductase inhibitors or in a pharmaceutically acceptable combination with any flushing inhibiting agent can be employed.
  • the disclosure provides for pharmaceutical compositions comprising metformin salts of EPA, DHA or a combination thereof; and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, and solvate thereof.
  • the disclosure provides for unit dose formulations comprising metformin salts of EPA, DHA or a combination thereof; and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, and solvate.
  • the disclosure provides for methods of treating a diabetic
  • cardiovascular complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth herein below.
  • diabetic complications are, for example, atrial fibrillation, arrhythmia, myocardial infarction, stroke and cardiomyopathy.
  • the disclosure provides for methods of treating T2D in a mammal comprising administering to said mammal metformin salts of EPA, DHA or a combination thereof , and an antihyperlipidemic agent or a hydrate, and solvate hereof.
  • the disclosure provides for methods wherein the metformin salts of EPA, DHA or a combination thereof, and an antihyperlipidemic agent or a hydrate, and solvate thereof, are administered separately.
  • the disclosure provides for methods wherein the metformin salts of EPA, DHA or a combination thereof, and the antihyperlipidemic agent or a hydrate, and solvate thereof, are administered in a single dosage form, for example, a tablet, a capsule or a caplet.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, where appropriate.
  • pharmaceutically-acceptable cationic salts is intended to define but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzyl phenethylamine) , diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l ,3- propanediol) and procaine.
  • alkali metal salts e.g., sodium and potassium
  • alkaline earth metal salts e.g., calcium and magnesium
  • aluminum salts
  • salts are, for example, inorganic acids, such as hydrohalic acid(e.g., hydrochloric, hydrobromic, or the like), sulfuric acid, nitric acid, or phosphoric acid; or suitable organic acids, for example, suitable aliphatic acids (e.g., aliphatic mono- or dicarboxylic acids), hydroxyalkanoic, or hydro yalkanedioic acids (e.g., acetic, propanoic, hydro xyacetic, 2-hydroxypropanoic, 2- oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2- butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutane
  • inorganic acids such as hydrohalic acid(e.g., hydrochloric, hydrobromic, or the like)
  • sulfuric acid nitric acid, or phospho
  • acids are, for example, hydrobromic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic, ethanesulfonic, laurylsulfonic, benzenesulfonic, and para- toluenesulfonic acids.
  • the pharmaceutically acceptable salt is selected from the group consisting of an L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium hydroxide, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, l -(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, zinc hydroxide, sodium, calcium, potassium, magnesium, and zinc.
  • metformin docosahexaenoate metformin eicosapentaenoate, or a mixture thereof, in combination with a non-fatty acid salt form of metformin (e.g., metformin hydrochloride), succinate, or fumarate, or in combination with the free base of metformin.
  • metformin e.g., metformin hydrochloride
  • succinate e.g., succinate
  • fumarate e.g., a non-fatty acid salt form of metformin
  • combination therapies comprising, at least, the following combination of agents:
  • metformin docosahexaenoate and atorvastatin metformin docosahexaenoate and simvastatin; metformin docosahexaenoate and pravastatin; metformin docosahexaenoate and rosuvastatin; and metformin docosahexaenoate and ezitimibe; metformin docosahexaenoate and anacetrapib; metformin docosahexaenoate and atorvastatin calcium;
  • metformin eicosapentaenoate and atorvastatin metformin eicosapentaenoate and simvastatin; metformin eicosapentaenoate and pravastatin; metformin eicosapentaenoate and rosuvastatin; and metformin eicosapentaenoate and ezitimibe; metformin eicosapentaenoate and anacetrapib; and metformin eicosapentaenoate and atorvastatin calcium; .
  • the combination therapies of paragraphs 1 and 2, above can be further combined with additional metformin (e.g., metformin hydrochloride), eicosapentanoic acid, and/or docosahexaenoic acid.
  • additional metformin e.g., metformin hydrochloride
  • eicosapentanoic acid eicosapentanoic acid
  • docosahexaenoic acid e.g., metformin hydrochloride
  • the invention relates to methods of treating a disease, e.g., diabetic complications in which metformin eicosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, or a mixture of metformin eicosapentaenoate, metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent are administered together, as part of the same pharmaceutical composition.
