WO2008112166A2

WO2008112166A2 - Combination of metformin r-(+) lipoate and antihyperlipidemic agents for the treatment of diabetic hyperglycemia and diabetic complications

Info

Publication number: WO2008112166A2
Application number: PCT/US2008/003094
Authority: WO
Inventors: Banavara L. Mylari; Mary E. Vaman Rao
Original assignee: Indigene Pharmaceuticals Inc.
Priority date: 2007-03-09
Filing date: 2008-03-07
Publication date: 2008-09-18
Also published as: TW200901959A; WO2008112166A3; CL2008000684A1; EP2134169A2; AR065670A1

Abstract

Disclosed are pharmaceutical compositions, methods, and kits comprising metformin R-(+) lipoate and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof for the treatment of Type 2 diabetic hyperglycemia and diabetic complications.

Description

COMBINATION OF METFORMIN R-(+) LIPOATE AND

ANTIHYPERLIPIDEMIC AGENTS FOR THE TREATMENT OF

DIABETIC HYPERGLYCEMIA AND DIABETIC COMPLICATIONS

CROSS-REFERENCE TO RELATED APPLICATION This patent application claims the benefit of U.S. Provisional Application No.

60/905,990 filed on March 9, 2007. The specification of this application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION 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

In one aspect, the disclosure provides for combinations of metformin R-(+) lipoate and antihyperlipidemic agents to treat diabetes and hyperlipidemia exacerbated diabetic complications in diabetic patients. In one aspect, 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.

In certain embodiments, 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.

The term "HMG-CoA reductase inhibitor" as used herein 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), apolipoprotein B (a membrane transport complex for LDL-C), very low-density lipoprotein (VLDL), and plasma triglycerides. For a review on HMG-CoA inhibitors see, for example, Drug Discovery Today: Therapeutic Strategies, 1:189 (2004) and references cited therein.

The term "fibric acid derivatives" as used herein 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. For reviews on fibric acid derivatives see, for example, Br J Diabetes Vase Dis 3:204 (2003) and references cited therein.

The term "bile acid sequestrants" as used herein 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. For a review on bile acid sequestrants see, for example, Prog. Polym. ScL 24:485 (1999) and references cited therein.

The term "CETP inhibitor" as used herein 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. For a review on CETP inhibitors see, for example, Curr. Opin. Pharmacol. 6:162 (2006) and references cited therein.

The term "cholesterol absorption inhibitors" as used herein 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. For a review on cholesterol absorption inhibitors see, for example, Nutr. Metab. Cardiovasc. Dis. ,13:42 (2004) and references cited therein.

The term "nicotinic acid" as used herein 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. For a review on nicotinic acid see, for example, J. Nutr.

Biochem., 14:298 (2003) and references cited therein, J. Lipid Res. 22:24 (1981), Metabolism, 34:642 (1985) and references cited therein.

The term "flushing" as used herein 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. For a review on niacin flushing see, for example, PDR health, Thomson PDR Electronic Library, Edition 60 (2006). In the practice of the compositions and methods of the disclosure, 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. In one aspect, the disclosure provides for pharmaceutical compositions comprising

MR-(+) LA; and an antihyperlipidemic agent or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In one aspect, 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.

In one aspect, 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. In certain embodiments, such 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.

In one aspect, 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. In one aspect, 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.

In one aspect, 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.

In one aspect, 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. In one aspect, 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.

In certain embodiments as disclosed herein, 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.

In certain embodiments, 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. In certain embodiments of the disclosure, HMG-coA reductase inhibitors include atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, rosuvastatin and cerivastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, fibric acid derivatives include, but are not limited to: clofibrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate, beclobrate, etofibrate, gemfibrozil, clinofϊbrate, binifibrate, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments of the disclosure, fibric acid derivatives include clofibrate, gemfibrozil, fenofibrate or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, 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. In certain embodiments, CETP inhibitors include, but are not limited to: torcetrapib or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, cholesterol absorption inhibitors include, but are not limited to ezetimibe (Zetia) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

Nicotinic acid, 3-pyridinecaboxylic acid or niacin or a derivative of nicotinic acid or a compound other than nicotinic acid itself which the body metabolizes into nicotinic acid and mixtures thereof, thus producing same effect as described herein. 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-δ-carboxamide, N-methyl-4-pyridone-5- carboxamide, bradilian, sorbinicate, hexanicite, ronitol and esters like methyl, ethyl, propyl or butyl esters. In certain embodiments flushing inhibiting agents include, but are not limited to: MK-

