+

WO2008112166A2 - Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques - Google Patents

Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques Download PDF

Info

Publication number
WO2008112166A2
WO2008112166A2 PCT/US2008/003094 US2008003094W WO2008112166A2 WO 2008112166 A2 WO2008112166 A2 WO 2008112166A2 US 2008003094 W US2008003094 W US 2008003094W WO 2008112166 A2 WO2008112166 A2 WO 2008112166A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
acceptable salt
hmg
coa reductase
Prior art date
Application number
PCT/US2008/003094
Other languages
English (en)
Other versions
WO2008112166A3 (fr
Inventor
Banavara L. Mylari
Mary E. Vaman Rao
Original Assignee
Indigene Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Indigene Pharmaceuticals Inc. filed Critical Indigene Pharmaceuticals Inc.
Priority to EP08726603A priority Critical patent/EP2134169A2/fr
Publication of WO2008112166A2 publication Critical patent/WO2008112166A2/fr
Publication of WO2008112166A3 publication Critical patent/WO2008112166A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the invention is directed to methods, pharmaceutical compositions and kits comprising metformin R-(+) lipoate [MR-(+) LA], and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the invention further relates to methods of using those pharmaceutical compositions for the treatment of Type 2 diabetic hyperglycemia and diabetic complications.
  • Metabolic syndrome is intricately intertwined with diabetes, 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 and hyperlipidemia. The long-term consequences of these co-morbidities include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and cataracts. Metformin R-(+) lipoate has been described and claimed as novel treatment for control of chronic hyperglycemia in a pending application. Thus, a need exists in the art for a combination therapy of metformin R-(+)-lipoate and antihyperlipidemic agents to treat diabetes and diabetic complications in diabetic patients. SUMMARY OF THE INVENTION
  • the disclosure provides for combinations of metformin R-(+) lipoate and antihyperlipidemic agents to treat diabetes and hyperlipidemia exacerbated diabetic complications in diabetic patients.
  • the disclosure provides for methods, pharmaceutical compositions and kits comprising MR-(+) LA, and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the disclosure further provides for methods of using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardial infarction, cataracts and diabetic cardiomyopathy.
  • antihyperlipidemic agents may include HMG-CoA reductase inhibitors (statins), fibric acid derivatives, CETP inhibitors, bile acid sequestrants and nicotinic acid (niacin) in combination with flushing inhibiting agent.
  • HMG-CoA reductase inhibitor refers to a compound that competitively blocks the enzyme 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA) reductase.
  • 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), apolipoprotein B (a membrane transport complex for LDL-C), very low-density lipoprotein (VLDL), and plasma triglycerides.
  • LDL-C low-density lipoprotein cholesterol
  • VLDL very low-density lipoprotein
  • fibric acid derivatives refers to compounds that involve activation of the peroxisome proliferator-activated receptor-alpha (PPAR-) 1 receptor in the liver and the stimulation of lipoprotein lipase and/or hepatic lipase activity, resulting in enhanced lipoprotein catabolism.
  • PPAR- peroxisome proliferator-activated receptor-alpha
  • bile acid sequestrants refers to polymeric compounds.
  • the bile acid sequestrants act as anion exchange resins binding bile acids in the lumen of the small intestine; bile acid sequestrants are able to interrupt the enterohepatic circulation of bile acids. This results in an increased hepatic synthesis of bile acids from cholesterol because bile acids suppress the microsomal hydroxylase that catalyzes the rate-determining step in the conversion of cholesterol to bile acids. Due to this depletion of the hepatic pool of cholesterol, there is an increase in the activity of the LDL receptor in the liver. This stimulates the removal of LDL from plasma, resulting in a decrease in the concentration of LDL cholesterol.
  • bile acid sequestrants see, for example, Prog. Polym. ScL 24:485 (1999) and references cited therein.
  • 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.
  • 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.
  • nicotinic acid refers to a compound which has the ability to modulate triglyceride lipolysis in the adipose tissue by reducing the concentrations of cAMP levels in adipose tissue and also modulating the synthesis of triglycerides and secretion of VLDL particles by liver.
  • flush refers to manifestations due to vasodilation of cutaneous blood vessels resulting in increased blood flow, principally in the face, neck and chest.
  • the niacin-flush is thought to be mediated via the prostaglandin prostacyclin.
  • Histamine may also play a role in the niacin-flush. Flushing is the adverse reaction first observed after intake of a large dose of nicotinic acid, and the most bothersome one. The symptoms of flushing include a burning, tingling and itching sensation.
  • any HMG Co-A reductase inhibitors or) any fabric acid derivatives (or) any CETP inhibitors (or) any bile acid sequestrants (or) nicotinic acid individually or in a pharmaceutically acceptable combination with any flushing inhibiting agent may be employed.
  • the disclosure provides for pharmaceutical compositions comprising
  • the disclosure provides for unit dose formulations comprising MR-(+) LA; and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the disclosure provides for methods of treating a diabetic complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth herein below.
  • diabetic complications as, for example, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy can be treated by the methods of the disclosure.
  • the disclosure provides for methods of treating a diabetic complication in a mammal comprising administering to said mammal MR-(+) LA, and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the disclosure provides for methods of treating Type 2 diabetes in a mammal comprising administering to said mammal MR-(+) LA, and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the disclosure provides for methods wherein the MR-(+) LA, and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof, are administered separately.
  • the disclosure provides for methods wherein the MR-(+) LA, and the antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof, are administered in a single dosage form, for example, a tablet, a capsule or a caplet.
  • the disclosure provides for kits comprising: a) a first unit dosage form comprising MR-(+) LA; b) a second unit dosage form comprising an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof; and c) a container.
  • the antihyperlipidemic agent is a compound selected from the following classes of antihyperlipidemic agents: HMG-CoA reductase inhibitors (statins), fibric acid derivatives, CETP inhibitors, bile acid sequesterants and nicotinic acid individually or in a pharmaceutically acceptable combination with any flushing inhibiting agent.
  • HMG-CoA reductase inhibitors include, but are not limited to: atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin , velostatin, fluindostatin, didydrocompactin, compactin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • HMG-coA reductase inhibitors include atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin and cerivastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • fibric acid derivatives include, but are not limited to: clofibrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate, beclobrate, etofibrate, gemfibrozil, clinof ⁇ brate, binifibrate, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • fibric acid derivatives include clofibrate, gemfibrozil, fenofibrate or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • bile acid sequestrants include but are not limited to: cholestyramine, colestipol, colesevalam, benzothiepine compounds, polydexide, polyether based bile acid sequestrants, poly(diallylamine) based bile acid sequestrants, poly-[ ⁇ methyl- (3-trimethylammoniopropyl) iminio ⁇ trimethylene dichloride] based bile acid sequestrants, polymers containing guanidinium groups as bile acid sequestrants, polymers containing spirobicyclic ammonium moieties as bile acid sequestrants, polystyrene-b-poly(acrylic acid) (ps-b-paa) cross linked with one or more polyamine ( knedels) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • CETP inhibitors include, but are not limited to: torcetrapib or a