  • a disease e.g., diabetic complications in which metformin eicosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, or a mixture of metformin eicosapentaen
  • the invention relates to methods of treating a disease, e.g., diabetic complications in which metformin eicosapentaenoate or metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, or a mixture of metformin eicosapentaenoate and metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent are administered separately, as part of an appropriate dosage regimen designed to obtain the benefits of the combination therapy.
  • a disease e.g., diabetic complications in which metformin eicosapentaenoate or metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, or a mixture of metformin eicosapentaenoate and metformin docosapentaenoate and an antihyperglycemic agent or an anti
  • an effective dosage for the treatment of a warmblooded animal, including a mammal, such as a human, for metformin eicosapentaenoate is in the range of about 5 mg/kg/day to about 100 mg/kg/day in single or divided doses.
  • the antihyperglycemic agent or the antihyperlipidemic agent can be administered in single or divided doses.
  • Antihyperglycemic agents or antihyperlipidemic agents will generally be administered in combination in amounts ranging from about 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses, preferably 0.01 mg/kg/day to about 20 mg/kg/day for an average subject, depending upon the antihyperglycemic agent or the antihyperlipidemic agent and the route of administration. Some variation in dosage can necessarily occur depending on the condition of the subject being treated. The prescribing physician can determine the appropriate dose for the individual subject.
  • an effective dosage for the treatment of a warm-blooded animal including a mammal, such as a human, for metformin eicosapentaenoate or for metformin docosahexaenoate is in the range of about 5 mg/kg/day to about 100 mg/kg/day in single or divided doses.
  • the antihyperglycemic agent or the antihyperlipidemic agent can be administered in single or divided doses.
  • either the antihyperglycemic agents or the antihyperlipidemic agents will be administered in combination in amounts ranging from about 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses, preferably 0.01 mg/kg/day to about 20 mg/kg/day for an average subject, depending upon the antihyperlipidemic agent and the route of administration. Some variation in dosage can necessarily occur depending on the condition of the subject being treated. The prescribing physician can determine the appropriate dose for the individual subject.
  • an effective dosage for the treatment of a warm-blooded animal including a mammal, such as a human, for a mixture of metformin eicosapentaenoate and metformin docosahexaenoate is in the range of about 5 mg/kg/day to about 100 mg/kg/day in single or divided doses.
  • a mammal such as a human
  • antihperglycemic agent or the antihyperlipidemic agent can be administered in single or divided doses.
  • either the antihyperglycemic agents or the antihyperlipidemic agents will be administered in combination in amounts ranging from about 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses, preferably 0.01 mg/kg/day to about 20 mg/kg/day for an average subject, depending upon the antihyperglycemic agent or the antihyperlipidemic agent and the route of administration. Some variation in dosage can necessarily occur depending on the condition of the subject being treated. The prescribing physician can determine the appropriate dose for the individual subject.
  • metformin eicosapentaenoate metformin docosahexaenoate and a mixture of these two can occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention.
  • the invention provides for methods of treating diabetic complications in which the metformin eicosapentaenoate, metformin docosapentaenoate or a mixture of metformin eicosapentaenoate and metformin docosapentaenoate and antihyperglycemic agents or antihyperlipidemic agents are administered in combination, to obtain the benefits of the combination therapy.
  • the appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the active agents will depend upon the metformin eicosapentaenoate and the doses of antihyperglycemic agent or of
  • an effective dosage for the treatment of a warmblooded animal including a mammal, like a human, for metformin eicosapentaenoate, metformin docosapentaenoate or a mixture of metformin eicosapentaenoate and metformin docosapentaenoate is in the range of about 1000 mg per day to about 7000 mg per day in single or divided doses, such as about 1000 mg per day to about 6000 mg per day, about 1000 mg to about 5000 mg per day; about 1000 mg per day to about 4000 mg per day; or about 1000 mg per day to about 3000 mg per day; about 1000 mg per day to about 20000 mg per day.