0524 and 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; [( 1 R )-6- fluoro-9- [(I S )-l-(4- fluorophenyl )ethyl] -8-( methyl-sulfonyl)-2,3,4,9- tetrahydro-lH -carbazol-1-yl] acetic acid; [(I R)-9-[(l S)-l-( 4-chloro-3-fiuorophenyl)ethyl]- 6-fluoro-8-(methyl-sulfonyl)-2,3,4,9-tetrahydro-l H -carbazol-1-yl] acetic acid; [( 1 R )-9- [( 1 S )-l-(3-chlorophenyl)ethyl 1 ]-6- fluoro-8-(methyl-sulfonyl)-2,3,4,9-tetrahydro-lH - carbazol-l-yl]acetic acid; [(I R)-9-[(l S)-l-(4-chloro-2-fluorophenyl)ethyl]-6-fluoro^-8- (methyl-sulfonyl)-2,3,4,9- tetrahydro-1 H -carbazol-1-yl] acetic acid; [(I R)-9-[(l S)-l-( 4- bromophenyl)ethyl]-6-fluoro-8-(methyl-sulfonyl)-2,3,4,9-tetrahydro-lH -carbazol-l- yl]acetic acid; [(I R)-9-[(l S)-l-( 4-cyanophenyl)ethyl] -6-fluoro-8-(methyl-sulfonyl)-2,3,4,9- tetrahydro-lH -carbazol-l-yl]acetic acid; ((I R)-6-fluoro-8-(methyl-sulfonyl)-9-{ ((l S)-l-[ 4- (methyl-sulfonyl)phenyl] ethyl} -2,3 ,4,9-tetrahydro-l H -carbazol-l-yl)acetic acid and or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. In certain embodiments, the disclosure provides for the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the disclosure. In certain embodiments, contemplated salts of the disclosure include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, 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. In certain embodiments, contemplated salts of the disclosure include Na, Ca, K, Mg, Zn or other metal salts.

In one aspect, the disclosure provides for 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.

In certain embodiments, the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.

In certain embodiments, 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.

In certain embodiments, the HMG-CoA reductase inhibitor is atorvastatin calcium.

In certain embodiments, 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.

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 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.

In certain embodiments, 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.) In certain embodiments, 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.

In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin.

In certain embodiments, 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. In certain embodiments, 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.).

In certain embodiments, 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.

In one aspect, the disclosure provides for 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.

In certain embodiments, 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. In certain embodiments, 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.

In certain embodiments, 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.).

In one aspect, the disclosure provides for a unit dose formulation comprising:

(i) metformin R-(+) lipoate; and

(ii) 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.

In certain embodiments, the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof. In certan embodiments, 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.

In certain embodiments, 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.

In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin. In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, 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. In certain embodiments, the composition is a tablet.

In one aspect, the disclosure provides for a unit dose formulation comprising: (i) metformin R-(+) lipoate; and

(ii) a cholesterol absorption inhibitor (e.g., ezetimibe) or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

In certain embodiments, 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. In certain embodiments, 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.

In certain embodiments, the pharmaceutical composition is a tablet.

In one aspect, 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.

In certain embodiments, the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof. In certain embodiments, 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.

In certain embodiments, 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.

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 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. In certain embodiments, 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.).

In certain embodiments, the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof. In certain embodiments,sthe HMG-CoA reductase inhibitor is simvastatin. In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, 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. In certain embodiments, the pharmaceutical composition is a tablet.

In certain embodiments, the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.

In certain embodiments, 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. In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, the pharmaceutical composition 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.). In certain embodiments, 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. In certain embodiments, the pharmaceutical composition is a tablet.

In one aspect, 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.

In certain embodiments, 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.

In certain embodiments, the the HMG-CoA reductase inhibitor is atorvastatin calcium.

In certain embodiments, the 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. In certain embodiments, the 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,. 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. In certain embodiments, the pharmaceutical composition is formulated as a tablet.

In certain embodiments, the pharmaceutical composition is a tablet.

In certain embodiments, 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. In certain embodiments, 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.

In certain embodiments, 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.).

In certain embodiments, 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. In one aspect, 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.

In certain embodiments, the cholesterol absorption inhibitor is ezetimibe.