  • cholesterol absorption inhibitors include, but are not limited to ezetimibe (Zetia) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the nicotinic acid derivatives and other compounds specifically include, but are not limited to the following: nicotinyl alcohol tartrate, D-glucitol hexanicotinate, aluminum nicotinate, niceritrol, D,l- alpha - tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide-N-oxide, 6- OH- nicotinamide, NAD, N-methyl ⁇ -pyrridine- ⁇ -carboxamide, N-methyl-4-pyridone-5- carboxamide, bradilian, sorbinicate, hexanicite, ronitol and esters like methyl, ethyl, propyl or butyl esters.
  • flushing inhibiting agents include, but are not limited to: MK-
  • substituted tetrahydrocarbazole and cyclopentanoindole derivatives which include ((lR)-6-fluoro-8-(methyl-sulfonyl)-9- ⁇ (1 S)-l-[ 4-(trifluoromethyl)phenyl]ethyI ⁇ - 2,3 A,9- tetrahydro-1 H -carbazoll-yl)acetic acid; [(I R)-9-[(lS)-l-(3,4-dichlorophenyl)ethyl]-6- fluoro-8-(methyl-sulfonyl)-2,3,4,9-tetra hydro -IH -carbazol-1-yl] acetic acid; ⁇ (lR)-6-fluoro- 8-(methylsulfonyl)-9-[ (1 S)-l-phenylethyl]-2,3,4,9-tetrahydro-lH-carbazol-l-yl ⁇ acetic acid;
  • the disclosure provides for the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the disclosure.
  • contemplated salts of the disclosure include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the disclosure include L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethyl enediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium hydroxide, L- lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)pyrrolidine, sodium hydroxide, tri ethanolamine, tromethamine, and zinc hydroxide salts.
  • contemplated salts of the disclosure include Na, Ca, K, Mg, Zn or other metal salts.
  • the disclosure provides for a pharmaceutical composition
  • a pharmaceutical composition comprising metformin R-(+) lipoate [MR-(+) LA], and an HMG-CoA reductase inhibitor (e.g., atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin , velostatin, fluindostatin,didydrocompactin, compactin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • HMG-CoA reductase inhibitor e.g., atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosu
  • the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.
  • 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.
  • the HMG-CoA reductase inhibitor is atorvastatin calcium.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 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.
  • the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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.
  • the disclosure provides for a pharmaceutical composition
  • a pharmaceutical composition comprising metformin R-(+) lipoate [MR-(+) LA], and a cholesterol absorption inhibitor (e.g., ezetimibe) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • a cholesterol absorption inhibitor e.g., ezetimibe
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to 1 g; 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.
  • 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. In certain embodiments, 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.
  • the disclosure provides for a unit dose formulation comprising:
  • an HMG-CoA reductase inhibitor e.g., atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin , velostatin, fluindostatin,didydrocompactin, compactin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • HMG-CoA reductase inhibitor e.g., atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastat
  • the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.
  • 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, ethyl enediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium hydroxide, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, zinc hydroxide, sodium, calcium, potassium, magnesium, and zinc.
  • the HMG-CoA reductase inhibitor is atorvastatin calcium.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 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 HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 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.
  • the composition is a tablet.
  • the disclosure provides for a unit dose formulation comprising: (i) metformin R-(+) lipoate; and
  • a cholesterol absorption inhibitor e.g., ezetimibe
  • a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof e.g., ezetimibe
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 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.
  • the pharmaceutical composition is a tablet.
  • the disclosure provides for a method of treating a diabetic complication in a human or mammal subject, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising comprising metformin R-(+) lipoate [MR-(+) LA], and an HMG-CoA reductase inhibitor (e.g., atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin , velostatin, fluindostatin,didydrocompactin, compactin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • a pharmaceutical composition comprising comprising metformin R-
  • the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.
  • 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.
  • the HMG-CoA reductase inhibitor is atorvastatin calcium.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to 1 g; 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.
  • 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 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 pharmaceutical composition is administered on a daily regimen (e.g., once daily, twice daily, 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.
  • the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments,sthe HMG-CoA reductase inhibitor is simvastatin.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 pharmaceutical composition is administered on a daily regimen (e.g., once daily, twice daily, 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.
  • the pharmaceutical composition is a tablet.
  • the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.
  • the disclosure provides for a method of treating a diabetic complication in a subject in need thereof comprising administering to the human or mammal subject a therapeutically effective amount of a pharmaceutical composition comprising comprising metformin R-(+) lipoate [MR-(+) LA], and a cholesterol absorption inhibitor (ezetimibe) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • a pharmaceutical composition comprising comprising metformin R-(+) lipoate [MR-(+) LA], and a cholesterol absorption inhibitor (ezetimibe) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 formulated as a tablet.
  • the pharmaceutical composition is administered on a daily regimen (e.g., once daily, twice daily, 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.
  • the pharmaceutical composition is a tablet.
  • the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.
  • the disclosure provides for a method of treating Type 2 diabetes in a subject in need thereof comprising administering to the human or mammal subject a therapeutically effective amount of a unit dose comprising comprising metformin R-(+) lipoate [MR-(+) LA], and an angiotensin-converting enzyme (ACE) inhibitor (atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin, cerivastatin, mevastatin, rivastatin, pitavastatin, nisvastatin, itavastatin , velostatin, fluindostatin,didydrocompactin, compactin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • ACE angiotensin-converting enzyme
  • the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.
  • 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, ethyl enediamine, N-m ethyl glucamine, hydrabamine, 1 H-imidazole, lithium hydroxide, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, zinc hydroxide, sodium, calcium, potassium, magnesium, and zinc.
  • the HMG-CoA reductase inhibitor is atorvastatin calcium.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • the atorvastatin is present in the amount ranging from2.5 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,.
  • the pharmaceutical composition is formulated as a tablet.