  • the effective dosage is in the range of about 1000 mg per day to about 6000 mg per day
  • antihyperglycemic agents or antihyperlipidemic agents will be administered in amounts ranging from about 1 mg to about 500 mg per day in single or divided doses, for example, about 1 mg to about 500 mg per day, such as about 1 mg to about
  • 300 mg per day about 1 mg to about 200 mg per day; or about 1 mg to about 100 mg per day; about 1 to about 50 mg per day; about 1 mg to about 25 mg per day; about 1 mg to about
  • compositions of the invention can be via any method which delivers a composition of the invention preferentially to the desired tissue (e.g., nerve, kidney, retina, and/or cardiac tissues). Such methods include oral routes, parenteral, intraduodenal routes, etc.
  • the compositions of the present invention can be administered in single (e.g., once daily) or multiple doses or via constant infusion.
  • compositions comprising metformin eicosapentaenoate, and an antihyperglycemic agent or an antihyperlipidemic agent, or metformin docosapentaenoate and an antihyperglycemic agent or an antihyperlipidemic agent, or a mixture of metformin eicosapentaenoate and metformin docosapentaenoate or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically-acceptable salt of said prodrug, are hereinafter referred to, collectively, as "the active compositions of the invention.”
  • the active compositions of the invention can be administered to a subject in need thereof by any conventional routes of administration, including orally, topically, or parenterally (e.g., intravenously, subcutaneously, or intramedullary). Further, the active compositions of the invention can be administered intranasally, as a rectal suppository, or using a "flash" formulation (i.e., allowing the medication to dissolve in the mouth without the need to use water).
  • the active compositions of the invention can be administered alone or in combination with pharmaceutically-acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • a pharmaceutical composition comprising metformin eicosapentaenoate, an antihyperglycemic or an antihyperlipidemic agent, and a pharmaceutically-acceptable carrier, vehicle or diluent; a pharmaceutical composition comprising metformin docosahexaenoate, an antihyperglycemic or an antihyperlipidemic agent, and a pharmaceutically-acceptable carrier, vehicle or diluent; and a pharmaceutical composition comprising metformin eicosapentaenoate, metformin docosahexaenoate , an antihyperglycemic or an antihyperlipidemic agent, and a
  • a combination therapy comprising a pharmaceutical composition comprising metformin docosahexaenoate and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising an antihyperglycemic or an antihyperlipidemic agent and a pharmaceutically acceptable carrier, wherein each pharmaceutical composition is administered separately to a subject.
  • a combination therapy comprising a pharmaceutical composition comprising metformin eicosapentaenoate and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising an antihyperglycemic or an antihyperlipidemic agent and a pharmaceutically acceptable carrier, wherein each pharmaceutical composition is administered separately to a subject.
  • a combination therapy comprising a pharmaceutical composition comprising a mixture of metformin eicosapentaenoate and metformin docosahexaenoate and a pharmaceutically acceptable carrier; and a pharmaceutical composition comprising an antihyperglycemic or an antihyperlipidemic agent and a pharmaceutically acceptable carrier; wherein each pharmaceutical composition is administered separately to a subject...
  • Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the active compositions of the invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients, and the like.
  • additional ingredients such as flavorings, binders, excipients, and the like.
  • tablets containing various excipients including, but are not limited to, sodium citrate, calcium carbonate and calcium phosphate
  • various excipients including, but are not limited to, sodium citrate, calcium carbonate and calcium phosphate
  • various disinte grants e.g., starch and alginic acid
  • binding agents e.g., polyvinylpyrrolidone, sucrose, gelatin and acacia
  • binding agents e.g., polyvinylpyrrolidone, sucrose, gelatin and acacia
  • lubricating agents e.g., magnesium stearate, sodium lauryl sulfate and talc
  • Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules.
  • Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • Aqueous suspensions or elixirs can be desired for oral administration, including various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • solutions of the active compositions of the invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions can be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • composition of the invention is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous, or intramedullary). Topical administration can also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.
  • composition for buccal administration, can take the form of tablets or lozenges formulated in a conventional manner.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifiuoromethane, trichlorofiuorome thane, dichlorotetrafiuoroethane, carbon dioxide, or other suitable gas).
  • a suitable propellant e.g., dichlorodifiuoromethane, trichlorofiuorome thane, dichlorotetrafiuoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer can contain a solution or suspension of the active compound.