In certain embodiments, 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. In certain embodiments, the pharmaceutical composition is formulated as a tablet.

DETAILED DESCRIPTION OF THE INVENTION

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.

The term "treating", as used herein, 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. The term "treatment", as used herein, refers to the act of treating a disorder, symptom or condition, as the term "treating" is defined above.

The 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.

The specific 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. 4,448,784 and 4,450,171; 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. 3,674, 836; clinofibrate, which may be prepared as disclosed in U.S. Pat. No. 3,716, 583; binifibrate, which may be prepared as disclosed in BE 8,847,22. Compounds which are 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. 6,517,825 and in PCT/US2000/010808 (WO 2000/064428); 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. No.6,294,163 ; 325 polymers containing spirobicyclic ammonium moieties as bile acid sequestrants, which may be prepared as disclosed in U.S. Pat. No. 6,271,264; selected benzothiepines used as bile acid sequestrants are disclosed in world patent application number: WO 93/321146 and in EP 508425. The disclosures thereof are incorporated herein by reference.

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. 5,126,145, 6,746,691 ; 5,268,181, respectively; 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]-2,3,4,9- tetrahydro-lH-carbazol-1-yl } acetic acid; [( 1 R )-6- fluoro-9- [(I S )-l-(4- fluorophenyl )ethyl] -8-( methyl-sulfonyl)-2,3,4,9-tetrahydro-lH -carbazol-l-yl]acetic acid; [(I R)-9-[(l S)-l-( 4-chloro-3-fluorophenyl)ethyl]-6-fluoro-8-(methyl-sulfonyl)-2,3,4,9-tetrahydro-l H - carbazol-1-yl] acetic acid; [( 1 R )-9- [( 1 S )-l-(3-chlorophenyl)ethyl 1 ]-6- fluoro-8-(methyl- sulfonyl)-2,3,4,9-tetrahydro-lH -carbazol-l-yl]acetic acid; [(I R)-9-[(l S)-l-(4-chloro-2- fluorophenyl)ethyl]-6-fluoro-'-8-(methyl-sulfonyl)-2,3,4,9- tetrahydro-1 H -carbazol-1-yl] acetic acid; [(I R)-9-[(l S)-l-( 4-bromophenyl)ethyl]-6-fluoro-8-(methyl-sulfonyl)-2,3,4,9- tetrahydro-lH -carbazol-1-yl] acetic acid; [(I R)-9-[(l S)-l-( 4-cyanophenyl)ethyl] -6-fluoro- 8-(methyl-sulfonyl)-2,3,4,9-tetrahydro-lH -carbazol-1-yl] acetic acid; ((I R)-6-fluoro-8- (methyl-sulfonyl)-9-{ ((l S)-l-[ 4-(methyl-sulfonyl)phenyl] ethyl} -2,3 ,4,9-tetrahydro-l H - carbazol-l-yl)acetic acid ; as disclosed in U.S. Pat. No. 7,019,022, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof. The expression "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, where appropriate. The expression "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, ethylene diamine, meglumine (N-methylglucamine), benethamine (N-benzyl phenethylamine) , diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-l,3- propanediol) and procaine. The expression "pharmaceutically-acceptable acid addition salts" is intended to define but is not limited to such salts as those with pharmaceutically acceptable mineral or organic acids classically used in pharmacy. Appropriate acids 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. acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2- oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, or 2-hydroxy-l,2,3-propanetricarboxylic acid; phenyl substituted alkanoic acids; or suitable aromatic acids, like 2-hydroxybenzoic, or 4-amino-2-hydroxybenzoic acid; or suitable sulfonic acids, like alkanesulfonic acids, e.g. methanesulfonic, or ethanesulfonic acid, or aromatic sulfonic acids, e.g. benzenesulfonic, or 4-methylbenzenesulfonic acid; or cyclohexanesulfamic acid, hi certain embodiments of the disclosure, 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.

In one aspect, 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. Generally, in carrying out the methods, 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. However, 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.

In certain embodiments of the disclosure, 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. Generally, the compositions of the disclosure are administered in single (e.g., once daily) or multiple doses or via constant infusion.

Pharmaceutical 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."

In certain embodiments 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. Thus, for purposes of oral administration, 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. When aqueous suspensions or elixirs are desired for oral administration, 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.

In certain embodiments of the disclosure, for parenteral administration, solutions of the active compositions in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

Generally, a 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.