  • the pharmaceutical composition is administered on a daily regimen (e.g., once daily, twice daily, 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.
  • the pharmaceutical composition is a tablet.
  • the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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. In certain embodiments, the pharmaceutical composition is administered on a daily regimen (e.g., once daily, twice daily, 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 mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
  • the disclosure provides for a method of treating Type 2 diabetes in a human or mammal subject, comprising administering to a subject in need thereof a therapeutically effective amount of a unit dose comprising comprising metformin R-(+) lipoate [MR-(+) LA], and a cholesterol absorption inhibitor (ezetimibe) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 2.5 mg to Ig; 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.
  • 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 pharmaceutical composition is administered on a daily regimen (e.g., once daily, twice daily, 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.
  • the methods, compositions and kits of disclosure 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.
  • antihyperlipidemic agents which may be used in accordance with the disclosure, are members of different classes of antihyperlipidemic agents, including HMG-CoA reductase inhibitors (statins), fibric acid derivatives, CETP inhibitors, bile acid sequestrants and nicotinic acid (niacin) in pharmaceutically acceptable combination with flushing inhibiting agent.
  • HMG-CoA reductase inhibitors statins
  • fibric acid derivatives including cystic acid derivatives, CETP inhibitors, bile acid sequestrants and nicotinic acid (niacin) in pharmaceutically acceptable combination with flushing inhibiting agent.
  • HMG-CoA reductase inhibitors which may be used in accordance with the disclosure include, but are not limited to: atorvastatin, which may be prepared as disclosed in U.S. Pat. No. 7,030,151 ; pravastatin and related compounds which may be prepared as disclosed in U.S. Pat. Nos.4, 346,227 and 4,448,979; rosuvastatin, which may be prepared as disclosed in U.S. Pat. No.6, 858,618; mevastatin, which may be prepared as disclosed in U.S. Pat. No. 3,983,140; velostatin and simvastatin and related compounds which may be prepared as disclosed in U.S. Pat. Nos.
  • lovastatin which may be prepared as disclosed in U.S. Pat. No. 6,558,659
  • fluvastatin which may be prepared as disclosed in U.S. Pat. No.6,858,643
  • cerivastatin which may be prepared as disclosed in U.S. Pat. No. US 2004/0063961
  • pitavastatin which may be prepared as disclosed in U.S. Pat. No. 5,856,336;
  • Fibric acid derivatives which may be used in accordance with the disclosure include, but are not limited to: clofibrate, which may be prepared as disclosed in U.S. Pat. No. 3,262,850; gemfibrozil, which may be prepared as disclosed in U.S. Pat. No. 3,674, 836; fenofibrate, which may be prepared as disclosed in U.S. Pat. No. 4,058,552; ciprofibrate, which may be prepared as disclosed in U.S. Pat. No.3,948,973; bezafibrate, which may be prepared as disclosed in U.S. Pat. No. 3,781 ,328; gemfibrozil, which may be prepared as disclosed in U.S. Pat. No.
  • PPAR agonists include compounds such as those described in U.S. Pat. No. 6,008,239, WO 9727847, WO 9727857, WO 9728115, WO 9728137 and WO 9728149.
  • PPAR alpha, gamma and delta agonists may be identified according to an assay described in U.S. Pat. No.6,008, 239. The disclosures thereof are incorporated herein by reference.
  • Bile acid sequestrants which may be used in accordance with the disclosure include, but are not limited to: cholestyramine, which may be prepared as disclosed in U.S. Pat. Nos.3,308,020 and 4,895,723; colestipol, which may be prepared as disclosed in U.S. Pat. No.3,692, 895; colesevalam, which may be prepared as disclosed in U.S. Pat. No. 7,026,295; polyether based bile acid sequestrants, which may be prepared as disclosed in U.S. Pat. No.
  • poly(diallylamine) based bile acid sequestrants which may be prepared as disclosed in U.S. Pat. Nos. 7,125,547 and 6,203,785; poly-[ ⁇ alkyl-(3- trimethylammoniopropyl) iminio ⁇ trimethylene dichloride] based bile acid sequestrants, which may be prepared as disclosed in U.S. Pat. No. 4,205,064 ; polymers containing guanidinium groups as bile acid sequestrants, which may be prepared as disclosed in U.S. Pat.
  • CETP inhibitors which may be used in accordance with the disclosure are not limited by any structure or group of CETP inhibitors.
  • CETP inhibitors which may be used in accordance with the disclosure include, but are not limited to: torcetrapib, which may be prepared as disclosed in U.S. Pat. Nos. 6,197,786 and 6,313,142, in PCT Application Nos. WO 01/40190, WO 02/088085 and WO 02/088069. The disclosures thereof are incorporated herein by reference.
  • Cholesterol absorption inhibitors which may be used in accordance with the disclosure include, but are not limited to ezetimibe (Zetia), which may be prepared as disclosed in U.S. Pat. Nos. 5,767,115 and 5, 846,966. The disclosures thereof are incorporated herein by reference.
  • Nicotinic acid, 3- pyridine carboxylic acid or niacin which may be used in accordance with the disclosure, was the only agent studied by the Coronary Drug Project which produced a significant decrease in coronary events: Niacin and Coronary Heart Disease, JAMA 231:360 (1975) and JAMA 279: 1615 (1998), which may be prepared as disclosed in U.S. Pat. No. 2,513,251. Dosage forms of nicotinic acid with sustained and intermediate release, are disclosed in U.S. Pat.Nos.
  • nicotinic acid derivatives nicotinyl alcohol tartrate , D-glucitol hexanicotinate, aluminum nicotinate, niceritol, D,l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-Oxide, 6-OH- nicotinamide, NAD, N- methyl-2-pyrridine-8-carboxamide, N-methyl-4-pyridone-5-carboxamide, bradilian, sorbinicate, hexanicite, ronitol and esters like methyl, ethyl, propyl or butyl esters, their use may be disclosed in U.S. Pat. No.6,469,035. The disclosures thereof are incorporated herein by reference.
  • Flushing inhibiting agents which may be used in accordance with the disclosure are prostaglandin DP receptor selective antagonists. They include, but are not limited to MK- 0524, as described in PNAS, 103, 17 (2006); ((lR)-6-fluoro-8-(methyl-sulfonyl)-9- ⁇ (1 S)-l-[ 4-(trifluoromethyl)phenyl] ethyl ⁇ - 2,3A,9-tetrahydro-l H -carbazoll-yl)acetic acid; [(I R)-9- [(l S)-l-(3,4-dichlorophenyl)ethyl]-6-fluoro-8-(methyl-sulfonyl)-2,3,4,9-tetra hydro -IH - carbazol-l-yl]acetic acid; ⁇ (lR)-6-fluoro-8-(methylsulfonyl)-9-[ (1 S)-l-phenylethyl]-2,3,4,
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, where appropriate.
  • salts are 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, ethylene diamine, 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 e.g., ammonium salts
  • salts with organic amines such as benzathine (N,N'-dibenzylethylene
  • salts are, for example, inorganic acids, such as hydrohalic acid, e. g. hydrochloric, hydrobromic or the like, or sulfuric acid, nitric acid, or phosphoric acid; or suitable organic acids, for example suitable aliphatic acids, like aliphatic mono or dicarboxylic acids, hydroxyalkanoic or hydroxyalkanedioic acids, e.g.
  • acids are e.g. hydrobromic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic, ethanesulfonic, laurylsulfonic, benzenesulfonic, and para-toluenesulfonic acids.
  • the disclosure provides for methods of treating diabetic complications in which the MR-(+) LA and antihyperlipidemic agent are administered together, as part of the same pharmaceutical composition, and to methods in which these two active agents are administered separately, as part of an appropriate dosage regimen designed 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 MR-(+) LA and the antihyperlipidemic agent being used, the type of pharmaceutical formulations being used, the characteristics of the subject being treated and the severity of the complications.