  • Capsules and cartridges e.g., made from gelatin
  • an inhaler or insufflator can be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
  • dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, can be prepared.
  • compositions of the invention contain an amount of metformin eicosapentaenoate, metformin docosahexaenoate, or a mixture of the two, and an antihyperglycemic or an antihyperlipidemic agent, or pharmaceutically-acceptable salts or prodrugs thereof, or pharmaceutically-acceptable salts of said prodrugs.
  • the amount of each of those ingredients can independently be, for example, 0.0001 %-95% of the total amount of the composition, where the total amount cannot, of course, exceed 100%.
  • the composition or formulation to be administered will contain a quantity of each of the components of the composition according to the invention in an amount effective to treat the disease or condition of the subject being treated.
  • kits can comprise two separate pharmaceutical compositions: metformin eicosapentaenoate, and antihyperglycemic or an antihyperlipidemic agent, or metformin docosapentaenoate and an antihyperglycemic or an antihyperlipidemic agent, or a mixture of metformin eicosapentaenoate and metformin docosapentaenoate or pharmaceutically- acceptable salts or prodrugs thereof, or pharmaceutically-acceptable salts of said prodrugs as described above.
  • the kit can comprise a container for containing the separate compositions, such as a divided bottle or a divided foil packet.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card (e.g., as follows "First Week, Monday, Tuesday, . . . etc ...Second Week, Monday, Tuesday,. . . etc.”).
  • Other variations of memory aids will be readily apparent.
  • a "daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of the aldose reductase inhibitor can consist of one tablet or capsule while a daily dose of the antihyperglycemic or the antihyperlipidemic agent can consist of several tablets or capsules and vice versa. The memory aid can reflect this.
  • a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • the compositions of the invention generally will be administered in a convenient formulation. The following examples are produced for illustrative purposes.
  • the metformin eicosapentaenoate is present in an amount ranging from about 1000 mg to about 6000 mg; about 1000 mg to about 5000 mg; about 1000 mg to about 40000 mg; about 1000 mg to about 5000mg; or about 1000 mg to about 2000 mg.
  • the antihyperglycemic agent or the antihyperlipidemic agent is present in an amount ranging from about 1 mg to about 300 mg; about 1 mg to about 200 mg; about 1 mg to about 100 mg; about 1 mg to about 50 mg; about 1 mg to about 20 mg; about 1 mg to about 10 mg; about 1 mg to about 5 mg; about 1 mg to about 2.5 mg.
  • a preferred dosage range of metformin docosahexaenoate when administered orally is 750 to 7500 mg, in particular 1000 to 6000 or 1250 to 5000 mg per day.
  • the preferred range of amounts in the pharmaceutical composition is 1000 mg to 3000 mg per day. Examples are 1000, 1500, 2000, 2500 or 3000 mg.
  • Preferably the administration of said amounts is once, twice or three times daily.
  • a preferred dosage range of a mixture of metformin eicosapentaenoate and metformin docosahexaenoate when administered orally is 750 to 7500 mg, in particular 1000 to 6000 or 1250 to 5000 mg per day.
  • the preferred range of amounts in the pharmaceutical composition is 1000 mg to 3000. Examples are 1000, 1500, 2000, 2500 or 3000 mg. Preferably the administration of said amounts is once, twice or three times daily.
  • a preferred dosage range of linagliptin when administered orally is 0.5 mg to 10 mg per day, preferably 2.5 mg to 10 mg, most preferably 1 mg to 5 mg per day.
  • the preferred range of amounts in the pharmaceutical composition is 0.5 to 10 mg, in particular 1 to 5 mg. Examples of particular dosage strengths are 1, 2.5, 5 or 10 mg.
  • the application of the active ingredient can occur up to three times a day, preferably one or two times a day.
  • Suitable formulations for linagliptin can be those formulations disclosed in the application WO 2007/128724, the disclosure of which is incorporated herein in its entirety.
  • a preferred dosage range of sitagliptin when administered orally is from 10 to 200 mg, in particular 25 to 150 mg per day.
  • a recommended dose of sitagliptin is 100 mg calculated for the active moiety (free base anhydrate) once daily or 50 mg twice daily.