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.

In certain embodiments of the disclosure, for intranasal administration or administration by inhalation, the active compounds (two active agents administered together or separately) 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. In the case of a pressurized aerosol, 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) for use in 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.

For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1 % to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

In certain embodiments of the disclosure, 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%. In any event, 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. In one aspect, 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. Typically 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.

An example of such a kit is a so-called blister pack. 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.

It may be desirable to provide 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. Another example of such 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 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. In certain embodiments, 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. Preferably, 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. Another example of such a memory-aid is 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 this disclosure generally will be administered in a convenient formulation.

The following examples illustrate certain embodiments of the disclosure.

EXEMPLIFICATION Example 1: Preparation of metformin R-(+)-alpha-lipoate

Sodium methoxide (0.31 g) was dissolved in methanol (2 mL) and to this solution was added metformin hydrochloride (1 g) while stirring. The stirring was continued for an additional 10 min. Acetone (40 mL) was then added, stirred for 20 min, and the mixture was filtered. To the filtrate, containing metformin in the form of its free base, R-(+) lipoic acid (1.25 g dissolved in 15 mL acetone) was added dropwise with constant stirring resulting in the precipitation of a pale yellow solid. The mixture was stirred for an additional 20 min and filtered. The light yellow solid was washed with acetone (30 mL), filtered, and dried to yield metformin R-(+)-lipoate; m.p. 148-150° C; [α]D20 = + 67.7° (c=l, water); Ci₂H₂₅N₅O₂S₂ calculated C 42.99, H 7.46, N 20.89, S 19.10; found C 43.09, H 7.62, N 20.84, S 19.23.

Example 2: Animals models to determine biological effects of pharmaceutical composition(s)

Diabetic Rats Model

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.

Spontaneously diabetic Bio-Bred (BBAV) 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 BBΛV rats have been considered a useful model of autoimmune human insulin-dependent diabetes (IDDM). Like human IDDM, spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria. As in the case of human diabetics, pathological changes in retina, myocardium, liver, kidney, bone metabolism and peripheral nerves have all been well documented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992). The BB/W rats were 3-4 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.

Isolated Perfused Heart Model

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. 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 KCl, 12 mM CaCl₂, 12 mM MgCl₂, 25 mM

NaHCO₃, and the substrate 11 mM glucose. The perfusion apparatus is tightly temperature- controlled, with heated baths being used for the perfusate and for the water jacketing around the perfusion tubing to maintain heart temperature at 37 ± 0.5° C. under all conditions. The oxygenated perfusate in the room temperature reservoir is passed through 25 ft. of thin- walled silicone tubing surrounded by distilled water at 37° C saturated with 95% oxygen. The perfusate then enters the 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 μM metformin lipoate. In the metformin lipoate treated diabetic group (DZ), hearts are subjected to 10 min. of normoxic perfusion with normal Krebs-Henseleit buffer and 10 min. of normoxic perfusion with Krebs-Henseleit buffer containing 1 μM metformin lipoate.

The hearts are then subjected to 20 min. of zero-flow ischemia followed by 60 min. of reperfusion. In order to avoid any variability in reperfusion conditions, both DC and DZ hearts are reperfused with normal Krebs-Henseleit buffer.

zModelfor Low-flow Ischemia

This example describes a procedure used for study of low- flow ischemia in diabetic controls, diabetic treated, non-diabetic treated and non-diabetic control isolated hearts.

Diabetic control hearts (DC) are subjected to 20 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).

In the 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 μM 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).

Animal models to determine the effects of compounds of the disclosure on diabetes and complications of diabetes have been reviewed by Tirabassi et al., ILAR Journal, 45, 292 (2004). Antidiabetic activity of compounds of Formula I may also be tested according to protocols described in the following patents: U.S. Pat. Nos. 4,340,605; 4,342,771 ; 4,367,234; 4,617,312; 4,687,777 and 4,703,052. Additional references relevant to this application include the following: French Pat. No. 2796551 and U.S. Published Pat. Application No. 20030220301.

It should be understood that the disclosure is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing from the spirit and scope of the disclosure as defined by the following claims.

The journal articles, scientific references, and patent publications cited above are wholly incorporated herein by reference.

Claims

What is claimed is:

1. A pharmaceutical composition comprising metformin R-(+) lipoate [MR-(+) LA], and an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

2. The pharmaceutical composition of claim 1, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of 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.