  • an effective dosage for the treatment of a warm-blooded animal, including a mammal, like a human, for MR-(+) LA is in the range of about 2.5 mg per day to about 1 g per day in single or divided doses, such as about 2.5 mg per day to about 750 mg per day, such as about 2.5 mg to about 500 mg per day; about 2.5 mg per day to about 250 mg per day; or about 2.5 mg per day to about 200 mg per day; about 2.5 mg per day to about 150 mg per day; about 2.5 mg per day to about 100 mg per day; about 2.5 mg per day to about 50 mg per day; about 2.5 mg per day to about 25 mg per day; about 2.5 mg per day to about 20 mg per day; about 2.5 mg per day to about 10 mg per day and about 2.5 mg per day to about 5 mg per day.
  • Antihyperlipidemic agents will generally be administered in amounts ranging from about 2.5 mg per day to about 250 mg per day in single or divided doses, such as about 2.5 mg per day to about 200 mg per day; about 2.5 mg per day to about 150 mg; about 2.5 mg per day to about 100 mg per day, about 2.5 mg per day to about 80 mg per day,, about 2.5 mg per day to about 60 mg per day, about 2.5 mg per day to about 40 mg per day, about 2.5 mg per day to about 20 mg per day, and about 2.5 mg per day to about 10 mg; about 2.5 mg per day to about 50 mg; about 2.5 mg per day to about 25 mg; about 2.5 mg per day to about 20 mg; about 2.5 mg per day to about 10 mg per day and about 2.5 mg per day to about 5 mg per day.
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated. The prescribing physician will, in any event, determine the appropriate dose for the individual subject.
  • administration of the pharmaceutical compositions can be via any method which delivers it to the desired tissue (e.g., nerve, kidney, retina and/or cardiac tissues). These methods include oral routes, parenteral, intraduodenal routes, etc.
  • the compositions of the disclosure are administered in single (e.g., once daily) or multiple doses or via constant infusion.
  • compositions comprising MR-(+) LA and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof are hereinafter referred to, collectively, as "the active compositions of the disclosure.”
  • the active compositions may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the active compositions of the disclosure may 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. In certain embodiments of the disclosure, the active compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • 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 disclosure 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.
  • tablets containing various excipients but not limited to sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. In certain embodiments of the disclosure, the materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with 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 in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may 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 disclosure is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may 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 the composition (two active agents administered together or separately) may take the form of tablets or lozenges formulated in a conventional manner.
  • the active compounds 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., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra fluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra fluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges made, for example, from gelatin
  • an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the disclosure and a suitable powder base such as lactose or starch.
  • aqueous or partially aqueous solutions are prepared.
  • the active compositions contain an amount of MR-(+) LA, and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.
  • the amount of each of those ingredients may independently be, for example, 0.0001 %-95% of the total amount of the composition, where the total amount may not, 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 disclosure in an amount effective to treat the disease/condition of the subject being treated.
  • the disclosure provides for combining separate pharmaceutical compositions in kit form.
  • the kit comprises two separate pharmaceutical compositions: MR- (+) LA, and an antihyperlipidemic agent as described above.
  • the kit comprises 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. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, 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. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably 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.
  • a "daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of the MR- (+) LA may consist of one tablet or capsule while a daily dose of the antihyperlipidemic agent may consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • the disclosure provides for 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.
  • An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • compositions of this disclosure generally will be administered in a convenient formulation.
  • Example 2 Animals models to determine biological effects of pharmaceutical composition(s)
  • This example describes a diabetic rat model used for determination of conditions leading to a method for treatment and prevention of post-ischemic damage of the heart and heart tissue.
  • BBAV Spontaneously diabetic Bio-Bred rats from the colony maintained at the University of Massachusetts Medical Center, Worcester, were used in this study.
  • BB/W rats were chosen for the current study because the BB ⁇ V rats have been considered a useful model of autoimmune human insulin-dependent diabetes (IDDM).
  • IDDM autoimmune human insulin-dependent diabetes
  • spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria.
  • pathological changes in retina, myocardium, liver, kidney, bone metabolism and peripheral nerves have all been well documented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992).
  • the BB/W rats were 3-4 months old and weighed about 300-350 g.
  • the BB/W rats received daily insulin, which was discontinued 24 h prior to performing the isolated heart perfusion studies, leading to a hyperglycemic state.
  • the rats were acutely diabetic, receiving 2.02 ⁇ 0.04 units of insulin daily, and had been diabetic for at least 12 ⁇ 3 days.
  • the mean blood glucose levels in these diabetic rats were 386 ⁇ 24 mg/dL.
  • the age- matched non-diabetic controls had mean blood glucose levels of 92 ⁇ 12 mg/dL.
  • This example describes an isolated perfused rat heart model used in development of the disclosure. 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). After deep anesthesia is achieved as determined by the absence of a foot reflex, the hearts are rapidly excised and placed into iced saline. The arrested hearts are retrograde perfused in a non-recirculating model through the aorta within 2 min. following their excision.
  • LVDP Left ventricular developed pressure
  • LVDP Left ventricular developed pressure
  • Perfusion pressure is monitored using high pressure tubing off the perfusion line. Hemodynamic measurements are recorded on a 4-channel Gould recorder.
  • the system has two parallel perfusion lines with separate oxygenators, pumps and bubble traps, but common temperature control allowing rapid change perfusion media.
  • the hearts are perfused using an accurate roller pump.
  • the perfusate consists of 118 mM NaCl, 47 mM KCl, 12 mM CaCl 2 , 12 mM MgCl 2 , 25 mM
  • 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 waterjacketed (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.
  • Model for Zero-flow Ischemia This example describes a procedure used for study of zero-flow ischemia in diabetic control, diabetic treated, non-diabetic treated and control isolated hearts.
  • Diabetic control (DC) diabetic treated (DZ) normal ⁇ 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 1 ⁇ M metformin lipoate.
  • 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 12.5 mL/min. followed by 30 minutes of low-flow ischemia where the perfusate flow is slowed down to 1.25 mL/min, that is about 10% of normal perfusion, followed by 30 min. of reperfusion at a normal flow rate (12.5 mL/min).
  • metformin lipoate treated diabetic or non-diabetic groups DZ or CZ
  • hearts are subjected to 10 min. of normoxic perfusion (flow rate 12.5 mL/min) with normal Krebs- Henseleit buffer and 10 min. of normoxic perfusion with Krebs-Henseleit buffer containing 1 ⁇ M metformin lipoate.
  • 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).