  • the preferred range of amounts in the pharmaceutical composition is 10 to 150 mg, in particular 25 to 100 mg. Examples are 25, 50, 75 or 100 mg.
  • the application of the active ingredient can occur up to three times a day, preferably one or two times a day. Equivalent amounts of salts of sitagliptin, in particular of the phosphate monohydrate can be calculated accordingly. Adjusted dosages of sitagliptin, for example 25 and 50 mg, are preferably used for patients with renal failure.
  • a preferred dosage range of vildagliptin when administered orally is from 10 to 150 mg daily, in particular from 25 to 150 mg, 25 and 100 mg or 25 and 50 mg or 50 and 100 mg daily.
  • the daily administration of vildagliptin is 50 or 100 mg.
  • the preferred range of amounts in the pharmaceutical composition is 10 to 150 mg, in particular 25 to 100 mg. Examples are 25, 50, 75 or 100 mg.
  • the application of the active ingredient can occur up to three times a day, preferably one or two times a day.
  • a preferred dosage range of alogliptin when administered orally is from 5 to 250 mg daily, in particular from 10 to 150 mg daily.
  • the preferred range of amounts in the pharmaceutical composition is 5 to 150 mg, in particular 10 to 100 mg. Examples are 10, 12.5, 20, 25, 50, 75 and 100 mg.
  • the application of the active ingredient can occur up to three times a day, preferably one or two times a day.
  • a preferred dosage range of saxagliptin when administered orally is from 2.5 to 100 mg daily, in particular from 2.5 to 50 mg daily.
  • the preferred range of amounts in the pharmaceutical composition is from 2.5 to 100 mg, in particular from 2.5 and 50 mg.
  • Examples are 2.5, 5, 10, 15, 20, 30, 40, 50 and 100 mg.
  • the application of the active ingredient can occur up to three times a day, preferably one or two times a day.
  • a preferred dosage range of dutogliptin when administered orally is from 50 to 400 mg daily, in particular from 100 to 400 mg daily.
  • the preferred range of amounts in the pharmaceutical composition is from 50 to 400 mg. Examples are 50, 100, 200, 300 and 400 mg.
  • the application of the active ingredient can occur up to three times a day, preferably one or two times a day.
  • the preferred dosage range of the SGLT2 inhibitor is in the range from 0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferably from 1 to 50 mg per day.
  • the oral administration is preferred. Therefore, a pharmaceutical composition can comprise the hereinbefore mentioned amounts, in particular from 1 to 50 mg or 1 to 25 mg.
  • Particular dosage strengths e.g. per tablet or capsule are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, or 50 mg, in particular of the compound dapagliflozin.
  • the metformin salts of EPA, DHA or a combination thereof is present in an amount ranging from 2.5 mg to lg; 2.5 mg to 750 mg; 2.5 mg to 500 mg; 2.5 mg to 250 mg; or 2.5 mg to 200 mg; 2.5 mg to 150 mg; 2.5 mg to 100 mg; 2.5 mg to 50 mg; 2.5 mg to 25 mg; 2.5 mg to 20 mg; 2.5 mg to 10 mg and 2.5 mg to 5 mg.
  • a preferred dosage range of atorvastatin calcium is an amount ranging from 5 mg to 40 mg. In certain embodiments, the atorvastatin is present in the amount ranging from 2.5 mg to 250 mg; or 2.5 mg to 200 mg; 2.5 mg to 150 mg; 2.5 mg to
  • the pharmaceutical composition is formulated as a tablet.
  • the composition is administered on a daily regimen (e.g., once daily, twice daily, or three times daily, etc.).
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • a preferred dosage range of rosuvastatin is an amount ranging from 5 mg to 40 mg.
  • the pharmaceutical composition is formulated as a tablet.
  • the composition is administered on a daily regimen (e.g., once daily, twice daily, or three times daily, etc.).
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • a preferred dosage range of simvastatin is an amount ranging from 10 mg to 100 mg.