3. The pharmaceutical composition of claim 2, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin and simvastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

4. The pharmaceutical composition of claim 3, wherein the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable salt is selected from the group consisting of an L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-

(di ethyl amino) 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.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt is a calcium.

7. The pharmaceutical composition of claim 4, wherein the HMG-CoA reductase inhibitor is atorvastatin calcium.

8. The pharmaceutical composition of claim 7, wherein 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.

9. The pharmaceutical composition of claim 8, wherein 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.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is formulated as a tablet.

11. The pharmaceutical composition of claim 10, wherein the composition is administered on a regimen selected from once daily, twice daily, or three times daily.

12. The pharmaceutical composition of claim 11, wherein the regimen is once daily.

13. The pharmaceutical composition of claim 7, wherein 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.

14. The pharmaceutical composition of claim 3, wherein the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 14, wherein the HMG-CoA reductase inhibitor is simvastatin.

16. The pharmaceutical composition of claim 15, wherein 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.

17. The pharmaceutical composition of claim 16, wherein 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.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is formulated as a tablet.

19. The pharmaceutical composition of claim 18, wherein the composition is administered on a regimen selected from once daily, twice daily, or three times daily.

20. The pharmaceutical composition of claim 19, wherein the regimen is once daily.

21. The pharmaceutical composition of claim 17, wherein 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.

22. A pharmaceutical composition comprising metformin R-(+) lipoate [MR-(+) LA], and a cholesterol absorption inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

23. The pharmaceutical composition of claim 22, wherein the cholesterol absorption inhibitor is ezetimibe, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

24. The pharmaceutical composition of claim 23, wherein the cholesterol absorption inhibitor is ezetimibe.

25. The pharmaceutical composition of claim 24, wherein 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.

26. The pharmaceutical composition of claim 25, wherein 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.

27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition is formulated as a tablet.

28. The pharmaceutical composition of claim 27, wherein the composition is administered on a regimen selected from once daily, twice daily, or three times daily.

29. The pharmaceutical composition of claim 28, wherein the regimen is once daily.

30. The pharmaceutical composition of claim 24, wherein 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.

31. A unit dose formulation comprising: (i) metformin R-(+) lipoate; and

(ii) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

32. The unit dose formulation of claim 31 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of 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.

33. The unit dose formulation of claim 32, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin and simvastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

34. The unit dose formulation of claim 33, wherein the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.

35. The unit dose formulation of claim 34, wherein 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.

36. The unit dose formulation of claim 35, wherein the pharmaceutically acceptable salt is a calcium.

37. The unit dose formulation of claim 34, wherein the HMG-CoA reductase inhibitor is atorvastatin calcium.

38. The unit dose formulation of claim 37, wherein 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.

39. The unit dose formulation of claim 38, wherein 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.

40. The unit dose formulation of claim 33, wherein the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof.

41. The unit dose formulation of claim 40, wherein the HMG-CoA reductase inhibitor is simvastatin.

42. The unit dose formulation of claim 41 , wherein 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.

43. The unit dose formulation of claim 42, wherein 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.

44. The unit dose formulation of claim 43, wherein 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.

45. The unit dose formulation of claim 44, wherein the mode of administration is oral.

46. The unit dose formulation of claim 45, wherein the composition is a tablet.

47. A unit dose formulation comprising: (i) metformin R-(+) lipoate; and

(ii) a cholesterol absorption inhibitor or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

48. The unit dose formulation of claim 47, wherein the cholesterol absorption inhibitor is ezetimibe, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

49. The unit dose formulation of claim 48, wherein the cholesterol absorption inhibitor is ezetimibe.

50. The unit dose formulation of claim 49, wherein 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.

51. The unit dose formulation of claim 50, wherein 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.

52. The unit dose formulation of claim 51, wherein 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.

53. The unit dose formulation of claim 52, wherein the mode of administration is oral.

54. The unit dose formulation of claim 53, wherein the pharmaceutical composition is a tablet.

55. 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 or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

56. The method of claim 55, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of 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.

57. The method of claim 56, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin and simvastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

58. The method of claim 57, wherein the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.

59. The method of claim 58, wherein 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, 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.