Landscapes

  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques, des procédés, et des trousses comprenant du lipoate de metformine R-(+) et un agent antihyperlipidémique ou un sel, un hydrate, un solvate et un promédicament pharmaceutiquement acceptable dérivé de celui-ci pour le traitement de l'hyperglycémie diabétique de type 2, et de complications diabétiques.
PCT/US2008/003094 2007-03-09 2008-03-07 Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques WO2008112166A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08726603A EP2134169A2 (fr) 2007-03-09 2008-03-07 Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90599007P 2007-03-09 2007-03-09
US60/905,990 2007-03-09

Publications (2)

Publication Number Publication Date
WO2008112166A2 true WO2008112166A2 (fr) 2008-09-18
WO2008112166A3 WO2008112166A3 (fr) 2008-10-30

Family

ID=39760278

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/003094 WO2008112166A2 (fr) 2007-03-09 2008-03-07 Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques

Country Status (5)

Country Link
EP (1) EP2134169A2 (fr)
AR (1) AR065670A1 (fr)
CL (1) CL2008000684A1 (fr)
TW (1) TW200901959A (fr)
WO (1) WO2008112166A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009085223A1 (fr) * 2007-12-20 2009-07-09 Indigene Pharmaceuticals, Inc. Combinaison de r-(+)-lipoate de metformine et d'agents antihyperglycémiques pour le traitement de l'hyperglycémie diabétique et des complications diabétiques
WO2012073256A1 (fr) * 2010-11-29 2012-06-07 Cadila Healthcare Limited Sels de rosuvastatine
WO2015001568A3 (fr) * 2013-07-01 2015-06-11 Laurus Labs Private Limited Sel de lipoate sitagliptin, son procédé de préparation et composition pharmaceutique le contenant
WO2015183794A1 (fr) * 2014-05-27 2015-12-03 City Of Hope Complexes d'agonistes de tgr5 pour le traitement du diabète et du cancer
CN113166195A (zh) * 2018-08-24 2021-07-23 艾斯柏伦治疗公司 在正在治疗高胆固醇相关疾病的患者中降低糖尿病风险的方法

Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2513251A (en) 1947-06-21 1950-06-27 Allied Chem & Dye Corp Preparation of pyridine carboxylic acids
US3262850A (en) 1958-06-20 1966-07-26 Ici Ltd Methods for reducing cholesterol in the blood
US3308020A (en) 1961-09-22 1967-03-07 Merck & Co Inc Compositions and method for binding bile acids in vivo including hypocholesteremics
US3674836A (en) 1968-05-21 1972-07-04 Parke Davis & Co 2,2-dimethyl-{11 -aryloxy-alkanoic acids and salts and esters thereof
US3692895A (en) 1970-09-08 1972-09-19 Norman A Nelson Method of reducing hypercholesteremia in humans employing a copolymer of polyethylenepolyamine and a bifunctional substance, such as epichlorohydria
US3716583A (en) 1969-04-16 1973-02-13 Sumitomo Chemical Co Phenoxy carboxylic acid derivative
US3781328A (en) 1971-10-01 1973-12-25 Boehringer Mannheim Gmbh Phenoxy-alkyl-carboxylic acid compounds
US3948973A (en) 1972-08-29 1976-04-06 Sterling Drug Inc. Halocyclopropyl substituted phenoxyalkanoic acids
US3983140A (en) 1974-06-07 1976-09-28 Sankyo Company Limited Physiologically active substances
US4205064A (en) 1973-06-11 1980-05-27 Merck & Co., Inc. Bile acid sequestering composition containing poly[{alkyl-(3-ammoniopropyl)imino}-trimethylenedihalides]
BE884722A (fr) 1980-02-15 1980-12-01 Es De Especialidades Farmaco T Nouvel ester mixte symetrique de 1,2,3-trihydroxypropane, son procede d'obtention et ses applications therapeutiques
US4340605A (en) 1978-08-04 1982-07-20 Takeda Chemical Industries, Ltd. Thiazolidine derivatives
US4342771A (en) 1981-01-02 1982-08-03 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4367234A (en) 1980-07-28 1983-01-04 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4448979A (en) 1980-06-06 1984-05-15 Sankyo Company, Limited ML-236B Derivatives
US4617312A (en) 1983-01-17 1986-10-14 Pfizer Inc. Aldose reductase inhibiting 5-(2-alkoxyphenyl) thiazolidinediones
US4687777A (en) 1985-01-19 1987-08-18 Takeda Chemical Industries, Ltd. Thiazolidinedione derivatives, useful as antidiabetic agents
US4703052A (en) 1985-05-21 1987-10-27 Pfizer Inc. Hypoglycemic thiazolidinediones
US4895723A (en) 1986-09-08 1990-01-23 Amer And Company Cholestyramine compositions and method for preparation thereof
US5126145A (en) 1989-04-13 1992-06-30 Upsher Smith Laboratories Inc Controlled release tablet containing water soluble medicament
EP0508425A1 (fr) 1991-04-12 1992-10-14 Schering Corporation Amides bicycliques inhibiteurs de l'acyl-coenzyme A, cholestérol acyltransférase
WO1993021146A1 (fr) 1992-04-22 1993-10-28 Ligand Pharmaceuticals Incorporated Composes presentant une activite selective par rapport a des recepteurs de retinoide x
US5268181A (en) 1989-04-13 1993-12-07 Upsher-Smith Laboratories, Inc. Method of using niacin to control nocturnal cholesterol synthesis
WO1997027847A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Methode de traitement du diabete et d'etats pathologiques associes
WO1997027857A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Agents antidiabetiques
WO1997028149A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Procede pour augmenter les niveaux de cholesterol hdl
WO1997028115A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Agents anti-diabete
WO1997028137A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Derives heterocycliques utilises comme agents contre le diabete et contre l'obesite
US5767115A (en) 1993-09-21 1998-06-16 Schering-Plough Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US5856336A (en) 1987-08-20 1999-01-05 Nissan Chemical Industries Ltd. Quinoline type mevalonolactones
US6008239A (en) 1997-08-29 1999-12-28 Ssp Co., Ltd. Triazole derivative or salt thereof
WO2000064428A2 (fr) 1999-04-23 2000-11-02 Geltex Pharmaceuticals, Inc. Agent sequestrant les acides biliaires a base de polyether
FR2796551A1 (fr) 1999-07-23 2001-01-26 Lipha Nouveaux sels de metformine, leur procede d'obtention et les compositions pharmaceutiques en renfermant
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6203785B1 (en) 1996-12-30 2001-03-20 Geltex Pharmaceuticals, Inc. Poly(diallylamine)-based bile acid sequestrants
WO2001040190A1 (fr) 1999-11-30 2001-06-07 Pfizer Products Inc. Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine utilises en tant qu'inhibiteurs de cetp
US6271264B1 (en) 1998-12-01 2001-08-07 Geltex Pharmaceuticals, Inc. Polymers containing spirobicyclic ammonium moieties as bile acid sequestrants
US6294163B1 (en) 1998-10-02 2001-09-25 Geltex Pharmaceuticals, Inc. Polymers containing guanidinium groups as bile acid sequestrants
US6313142B1 (en) 1999-11-30 2001-11-06 Pfizer Inc. Method for making 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline
US6469035B1 (en) 1997-07-31 2002-10-22 Eugenio A. Cefali Methods of pretreating hyperlipidemic individuals with a flush inhibiting agent prior to the start of single daily dose nicotinic acid therapy to reduce flushing provoked by nicotinic acid
WO2002088069A2 (fr) 2001-04-30 2002-11-07 Pfizer Products Inc. Composes utiles comme intermediaires
US6558659B2 (en) 2000-04-10 2003-05-06 Teva Pharmaceutical Industries Ltd. Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
US20030220301A1 (en) 2002-02-14 2003-11-27 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
US20040063961A1 (en) 2000-12-21 2004-04-01 Van Der Schaaf Paul Adriaan Crystalline forms of cerivastatin sodium
US6746691B2 (en) 1993-09-20 2004-06-08 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics
US6858643B2 (en) 2000-10-31 2005-02-22 Ciba Specialty Chemicals Corporation Crystalline forms of Fluvastatin sodium
US7019022B2 (en) 2003-12-15 2006-03-28 Merck Frosst Canada & Co. Substituted tetrahydrocarbazole and cyclopentanoindole derivatives
US7026295B2 (en) 2002-12-04 2006-04-11 Agennix Incorporated Lactoferrin in the reduction of circulating cholesterol, vascular inflammation, atherosclerosis and cardiovascular disease
US7030151B2 (en) 2001-03-14 2006-04-18 Lek Pharmaceuticals D.D. Atorvastatin calcium in a pharmaceutical form composition thereof and pharmaceutical formulation comprising atorvastatin calcium

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6693094B2 (en) * 2001-03-22 2004-02-17 Chrono Rx Llc Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus
MXPA05010945A (es) * 2003-04-09 2005-11-25 Japan Tobacco Inc Compuesto pentaciclico heteroaromatico y uso medicinal del mismo.
EP1642593A1 (fr) * 2003-06-06 2006-04-05 Takeda Pharmaceutical Company Limited Preparation pharmaceutique solide
US20060089374A1 (en) * 2003-07-17 2006-04-27 Glenn Cornett Enantiomeric compositions of cicletanine, alone and in combination with other agents, for the treatment of disease