  • the simvastatin is present in the amount ranging from 2.5 mg to 250 mg; or 2.5 mg to 200 mg; 2.5 mg to 150 mg; 2.5 mg to 100 mg, 2.5 mg to 80 mg, 2.5 mg to 60 mg, 2.5 mg to 40 mg, 2.5 mg to 20 mg, and 2.5 mg to 10 mg; 2.5 mg to 50 mg; 2.5 mg to 25 mg; 2.5 mg to 20 mg; 2.5 mg to 10 mg and 2.5 mg to 5 mg.
  • the pharmaceutical composition is formulated as a tablet.
  • the composition is administered on a daily regimen (e.g., once daily, twice daily, or three times daily, etc.).
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • a preferred dosage range of pravastatin is an amount ranging from 10 mg to 100 mg.
  • the pharmaceutical composition is formulated as a tablet.
  • the composition is administered on a daily regimen (e.g., once daily, twice daily, or three times daily, etc.).
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • a preferred dosage range of ezetimibe is an amount ranging from 5 mg to 50 mg.
  • the ezetimibe is present in the amount ranging from 2.5 mg to 100 mg, 2.5 mg to 80 mg, 2.5 mg to 60 mg, 2.5 mg to 40 mg, 2.5 mg to 20 mg, and 2.5 mg to 10 mg; 2.5 mg to 50 mg; 2.5 mg to 25 mg; 2.5 mg to 20 mg; 2.5 mg to 10 mg and 2.5 mg to 5 mg.
  • the pharmaceutical composition is formulated as a tablet.
  • the composition is administered on a daily regimen (e.g., once daily, twice daily, or three times daily, etc.).
  • the pharmaceutical composition is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • N,N-dimethylimidodicarbonimidic diamide (Metformin free base).
  • N,N-dimethylimidodicarbonimidic diamide hydrochloride (4.01 g, 24.3 mmol) was dissolved in IN 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 EtOH (80 mL). 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 free base as a white solid, and placed under high vac. The material was left under high vac overnight to yield 6.53 g (84%) of metformin. f [Amino( imino )methyl]amino !( dimethylamino )methaniminium ( 5Z,8Z,11Z, 14Z, 17Z)-eicosa-
  • Metformin free base (2.67 g, 20.7 mmol) was dissolved in acetonitrile (100 mL) and the resulting solution was filtered rough 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,l lZ,14Z,17Z)-eicosa-5,8,l l ,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.
  • 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 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 (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.
  • 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 metformin EPA, 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 ethyl ester 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
  • water soluble preparations are especially suitable for parenteral administration, for example, intravenous administration.
  • Test compounds were administered by oral gavage in deionized water.
  • Metformin EPA exhibits a peak plasma concentration that is significantly greater than that of EE EPA. As can be seen, EE EPA exhibits a peak plasma concentration (Cmax) of only 1.4 ⁇ g/mL. In contrast, metformin EPA exhibits a peak plasma concentration (Cmax) of 23.3 ⁇ g/mL. Surprisingly, metformin EPA exhibits a peak plasma concentration that is more than ten times greater than that of EE EPA.
  • Treating patients with type 2 diabetes with the pharmaceutical composition according to the invention in addition to producing an acute improvement in the glucose metabolic situation, prevents deterioration in the metabolic situation in the long term. This can be observed when patients are treated for a longer period ( e.g. 3 months to 1 year or even 1 to 6 years), with the pharmaceutical composition according to the invention and are compared with patients who have been treated with other antidiabetic medicaments. There is evidence of therapeutic success compared with patients treated with other antidiabetic medicaments if no or only a slight increase in the fasting glucose and/or HbAlc value is observed.
  • the efficacy of a pharmaceutical composition according to the invention can be tested in clinical studies with varying run times (e.g. 12 weeks to 6 years) by determining the fasting glucose or non-fasting glucose (e.g. after a meal or a loading test with oGTT or a defined meal) or the HbAlc value.
  • Examples of this are a reduction in systolic and/or diastolic blood pressure, a lowering of the plasma triglycerides, a reduction in total or LDL cholesterol, an increase in HDL cholesterol or a reduction in weight, either compared with the starting value at the beginning of the study or in comparison with a group of patients treated with placebo or a different therapy.