60. The method of claim 59, wherein the pharmaceutically acceptable salt is a calcium.

61. The method of claim 59, wherein the HMG-CoA reductase inhibitor is atorvastatin calcium.

62. The method of claim 61, wherein 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.

63. The method of claim 62, wherein 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.

64. The method of claim 63, wherein the pharmaceutical composition is formulated as a tablet.

65. The method of claim 64, wherein the pharmaceutical composition is administered on a regimen selected from once daily, twice daily, and three times daily..

66. The method of claim 65, wherein the regimen is once daily.

67. The method of claim 61 , wherein 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.

68. The method of claim 67, wherein the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof.

69. The method of claim 68, wherein the HMG-CoA reductase inhibitor is simvastatin.

70. The method of claim 69, wherein 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.

71. The method of claim 70, wherein 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.

72. The method of claim 71, wherein the pharmaceutical composition is formulated as a tablet.

73. The method of claim 72, wherein the composition is administered on a regimen selected from once daily, twice daily, and three times daily.

74. The method of claim 73, wherein the regimen is once daily.

75. The method of claim 71, wherein 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.

76. The method of claim 75, wherein the mode of administration is oral.

77. The method of claim 76, wherein the pharmaceutical composition is a tablet.

78. The method of claim 55, wherein the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.

79. 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 or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

80. The method of claim 79, wherein the cholesterol absorption inhibitor is ezetimibe, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

81. The method of claim 80, wherein the cholesterol absorption inhibitor is ezetimibe.

82. The method of claim 81, wherein 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.

83. The method of claim 82, wherein 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.

84. The method of claim 83, wherein the pharmaceutical composition is formulated as a tablet.

85. The method of claim 84, wherein the composition is administered on a regimen selected from once daily, twice daily, and three times daily.

86. The method of claim 85, wherein the regimen is once daily.

87. The method of claim 79, wherein 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.

88. The method of claim 87, wherein the mode of administration is oral.

89. The method of claim 88, wherein the pharmaceutical composition is a tablet.

90. The method of claim 79, wherein the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.

91. 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 or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

92. The method of claim 91 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of 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.

93. The method of claim 92, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin and simvastatin, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

94. The method of claim 92, wherein the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.

95. The method of claim 94, wherein 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, 1 H-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.

96. The method of claim 95, wherein the pharmaceutically acceptable salt is a calcium.

97. The method of claim 94, wherein the HMG-CoA reductase inhibitor is atorvastatin calcium.

98. The method of claim 97, wherein the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 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.

99. The method of claim 98, wherein 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.

100. The method of claim 99, wherein the pharmaceutical composition is formulated as a tablet.

101. The method of claim 100, wherein the pharmaceutical composition is administered on a regimen selected from once daily, twice daily, and three times daily..

102. The method of claim 101, wherein the regimen is once daily.

103. The method of claim 98, wherein 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.

104. The method of claim 103, wherein the mode of administration is oral.

105. The method of claim 104, wherein the pharmaceutical composition is a tablet.

106. The method of claim 93, wherein the HMG-CoA reductase inhibitor is simvastatin, or a pharmaceutically acceptable salt thereof.

107. The method of claim 106, wherein the HMG-CoA reductase inhibitor is simvastatin.

108. The method of claim 107, wherein the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 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.

109. The method of claim 108, wherein 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.

110. The method of claim 109, wherein the pharmaceutical composition is formulated as a tablet.

111. The method of claim 110, wherein the composition is administered on a regimen selected from once daily, twice daily, and three times daily.

112. The method of claim 111, wherein the regimen is once daily.

113. The method of claim 111, wherein 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.

114. The method of claim 113, wherein the mode of administration is oral.

115. 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 or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

116. The method of claim 115, wherein the cholesterol absorption inhibitor is ezetimibe, or a pharmaceutically acceptable salt, hydrate, solvate and prodrug derivative thereof.

1 17. The method of claim 1 16, wherein the cholesterol absorption inhibitor is ezetimibe.

118. The method of claim 117, wherein the metformin R-(+) lipoate [MR-(+) LA] is present in an amount ranging from 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.

1 19. The method of claim 118, wherein 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.

120. The method of claim 119, wherein the pharmaceutical composition is formulated as a tablet.

121. The method of claim 120, wherein the composition is administered on a regimen selected from once daily, twice daily, and three times daily.

122. The method of claim 121, wherein the regimen is once daily.

123. The method of claim 115, wherein 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.

124. The method of claim 123, wherein the mode of administration is oral.

125. The method of claim 115, wherein the diabetic complication is selected from diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, and myocardial infarction.