Patent Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2513251A (en) 1947-06-21 1950-06-27 Allied Chem & Dye Corp Preparation of pyridine carboxylic acids
US3262850A (en) 1958-06-20 1966-07-26 Ici Ltd Methods for reducing cholesterol in the blood
US3308020A (en) 1961-09-22 1967-03-07 Merck & Co Inc Compositions and method for binding bile acids in vivo including hypocholesteremics
US3674836A (en) 1968-05-21 1972-07-04 Parke Davis & Co 2,2-dimethyl-{11 -aryloxy-alkanoic acids and salts and esters thereof
US3716583A (en) 1969-04-16 1973-02-13 Sumitomo Chemical Co Phenoxy carboxylic acid derivative
US3692895A (en) 1970-09-08 1972-09-19 Norman A Nelson Method of reducing hypercholesteremia in humans employing a copolymer of polyethylenepolyamine and a bifunctional substance, such as epichlorohydria
US3781328A (en) 1971-10-01 1973-12-25 Boehringer Mannheim Gmbh Phenoxy-alkyl-carboxylic acid compounds
US3948973A (en) 1972-08-29 1976-04-06 Sterling Drug Inc. Halocyclopropyl substituted phenoxyalkanoic acids
US4205064A (en) 1973-06-11 1980-05-27 Merck & Co., Inc. Bile acid sequestering composition containing poly[{alkyl-(3-ammoniopropyl)imino}-trimethylenedihalides]
US3983140A (en) 1974-06-07 1976-09-28 Sankyo Company Limited Physiologically active substances
US4340605A (en) 1978-08-04 1982-07-20 Takeda Chemical Industries, Ltd. Thiazolidine derivatives
BE884722A (fr) 1980-02-15 1980-12-01 Es De Especialidades Farmaco T Nouvel ester mixte symetrique de 1,2,3-trihydroxypropane, son procede d'obtention et ses applications therapeutiques
US4448979A (en) 1980-06-06 1984-05-15 Sankyo Company, Limited ML-236B Derivatives
US4367234A (en) 1980-07-28 1983-01-04 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4342771A (en) 1981-01-02 1982-08-03 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4617312A (en) 1983-01-17 1986-10-14 Pfizer Inc. Aldose reductase inhibiting 5-(2-alkoxyphenyl) thiazolidinediones
US4687777A (en) 1985-01-19 1987-08-18 Takeda Chemical Industries, Ltd. Thiazolidinedione derivatives, useful as antidiabetic agents
US4703052A (en) 1985-05-21 1987-10-27 Pfizer Inc. Hypoglycemic thiazolidinediones
US4895723A (en) 1986-09-08 1990-01-23 Amer And Company Cholestyramine compositions and method for preparation thereof
US5856336A (en) 1987-08-20 1999-01-05 Nissan Chemical Industries Ltd. Quinoline type mevalonolactones
US5126145A (en) 1989-04-13 1992-06-30 Upsher Smith Laboratories Inc Controlled release tablet containing water soluble medicament
US5268181A (en) 1989-04-13 1993-12-07 Upsher-Smith Laboratories, Inc. Method of using niacin to control nocturnal cholesterol synthesis
EP0508425A1 (fr) 1991-04-12 1992-10-14 Schering Corporation Amides bicycliques inhibiteurs de l'acyl-coenzyme A, cholestérol acyltransférase
WO1993021146A1 (fr) 1992-04-22 1993-10-28 Ligand Pharmaceuticals Incorporated Composes presentant une activite selective par rapport a des recepteurs de retinoide x
US6746691B2 (en) 1993-09-20 2004-06-08 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics
US5846966A (en) 1993-09-21 1998-12-08 Schering Corporation Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors
US5767115A (en) 1993-09-21 1998-06-16 Schering-Plough Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
WO1997028115A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Agents anti-diabete
WO1997028149A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Procede pour augmenter les niveaux de cholesterol hdl
WO1997027857A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Agents antidiabetiques
WO1997027847A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Methode de traitement du diabete et d'etats pathologiques associes
WO1997028137A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Derives heterocycliques utilises comme agents contre le diabete et contre l'obesite
US7125547B2 (en) 1996-12-30 2006-10-24 Genzyme Corporation Poly(diallylamine)-based bile acid sequestrants
US6203785B1 (en) 1996-12-30 2001-03-20 Geltex Pharmaceuticals, Inc. Poly(diallylamine)-based bile acid sequestrants
US6469035B1 (en) 1997-07-31 2002-10-22 Eugenio A. Cefali Methods of pretreating hyperlipidemic individuals with a flush inhibiting agent prior to the start of single daily dose nicotinic acid therapy to reduce flushing provoked by nicotinic acid
US6008239A (en) 1997-08-29 1999-12-28 Ssp Co., Ltd. Triazole derivative or salt thereof
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6294163B1 (en) 1998-10-02 2001-09-25 Geltex Pharmaceuticals, Inc. Polymers containing guanidinium groups as bile acid sequestrants
US6271264B1 (en) 1998-12-01 2001-08-07 Geltex Pharmaceuticals, Inc. Polymers containing spirobicyclic ammonium moieties as bile acid sequestrants
US6517825B1 (en) 1999-04-23 2003-02-11 Geltex Pharmaceuticals, Inc. Polyether-based bile acid sequestrants
WO2000064428A2 (fr) 1999-04-23 2000-11-02 Geltex Pharmaceuticals, Inc. Agent sequestrant les acides biliaires a base de polyether
FR2796551A1 (fr) 1999-07-23 2001-01-26 Lipha Nouveaux sels de metformine, leur procede d'obtention et les compositions pharmaceutiques en renfermant
WO2001040190A1 (fr) 1999-11-30 2001-06-07 Pfizer Products Inc. Cristaux de 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoleine utilises en tant qu'inhibiteurs de cetp
US6313142B1 (en) 1999-11-30 2001-11-06 Pfizer Inc. Method for making 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline
US6558659B2 (en) 2000-04-10 2003-05-06 Teva Pharmaceutical Industries Ltd. Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
US6858643B2 (en) 2000-10-31 2005-02-22 Ciba Specialty Chemicals Corporation Crystalline forms of Fluvastatin sodium
US20040063961A1 (en) 2000-12-21 2004-04-01 Van Der Schaaf Paul Adriaan Crystalline forms of cerivastatin sodium
US7030151B2 (en) 2001-03-14 2006-04-18 Lek Pharmaceuticals D.D. Atorvastatin calcium in a pharmaceutical form composition thereof and pharmaceutical formulation comprising atorvastatin calcium
WO2002088085A2 (fr) 2001-04-30 2002-11-07 Pfizer Products Inc. Procedes pour preparer des inhibiteurs de cetp
WO2002088069A2 (fr) 2001-04-30 2002-11-07 Pfizer Products Inc. Composes utiles comme intermediaires
US20030220301A1 (en) 2002-02-14 2003-11-27 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
US7026295B2 (en) 2002-12-04 2006-04-11 Agennix Incorporated Lactoferrin in the reduction of circulating cholesterol, vascular inflammation, atherosclerosis and cardiovascular disease
US7019022B2 (en) 2003-12-15 2006-03-28 Merck Frosst Canada & Co. Substituted tetrahydrocarbazole and cyclopentanoindole derivatives