  • the treatment of type 2 diabetes or pre-diabetes patients with a pharmaceutical composition according to the invention prevents or reduces or reduces the risk of developing microvascular complications (e.g., diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer) or macro vascular complications (e.g., myocardial infarct, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis).
  • microvascular complications e.g., diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer
  • macro vascular complications e.g., myocardial infarct, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis.
  • Type 2 diabetes or patients with pre-diabetes are treated long-term (e.g., for 1-6 years), with a pharmaceutical composition according to the invention or a combination of active ingredients according to the invention and compared with patients who have been treated with other antidiabetic medicaments or with placebo.
  • Evidence of the therapeutic success compared with patients who have been treated with other antidiabetic medicaments or with placebo can be found in the smaller number of single or multiple complications.
  • the numbers are counted by anamnesis and various test methods.
  • the success of the treatment is determined by computer-controlled illumination and evaluation of the background to the eye or other ophthalmic methods.
  • the nerve conduction rate can be measured using a calibrated tuning fork, for example.
  • the following parameters can be investigated before the start, during and at the end of the study: secretion of albumin, creatinine clearance, serum creatinin values, time taken for the serum creatinine values to double, time taken until dialysis becomes necessary.
  • a diabetic rat model that can be used for determination of conditions leading to a method for treatment and prevention of post-ischemic damage of the heart and heart tissue is the spontaneously diabetic bio-bred (BB/W) rats. These rats are a useful model of autoimmune human insulin-dependent diabetes.
  • 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 (3-4 months old) control are pretreated with heparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP).
  • heparin 1000 u; IP
  • sodium pentobarbital 65 mg/kg; IP
  • 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 min 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 allowing rapid change perfusion media.
  • the hearts are perfused using an accurate roller pump.
  • the perfusate consists of 118 mM NaCl, .47 mM KC1, 12 mM CaCl 2 , 12 mM MgC12, 25 mM NaHCC , 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 3-4 hours.
  • Diabetic control (DC) diabetic treated (DZ) normal (C) control and normal treated (CZ) hearts are subjected to 20 min. of normoxic perfusion followed by 20 min. of zero-flow ischemia where the perfusate flow is completely shut off, followed by 60 min. of reperfusion.
  • Hearts are treated with 10 ⁇ metformin eicosapentaenoate.
  • metformin eicosapentaenoate treated diabetic group (DZ) are subjected to 10 min. of normoxic perfusion with normal Krebs-Henseleit buffer and 10 min.
  • 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 are subjected to 20 min. of normoxic perfusion at a flow rate of
  • the hearts are subjected to 30 min. of low-flow ischemia (flow rate 1.25 mL/min) and 30 minutes of reperfusion at normal flow rate (12.5 mL/min).
  • active ingredient denotes two compounds according to the invention [i.e., denotes metformin eicosapentaenoate, metformin docosahexaenoate, or a mixture thereof (first component of the active ingredient) and other antidiabetic agents such as statins, cholesterol absorption inhibitors, and CETP inhibitors or a pharmaceutically-acceptable salt or prodrug thereof, or a pharmaceutically- acceptable salt of said prodrug (second component of the active ingredient)].
  • Additional suitable formulations can be prepared according to the procedures described in, for example in the application WO 2007/128724, and in the U.S. Patent Application, 2010/032011 the disclosure of which are incorporated herein in its entirety.
  • Additional suitable formulations for the sulfonylureas, DPP IV inhibitors can be those formulations which are available on the market, or formulations described in the patent applications cited above in paragraph "background of the invention", or those described in the literature, for example as disclosed in current issues of "Rote Liste S" (Germany) or of "Physician's Desk Reference".
  • Example 1 Example 1
  • Diameter of the tablets 9 mm.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine

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Abstract

La présente invention concerne une thérapie combinée comprenant de l'eicosapentaénoate de metformine ou du docosahexaénoate de metformine ou un mélange de ceux-ci, et un agent antihyperglycémique ou un agent antihyperlipidémique ou un sel ou un promédicament pharmaceutiquement acceptable de ceux-ci, ou un sel pharmaceutiquement acceptable dudit promédicament. L'invention comprend en outre des procédés de traitement d'un trouble métabolique choisi dans l'ensemble consistant en diabète type 2 (DT2), pré-diabète, obésité, syndrome métabolique, hypertrilipidémie et des complications du DT2 comme la neuropathie, la néphropathie, la rétinopathie, la cataracte et des complications cardiovasculaires, notamment l'arythmie cardiaque, l'infarctus du myocarde, une attaque et la myocardiopathie chez les patients diabétiques.
PCT/US2013/049285 2012-07-06 2013-07-03 Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie WO2014008374A2 (fr)

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Publication number Priority date Publication date Assignee Title
WO2016075539A1 (fr) * 2014-11-10 2016-05-19 Промомед Холдинге Лимитед Composition pour le traitement de troubles liés à un poids excessif ou à l'obésité
US20210236442A1 (en) * 2018-08-09 2021-08-05 Dalcor Pharma Uk Ltd., Leatherhead, Zug Branch Methods for delaying occurrence of new-onset type 2 diabetes and for slowing progression of and treating type 2 diabetes
CN115192625A (zh) * 2022-06-30 2022-10-18 山东海赜生物科技有限公司 一种口服组合物
WO2023129595A1 (fr) * 2021-12-30 2023-07-06 Newamsterdam Pharma B.V. Combinaison d'obicetrapib et d'inhibiteur de sglt2
WO2024141073A1 (fr) * 2022-12-30 2024-07-04 Shenzhen Hightide Biopharmaceutical Ltd. Combinaisons et compositions pharmaceutiques, et leurs procédés d'utilisation
WO2024226537A1 (fr) * 2023-04-24 2024-10-31 Newamsterdam Pharma B.V. Combinaison d'inhibiteur de sglt2 et d'obicetrapib amorphe

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AU2003211131A1 (en) * 2002-02-14 2003-09-04 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
CA2385529A1 (fr) * 2002-05-21 2003-11-21 Bernard Charles Sherman Formulations posologiques stables contenant de l'atorvastatin calcium
JP4781347B2 (ja) * 2004-02-23 2011-09-28 トラスティーズ オブ タフツ カレッジ グルコース代謝を制御するためのペプチジルペプチダーゼｉｖ阻害剤
EP1752147A4 (fr) * 2004-06-04 2007-10-31 Kowa Co Médicament pour la prévention ou le traitement du diabète
WO2008053340A1 (fr) * 2006-11-03 2008-05-08 Pronova Biopharma Norge As Produit de combinaison comprenant au moins un lipide substitué en position alpha et au moins un agent hypoglycémique
TW200904454A (en) * 2007-03-22 2009-02-01 Bristol Myers Squibb Co Methods for treating obesity employing an SGLT2 inhibitor and compositions thereof
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WO2010045656A2 (fr) * 2008-10-17 2010-04-22 Nectid, Inc. Nouvelles formes posologiques d'inhibiteur sglt2
TW201036975A (en) * 2009-01-07 2010-10-16 Boehringer Ingelheim Int Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016075539A1 (fr) * 2014-11-10 2016-05-19 Промомед Холдинге Лимитед Composition pour le traitement de troubles liés à un poids excessif ou à l'obésité
US20210236442A1 (en) * 2018-08-09 2021-08-05 Dalcor Pharma Uk Ltd., Leatherhead, Zug Branch Methods for delaying occurrence of new-onset type 2 diabetes and for slowing progression of and treating type 2 diabetes
WO2023129595A1 (fr) * 2021-12-30 2023-07-06 Newamsterdam Pharma B.V. Combinaison d'obicetrapib et d'inhibiteur de sglt2
CN115192625A (zh) * 2022-06-30 2022-10-18 山东海赜生物科技有限公司 一种口服组合物
CN116999398A (zh) * 2022-06-30 2023-11-07 山东海赜生物科技有限公司 一种口服组合物
WO2024141073A1 (fr) * 2022-12-30 2024-07-04 Shenzhen Hightide Biopharmaceutical Ltd. Combinaisons et compositions pharmaceutiques, et leurs procédés d'utilisation
WO2024226537A1 (fr) * 2023-04-24 2024-10-31 Newamsterdam Pharma B.V. Combinaison d'inhibiteur de sglt2 et d'obicetrapib amorphe

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