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
"Niacin and Coronary Heart Disease", JAMA, vol. 231, 1975, pages 360
"PDR health", THOMSON PDR ELECTRONIC LIBRARY, 2006
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
"Thomson PDR Electronic Library", 2006, pages: 60
BR J DIABETES VASC DIS, vol. 3, 2003, pages 204
CURR. OPIN. PHARMACOL., vol. 6, 2006, pages 162
DIAB. METAB. REV., vol. 8, 1992, pages 9
DRUG DISCOVERY TODAY: THERAPEUTIC STRATEGIES, vol. 1, 2004, pages 189
J. LIPID RES., vol. 22, 1981, pages 24
J. NUTR. BIOCHEM., vol. 14, 2003, pages 298
JAMA, vol. 279, 1998, pages 1615
METABOLISM, vol. 34, 1985, pages 642
NUTR. METAB. CARDIOVASC. DIS., vol. 13, 2004, pages 42
PNAS, vol. 103, 2006, pages 17
PROG. POLYM. SCI., vol. 24, 1999, pages 485
TIRABASSI ET AL., ILAR JOURNAL, vol. 45, 2004, pages 292

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009085223A1 (fr) * 2007-12-20 2009-07-09 Indigene Pharmaceuticals, Inc. Combinaison de r-(+)-lipoate de metformine et d'agents antihyperglycémiques pour le traitement de l'hyperglycémie diabétique et des complications diabétiques
WO2012073256A1 (fr) * 2010-11-29 2012-06-07 Cadila Healthcare Limited Sels de rosuvastatine
WO2015001568A3 (fr) * 2013-07-01 2015-06-11 Laurus Labs Private Limited Sel de lipoate sitagliptin, son procédé de préparation et composition pharmaceutique le contenant
WO2015183794A1 (fr) * 2014-05-27 2015-12-03 City Of Hope Complexes d'agonistes de tgr5 pour le traitement du diabète et du cancer
US10166246B2 (en) 2014-05-27 2019-01-01 City Of Hope TGR5 agonist complexes for treating diabetes and cancer
CN113166195A (zh) * 2018-08-24 2021-07-23 艾斯柏伦治疗公司 在正在治疗高胆固醇相关疾病的患者中降低糖尿病风险的方法

Also Published As

Publication number Publication date
TW200901959A (en) 2009-01-16
AR065670A1 (es) 2009-06-24
WO2008112166A3 (fr) 2008-10-30
CL2008000684A1 (es) 2008-08-01
EP2134169A2 (fr) 2009-12-23

Similar Documents

Publication Publication Date Title
JPH01503539A (ja) 非鎮静抗ヒスタミン薬を含んでなる咳／風邪用混合物
JP2005533810A (ja) 新規な抗コレステロール組成物及びその使用方法
MX2014008180A (es) Metodos para reducir el riesgo de padecer una enfermedad cardiovascular.
JP2007509990A (ja) Ｈｄｌを高める併用療法用複合物
KR20050012771A (ko) 치환된 시아노피롤리딘의 용도 및 이들을 함유하는고지혈증 및 관련 질환의 치료를 위한 조합 제제
EP2134169A2 (fr) Combinaison de metformine r-(+) lipoate et d'agents antihyperlipidémiques pour le traitement de l'hyperglycémie diabétique et de complications diabétiques
CN101627021A (zh) 高脂血症的预防和/或治疗剂
AU2006304689A1 (en) Compositions for lowering serum cholesterol and/or triglycerides
EP2872483A1 (fr) Forme à trois sels de metformine
WO2010107610A1 (fr) Méthode de traitement du diabète et des états pathologiques correspondants par thérapie combinatoire et compositions contenant de tels composés
US20150272944A1 (en) Novel triglyceride reducing agent
US20050281868A1 (en) Transdermal delivery system for statin combination therapy
WO2014008374A2 (fr) Thérapies combinées comprenant des sels de metformine et des agents antihyperglycémie ou des agents antihyperlipidémie
US20100240683A1 (en) Combination therapy, composition and methods for the treatment of cardiovascular disorders
AU2003244913A1 (en) Pharmaceutical combination of a thromboxane A2 receptor antagonist and a COX-2 inhibitor
WO2014008379A2 (fr) Formes salines diamine et méglumine d'acides gras
EP2395837A1 (fr) Inhibiteur de phospholipase a2 (spla2) sécrétoire, compositions de médicament à base de niacine et méthodes de traitement des maladies cardiovasculaires et de la dyslipidémie
US20080033019A1 (en) Cholesterol lowering drug combination
US9382187B2 (en) Tri-salt form of metformin
JP6227535B2 (ja) 脂質異常症の予防又は治療薬
CA2492781A1 (fr) Composition medicale pour reduire le taux de lipides sanguins ou le taux d'homocysteine sanguine
US20080070938A1 (en) Medicinal composition for mitigating blood lipid or lowering blood homocysteine
JP7356968B2 (ja) 心血管疾患に有用な医薬
ES2359910T3 (es) Composición medicinal para inhibir la expresión de atp-citrato liasa y su uso.
CA2309588A1 (fr) Associations statine-inhibiteur de metalloprotease matricielle

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08726603

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008726603

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载